leptin and Glucose-Intolerance

Gestational diabetes mellitus (GDM) is a serious complication of pregnancy and is defined as a state of glucose intolerance that is first diagnosed and arises during gestation. Although the pathophysiology of GDM has not yet been thoroughly clarified, insulin resistance and pancreatic β-cell dysfunction are considered critical components of its etiopathogenesis. To sustain fetus growth and guarantee mother health, many significant changes in maternal metabolism are required in normal and high-risk pregnancy accompanied by potential complications. Adipokines, adipose tissue-derived hormones, are proteins with pleiotropic functions including a strong metabolic influence in physiological conditions and during pregnancy too. A growing number of studies suggest that various adipokines including adiponectin, leptin, visfatin, resistin and tumor necrosis factor α (TNF-α) are dysregulated in GDM and might have pathological significance and a prognostic value in this pregnancy disorder. In this review, we will focus on the current knowledge on the role that the aforementioned adipokines play in the development and progression of GDM.

Topics: Adipokines; Adiponectin; Adipose Tissue; Cytokines; Diabetes, Gestational; Female; Gene Expression; Gene Expression Regulation; Glucose Intolerance; Humans; Insulin Resistance; Insulin-Secreting Cells; Leptin; Nicotinamide Phosphoribosyltransferase; Pregnancy; Resistin; Tumor Necrosis Factor-alpha

The purposeful use of plant minor biologically active food substances (with demonstrated evident hypoglycemic, hypocholesterolemic and antioxidant action) in the composition of specialized dietary products can become the inno- vative approach for the dietary treatment of type 2 diabetes mellitus. Clinical testing of minor biologically active food substances of plant origin and their further use in the composition of specialized dietary products should be preceded by the stage of complex physiological and biochemical studies in vivo. It all turns on the question: to which extent the results obtained with the biomodel can be extrapolated on the human body. Hence, this review comparatively evaluates the rat models of type 2 diabetes. In this paper, we overview the most frequently used monogenic models of obesity with the damage of the leptin signaling path- way, when the animal loses control over saturation, hyperphagia and subsequent obesity appear. We describe polygenic models of obesity-related diabetes with fatty rats, which are more approximated to type 2 diabetes mellitus in humans. The characteristic of the type 2 diabetes model without obesity is given in the article: the SDT (Spontaneously Diabetic Torii) rats are genetically predisposed to glucose intolerance. Spontaneously Diabetic Torii-fa/fa (SDT fatty) rat is a new model of obese type 2 diabetes. Both male and female SDT fatty rats show overt obesity, and hyperglycemia and hyperlipidemia are observed at a younger age as compared with SDTrats. In conclusion, the SDT fatty rats are useful as a model for the development of new drugs and/or specialized dietary products to reduce body fat mass.

Topics: Animal Feed; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dietary Supplements; Genetic Testing; Glucose Intolerance; Insulin Resistance; Leptin; Micronutrients; Nutritional Status; Obesity; Rats; Signal Transduction

The use of highly active antiretroviral therapy (HAART) in the treatment of human immunodeficiency virus has dramatically altered both the landscape of this disease and the prognosis for those affected. With more patients now receiving HAART, adverse effects such as lipodystrophy and metabolic syndrome have emerged. In HIV/HAART-associated lipodystrophy syndrome (HALS), patients demonstrate fat maldistribution with dyslipidemia, insulin resistance, and other metabolic complications. Recent studies have contributed to the elucidation of the pathophysiological abnormalities seen in this syndrome and have provided guidance for the study and use of potential treatments for these patients, but widely accepted guidelines have not yet been established. Two adipokines, leptin and adiponectin, are decreased in patients with HALS and lipoatrophy or lipodystrophy. Further, recent proof-of-concept clinical trials have proven the efficacy of leptin replacement and medications that increase circulating adiponectin levels in improving the metabolic profile of HALS patients. This review article highlights recent evidence on leptin replacement and compares leptin's efficacy to that of other treatments, including metformin and thiazolidinediones, on metabolic abnormalities such as impaired insulin-glucose homeostasis associated with lipodystrophy in patients receiving HAART. It is hoped that forthcoming large phase III clinical trials will allow the addition of leptin to our therapeutic armamentarium for use in patients suffering from this disease state.

Topics: Adiponectin; Glucose Intolerance; HIV-Associated Lipodystrophy Syndrome; Humans; Leptin; Metformin; Thiazolidinediones

Although the state of prediabetes is defined by its role as a diabetes risk factor, it also carries a significant risk of cardiovascular disease, independent of progression to diabetes. Typical diabetic microvascular complications also occur, albeit at low rates, in prediabetes. There is evidence that both glucose-related and glucose-independent mechanisms contribute to these vascular complications. Effective preventive strategies will likely require control of glycemia, as well as other metabolic risk factors. This article reviews some of the proposed mechanisms for the vascular complications of the prediabetic state.

Topics: Adiponectin; Adipose Tissue; Blood Glucose; Cardiovascular Diseases; Diabetes Complications; Endothelium, Vascular; Glucose Intolerance; Humans; Insulin Resistance; Leptin; Obesity; Oxidative Stress; Prediabetic State

This review summarizes the most recent evidence linking decreased sleep duration and poor sleep quality to obesity, focusing upon studies in adults.. Published and unpublished health examination surveys and epidemiological studies suggest that the worldwide prevalence of obesity has doubled since 1980. In 2008, 1 in 10 adults was obese, with women more likely to be obese than men. This obesity epidemic has been paralleled by a trend of reduced sleep duration. Poor sleep quality, which leads to overall sleep loss has also become a frequent complaint. Growing evidence from both laboratory and epidemiological studies points to short sleep duration and poor sleep quality as new risk factors for the development of obesity.. Sleep is an important modulator of neuroendocrine function and glucose metabolism and sleep loss has been shown to result in metabolic and endocrine alterations, including decreased glucose tolerance, decreased insulin sensitivity, increased evening concentrations of cortisol, increased levels of ghrelin, decreased levels of leptin, and increased hunger and appetite. Recent epidemiological and laboratory evidence confirm previous findings of an association between sleep loss and increased risk of obesity.

Topics: Adult; Appetite; Blood Glucose; Female; Ghrelin; Glucose Intolerance; Homeostasis; Humans; Insulin Resistance; Leptin; Male; Neurosecretory Systems; Obesity; Prevalence; Risk Factors; Sleep; Sleep Apnea, Obstructive

The present review evaluates the role of sleep and its alteration in triggering problems of glucose metabolism and the possible involvement of adipokines in this process. A reduction in the amount of time spent sleeping has become an endemic condition in modern society, and a search of the current literature has found important associations between sleep loss and alterations of nutritional and metabolic contexts. Studies suggest that sleep loss is associated with problems in glucose metabolism and a higher risk for the development of insulin resistance and type 2 diabetes mellitus. The mechanism involved may be associated with the decreased efficacy of regulation of the hypothalamus-pituitary-adrenal axis by negative feedback mechanisms in sleep-deprivation conditions. In addition, changes in the circadian pattern of growth hormone (GH) secretion might also contribute to the alterations in glucose regulation observed during sleep loss. On the other hand, sleep deprivation stress affects adipokines - increasing tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and decreasing leptin and adiponectin -, thus establishing a possible association between sleep-debt, adipokines and glucose metabolism. Thus, a modified release of adipokines resulting from sleep deprivation could lead to a chronic sub-inflammatory state that could play a central role in the development of insulin resistance and type 2 diabetes mellitus. Further studies are necessary to investigate the role of sleep loss in adipokine release and its relationship with glucose metabolism.

Topics: Adipokines; Adiponectin; Diabetes Mellitus, Type 2; Glucose Intolerance; Humans; Insulin Resistance; Interleukin-6; Leptin; Sleep Deprivation; Tumor Necrosis Factor-alpha

Obesity induced by high-fat (HF) feeding is associated with low-grade inflammation in peripheral tissues that predisposes to insulin resistance. Recent evidence suggests the occurrence of a similar process in the hypothalamus, which favors weight gain through impairment of leptin and insulin signaling. In addition to its implications for obesity pathogenesis, this hypothesis suggests that centrally targeted antiinflammatory therapies may prove effective in prevention and treatment of this disorder. This article highlights molecular and cellular mechanisms by which hypothalamic inflammation predisposes to diet-induced obesity.

Topics: Animals; Glucose Intolerance; Humans; Hypothalamus; Inflammation; Insulin Resistance; Leptin; Models, Biological; Obesity; Weight Gain

Topics: Animals; Brain; Diabetes Mellitus, Type 2; Energy Metabolism; Feedback, Physiological; Ghrelin; Glucose; Glucose Intolerance; Humans; Hypothalamus; Insulin; Leptin; Neurotransmitter Agents; Nutritional Status; Obesity

In previously apparently healthy women, glucose intolerance and high blood pressure during pregnancy are common and frequently occur together. This article reviews the role of these gestational disorders as markers of vascular dysfunction and its pathophysiology. Mechanisms include alterations to function of large arteries and resistance vessels and to capillary blood flow. Much of the vessel pathology is seen in both gestational diabetes and hypertension. In women who have had transient diabetes during pregnancy and later redeveloped overt diabetes, cardiovascular risk is already elevated nearly fourfold before diagnosis, which is almost as high as the average risk after a clinical diagnosis of diabetes is made. This key finding suggests that vascular risk in such women is at least partly independent of overt hyperglycemia.

Topics: Adiponectin; Brachial Artery; Cardiovascular Diseases; Diabetes, Gestational; Endothelium, Vascular; Female; Glucose Intolerance; Humans; Hypertension, Pregnancy-Induced; Leptin; Pregnancy; Risk Factors; Vasodilation

Topics: Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Disease Progression; Endothelial Cells; Glucose Intolerance; Humans; Hypertension; Insulin Resistance; Leptin; Life Style; Obesity

We describe clinical features, body fat distribution, and prevalence of metabolic abnormalities in 35 patients with acquired partial lipodystrophy (APL) seen by us over 8 years, and also review 220 cases of APL described in the literature. Based on the review and our experience, we propose that the essential diagnostic criterion for APL is the gradual onset of bilaterally symmetrical loss of subcutaneous fat from the face, neck, upper extremities, thorax, and abdomen, in the "cephalocaudal" sequence, sparing the lower extremities. Analysis of the pooled data revealed that female patients were affected approximately 4 times more often than males. The median age of the onset of lipodystrophy was 7 years. Several autoimmune diseases, in particular systemic lupus erythematosus and dermatomyositis, were associated with APL. The prevalence rates of diabetes mellitus and impaired glucose tolerance were 6.7% and 8.9%, respectively. Approximately 83% of APL patients had low complement (C) 3 levels and the presence of polyclonal immunoglobulin C3 nephritic factor. Twenty-two percent of patients developed membranoproliferative glomerulonephritis (MPGN) after a median of approximately 8 years following the onset of lipodystrophy. Compared with patients without renal disease, those with MPGN had earlier age of onset of lipodystrophy (12.6 +/- 10.3 yr vs 7.7 +/- 4.4 yr, respectively; p < 0.001) and a higher prevalence of C3 hypocomplementemia (78% vs 95%, respectively; p = 0.02). The pathogenesis of fat loss and MPGN in patients with APL remains unclear, but activation of an alternate complement pathway has been implicated. Treating the cosmetic disfigurement by surgical procedures has yielded inconsistent results. The use of thiazolidinediones to treat fat loss in patients with APL remains anecdotal. Prognosis is mainly determined by renal insufficiency due to MPGN.

Topics: Adipose Tissue; Adolescent; Adult; Body Composition; Child; Diabetes Complications; Diabetes Mellitus; Female; Glomerulonephritis, Membranoproliferative; Glucose Intolerance; Humans; Hypertriglyceridemia; Hypolipidemic Agents; Leptin; Lipodystrophy; Magnetic Resonance Imaging; Male; Middle Aged; Plastic Surgery Procedures; Radiography; Treatment Outcome

We present clinical descriptions, metabolic features, and patterns of body fat loss of 16 patients with acquired generalized lipodystrophy (AGL) seen by us over the last 10 years. In addition, we review 63 cases of AGL reported in the literature. Based on these data, we propose new diagnostic criteria for AGL, the essential criterion being selective loss of body fat from large regions of the body occurring after birth. We also propose a subclassification of AGL into 3 varieties, type 1, the panniculitis variety; type 2, the autoimmune disease variety; and type 3, the idiopathic variety, which affect nearly 25%, 25%, and 50% of patients, respectively. Most of the patients presented in childhood and adolescence. Females were affected approximately 3 times more than males. Subcutaneous fat loss was severe and usually affected the face, trunk, abdomen, and extremities. In some patients, fat loss also involved the palms and soles and intraabdominal region; however, the bone marrow and retroorbital fat were preserved in all patients. Clinically, patients may have voracious appetite, fatigue, and acanthosis nigricans. Hepatomegaly was common, mostly due to hepatic steatosis. Most AGL patients had fasting and/or postprandial hyperinsulinemia, diabetes mellitus, hypertriglyceridemia, and low serum levels of high-density lipoprotein cholesterol, leptin, and adiponectin. Diabetes mellitus and hypertriglyceridemia were less prevalent in the panniculitis variety compared with the idiopathic and autoimmune varieties. The management of AGL includes cosmetic surgery for loss of fat. Severe hypertriglyceridemia should be treated with a very low-fat diet and omega-3 polyunsaturated fatty acid supplementation from fish oils. Management of diabetes is difficult and may necessitate insulin therapy in large doses. Insulin sensitizers such as metformin and thiazolidinediones have been used, although their long-term efficacy and safety remain unknown. Subcutaneous administration of recombinant leptin in AGL patients with hypoleptinemia effectively improves hyperglycemia, hypertriglyceridemia, and hepatic steatosis. Leptin therapy, however, remains investigational. Fibrates alone or in combination with statins may be used to treat hypertriglyceridemia.

Topics: Adipose Tissue; Adolescent; Adult; Body Composition; Child; Child, Preschool; Diabetes Complications; Diabetes Mellitus; Female; Glucose Intolerance; Humans; Hypertriglyceridemia; Hypolipidemic Agents; Leptin; Lipodystrophy; Magnetic Resonance Imaging; Male; Middle Aged; Plastic Surgery Procedures; Radiography; Treatment Outcome

Topics: Adiponectin; Adipose Tissue; Aquaporins; Glucose Intolerance; Humans; Hyperlipidemias; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Lipid Metabolism; Obesity; Proteins; Syndrome; Viscera

Insulin resistance syndrome is the theory that glucose intolerance, hyperinsulinemia, increased very low density lipoprotein triglyceride level, decreased high density lipoprotein cholesterol level, and hypertension are proposed consequences of insulin resistance. These metabolic disturbances have been shown to increase the risk of coronary artery disease. In this theory, insulin resistance and the resultant hyperinsulinemia are considered to raise blood pressure through 1) sympathetic nervous system activation, 2) renal sodium retention, 3) renin-angiotensin system stimulation, and 4) intracellular calcium accumulation in vascular smooth muscle. Indeed, metabolic disturbance and insulin resistance have been pointed out in essential hypertensives. Leptin is a recently discovered hormone produced by an adipocyte-specific ob gene, that contributes to the regulation of energy balance by informing the hypothalamus of the amount of adipose tissue in the body. As a result, the hypothalamus adjusts food intake, thermogenesis, and energy expenditure appropriately. It was clarified that ob gene expression and plasma leptin level in humans were highly correlated with the body mass index, insulin sensitivity and blood pressure. Thus, leptin could play a role in the pathophysiology of insulin-resistant hypertension.

Topics: Coronary Disease; Glucose Intolerance; Humans; Hyperinsulinism; Hyperlipidemias; Hypertension; Hypothalamus; Insulin Resistance; Leptin; Risk; Syndrome

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Glucose Intolerance; Humans; Insulin Resistance; Leptin; Male; Proteins; Research

A diet in which fat is mainly eaten in the morning and carbohydrates mainly in the evening (compared with the reverse order) was recently shown to worsen glycemic control in people with prediabetes.. We investigated the effects of these dietary patterns on energy metabolism, and on the daily profiles of circulating lipids, adipokines, and inflammatory markers.. In a randomized controlled crossover trial, 29 nonobese men (with normal glucose tolerance, n = 18; or impaired fasting glucose/glucose tolerance, n = 11) underwent 2 isocaloric 4-wk diets: 1) carbohydrate-rich meals until 1330 and fat-rich meals between 1630 and 2200 (HC/HF); or 2) the inverse sequence of meals (HF/HC). During a 12-h clinical investigation day after each intervention period, 2 meal tolerance tests were performed, at 0900 and 1540, respectively. Substrate oxidation and concentrations of circulating lipids, adipokines, and cytokines were assessed pre- and postprandially. The postprandial inflammatory response in leukocytes was analyzed ex vivo.. Fasting carbohydrate oxidation decreased (P = 0.004) and lipid oxidation increased (P = 0.012) after the HC/HF diet. Fasting concentrations of blood markers did not differ between diets. The diets modulated the daily profiles of carbohydrate oxidation, lipid oxidation, and β-hydroxybutyrate, although the average daily values of these parameters showed no difference between the diets, and no interaction between diet and glucose tolerance status. Diurnal patterns of triglycerides, low-density lipoprotein cholesterol, leptin, visfatin, and of LPS-induced cytokine secretion in blood leukocytes were also modulated by the diets. Average daily concentrations of leptin (P = 0.017) and visfatin (P = 0.041) were lower on the HF/HC diet than on the HC/HF diet.. Diurnal distribution of carbohydrates and fat affects the daily profiles of substrate oxidation, circulating lipids, and cytokine secretion, and alters the average daily concentrations of adipokine secretion in nonobese nondiabetic humans. The study was registered at clinicaltrials.gov as NCT02487576.

Topics: Adipokines; Adult; Biomarkers; Body Mass Index; Circadian Rhythm; Cross-Over Studies; Cytokines; Dietary Carbohydrates; Dietary Fats; Energy Metabolism; Fasting; Glucose Intolerance; Humans; Inflammation; Leptin; Lipids; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Oxidation-Reduction; Postprandial Period

The present study is a secondary analysis of the ROLO study, a randomised control trial of a low-glycaemic index (GI) diet in pregnancy to prevent the recurrence of fetal macrosomia. The objectives of the present study were to identify which women are most likely to respond to a low-GI dietary intervention in pregnancy with respect to three outcome measures: birth weight; maternal glucose intolerance; gestational weight gain (GWG). In early pregnancy, 372 women had their mid-upper arm circumference recorded and BMI calculated. Concentrations of glucose, insulin and leptin were measured in early pregnancy and at 28 weeks. At delivery, infant birth weight was recorded and fetal glucose, C-peptide and leptin concentrations were measured in the cord blood. Women who benefited in terms of infant birth weight were shorter, with a lower education level. Those who maintained weight gain within the GWG guidelines were less overweight in both their first and second pregnancies, with no difference being observed in maternal height. Women who at 28 weeks of gestation developed glucose intolerance, despite the low-GI diet, had a higher BMI and higher glucose concentrations in early pregnancy with more insulin resistance. They also had significantly higher-interval pregnancy weight gain. For each analysis, women who responded to the intervention had lower leptin concentrations in early pregnancy than those who did not. These findings suggest that the maternal metabolic environment in early pregnancy is important in determining later risks of excessive weight gain and metabolic disturbance, whereas birth weight is mediated more by genetic factors. It highlights key areas, which warrant further interrogation before future pregnancy intervention studies, in particular, maternal education level and inter-pregnancy weight gain.

Topics: Adiposity; Adult; Birth Weight; Body Mass Index; Cohort Studies; Diet, Carbohydrate-Restricted; Educational Status; Female; Fetal Blood; Fetal Macrosomia; Glucose Intolerance; Glycemic Index; Humans; Insulin; Insulin Resistance; Leptin; Maternal Nutritional Physiological Phenomena; Patient Education as Topic; Pregnancy; Pregnancy Complications; Secondary Prevention; Weight Gain

The objective was to determine the effect of metformin on the concentrations of resistin and other markers of insulin resistance or inflammation (C-reactive protein, cytokines, body weight, HbA1c, among others) in minors with glucose intolerance. Patients aged 4 to 17 years with glucose intolerance were studied. They were randomized to receive 850 mg of either metformin or placebo twice daily for 12 weeks, during which all followed an iso-caloric diet and an exercise program. High sensitivity C-reactive protein, TNF-alpha, IL-6, IL1-beta, resistin, leptin, adiponectin, glucose, insulin, HbA1c, lipid profile and transaminases were measured at the beginning and at the end of the period. Fifty-two patients were included, 11.9±2.6 years old; 28 (12 males/16 females) received metformin and 24 placebo (11 males/13 females). Baseline characteristics were similar between groups (except for body mass index, which in the metformin group was slightly higher). Percentage weight loss was greater in the metformin group (-5.86% vs 2.75%, P<.05). At study end, there were statistically significant differences in resistin concentrations, even after adjusting for confounding variables (F=7.714; P<.006). Also, metformin was associated with a significant decrease in HOMA-IR index (P=.032) and HbA1c levels (P=.001), but no change was observed in the concentration of other markers of inflammation. Metformin resulted in significant reductions of plasma resistin levels in minors with glucose intolerance. This change is independent of its effects on body weight. In contrast, metformin did not alter the concentration of inflammatory markers.

Topics: Adiponectin; Adolescent; Biomarkers; C-Reactive Protein; Child; Child, Preschool; Drug Administration Schedule; Energy Intake; Exercise; Female; Glucose Intolerance; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Inflammation; Interleukin-1beta; Interleukin-6; Leptin; Male; Metformin; Resistin; Tumor Necrosis Factor-alpha; Weight Loss

We investigated whether circulating adipokine concentrations can be altered by lifestyle intervention according to general recommendations in subjects at risk for diabetes as well as the potential of leptin, adiponectin, and resistin as biomarkers for lifestyle-induced improvements in glucose metabolism and insulin resistance.. In the Study on Lifestyle intervention and Impaired glucose tolerance Maastricht, 147 men and women with impaired glucose tolerance (IGT) were randomized to either a combined diet-and-exercise intervention or a control program. At baseline and after 1 year, an oral glucose tolerance test, an exercise test, and anthropometric measurements were performed. After 1 year, complete data of 103 subjects (50 intervention and 53 control subjects) were obtained.. Lifestyle intervention reduced plasma leptin concentrations (-14.2%) in IGT subjects but did not alter plasma adiponectin (-0.3%) or resistin (-6.5%) concentrations despite marked improvements in glucose tolerance and insulin resistance.. Changes in leptin concentration were related to improvements in insulin sensitivity independent of changes in body composition.

Topics: Adipokines; Adiponectin; Biomarkers; Body Size; Diabetes Mellitus, Type 2; Diet, Diabetic; Exercise; Female; Glucose Intolerance; Humans; Leptin; Life Style; Male; Reference Values; Resistin

The consumption of arabinoxylan, a soluble fibre fraction, has been shown to improve glycemic control in type 2 diabetic subjects. Soluble dietary fibre may modulate gastrointestinal or adipose tissue hormones regulating food intake. The present study investigated the effects of arabinoxylan consumption on serum glucose, insulin, lipids, leptin, adiponectin and resistin in subjects with impaired glucose tolerance. In a randomized, single-blind, controlled, crossover intervention trial, 11 adults consumed white bread rolls as either placebo or supplemented with 15 g arabinoxylan for 6 weeks with a 6-week washout period. Fasting serum glucose, insulin, triglycerides, unesterified fatty acids, apolipoprotein A1 and B, adiponectin, resistin and leptin were assessed before and after intervention. Fasting serum glucose, serum triglycerides and apolipoprotein A-1 were significantly lower during arabinoxylan consumption compared to placebo (p=0.029, p=0.047; p=0.029, respectively). No effects of arabinoxylan were observed for insulin, adiponectin, leptin and resistin as well as for apolipoprotein B, and unesterified fatty acids. In conclusion, the consumption of AX in subjects with impaired glucose tolerance improved fasting serum glucose, and triglycerides. However, this beneficial effect was not accompanied by changes in fasting adipokine concentrations.

Topics: Adiponectin; Adult; Aged; Blood Glucose; Body Composition; Body Mass Index; Cholesterol; Dietary Fiber; Female; Glucose; Glucose Intolerance; Glycated Hemoglobin; Humans; Insulin; Leptin; Lipids; Male; Middle Aged; Resistin; Single-Blind Method; Triglycerides; Xylans

Weight reduction after gastric bypass surgery has been attributed to a decrease of the orexigenic peptide ghrelin, which may be regulated by insulin and leptin. This study examined effects of long-term weight loss after laparoscopical adjustable gastric banding on plasma ghrelin and leptin concentrations and their relationship with insulin action. Severely obese patients (15 women, three men, 36 +/- 12 yr) underwent clinical examinations every 3 months and modified oral glucose tolerance tests to assess parameters of insulin sensitivity and secretion every 6 months. After surgery, body mass index fell from 45.3 +/- 5.3 to 37.2 +/- 5.3 and 33.6 +/- 5.5 kg/m(2) at 6 and 12 months, respectively (P < 0.0001). This was associated with lower (P < 0.0001) plasma glucose, insulin, insulin resistance, waist circumference, and blood pressure. Plasma leptin decreased from 27.6 +/- 9.5 to 17.7 +/- 9.8 (P = 0.0005) and 12.7 +/- 5.1 ng/ml (P < 0.0001). Plasma ghrelin was comparable before and at 6 months (234 +/- 53; 232 +/- 53 pmol/liter) but increased at 12 months (261 +/- 72 pmol/liter; P = 0.05 vs. 6 months). At 6 and 12 months, ghrelin levels correlated negatively with fasting plasma insulin levels and hepatic insulin extraction but not with body mass or insulin action. In conclusion, prolonged weight loss results in a rise of fasting ghrelin concentrations that correlates with fasting insulin concentrations but not improvement of insulin sensitivity.

Topics: Adult; Body Mass Index; Female; Gastric Bypass; Gastroplasty; Ghrelin; Glucose Intolerance; Glucose Tolerance Test; Hormones; Humans; Insulin; Insulin Resistance; Leptin; Liver; Longitudinal Studies; Male; Middle Aged; Obesity, Morbid; Osmolar Concentration; Peptide Hormones; Postoperative Period; Weight Loss

The aim of this study was to determine whether serum leptin concentrations are reduced in response to short-term energy restriction in centrally obese individuals with impaired glucose tolerance or non-insulin-dependent diabetes mellitus. Twenty African Americans [16 females and 4 males, 44 +/- 7 y (x +/- SD), 107.2 +/- 23.8 kg, 39 +/- 7% body fat] consumed a 7-d energy-restricted diet (4.03 +/- 0.72 MJ/d) of whole foods. Oral-glucose-tolerance tests (OGTTs) were performed before and immediately after the diet to assess changes in serum leptin, glucose, and insulin concentrations. Baseline leptin concentration correlated significantly with percentage body fat (r = 0.80), body mass index (r = 0.72), fat mass (4 = 0.64), waist-height ratio (r = 0.6), body weight (r = 0.59, all P < 0.01), waist circumference (r = 0.49), and basal insulin concentration (r = 0.48, both P < 0.05). Seven days of energy restriction resulted in significant reductions (P < 0.005) in leptin (-6.1 +/- 8.4 micrograms/L), basal glucose (-0.9 +/- 0.8 mmol/L), OGTT glucose area under the curve (-158 +/- 164 mmol/L), and basal insulin concentration (-34 +/- 69 pmol/L, P < 0.05). In addition, there was a trend for a reduction in OGTT insulin area under the curve (-15,567 +/- 3,658 pmol/L, P = 0.05), and a tendency for basal insulin and leptin to change together (r = 0.41, P = 0.07). Despite the weight loss of 3.1 +/- 1.3 kg (P < 0.0001), the loss of fat mass was calculated to be only -1.0 +/- 0.1 kg. These results suggest that negative energy balance or improved insulin action was responsible for the changes in leptin, glucose, and insulin concentrations. In summary, short-term energy restriction effectively reduced serum leptin concentrations and improved glucose tolerance and insulin action in obese individuals with impaired or diabetic glucose tolerance.

Topics: Adult; Area Under Curve; Black People; Blood Glucose; Diabetes Mellitus, Type 2; Energy Intake; Female; Glucose Intolerance; Humans; Insulin; Leptin; Male; Middle Aged; Obesity; Proteins; Weight Loss

More than 50% of people with asthma in the United States are obese, and obesity often worsens symptoms of allergic asthma and impairs response to treatment. Based on previously established roles of the epithelial NADPH oxidase DUOX1 in allergic airway inflammation, we addressed the potential involvement of DUOX1 in altered allergic inflammation in the context of obesity. Intranasal house dust mite (HDM) allergen challenge of subjects with allergic asthma induced rapid secretion of IL-33, then IL-13, into the nasal lumen, responses that were significantly enhanced in obese asthmatic subjects (BMI >30). Induction of diet-induced obesity (DIO) in mice by high-fat diet (HFD) feeding similarly enhanced acute airway responses to intranasal HDM challenge, particularly with respect to secretion of IL-33 and type 2/type 3 cytokines, and this was associated with enhanced epithelial DUOX1 expression and was avoided in DUOX1-deficient mice. DIO also enhanced DUOX1-dependent features of chronic HDM-induced allergic inflammation. Although DUOX1 did not affect overall weight gain by HFD feeding, it contributed to glucose intolerance, suggesting a role in glucose metabolism. However, glucose intolerance induced by short-term HFD feeding, in the absence of adiposity, was not sufficient to alter HDM-induced acute airway responses. DIO was associated with enhanced presence of the adipokine leptin in the airways, and leptin enhanced DUOX1-dependent IL-13 and mucin production in airway epithelial cells. In conclusion, augmented inflammatory airway responses to HDM in obesity are associated with increases in airway epithelial DUOX1, and by increased airway epithelial leptin signaling.

Topics: Allergens; Animals; Asthma; Diet; Disease Models, Animal; Dual Oxidases; Glucose Intolerance; Inflammation; Interleukin-13; Interleukin-33; Leptin; Mice; Obesity; Pyroglyphidae

Accumulating evidence has demonstrated that arcuate nucleus (ARC) of the hypothalamus is likely responsible for the close association between chronic stress, depression, and diabetes. Xiaoyaosan (XYS), a Chinese herbal formula, remarkably improves depressive-like behavior and glucose intolerance, but the mechanism remains unclear. Leptin receptor (LepR) regulates energy expenditure and depression by mediating the action of leptin on the ARC. Therefore, we hypothesized that XYS may regulate depressive-like behavior and glucose intolerance via the leptin and its cascade LepR-STAT3/PI3K pathway in the ARC.. A rat model of depressive-like behavior and susceptibility to glucose intolerance was induced by exposure to chronic unpredictable mild stress (CUMS) for six weeks. XYS (2.224 g/kg) was orally gavaged for six weeks, and fluoxetine (2.0 mg/kg) was administrated to the positive control group. Depressive-like behaviors were assessed using the open field test (OFT), sucrose preference test (SPT) and forced swim test (FST). Fasting blood glucose (FBG) and oral glucose tolerance test (OGTT) were performed to evaluate the effects of XYS on blood glucose. Peripheral leptin and blood lipids were detected using enzyme-linked immunosorbent assay and an automatic biochemical analyzer, respectively. The effects of XYS on the LepR-STAT3/PI3K pathway were detected by quantitative real-time PCR and western blotting.. XYS ameliorated CUMS-induced depressive-like behaviors and elevated blood glucose. XYS improved the food intake but have no significant effects on the body weight. Peripheral leptin and its central receptor were also suppressed by XYS, accompanied by the downregulation of JAK2/STAT3 and PI3K/AKT pathway in the ARC. Additionally, XYS increased AGRP and NPY expression but inhibited POMC in the ARC.. XYS improves depressive-like behaviors and susceptibility to glucose intolerance induced by CUMS, which may be achieved by the downregulation of the LepR-STAT3/PI3K signaling pathway in the ARC.

Topics: Animals; Antidepressive Agents; Arcuate Nucleus of Hypothalamus; Blood Glucose; Glucose Intolerance; Leptin; Phosphatidylinositol 3-Kinases; Rats; Receptors, Leptin

There is significant overlap between non-alcoholic fatty liver disease (NAFLD) and alcohol-associated liver disease (ALD) with regards to risk factors and disease progression. However, the mechanism by which fatty liver disease arises from concomitant obesity and overconsumption of alcohol (syndrome of metabolic and alcohol-associated fatty liver disease; SMAFLD), is not fully understood.. Male C57BL6/J mice were fed chow diet (Chow) or high-fructose, high-fat, high-cholesterol diet (FFC) for 4 weeks, then administered either saline or ethanol (EtOH, 5% in drinking water) for another 12 weeks. The EtOH treatment also consisted of a weekly 2.5 g EtOH/kg body weight gavage. Markers for lipid regulation, oxidative stress, inflammation, and fibrosis were measured by RT-qPCR, RNA-seq, Western blot, and metabolomics.. Combined FFC-EtOH induced more body weight gain, glucose intolerance, steatosis, and hepatomegaly compared to Chow, EtOH, or FFC. Glucose intolerance by FFC-EtOH was associated with decreased hepatic protein kinase B (AKT) protein expression and increased gluconeogenic gene expression. FFC-EtOH increased hepatic triglyceride and ceramide levels, plasma leptin levels, hepatic Perilipin 2 protein expression, and decreased lipolytic gene expression. FFC and FFC-EtOH also increased AMP-activated protein kinase (AMPK) activation. Finally, FFC-EtOH enriched the hepatic transcriptome for genes involved in immune response and lipid metabolism.. In our model of early SMAFLD, we observed that the combination of an obesogenic diet and alcohol caused more weight gain, promoted glucose intolerance, and contributed to steatosis by dysregulating leptin/AMPK signaling. Our model demonstrates that the combination of an obesogenic diet with a chronic-binge pattern alcohol intake is worse than either insult alone.

Topics: AMP-Activated Protein Kinases; Animals; Diet, High-Fat; Diet, Western; Ethanol; Glucose Intolerance; Leptin; Lipid Metabolism; Liver; Liver Diseases, Alcoholic; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity

Leptin is an adipokine secreted in proportion to adipocyte mass and is therefore increased in obesity. Leptin signaling has been shown to directly promote inflammatory T helper 1 (Th1) and T helper 17 (Th17) cell number and function. Since T cells have a critical role in driving inflammation and systemic glucose intolerance in obesity, we sought to determine the role of leptin signaling in this context.. Male and female T cell-specific leptin receptor knockout mice and littermate controls were placed on low-fat diet or high-fat diet to induce obesity for 18 weeks. Weight gain, serum glucose levels, systemic glucose tolerance, T cell metabolism, and T cell differentiation and cytokine production were examined.. In both male and female mice, T cell-specific leptin receptor deficiency did not reverse impaired glucose tolerance in obesity, although it did prevent impaired fasting glucose levels in obese mice compared to littermate controls, in a sex dependent manner. Despite these minimal effects on systemic metabolism, T cell-specific leptin signaling was required for changes in T cell metabolism, differentiation, and cytokine production observed in mice fed high-fat diet compared to low-fat diet. Specifically, we observed increased T cell oxidative metabolism, increased CD4+ T cell IFN-γ expression, and increased proportion of T regulatory (Treg) cells in control mice fed high-fat diet compared to low-fat diet, which were not observed in the leptin receptor conditional knockout mice, suggesting that leptin receptor signaling is required for some of the inflammatory changes observed in T cells in obesity.. T cell-specific deficiency of leptin signaling alters T cell metabolism and function in obesity but has minimal effects on obesity-associated systemic metabolism. These results suggest a redundancy in cytokine receptor signaling pathways in response to inflammatory signals in obesity.

Topics: Animals; Cytokines; Diet, High-Fat; Female; Glucose; Glucose Intolerance; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Receptors, Leptin

(1) Objective: The aim of this study was to clarify the role of adipokines in the regulation of glucose metabolism in middle-aged obese subjects with impaired glucose tolerance in response to a long-term exercise and dietary intervention. (2) Methods: Skeletal muscle, plasma and serum samples were examined in 22 subjects from an exercise−diet intervention study aiming to prevent type 2 diabetes. The subjects were further divided into two subgroups (non-responders n = 9 and responders n = 13) based on their achievement in losing at least 3 kg. (3) Results: The two-year exercise−diet intervention reduced leptin levels and increased adiponectin levels in responders; the changes in leptin levels were significantly associated with changes in their weights (r = 0.662, p < 0.01). In responders, insulin sensitivity (Bennett and McAuley index) increased and was associated with changes in maximal oxygen uptake (VO2peak) (r = 0.831, p < 0.010 and r = 0.890, p < 0.01). In addition, the VO2peak and oxidative capacity of skeletal muscle improved in responders, but not in non-responders. However, there were no changes between the two groups in expressions of the glucose transporter protein-4 (GLUT-4) gene or of AMP-activated protein kinase (AMPK)-α1 or AMPK-α2 proteins. (4) Conclusions: The exercise−diet intervention decreased serum leptin and increased serum adiponectin concentrations, improved glucose control without affecting GLUT-4 gene expression in the skeletal muscle in responders.

Topics: Adipokines; Adiponectin; AMP-Activated Protein Kinases; Blood Glucose; Diabetes Mellitus, Type 2; Gene Expression; Glucose Intolerance; Glucose Transporter Type 4; Glycemic Control; Humans; Insulin Resistance; Leptin; Middle Aged; Muscle, Skeletal; Weight Loss

To explore how systemic factors that modify knee osteoarthritis risk are connected to 'whole-joint' structural changes by evaluating the effects of high-fat diet and wheel running exercise on synovial fluid (SF) metabolomics.. Male mice were fed a defined control or high-fat (60% kcal fat) diet from 6 to 52 weeks of age, and half the animals were housed with running wheels from 26 to 52 weeks of age (n = 9-13 per group). Joint tissue structure and osteoarthritis pathology were evaluated by histology and micro-computed tomography. Systemic metabolic and inflammatory changes were evaluated by body composition, glucose tolerance testing, and serum biomarkers. SF metabolites were analyzed by high performance-liquid chromatography mass spectrometry. We built correlation-based network models to evaluate the connectivity between systemic and local metabolic biomarkers and osteoarthritis structural pathology within each experimental group.. High-fat diet caused moderate osteoarthritis, including cartilage pathology, synovitis and increased subchondral bone density. In contrast, voluntary exercise had a negligible effect on these joint structure components. 1,412 SF metabolite features were detected, with high-fat sedentary mice being the most distinct. Diet and activity uniquely altered SF metabolites attributed to amino acids, lipids, and steroids. Notably, high-fat diet increased network connections to systemic biomarkers such as interleukin-1β and glucose intolerance. In contrast, exercise increased local joint-level network connections, especially among subchondral bone features and SF metabolites.. Network mapping showed that obesity strengthened SF metabolite links to blood glucose and inflammation, whereas exercise strengthened SF metabolite links to subchondral bone structure.

Topics: Animals; Biomarkers; Chemokine CCL2; Chondrocytes; Diet, High-Fat; Glucose Intolerance; Hypertrophy; Interleukin-10; Interleukin-1beta; Interleukin-8; Leptin; Metabolomics; Mice, Inbred C57BL; Osteoarthritis; Physical Conditioning, Animal; Stifle; Synovial Fluid; X-Ray Microtomography

Prediabetes is a strong predictor of type 2 diabetes and its associated cardiovascular complications, but few studies explore sexual dimorphism in this context. Here, we aim to determine whether sex influences physiological response to high-fat high-sucrose diet (HFS) and myocardial tolerance to ischemia-reperfusion injury. Male and female Wistar rats were subjected to standard (CTRL) or HFS diet for 5 months. Then, ex-vivo experiments on isolated perfused heart model were performed to evaluate tolerance to ischemia-reperfusion injury. HFS diet induced fasting hyperglycemia and increased body fat percent to a similar level in both sexes. However, glucose intolerance was more pronounced in female HFS. Cholesterol was increased only in female while male displayed higher level of plasmatic leptin. We observed increased heart weight to tibia length ratio only in males, but we showed a similar decrease in tolerance to ischemia-reperfusion injury in female and male HFS compared with respective controls, characterized by impaired cardiac function, energy metabolism and coronary flow during reperfusion. In conclusion, as soon as glucose intolerance and hyperglycemia develop, we observe higher sensitivity of hearts to ischemia-reperfusion injury without difference between males and females.

Topics: Animals; Cholesterol; Diabetes Mellitus, Type 2; Diet, High-Fat; Dietary Sucrose; Energy Metabolism; Female; Glucose Intolerance; Humans; Hyperglycemia; Leptin; Male; Myocardial Reperfusion Injury; Myocardium; Oxidative Stress; Prediabetic State; Rats; Rats, Wistar; Sex Factors; Weight Gain

Obesity has emerged as a major risk factor for insulin resistance leading to the development of type 2 diabetes (T2D). The condition is characterized by high circulating levels of the adipose-derived hormone leptin and a state of chronic low-grade inflammation. Pro-inflammatory signaling in the hypothalamus is associated with a decrease of central leptin- and insulin action leading to impaired systemic glucose tolerance. Intriguingly, leptin not only regulates body weight and glucose homeostasis but also acts as a pro-inflammatory cytokine. Here we demonstrate that increasing leptin levels (62,5 µg/kg/d, PEGylated leptin) in mice fed a high-fat diet (HFD) exacerbated body weight gain and aggravated hypothalamic micro- as well as astrogliosis. In contrast, administration of a predetermined dose of a long-acting leptin antagonist (100 µg/kg/d, PESLAN) chosen to block excessive leptin signaling during diet-induced obesity (DIO) showed the opposite effect and significantly improved glucose tolerance as well as decreased the total number of microglia and astrocytes in the hypothalamus of mice fed HFD. These results suggest that high levels of leptin, such as in obesity, worsen HFD-induced micro-and astrogliosis, whereas the partial reduction of hyperleptinemia in DIO mice may have beneficial metabolic effects and improves hypothalamic gliosis.

Topics: Animals; Anti-Obesity Agents; Diet, High-Fat; Gliosis; Glucose Intolerance; Hypothalamus; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Polyethylene Glycols

Cholecalciferol (D3) may improve inflammation, and thus provide protection from cardiometabolic diseases (CMD), although controversy remains. Omega-3 fatty acids (ω-3FA) may also prevent the development of CMD, but the combined effects of ω-3FA and D3 are not fully understood.. We determined the chronic independent and combined effects of D3 and ω-3FA on body weight, glucose homeostasis, and markers of inflammation in obese mice.. We gave 8-week-old male C57BL/6J mice, which had been fed a high-fat, high-sucrose (HF) diet (65.5% kcal fat, 19.8% kcal carbohydrate, and 14% kcal protein) for 12 weeks, either a standard D3 dose (+SD3; 1400 IU D3/kg diet) or a high D3 dose (+HD3; 15,000 IU D3/kg diet). We fed 1 +SD3 group and 1 +HD3 group with 4.36% (w/w) fish oil (+ω-3FA; 44% eicosapentaenoic acid, 25% docosahexaenoic acid), and fed the other 2 groups with corn oil [+omega-6 fatty acids (ω-6FA)]. A fifth group was fed a low-fat (LF; 15.5% kcal) diet. LF and HF+ω-6+SD3 differences were tested by a Student's t-test and HF treatment differences were tested by a 2-way ANOVA.. D3 supplementation in the +HD3 groups did not significantly increase plasma total 25-hydroxyvitamin D and 25-hydroxyvitamin D3 [25(OH)D3] versus the +SD3 groups, but it increased 3-epi-25-hydroxyvitamin D3 levels by 3.4 ng/mL in the HF+ω-6+HD3 group and 4.0 ng/mL in the HF+ω-3+HD3 group, representing 30% and 70%, respectively, of the total 25(OH)D3 increase. Energy expenditure increased in those mice fed diets +ω-3FA, by 3.9% in the HF+ω-3+SD3 group and 7.4% in the HF+ω-3+HD3 group, but it did not translate into lower body weight. The glucose tolerance curves of the HF+ω-3+SD3 and HF+ω-3+HD3 groups were improved by 11% and 17%, respectively, as compared to the respective +ω-6FA groups. D3 supplementation, within the ω-3FA groups, altered the gut microbiota by increasing the abundance of S24-7 and Lachnospiraceae taxa compared to the standard dose, while within the ω-6FA groups, D3 supplementation did not modulate specific taxa.. Overall, D3 supplementation does not prevent CMD or enhance the beneficial effects of ω-3FA in vitamin D-sufficient obese mice.

Topics: Animals; Cholecalciferol; Diet, High-Fat; Dietary Sucrose; Dietary Supplements; Drug Synergism; Fatty Acids, Omega-3; Glucose Intolerance; Humans; Leptin; Liver; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Random Allocation

Metabolic syndrome-related diseases affect millions of people worldwide. It is well established that changes in nutritional habits and lifestyle can improve or prevent metabolic-related pathologies such as type-2 diabetes and obesity. Previous reports have shown that nutritional supplements have the capacity to limit glucose intolerance and suppress diabetes development. In this study, we investigated the effect of dietary supplementation with fish-derived extracts on obesity and type 2 diabetes and their impact on gut microbial composition. We showed that nutritional supplements containing Fish Complex (FC), Fish Complex combined with Cod Powder (FC + CP), or Cod Powder combined with Collagen (CP + C) improved glucose intolerance, independent of abdominal fat accumulation, in a mouse model of diet-induced obesity and type 2 diabetes. In addition, collagen-containing supplements distinctly modulate the gut microbiome in high-fat induced obesity in mice. Our results suggest that fish-derived supplements suppress diet-induced type 2 diabetes, which may be partly mediated through changes in the gut microbiome. Thus, fish-derived supplements and particularly the ones containing fish collagen have potential beneficial properties as dietary supplements in managing type 2 diabetes and metabolic syndrome via modulation of the gut microbiome.

Topics: Abdominal Fat; Animals; Body Weight; Diabetes Mellitus, Type 2; Diet, High-Fat; Dietary Supplements; Disease Models, Animal; Female; Fishes; Gastrointestinal Microbiome; Glucose Intolerance; Hypoglycemic Agents; Insulin Resistance; Leptin; Mice, Inbred C57BL; Obesity; Tissue Extracts

Optimization of nutritional status is recommended in patients with cystic fibrosis (CF) given the association between lower body mass index (BMI) and poor clinical outcomes. However, higher BMI and body fat correlate with glucose impairment and higher leptin levels in the general population. Differences in body composition and leptin levels between the categories of glucose tolerance were assessed in youth with CF and healthy controls.. In a cross-sectional study, 59 adolescents and young adults with CF and 15 healthy controls matched by age and gender, underwent body composition analysis using dual energy X-ray absorptiometry (DXA) and a 2-hour oral glucose tolerance test (OGTT). Measures of insulin sensitivity, β-cell insulin secretion and fasting leptin levels were obtained.. Of the participants with CF, 62% were classified as abnormal glucose tolerant and 22% with cystic fibrosis related diabetes (CFRD). Patients with CFRD had a lower fat mass index (FMI) z-score, wt z-score and leptin levels compared to the control group (-1.86 vs. - 0.59, p=0.01; -1.86 vs 0.44, p=<0.001 and 7.9 vs vs. 27.7 µg/L, p=0.01). Leptin correlated positively with FMI z-score, BMI, weight z-score and indices of insulin secretion. FMI z-score correlated positively with higher insulin resistance (HOMA-IR), and lower insulin sensitivity (Matsuda index) (r=0.31; p =0.01 and r=-0.29; p=0.02, respectively) in the CF group.. This study shows that despite new therapeutic strategies, youth with CF have lower body fat, weight z-score and leptin levels, particularly in subjects with early onset CFRD.

Topics: Absorptiometry, Photon; Adolescent; Adult; Body Composition; Child; Cross-Sectional Studies; Cystic Fibrosis; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin Resistance; Insulin-Secreting Cells; Leptin; Male; Young Adult

Dietary polyphenols including anthocyanins target multiple organs.. We aimed to assess the involvement of glucagon-like peptide 1 (GLP-1), leptin, insulin and fibroblast growth factor 21 (FGF21) in mediating metabolic beneficial effects of purified anthocyanin cyanidin-3-glucoside (Cy3G).. Intestinal proglucagon gene (Gcg; encoding GLP-1) and liver Fgf21 expression were assessed in 6-wk-old male C57BL-6J mice fed a low-fat-diet (LFD; 10% of energy from fat), alone or with 1.6 mg Cy3G/L in drinking water for 3 wk [experiment (Exp.) 1; n = 5/group]. Similar mice were fed the LFD or a high-fat diet (HFD; 60% energy from fat) with or without Cy3G for 20 wk. Half of the mice administered Cy3G also received 4 broad-spectrum antibiotics (ABs) in drinking water between weeks 11 and 14, for a total of 6 groups (n = 8/group). Metabolic tolerance tests were conducted between weeks 2 and 16. Relevant hormone gene expression and plasma hormone concentrations were assessed mainly at the end of 20 wk (Exp. 2).. In Exp. 1, Cy3G administration increased ileal but not colonic Gcg level by 2-fold (P < 0.05). In Exp. 2, Cy3G attenuated HFD-induced body-weight gain (20.3% at week 16), and improved glucose tolerance (26.5% at week 15) but not insulin tolerance. Although Cy3G had no effect on glucose tolerance in LFD mice, LFD/Cy3G/AB mice showed better glucose tolerance than LFD/Cy3G mice (23%). In contrast, HFD/Cy3G/AB mice showed worse glucose tolerance compared with HFD/Cy3G mice (15%). Beneficial effects of Cy3G in HFD mice were not associated with changes in plasma leptin, insulin or GLP-1 concentrations. However, Cy3G increased hepatic Fgf21 expression in mice in Exp. 1 by 4-fold and attenuated Fgf21 overexpression in HFD mice (Exp. 2, 22%), associated with increased expression of genes that encode FGFR1 and β-klotho (>3-fold, P < 0.05).. Dietary Cy3G may reduce body weight and exert metabolic homeostatic effects in mice via changes in hepatic FGF21.

Topics: Animals; Anthocyanins; Diet, High-Fat; Dietary Fats; Fibroblast Growth Factors; Gene Expression Regulation; Glucagon-Like Peptide 1; Glucose Intolerance; Glucosides; Incretins; Leptin; Liver; Male; Mice; Random Allocation; Weight Gain; Weight Loss

Obesity is associated with several female reproductive complications, such as polycystic ovary syndrome (PCOS). The exact mechanism of this relationship remains unclear. Few previous studies using diet containing refined carbohydrate (HCD) leading to obesity have been performed and it is unclear if HCD is linked with reproductive dysfunctions. In this investigation, we assessed whether subchronic HCD exposure results in reproductive and other irregularities. Female rats were fed with HCD for 15 days and metabolic outcomes and reproductive tract morphophysiology were assessed. We further assessed reproductive tract inflammation, oxidative stress (OS) and fibrosis. HCD rats displayed metabolic impairments, such as an increase in body weight/adiposity, adipocyte hypertrophic, abnormal lipid profile, glucose tolerance and insulin resistance (IR) and hyperleptinemia. Improper functioning of the HCD reproductive tract was observed. Specifically, irregular estrous cyclicity, high LH levels and abnormal ovarian morphology coupled with reduction in primordial and primary follicle numbers was observed, suggesting ovarian reserve depletion. Improper follicular development and a reduction in antral follicles, corpora lutea and granulosa layer area together with an increase in cystic follicles were apparent. Uterine atrophy and reduction in endometrial gland (GE) number was observed in HCD rats. Reproductive tract inflammation, OS and fibrosis were seen in HCD rats. Further, strong positive correlations were observed between body weight/adiposity and IR with estrous cycle length, cystic follicles, ovarian reserve, GE and other abnormalities. Thus, these data suggest that the subchronic HCD exposure led to PCOS-like features, impaired ovarian reserve, GE number, and other reproductive abnormalities in female rats.

Topics: Adiposity; Animals; Body Weight; Diet; Dietary Carbohydrates; Estrous Cycle; Female; Fibrosis; Glucose Intolerance; Insulin Resistance; Leptin; Lipid Metabolism; Ovarian Follicle; Ovarian Reserve; Ovary; Oxidative Stress; Polycystic Ovary Syndrome; Rats; Rats, Wistar

The maternal organism undergoes numerous metabolic adaptations to become prepared for the demands associated with the coming offspring. These metabolic adaptations involve changes induced by several hormones that act at multiple levels, ultimately influencing energy and glucose homeostasis during pregnancy and lactation. Previous studies have shown that central growth hormone (GH) action modulates glucose and energy homeostasis. However, whether central GH action regulates metabolism during pregnancy and lactation is still unknown. In the present study, we generated mice carrying ablation of GH receptor (GHR) in agouti-related protein (AgRP)-expressing neurons, in leptin receptor (LepR)-expressing cells or in the entire brain to investigate the role played by central GH action during pregnancy and lactation. AgRP-specific GHR ablation led to minor metabolic changes during pregnancy and lactation. However, while brain-specific GHR ablation reduced food intake and body adiposity during gestation, LepR GHR knockout (KO) mice exhibited increased leptin responsiveness in the ventromedial nucleus of the hypothalamus during late pregnancy, although their offspring showed reduced growth rate. Additionally, both Brain GHR KO and LepR GHR KO mice had lower glucose tolerance and glucose-stimulated insulin secretion during pregnancy, despite presenting increased insulin sensitivity, compared with control pregnant animals. Our findings revealed that during pregnancy central GH action regulates food intake, fat retention, as well as the sensitivity to insulin and leptin in a cell-specific manner. Together, the results suggest that GH acts in concert with other "gestational hormones" to prepare the maternal organism for the metabolic demands of the offspring.

Topics: Adiposity; Animals; Brain Chemistry; Carrier Proteins; Eating; Female; Glucose Intolerance; Growth Hormone; Insulin Resistance; Leptin; Mice; Mice, Knockout; Neurons; Pregnancy; Pregnancy, Animal; Receptors, Leptin

Leptin regulates both feeding and glycaemia primarily through its receptors expressed on agouti-related peptide (AgRP) and pro-opiomelanocortin-expressing (POMC) neurons; however, it is unknown whether activity of these neuronal populations mediates the regulation of these processes. To determine this, we injected Cre-dependent designer receptors exclusively activated by designer drugs (DREADD) viruses into the hypothalamus of normoglycaemic and diabetic AgRP-ires-cre and POMC-cre mice to chemogenetically activate or inhibit these neuronal populations. Despite robust changes in food intake, activation or inhibition of AgRP neurons did not affect glycaemia, while activation caused significant (P = 0.014) impairment in insulin sensitivity. Stimulation of AgRP neurons in diabetic mice reversed leptin's ability to inhibit feeding but did not counter leptin's ability to lower blood glucose levels. Notably, the inhibition of POMC neurons stimulated feeding while decreasing glucose levels in normoglycaemic mice. The findings suggest that leptin's effects on feeding by AgRP neurons are mediated by changes in neuronal firing, while the control of glucose balance by these cells is independent of chemogenetic activation or inhibition. The firing-dependent glucose lowering mechanism within POMC neurons is a potential target for the development of novel anti-diabetic medicines.

Topics: Agouti-Related Protein; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Eating; Glucose; Glucose Intolerance; Insulin Resistance; Leptin; Mice; Models, Biological; Neurons; Proprotein Convertases

Obesity is the major risk factor for several cardiovascular and metabolic disorders. Previous studies reported that deletion of Angiotensin II type 2 receptor (AT2R) protects against metabolic dysfunctions induced by high fat (HF) diet. However, the role of AT2R in obesity-induced cardiac hypertrophy remains unclear. Male AT2R knockout (AT2RKO) and wild type (AT2RWT) mice were fed with control or HF diet for 10 weeks. HF diet increased cardiac expression of AT2R in obese mice. Deletion of AT2R did not affect body weight gain, glucose intolerance and fat mass gain induced by HF feeding. However, loss of AT2R prevented HF diet-induced hypercholesterolemia and cardiac remodeling. Mechanistically, we found that pharmacological inhibition or knockdown of AT2R prevented leptin-induced cardiomyocyte hypertrophy in vitro. Collectively, our results suggest that AT2R is involved in obesity-induced cardiac hypertrophy.

Topics: Animals; Cardiomegaly; Diet, High-Fat; Glucose Intolerance; Hypercholesterolemia; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocytes, Cardiac; Obesity; Receptor, Angiotensin, Type 2

Resistin promotes hypothalamic neuroinflammation and insulin resistance through Toll like receptor 4 (TLR4), this hormone is thought to be a link between obesity and insulin-resistance. Indeed, resistin plasma levels are higher in obese and insulin resistant subjects. However, the impact of maternal resistin on the predisposition of offspring to hypothalamic neuroinflammation is unknown. Here, female mice were treated with resistin during gestation/lactation periods, then hypothalamic neuroinflammation was investigated in male offspring at p28 and p90. At p28, resistin increased the expression of inflammation markers (IL6, TNFα and NFκB) and TLR4 in the hypothalamus and decreased both hypothalamic insulin and leptin receptors' expression. The hypothalamic up-regulation IL6, TNFα and TLR4 was sustained until p90 promoting most likely hypothalamic inflammation. Maternal resistin also increased IL6 and TNFα in the adipose tissue of offspring at p90 associated with a higher body weight gain. In contrast, liver and muscle were not affected. These findings reveal that the augmentation of maternal resistin during gestation and lactation promotes hypothalamic and adipose tissue inflammation of offspring as evidenced by sustained increase of inflammation markers from weaning to adulthood. Thus, maternal resistin programs offspring hypothalamic and adipose tissue inflammation predisposing then offspring to body weight gain.

Topics: Animals; Animals, Newborn; Body Weight; Female; Glucose Intolerance; Hypothalamus; Inflammation; Inflammation Mediators; Insulin Resistance; Insulinoma; Lactation; Leptin; Male; Maternal Nutritional Physiological Phenomena; Mice; Pregnancy; Resistin; Weaning; Weight Gain

Studies have implicated the extracellular matrix (ECM) of adipose tissue in insulin resistance. The proteoglycan decorin, a component of ECM, has been associated with glucose tolerance, but possible causal effects on metabolism remain to be explored. We here sought to determine metabolic consequences of loss of decorin in mice (DcnKO). DcnKO mice were fed a low-fat (LF) or high-fat (HF) diet for 10 weeks and body weight and food intake was recorded. An intraperitoneal glucose tolerance test was performed after eight weeks. Blood samples and adipose, liver and muscle tissues were collected at sacrifice. Global gene expression was measured in adipose tissue, and expression of decorin was also analyzed in human adipose samples. DcnKO mice showed increased feed efficiency during overfeeding and impaired glucose tolerance. Adipose leptin mRNA and circulating leptin levels were elevated in DcnKO mice, along with a downregulation of genes involved in ECM organization and triglyceride biosynthesis, and an upregulation of adipose genes involved in complement and coagulation cascades. Consistent with a protective metabolic role for decorin, in obese patients we found increased adipose decorin expression after profound fat loss, particularly in the stromal vascular fraction. Loss of decorin in mice caused impaired glucose tolerance in association with increased feed efficiency and altered gene expression in adipose tissue. Our data provide evidence that decorin is an important factor for maintaining glucose tolerance.

Topics: Adipose Tissue; Adiposity; Animals; Body Weight; Decorin; Diet, High-Fat; Glucose; Glucose Intolerance; Glucose Tolerance Test; Insulin; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Overnutrition; Proteoglycans

The enzyme dipeptidyl peptidase 4 (DPP4) has been recently recognized as an adipo-myokine. However, studies that associate its constitutive activity with body composition, anthropometry, and insulin resistance (IR) are very scarce and included only healthy people.. First, we investigated the relationships of constitutive DPP4 activity, body composition (assessed by bioelectrical impedance analysis), and measures of adiposity and IR in fifty-two subjects of both sexes, 18-50 years, and BMI ≥25.0 kg/m. DPP4 activity was no different among the three groups. At fasting, pooled analysis showed it was positively correlated with measures of central adiposity, such as WC (. Constitutive DPP4 activity is positively associated with lean mass, central adiposity, and IR and negatively to general adiposity. Furthermore, it seems to be influenced by body composition and IR and could also be viewed as an adipo-myokine in subjects with excessive adiposity and different stages of glucose tolerance.

Topics: Adiposity; Adolescent; Adult; Body Composition; Body Mass Index; Dipeptidyl Peptidase 4; Electric Impedance; Fasting; Female; Glucose Intolerance; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Young Adult

Sirtuin 1 (Sirt1) is an NAD-dependent class III deacetylase that functions as a cellular energy sensor. In addition to its well-characterized effects in peripheral tissues, evidence suggests that SIRT1 in neurons plays a role in the central regulation of energy balance and reproduction, but no studies have addressed the contribution of astrocytes. We show here that overexpression of SIRT1 in astrocytes causes markedly increased food intake, body weight gain, and glucose intolerance, but expression of a deacetylase-deficient SIRT1 mutant decreases food intake and body weight and improves glucose tolerance, particularly in female mice. Paradoxically, the effect of these SIRT1 mutants on insulin tolerance was reversed, with overexpression showing greater insulin sensitivity. The mice overexpressing SIRT1 were more active, generated more heat, and had elevated oxygen consumption, possibly in compensation for the increased food intake. The female overexpressing mice were also more sensitive to diet-induced obesity. Reproductively, the mice expressing the deacetylase-deficient SIRT1 mutant had impaired estrous cycles, decreased LH surges, and fewer corpora lutea, indicating decreased ovulation. The GnRH neurons were responsive to kisspeptin stimulation, but hypothalamic expression of Kiss1 was reduced in the mutant mice. Our results showed that SIRT1 signaling in astrocytes can contribute to metabolic and reproductive regulation independent of SIRT1 effects in neurons.

Topics: Animals; Astrocytes; Eating; Estrous Cycle; Female; Follicle Stimulating Hormone; Glucose; Glucose Intolerance; Gonadotropin-Releasing Hormone; Hypothalamus; Insulin Resistance; Leptin; Luteinizing Hormone; Male; Mice; Neurons; Sirtuin 1; Testis; Weight Gain

Women with gestational diabetes (GDM) are a high risk group for early type 2 diabetes (T2D). Depression is a risk factor for T2D in the general population. We investigated in women after a recent pregnancy with GDM and without a clinical diagnosis of depression, whether mild to moderate depressive symptoms associate with pathologic glucose metabolism. In a cross-sectional analysis, we examined 173 women, 9 ± 3 months after delivery with several psychopathological assessments, 5-point oral glucose tolerance test with insulin, anthropometrics, and laboratory chemistry. In a subgroup of 101 women, abdominal visceral fat was quantified by magnetic resonance imaging (MRI). A total of 22 women (13%) showed mild to moderate depressive symptoms, and the proportion of women with pathologic glucose metabolism (impaired fasting glucose, impaired glucose tolerance, or T2D) was higher in this group than in the women without depressive symptoms (59.1% vs. 33.1%, p = 0.018). Women with depressive symptoms also had higher body mass index (BMI), systolic blood pressure, plasma leptin, plasma resistin, and abdominal visceral fat volume. Pathologic glucose metabolism (OR = 2.594, 95% CI: 1.021-6.592), systolic blood pressure (OR = 1.076, 95% CI: 1.027-1.128), and abdominal visceral fat volume (OR = 2.491, 95% CI: 1.142-5.433) remained, even after adjustment for BMI, associated with the presence of depressive symptoms. Taken together, we found depressive symptoms at a level not generally diagnosed in clinical practice in a subgroup of women with recent GDM. This subgroup also showed an unfavorable metabolic profile. Mild to moderate depressive symptoms may therefore help to identify this special subgroup.

Topics: Adult; Biomarkers; Blood Pressure; Cross-Sectional Studies; Depression; Diabetes, Gestational; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Intra-Abdominal Fat; Leptin; Pregnancy; Resistin

The responsiveness of glucose sensing

Topics: Animals; Diet, High-Fat; Gene Expression Regulation, Enzymologic; Glucose; Glucose Intolerance; Glucose Tolerance Test; Homeostasis; Hypothalamus; Insulin Resistance; L-Lactate Dehydrogenase; Leptin; Male; Rats; Rats, Sprague-Dawley

The microtubule-associated protein tau is highly expressed in pancreatic islets. Abnormally phosphorylated tau aggregates assemble into neurofibrillary tangles linked to Alzheimer's disease pathology and has also been found in islets of patients with type 2 diabetes. However, the significance of tau in islet function remains relatively unexplored. Therefore, we investigated the role of tau on β cell function and glucose homeostasis using tau knockout (tauKO) mice. TauKO mice were hyperglycemic and glucose intolerant at an early age. Islet insulin content was reduced and proinsulin levels were significantly elevated in tauKO mice, resulting in impaired glucose-stimulated insulin secretion. Loss of tau also resulted in increased epididymal fat mass and leptin levels, reduced glucose production, and insulin resistance at later ages, leading to complete onset of diabetes. Transgenic expression of human tau in islets was unable to rescue those defects in glucose regulation, indicating structural and/or functional differences between mouse and human tau. Cumulatively, these results suggest an important role for tau in the proper maintenance of pancreatic β cell function and glucose homeostasis.-Wijesekara, N., Gonçalves, R. A., Ahrens, R., De Felice, F. G., Fraser, P. E. Tau ablation in mice leads to pancreatic β cell dysfunction and glucose intolerance.

Topics: Animals; Diabetes Mellitus, Type 2; Glucose; Glucose Intolerance; Humans; Insulin-Secreting Cells; Leptin; Male; Mice; Mice, Knockout; Proinsulin; Species Specificity; tau Proteins

Tumor necrosis factor (TNF) is a well-known cytokine that triggers insulin resistance during obesity development. On the other hand, it is also known that TNF induces a fat mass loss during acute diseases. However, whether TNF has a protective and physiological role to control adipose tissue expansion during obesity still needs to be verified. The aim of this study was to evaluate whether the ablation of TNF receptor 1 (TNFR1) alters fat mass and insulin resistance induced by a highly refined carbohydrate-containing (HC) diet.. Male C57 BL/6 wild-type (WT) mice and TNFR1 knockout (TNFR1. TNFR1. TNF signaling appears to have a paradoxical role on metabolism. Ablation of TNFR1 leads to a reduction of inflammatory cytokines in adipose tissue that is accompanied by higher adiposity in mice fed with chow diet. However, when these mice are given the HC diet, the loss of TNFR1 improves insulin sensitivity and protects mice against additional fat mass.

Topics: Adipose Tissue; Animals; Diet; Dietary Carbohydrates; Disease Models, Animal; Glucose Intolerance; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Receptors, Tumor Necrosis Factor, Type I; Resistin; Tumor Necrosis Factor-alpha

Disruptions to the circadian rhythm can lead to altered metabolism. Modification of thyroid function may be a reason why circadian misalignment may contribute to future metabolic disorders. We investigated whether circadian disruption through constant light (LL) can lead to variations in hormone levels associated with thyroid function. Mice were exposed to LL or a 12:12 Light:Dark (LD) cycle for 6 weeks; then glucose tolerance and thyroid hormone levels were measured at ZT 6 and ZT 18. There was day/night variation in glucose tolerance, but LL had no effect. LL reduced TSH, increased fT4, and abolished day/night variation in fT3 and leptin. These findings illustrate that LL alters thyroid-related hormones, providing evidence of a link between circadian disruption and thyroid function.

Topics: Animals; Blood Glucose; Glucose Intolerance; Leptin; Light; Male; Mice; Motor Activity; Photoperiod; Thyrotropin; Thyroxine; Triiodothyronine

Determine the metabolic profile and identify risk factors of women transitioning from gestational diabetes mellitus (GDM) to type 2 diabetes mellitus (T2DM).. 237 women diagnosed with GDM underwent an oral glucose tolerance test (OGTT), anthropometrics assessment, and completed lifestyle questionnaires six years after pregnancy. Blood was analysed for clinical variables (e.g., insulin, glucose, HbA1c, adiponectin, leptin, and lipid levels) and NMR metabolomics. Based on the OGTT, women were divided into three groups: normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and T2DM.. Six years after GDM, 19% of subjects had T2DM and 19% IGT. After BMI adjustment, the IGT group had lower HDL, higher leptin, and higher free fatty acid (FFA) levels, and the T2DM group higher triglyceride, FFA, and C-reactive protein levels than the NGT group. IGT and T2DM groups reported lower physical activity. NMR measurements revealed that levels of branched-chain amino acids (BCAAs) and the valine metabolite 3-hydroxyisobyturate were higher in T2DM and IGT groups and correlated with measures of insulin resistance and lipid metabolism.. In addition to well-known clinical risk factors, BCAAs and 3-hydroxyisobyturate are potential markers to be evaluated as predictors of metabolic risk after pregnancy complicated by GDM.

Topics: Adiponectin; Adult; Amino Acids, Branched-Chain; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Diabetes, Gestational; Disease Progression; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Hydroxybutyrates; Insulin Resistance; Leptin; Pregnancy; Risk Factors

RF-amide-related peptide-3 (RFRP-3), the mammalian ortholog of gonadotropin-inhibiting hormone, operates as inhibitory signal for the reproductive axis. Recently, RFRP-3 has been also suggested to stimulate feeding, and therefore might contribute to the control of body weight and its alterations. Yet, characterization of the metabolic actions of RFRP-3 has been so far superficial and mostly pharmacological. Here, we aim to investigate the physiological roles of RFRP-3 signaling in the control of feeding and metabolic homeostasis using a novel mouse model of genetic ablation of its canonical receptor, NPFF1R.. Food intake, body weight gain and composition, and key metabolic parameters, including glucose tolerance and insulin sensitivity, were monitored in mice with constitutive inactivation of NPFF1R.. Congenital elimination of NPFF1R in male mice resulted in changes in feeding patterns, with a decrease in spontaneous food intake and altered responses to leptin and ghrelin: leptin-induced feeding suppression was exaggerated in NPFF1R null mice, whereas orexigenic responses to ghrelin were partially blunted. Concordant with this pro-anorectic phenotype, hypothalamic expression of Pomc was increased in NPFF1R null mice. In contrast, spontaneous feeding and neuropeptide expression remained unaltered in NPFF1R KO female mice. Despite propensity for reduced feeding, ablation of NPFF1R signaling in male mice did not cause overt alterations in body weight (BW) gain or composition, neither it affected BW responses to high fat diet (HFD), total energy expenditure or RQ ratios. Yet, NPFF1R KO males showed a decrease in locomotor activity. Conversely, NPFF1R null female mice tended to be heavier and displayed exaggerated BW increases in response to obesogenic insults, such as HFD or ovariectomy. These were associated to increased fat mass, decreased total energy expenditure in HFD, and unaltered RQ ratios or spontaneous locomotor activity. Finally, lack of NPFF1R signaling worsened the metabolic impact of HFD on glycemic homeostasis in males, as revealed by impaired glucose tolerance and insulin sensitivity, while female mice remained unaffected.. Our data support a discernible orexigenic role of NPFF1R signaling selectively in males, which might modulate the effects of leptin and ghrelin on food intake. In addition, our study is the first to disclose the sex-biased, deleterious impact of the lack of NPFF1R signaling on body weight and fat composition, energy expenditure, locomotor activity and glucose balance, which exaggerates some of the metabolic consequences of concurrent obesogenic insults, such as HFD, in a sexually dimorphic manner.. Our data are the first to document the nature and magnitude of the regulatory actions of RFRP-3/NPFF1R signaling in the control of feeding and metabolic homeostasis in a physiological setting. Our results not only suggest an orexigenic action of endogenous RFRP-3, specifically in males, but reveal also the detrimental impact of ablation of NPFF1R signaling on body composition, energy expenditure, locomotor activity or glucose balance, especially when concurrent with other obesogenic insults, as HFD, thereby providing the first evidence for additional metabolic effects of RFRP-3, other that the mere control of feeding. Interestingly, alterations of such key metabolic parameters occurred in a sex-biased manner, with males being more sensitive to deregulation of locomotor activity and glycemic control, while females displayed clearer obesogenic responses and deregulated energy expenditure. While our study cannot discard the possibility of RFRP-3 actions via alternative pathways, such as NPFF2R, our data pave the way for future analyses addressing the eventual contribution of altered RFRP-3/NPFF1R signaling in the development of metabolic alterations (including obesity and its comorbidities), especially in conditions associated to reproductive dysfunction.

Topics: Animals; Body Composition; Diet, High-Fat; Eating; Energy Metabolism; Ghrelin; Glucose Intolerance; Homeostasis; Hypothalamus; Insulin Resistance; Leptin; Male; Mice; Mice, Knockout; Neuropeptides; Receptors, Neuropeptide; Sex Characteristics; Weight Gain

To evaluate the additional discriminatory performance of adiponectin, leptin, and their ratio in the identification of impaired glucose tolerance (IGT) in men and women without diabetes on top of conventional risk factors.. A total of 698 subjects underwent an oral glucose tolerance test (oGTT) and adipocytokine measurements. A comprehensive stepwise selection procedure was performed, followed by c-statistics and integrated discrimination improvement (IDI) analysis. In males, adiponectin levels were significantly lower in the IGT group compared to the non-IGT group (Whitney U test, p < 10-4), whereas leptin levels were significantly higher (p = 0.009) in IGT group. In females, adiponectin and leptin levels were not significantly different between groups (Mann-Whitney U test, p = 0.073 and p = 0.08, respectively). Adjusting for the most informative, sex-specific, clinical and biochemical factors, adiponectin, leptin and their ratio were not found to be significant predictors of the response to the glucose load, when modelled as continuous terms or tertiles. In males, the area-under-the-curve (AUC) for adiponectin was estimated at 0.620 (95% CI: 0.558-0.682) and the addition of adiponectin into the basic model provided a ΔAUC benefit of 0.004, showing no additional discriminatory benefit on top of conventional risk factors (IDI p-value: 0.27), nor did the addition of leptin or their ratio. The results were similar in females.. In Chinese individuals without diabetes, no significant evidence for the potential discriminatory value of adiponectin, leptin or their ratio in the identification of IGT on top of conventional risk factors was observed.

Topics: Adiponectin; Area Under Curve; Biological Specimen Banks; Biomarkers; Blood Glucose; Cardiovascular Diseases; Cross-Sectional Studies; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Leptin; Male; Odds Ratio; ROC Curve

Topics: Aging; Animals; Animals, Newborn; Blood Glucose; Brain; Brain Chemistry; Brain-Derived Neurotrophic Factor; Female; Fetus; Fluorodeoxyglucose F18; Genotype; Glucose; Glucose Intolerance; Humans; Hyperglycemia; Infant; Infant, Newborn; Leptin; Male; Obesity; Positron-Emission Tomography; Rats; Rats, Zucker

Diet-induced obesity, insulin resistance, impaired glucose tolerance, chronic inflammation, and oxidative stress represent the main features of type 2 diabetes mellitus. The present study was conducted to examine the efficacy and mechanisms of shrimp oil on glucose homeostasis in obese rats. Male CD rats fed a high-fat diet (52 kcal% fat) and 20% fructose drinking water were divided into 4 groups and treated with the dietary replacement of 0%, 10%, 15%, or 20% of lard with shrimp oil for 10 weeks. Age-matched rats fed a low-fat diet (10 kcal% fat) were used as the normal control. Rats on the high-fat diet showed impaired (p < 0.05) glucose tolerance and insulin resistance compared with rats fed the low-fat diet. Shrimp oil improved (p < 0.05) oral glucose tolerance, insulin response, and homeostatic model assessment-estimated insulin resistance index; decreased serum insulin, leptin, hemoglobin A1c, and free fatty acids; and increased adiponectin. Shrimp oil also increased (p < 0.05) antioxidant capacity and reduced oxidative stress and chronic inflammation. The results demonstrated that shrimp oil dose-dependently improved glycemic control in obese rats through multiple mechanisms.

Topics: Adiponectin; Animals; Anostraca; Biomarkers; Blood Glucose; Diet, High-Fat; Dietary Fats; Fatty Acids, Nonesterified; Glucose Intolerance; Glycated Hemoglobin; Insulin; Insulin Resistance; Leptin; Male; Obesity; Oils; Oxidative Stress; Rats; Shellfish; Vitamin A; Vitamin E; Xanthophylls

Branched chain amino acids (BCAA) may be involved in the pathogenesis of insulin resistance and are associated with type 2 diabetes mellitus (T2DM) development. Adipokines such as leptin and adiponectin influence insulin resistance and reflect adipocyte dysfunction. We examined the extent to which the association of BCAA with insulin resistance is attributable to altered leptin and adiponectin levels in individuals with varying degrees of glucose tolerance.. BCAA were measured by nuclear magnetic resonance, whereas leptin and adiponectin were measured by immunoassay, in subjects with normal fasting glucose (n = 30), impaired fasting glucose (n = 25), and T2DM (n = 15). Insulin resistance was estimated by homeostasis model assessment (HOMAir).. BCAA were higher in men than in women (P < 0.001) and tended to be higher in T2DM subjects (P = 0.10) compared to subjects with normal or impaired fasting glucose. In univariate regression analysis, BCAA were correlated with HOMAir (r = 0.46; P < 0.001) and inversely with adiponectin (r = -0.53; P < 0.001) but not with leptin (r = -0.08; P > 0.05). Multivariable linear regression analysis, adjusting for age, sex, T2DM, and body mass index (BMI), demonstrated that BCAA were positively associated with HOMAir (β = 0.242, P = 0.023). When BCAA, leptin, and adiponectin were included together, the positive relationship of HOMAir with BCAA (β = 0.275, P = 0.012) remained significant.. Insulin resistance was associated with BCAA. This association remained after adjusting for age, sex, T2DM, BMI, as well as leptin and adiponectin. It is unlikely that the relationship of insulin resistance with BCAA is to a major extent attributable to effects of leptin and adiponectin.

Topics: Adiponectin; Adult; Aged; Amino Acids, Branched-Chain; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Female; Glucose Intolerance; Glucose Tolerance Test; Healthy Volunteers; Humans; Insulin Resistance; Leptin; Magnetic Resonance Spectroscopy; Male; Middle Aged; Sex Characteristics

What is the central question of this study? Is the initial decline of spontaneous physical activity (SPA) in mice related to impaired insulin and leptin signalling or brain-derived neurotrophic factor expression in the hypothalamus? What is the main finding and its importance? We showed that SPA started to decline at an early stage, concomitantly with an impairment of hypothalamic leptin signalling. Consequently, energy expenditure decreased and glucose tolerance worsened. Our results demonstrate the need to counteract the initial decline in SPA to avoid metabolic impairments and indicate the possible involvement of central leptin in the reduction in SPA with age. The biological control of physical activity is poorly understood. Age decreases insulin, leptin and brain-derived neurotrophic factor (BDNF) signalling in the hypothalamus, and all have been shown to modulate spontaneous physical activity (SPA). We investigated the age at which SPA starts to decline and whether this is associated with the emergence of hypothalamic insulin and leptin resistance and reduced BDNF expression. Spontaneous physical activity (and other parameters of locomotion) and energy expenditure were determined monthly in mice from the 4th to the 10th month of age. Metabolic and hypothalamic analyses were performed in 4-, 6- and 10-month-old mice. Spontaneous physical activity, distance travelled and speed of locomotion started to decrease in 6-month-old mice. The reduction in SPA became more evident from 8 months of age. Energy expenditure decreased from the 8th month. Hypothalamic BDNF protein expression and insulin signalling did not change throughout the time span studied. Leptin signalling decreased at 6 and 10 months compared with 4 months. Also, compared with 4 months, 6- and 10-month-old mice were glucose intolerant. In conclusion, SPA begins to decline in parallel with reduced hypothalamic leptin signalling. Metabolic impairment also manifests as SPA decreases, highlighting the need to understand the regulation of SPA in order to combat its decline.

Topics: Adiposity; Age Factors; Aging; Animals; Blood Glucose; Brain-Derived Neurotrophic Factor; Energy Metabolism; Glucose Intolerance; Homeostasis; Hypothalamus; Insulin; Insulin Resistance; Leptin; Locomotion; Male; Mice, Inbred C57BL; Muscle, Skeletal; Physical Exertion; Sedentary Behavior; Signal Transduction

Here, we aimed to investigate the potential role of DUSP6, a dual specificity phosphatase, that specifically inactivates extracellular signal-regulated kinase (ERK), for the regulation of body weight and glucose homeostasis. We further assessed whether metabolic challenges affect Dusp6 expression in selected brain areas or white adipose tissue. Hypothalamic Dusp6 mRNA levels remained unchanged in chow-fed lean vs. high fat diet (HFD) fed obese C57Bl/6J mice, and in C57Bl/6J mice undergoing prolonged fasting or refeeding with fat free diet (FFD) or HFD. Similarly, Dusp6 expression levels were unchanged in selected brain regions of Lepob mice treated with 1 mg/kg of leptin for 6 days, compared to pair-fed or saline-treated Lepob controls. Dusp6 expression levels remained unaltered in vitro in primary adipocytes undergoing differentiation, but were increased in eWAT of HFD-fed obese C57Bl/6J mice, compared to chow-fed lean controls. Global chow-fed DUSP6 KO mice displayed reduced body weight and lean mass and slightly increased fat mass at a young age, which is indicative for early-age weight retardation. Subsequent exposure to HFD led to a significant increase in lean mass and body weight in DUSP6 deficient mice, compared to WT controls. Nevertheless, after 26 weeks of high-fat diet exposure, we observed comparable body weight, fat and lean mass in DUSP6 WT and KO mice, suggesting overall normal susceptibility to develop obesity. In line with the increased weight gain to compensate for early-age weight retardation, HFD-fed DUSP6 KO displayed increased expression levels of anabolic genes involved in lipid and cholesterol metabolism in the epididymal white adipose tissue (eWAT), compared to WT controls. Glucose tolerance was perturbed in both chow-fed lean or HFD-fed obese DUSP6 KO, compared to their respective WT controls. Overall, our data indicate that DUSP6 deficiency has limited impact on the regulation of energy metabolism, but impairs systemic glucose tolerance. Our data are in conflict to earlier reports that propose protection from diet-induced obesity and glucose intolerance in DUSP6 deficient mice. Reasons for the discrepancies remain elusive, but may entail differential genetic backgrounds, environmental factors such as the type and source of HFD, or alterations in the gut microbiome between facilities.

Topics: Adipose Tissue, White; Animals; Body Composition; Body Weight; Diet, High-Fat; Dual Specificity Phosphatase 6; Epididymis; Fasting; Gene Expression Profiling; Glucose Intolerance; Homeostasis; Leptin; Lipid Metabolism; Male; Mice, Inbred C57BL; Mice, Knockout; Nutritional Physiological Phenomena; Obesity; RNA, Messenger

Childhood obesity is associated with renal diseases. Maternal obesity is a risk factor linked to increased adipocytokines and metabolic disorders in the offspring. Therefore, we studied the impact of maternal obesity on renal-intrinsic insulin and adipocytokine signaling and on renal function and structure. To induce maternal obesity, female mice were fed a high-fat diet (HFD) or a standard diet (SD; control group) prior to mating, during gestation, and throughout lactation. A third group of dams was fed HFD only during lactation (HFD-Lac). After weaning at postnatal day (P)21, offspring of all groups received SD. Clinically, HFD offspring were overweight and insulin resistant at P21. Although no metabolic changes were detected at P70, renal sodium excretion was reduced by 40%, and renal matrix deposition increased in the HFD group. Mechanistically, two stages were differentiated. In the early stage (P21), compared with the control group, HFD showed threefold increased white adipose tissue, impaired glucose tolerance, hyperleptinemia, and hyperinsulinemia. Renal leptin/Stat3-signaling was activated. In contrast, the Akt/ AMPKα cascade and Krüppel-like factor 15 expression were decreased. In the late stage (P70), although no metabolic differences were detected in HFD when compared with the control group, leptin/Stat3-signaling was reduced, and Akt/AMPKα was activated in the kidneys. This effect was linked to an increase of proliferative (cyclinD1/D2) and profibrotic (ctgf/collagen IIIα1) markers, similar to leptin-deficient mice. HFD-Lac mice exhibited metabolic changes at P21 similar to HFD, but no other persistent changes. This study shows a link between maternal obesity and metabolic programming of renal structure and function and intrinsic-renal Stat3/Akt/AMPKα signaling in the offspring.

Topics: Adipokines; Adipose Tissue, White; AMP-Activated Protein Kinases; Animals; Collagen Type III; Connective Tissue Growth Factor; Cyclin D1; Cyclin D2; Diet, High-Fat; DNA-Binding Proteins; Female; Glucose Intolerance; Insulin; Insulin Resistance; Kidney; Kruppel-Like Transcription Factors; Leptin; Male; Mice; Obesity; Overweight; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Proto-Oncogene Proteins c-akt; Signal Transduction; Sodium; STAT3 Transcription Factor; Transcription Factors

Insulin and IGF1 signaling are important for adipose tissue development and function; however, their role in mature adipocytes is unclear. Mice with a tamoxifen-inducible knockout of insulin and/or IGF1 receptors (IR/IGF1R) demonstrate a rapid loss of white and brown fat due to increased lipolysis and adipocyte apoptosis. This results in insulin resistance, glucose intolerance, hepatosteatosis, islet hyperplasia with hyperinsulinemia, and cold intolerance. This phenotype, however, resolves over 10-30 days due to a proliferation of preadipocytes and rapid regeneration of both brown and white adipocytes as identified by mTmG lineage tracing. This cycle can be repeated with a second round of receptor inactivation. Leptin administration prior to tamoxifen treatment blocks development of the metabolic syndrome without affecting adipocyte loss or regeneration. Thus, IR is critical in adipocyte maintenance, and this loss of adipose tissue stimulates regeneration of brown/white fat and reversal of metabolic syndrome associated with fat loss.

Topics: Adipocytes; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Cell Differentiation; Cell Proliferation; Fatty Liver; Gene Deletion; Glucose Intolerance; Hyperglycemia; Insulin; Insulin Resistance; Insulin-Secreting Cells; Leptin; Lipodystrophy; Metabolic Syndrome; Mice; Organ Specificity; Receptor, IGF Type 1; Receptor, Insulin; Regeneration; Tamoxifen

Effectors of the phosphoinositide 3-kinase (PI3K) signal transduction pathway contribute to the hypothalamic regulation of energy and glucose homeostasis in divergent ways. Here we show that central nervous system (CNS) action of the PI3K signaling intermediate atypical protein kinase C (aPKC) constrains food intake, weight gain, and glucose intolerance in both rats and mice. Pharmacological inhibition of CNS aPKC activity acutely increases food intake and worsens glucose tolerance in chow-fed rodents and causes excess weight gain during high-fat diet (HFD) feeding. Similarly, selective deletion of the aPKC isoform

Topics: Animals; Diet, High-Fat; Eating; Energy Metabolism; Glucose; Glucose Intolerance; Hypothalamus; Insulin Resistance; Isoenzymes; Leptin; Male; Melanocortins; Mice; Neurons; Obesity; Paraventricular Hypothalamic Nucleus; Phosphatidylinositol 3-Kinases; Pro-Opiomelanocortin; Protein Kinase C; Rats; Signal Transduction; Weight Gain

To test the hypothesis that high-fat (HF) diet-induced obesity increases proinflammatory cytokine expression, macrophage infiltration, and M1 polarization in the infrapatellar fat pad (IFP) prior to knee cartilage degeneration.. We characterized the effect of HF feeding on knee OA pathology, body adiposity, and glucose intolerance in male C57BL/6J mice and identified a diet duration that induces metabolic dysfunction prior to cartilage degeneration. Magnetic resonance imaging and histomorphology were used to quantify changes in the epididymal, subcutaneous, and infrapatellar fat pads and in adipocyte sizes. Finally, we used targeted gene expression and protein arrays, immunohistochemistry, and flow cytometry to quantify differences in fat pad markers of inflammation and immune cell populations.. Twenty weeks of feeding with an HF diet induced marked obesity, glucose intolerance, and early osteoarthritis (OA), including osteophytes and cartilage tidemark duplication. This duration of HF feeding increased the IFP volume. However, it did not increase IFP inflammation, macrophage infiltration, or M1 macrophage polarization as observed in epididymal fat. Furthermore, leptin protein levels were reduced. This protection from obesity-induced inflammation corresponded to increased IFP fibrosis and the absence of adipocyte hypertrophy.. The IFP does not recapitulate classic abdominal adipose tissue inflammation during the early stages of knee OA in an HF diet-induced model of obesity. Consequently, these findings do not support the hypothesis that IFP inflammation is an initiating factor of obesity-induced knee OA. Furthermore, the profibrotic and antihypertrophic responses of IFP adipocytes to HF feeding suggest that intraarticular adipocytes are subject to distinct spatiotemporal structural and metabolic regulation among fat pads.

Topics: Abdominal Fat; Adipocytes; Adipose Tissue; Animals; Diet, High-Fat; Fibrosis; Glucose Intolerance; Hypertrophy; Inflammation Mediators; Knee Joint; Leptin; Macrophages; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Obesity; Osteoarthritis, Knee; Time Factors

Adiponectin and leptin are associated with insulin resistance and cardiovascular disease. Information on the prognostic value after an acute myocardial infarction is still conflicting.. Patients (n = 180) without known diabetes and with admission glucose of <11 mmol/L admitted for an acute myocardial infarction in 1998-2000 were followed for mortality and cardiovascular events (first of cardiovascular mortality/acute myocardial infarction/stroke/heart failure) until the end of 2011 (median: 11.6 years). Plasma adiponectin and leptin were related to outcome in Cox proportional-hazard regression analyses.. Median age was 64 years and 69% were male. Total mortality was 34% (n = 61) and 44% (n = 80) experienced a cardiovascular event. Adiponectin at discharge predicted cardiovascular events (hazard ratio; 95% confidence interval; 1.45; 1.02-2.07, p = 0.038), total mortality (2.53; 1.64-3.91, p < 0.001) and cancer mortality (3.64; 1.51-8.74, p = 0.004). After adjustment for age, sex, body mass index, previous myocardial infarction and heart failure, adiponectin predicted total mortality (1.79; 1.07-3.00, p = 0.027) but not cardiovascular events. High levels of leptin were associated with cardiovascular events during the first 7 years, after which the association was attenuated. Leptin did not predict total mortality.. In patients with acute myocardial infarction but without previously known diabetes, high levels of adiponectin at discharge predicted total mortality. The present results support the hypothesis that high rather than low levels of adiponectin predict mortality after acute myocardial infarction.

Topics: Adiponectin; Aged; Biomarkers; Blood Glucose; Cause of Death; Chi-Square Distribution; Female; Glucose Intolerance; Humans; Insulin Resistance; Kaplan-Meier Estimate; Leptin; Logistic Models; Male; Middle Aged; Myocardial Infarction; Odds Ratio; Patient Discharge; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Risk Factors; Sweden; Time Factors

Obesity, diabetes and fatty liver disease are extremely common in leptin-resistant patients. Dysfunction of leptin or its receptor is associated with obesity. The present study aimed to assess the effects of intramuscular injection of exogenous leptin or its receptor on fat deposition and leptin-insulin feedback regulation. Forty-five 40-day old female Sprague Dawley (SD) rats were injected thrice with leptin or its receptor intramuscularly. Adiposity and fat deposition were assessed by assessing the Lee's index, body weight, food intake, and total cholesterol, high density lipoprotein, low density lipoprotein, and triglyceride levels, as well as histological properties (liver and adipose tissue). Serum glucose, leptin, and insulin amounts were evaluated, and glucose tolerance assessed to monitor glucose metabolism in SD rats; pancreas specimens were analyzed immunohistochemically. Hypothalamic phosphorylated Janus kinase 2 (p-JAK2), phosphorylated signal transducer and activator of transcription 3 (p-STAT3), and phosphatidylinositol-3-kinase (PI3K) signaling, and hepatic sterol regulatory element binding protein-1 (SREBP-1) were qualified by Western blotting. Leptin receptor immunogen reduced fat deposition, increased appetite, and lowered serum leptin levels, enhancing STAT3 signaling in hypothalamus and down-regulating hepatic SREBP-1. In contrast, SD rats administered leptin immunogen displayed significantly increased body weight and fat deposition, with up-regulated SREBP-1, indicating adiposity occurrence. SD rats administered leptin immunogen also showed glucose intolerance, β- cell reduction in the pancreas, and deregulation of JAK2-STAT3/PI3K signaling, indicating that Lep rats were at risk of diabetes. In conclusion, intramuscular injection of exogenous leptin or its receptor, a novel rat model approach, can be used in obesity pathogenesis and therapeutic studies.

Topics: Adipose Tissue; Adiposity; Animals; Body Weight; Disease Models, Animal; Eating; Fatty Liver; Female; Glucose Intolerance; Hyperglycemia; Immunity; Injections, Intramuscular; Insulin; Insulin-Secreting Cells; Janus Kinase 2; Leptin; Lipids; Liver; Phosphatidylinositol 3-Kinase; Phosphorylation; Rats, Sprague-Dawley; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor; Sterol Regulatory Element Binding Protein 1

Fish oil (FO) elicits diverse beneficial effects. Reduction in or prevention of body mass (BM) gain in animal models may be associated with modulation of brown adipose tissue (BAT). We aimed to evaluate the effects of different high-fat diets with FO on BAT metabolism and thermogenic markers.. C57BL/6 male mice (3-month-old) were fed different diets during 8 weeks: standard-chow diet (SC 10% fat), high-fat lard diet (HF-L 50% fat), high-fat lard plus FO diet (HF-L+FO 50% fat), and high-fat FO diet (HF-FO 50% fat). We evaluated BM and performed an oral glucose tolerance test. At euthanasia, plasma was collected for leptin, and triacylglycerol measurement and interscapular BAT was dissected and stored for molecular analyses.. HF-L group showed elevated BM; glucose intolerance associated with diminished TC10 and GLUT4 expressions; hypertriglyceridemia associated with increased CD36 and diminished CPT1 expression; elevated expression of pro-inflammatory cytokines; and reduced PPAR expression. Furthermore, these animals showed hyperleptinemia with increased expression of thermogenic markers (beta3-AR, PGC1alpha, and UCP1). Conversely, HF-L+FO and HF-FO groups showed reduced BM gain with regularization of glucose tolerance and triglyceridemia, GLUT4, TC10, CD36, CPT1, and cytokines expressions. Both groups exhibited elevated PPAR and thermogenic markers expression in a dose-dependent way.. FO improves metabolic profile and upregulates thermogenic markers, suggesting an elevated thermogenesis that leads to reduced BM gain.

Topics: Adipose Tissue, Brown; Animals; Biomarkers; Blood Glucose; Carnitine O-Palmitoyltransferase; CD36 Antigens; Diet, High-Fat; Dietary Fats; Fish Oils; Glucose Intolerance; Glucose Tolerance Test; Glucose Transporter Type 4; Insulin; Interleukin-6; Ion Channels; Leptin; Male; Mice; Mice, Inbred C57BL; Mitochondrial Proteins; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Thermogenesis; Transcription Factors; Triglycerides; Tumor Necrosis Factor-alpha; Uncoupling Protein 1; Up-Regulation

Recent studies suggest that nutritional status during developmental periods is associated with subsequent development of metabolic abnormalities. In this study, we examined whether malnutrition by fasting for 3 days during the suckling-weaning transient period induces subsequent development of metabolic abnormalities in rats.. Male Sprague-Dawley rats were fasted for 3 days during the suckling-weaning transient period. They are subsequently fed a high-fat, high-sucrose (HF) or low-fat, high-starch (LF) diet for 14 weeks from 17 weeks of age, and the liver and blood samples were collected for measuring mRNA and protein levels of metabolic genes and blood concentrations of glucose and insulin, respectively.. Fasting for 3 days during the suckling-weaning transient period induced impaired glucose tolerance in rats fed the LF diet in adulthood. Liver triglycerides in rats fed the HF diet in adulthood increased to 140 % in rats fasted for 3 days during the suckling-weaning transient period compared with those non-fasted. Furthermore, liver expression of FBP1 and ACCα genes in adult rats fed the LF diet increased to 125 and 145 %, respectively, in rats fasted for 3 days during the suckling-weaning transient period compared to non-fasted rats. PEPCK1 protein expression levels in rats fed the LF diet were higher in rats fasted for 3 days during the suckling-weaning transient period than in non-fasted rats.. Fasting for 3 days in rats during the suckling-weaning transient period enhances metabolic abnormalities in animals fed a HF or LF diet in adulthood by confounding metabolism of lipid and sugar in the liver.

Topics: Adiponectin; Animal Nutritional Physiological Phenomena; Animals; Animals, Suckling; Blood Glucose; Body Weight; Diet, High-Fat; Dietary Fats; Disease Models, Animal; DNA-Binding Proteins; Fasting; Fatty Acids, Nonesterified; Gluconeogenesis; Glucose Intolerance; Insulin; Leptin; Lipogenesis; Liver; Male; Malnutrition; Metabolic Diseases; Organ Size; Rats; Rats, Sprague-Dawley; RNA, Messenger; Triglycerides; Weaning

Amylin enhances arcuate (ARC) and ventromedial (VMN) hypothalamic nuclei leptin signaling and synergistically reduces food intake and body weight in selectively bred diet-induced obese (DIO) rats. Since DIO (125)I-amylin dorsomedial nucleus-dorsomedial VMN binding was reduced, we postulated that this contributed to DIO ventromedial hypothalamus (VMH) leptin resistance, and that impairing VMH (ARC + VMN) calcitonin receptor (CTR)-mediated signaling by injecting adeno-associated virus (AAV) expressing a short hairpin portion of the CTR mRNA would predispose diet-resistant (DR) rats to obesity on high-fat (45%) diet (HFD). Depleting VMH CTR by 80-90% in 4-wk-old male DR rats reduced their ARC and VMN (125)I-labeled leptin binding by 57 and 51%, respectively, and VMN leptin-induced phospho-signal transducer and activator of transcription 3-positive neurons by 59% vs. AAV control rats. After 6 wk on chow, VMH CTR-depleted DR rats ate and gained the equivalent amount of food and weight but had 18% heavier fat pads (relative to carcass weight), 144% higher leptin levels, and were insulin resistant compared with control AAV DR rats. After 6 wk more on HFD, VMH CTR-depleted DR rats ate the same amount but gained 28% more weight, had 60% more carcass fat, 254% higher leptin levels, and 132% higher insulin areas under the curve during an oral glucose tolerance test than control DR rats. Therefore, impairing endogenous VMH CTR-mediated signaling reduced leptin signaling and caused DR rats to become more obese and insulin resistant, both on chow and HFD. These results suggest that endogenous VMH amylin signaling is required for full leptin signaling and protection from HFD-induced obesity.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Diet, High-Fat; Eating; Glucose Intolerance; Insulin Resistance; Iodine Radioisotopes; Islet Amyloid Polypeptide; Leptin; Male; Obesity; Radionuclide Imaging; Rats; Receptors, Calcitonin; RNA, Small Interfering; STAT3 Transcription Factor; Ventromedial Hypothalamic Nucleus; Weight Gain

The neuroendocrine effects of leptin on metabolism hold promise to be translated into a complementary therapy to traditional insulin therapy for diabetes and obesity. However, injections of leptin can provoke inflammation. We tested the effects of leptin, produced in the physiological adipocyte location, on metabolism in mouse models of genetic and dietary obesity. We generated 3T3-L1 adipocytes constitutively secreting leptin and encapsulated them in a poly-L-lysine membrane, which protects the cells from immune rejection. Ob/ob mice (OB) were injected with capsules containing no cells (empty, OB[Emp]), adipocytes (OB[3T3]), or adipocytes overexpressing leptin (OB[Lep]) into both visceral fat depots. Leptin was found in the plasma of OB[Lep], but not OB[Emp] and OB[3T3] mice at the end of treatment (72 days). The OB[Lep] and OB[3T3] mice have transiently suppressed appetite and weight loss compared to OB[Emp]. Only OB[Lep] mice have greater brown fat mass, metabolic rate, and reduced resistin plasma levels compared to OB[Emp]. Glucose tolerance was markedly better in OB[Lep] vs. OB[Emp] and OB[3T3] mice as well as in wild type mice with high-fat diet-induced obesity and insulin resistance treated with encapsulated leptin-producing adipocytes. Our proof-of-principle study provides evidence of long-term improvement of glucose tolerance with encapsulated adipocytes producing leptin.

Topics: 3T3-L1 Cells; Adipocytes; Adipose Tissue, Brown; Animals; Blotting, Western; Cell Differentiation; Cells, Cultured; Glucose Intolerance; Insulin Resistance; Leptin; Male; Mice; Mice, Obese; Obesity; Real-Time Polymerase Chain Reaction; Resistin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Adiposopathy, or sick fat, refers to adipose tissue dysfunction that can lead to several complications such as dyslipidemia, insulin resistance, and hyperglycemia. The relative contribution of adiposopathy in predicting insulin resistance remains unclear. We investigated the relationship between adiposopathy, as assessed as a low plasma adiponectin/leptin ratio, with anthropometry, body composition (hydrostatic weighing), insulin sensitivity (hyperinsulinemic-euglycemic clamp), inflammation, and fitness level (ergocycle VO2max, mL/kgFFM/min) in 53 men (aged 34-53 years) from four groups: sedentary controls without obesity (body mass index [BMI] <25 kg/m(2)), sedentary with obesity (BMI > 30 kg/m(2)), sedentary with obesity and glucose intolerance, and endurance trained active without obesity. The adiponectin/leptin ratio was the highest in trained men (4.75 ± 0.82) and the lowest in glucose intolerant subjects with obesity (0.27 ± 0.06; ANOVA p < 0.0001) indicating increased adiposopathy in those with obesity. The ratio was negatively associated with adiposity (e.g., waist circumference, r = -0.59, p < 0.01) and positively associated with VO2max (r = 0.67, p < 0.01) and insulin sensitivity (M/I, r = 0.73, p < 0.01). Multiple regression analysis revealed fitness as the strongest independent predictor of insulin sensitivity (partial R (2) = 0.61). While adiposopathy was also an independent and significant contributor (partial R (2) = 0.10), waist circumference added little power to the model (partial R (2) = 0.024). All three variables remained significant independent predictors when trained subjects were excluded from the model. Plasma lipids were not retained in the model. We conclude that low fitness, adiposopathy, as well as adiposity (and in particular abdominal obesity) are independent contributors to insulin resistance in men without diabetes.

Topics: Adiponectin; Adiposity; Adult; Aging; Body Mass Index; Cohort Studies; Cross-Sectional Studies; Exercise Tolerance; Glucose Intolerance; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Obesity, Abdominal; Oxygen Consumption; Panniculitis; Physical Fitness; Sedentary Behavior; Waist Circumference

Recent studies have demonstrated that epigenetic changes resulting from malnutrition might play important roles in transgenerational links with metabolic diseases. Previously, we observed that exposure to a high-fat diet (HFD) in utero caused a metabolic syndrome-like phenomenon through epigenetic modifications of the adiponectin and leptin genes that persisted for multiple generations. Recent etiological studies indicated that paternal BMI had effects on offspring BMI that were independent of but additive to maternal BMI effects. Thus, we examined whether paternal HFD-induced obesity affected the metabolic status of offspring through epigenetic changes in the adiponectin and leptin genes. Additionally, we investigated whether a normal diet during subsequent generations abolished the epigenetic changes associated with paternal HFD exposure before conception. We observed the effects of paternal HFD exposure before conception over multiple generations on offspring metabolic traits, including weight and fat gain, glucose intolerance, hypertriglyceridemia, abnormal adipocytokine levels, hypertension, and adiponectin and leptin gene expression and epigenetic changes. Normal diet consumption by male offspring during the subsequent generation following paternal HFD exposure diminished whereas consumption for two generations completely abolished the effect of paternal HFD exposure on metabolic traits and adipocytokine promoter epigenetic changes in the offspring. The effects of paternal HFD exposure on offspring were relatively weaker than those following HFD exposure in utero. However, paternal HFD exposure had an additive metabolic effect for two generations, suggesting that both paternal and maternal nutrition might affect offspring metabolism through epigenetic modifications of adipocytokine genes for multiple generations.

Topics: Adipokines; Adiponectin; Animals; Chromatin Immunoprecipitation; Diet, High-Fat; Epigenesis, Genetic; Female; Gene Expression; Glucose Intolerance; Hypertension; Hypertriglyceridemia; Leptin; Male; Metabolic Syndrome; Mice; Obesity; Paternal Exposure; Pregnancy; Prenatal Exposure Delayed Effects; Promoter Regions, Genetic; Real-Time Polymerase Chain Reaction; RNA, Messenger; Weight Gain

The impact of alpha linolenic acid (ALA), EPA, and DHA on obesity and metabolic complications was studied in mice fed a high-fat, high-sucrose (HF) diet. HF diets were supplemented with ALA, EPA, or DHA (1% w/w) and given to C57BL/6J mice for 16 weeks and to Ob/Ob mice for 6 weeks. In C57BL/6J mice, EPA reduced plasma cholesterol (-20%), limited fat mass accumulation (-23%) and adipose cell hypertrophy (-50%), and reduced plasma leptin concentration (-60%) compared with HF-fed mice. Furthermore, mice supplemented with EPA exhibited a higher insulin sensitivity (+24%) and glucose tolerance (+20%) compared with HF-fed mice. Similar effects were observed in EPA-supplemented Ob/Ob mice, although fat mass accumulation was not prevented. By contrast, in comparison with HF-fed mice, DHA did not prevent fat mass accumulation, increased plasma leptin concentration (+128%) in C57BL/6J mice, and did not improve glucose homeostasis in C57BL/6J and Ob/Ob mice. In 3T3-L1 adipocytes, DHA stimulated leptin expression whereas EPA induced adiponectin expression, suggesting that improved leptin/adiponectin balance may contribute to the protective effect of EPA. In conclusion, supplementation with EPA, but not ALA and DHA, could preserve glucose homeostasis in an obesogenic environment and limit fat mass accumulation in the early stage of weight gain.

Topics: 3T3-L1 Cells; Adipogenesis; Adipokines; Adipose Tissue, White; Adiposity; Animals; Anti-Obesity Agents; Cell Membrane; Diet, Western; Drug Evaluation, Preclinical; Eicosapentaenoic Acid; Erythrocytes; Gene Expression; Glucose Intolerance; Insulin Resistance; Leptin; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Phospholipids

Epacs (exchange proteins directly activated by cyclic AMP [cAMP]) act as downstream effectors of cAMP and play important roles in energy balance and glucose homeostasis. While global deletion of Epac1 in mice leads to heightened leptin sensitivity in the hypothalamus and partial protection against high-fat diet (HFD)-induced obesity, the physiological functions of Epac1 in white adipose tissue (WAT) has not been explored. Here, we report that adipose tissue-specific Epac1 knockout (AEKO) mice are more prone to HFD-induced obesity, with increased food intake, reduced energy expenditure, and impaired glucose tolerance. Despite the fact that AEKO mice on HFD display increased body weight, these mice have decreased circulating leptin levels compared to their wild-type littermates. In vivo and in vitro analyses further reveal that suppression of Epac1 in WAT decreases leptin mRNA expression and secretion by inhibiting cAMP response element binding (CREB) protein and AKT phosphorylation, respectively. Taken together, our results demonstrate that Epac1 plays an important role in regulating energy balance and glucose homeostasis by promoting leptin expression and secretion in WAT.

Topics: Adipose Tissue, White; Animals; Diet, High-Fat; Disease Models, Animal; Eating; Energy Metabolism; Gene Knockout Techniques; Glucose Intolerance; Guanine Nucleotide Exchange Factors; HEK293 Cells; Humans; Leptin; Male; Mice; NIH 3T3 Cells; Obesity

Animal studies demonstrate that circadian rhythm disruption during pregnancy can be deleterious to reproductive capacity and the long-term health of the progeny. Our previous studies in rats have shown that exposure of pregnant dams to an environment that significantly disrupts maternal circadian rhythms programs increased adiposity and poor glucose metabolism in offspring. In this study, we used mice with a ClockΔ19 mutation to determine whether foetal development within a genetically disrupted circadian environment affects pregnancy outcomes and alters the metabolic health of offspring. Ten female ClockΔ19+MEL mutant mice were mated with 10 wildtype males, and 10 wildtype females were mated with 10 ClockΔ19+MEL mutant males. While genetically identical, the heterozygote foetuses were exposed to either a normal (wildtype dams) or disrupted (ClockΔ19+MEL mutant dams) circadian environment during gestation. Pregnancy outcomes including time to mate, gestation length, litter size and birth weight were assessed. One male and one female offspring from each litter were assessed for postnatal growth, body composition, intraperitoneal glucose tolerance test and intraperitoneal insulin tolerance test at 3 and 12 months of age. There was no effect of maternal genotype on pregnancy outcomes, with days to plug, gestation length, litter size and perinatal mortality not significantly different between wildtype and ClockΔ19+MEL mutant dams. Similarly, there was no effect of maternal genotype on weight of the offspring at birth or at any stage of postnatal growth. While there was an effect of sex on various tissue weights at 3 and 12 months of age, there were minimal effects of maternal genotype. Relative adrenal weight was significantly reduced (-32%) in offspring from ClockΔ19+MEL mutant dams, whereas gastrocnemius muscle was significantly increased (+16%) at 3 months of age only. Intraperitoneal glucose tolerance tests at 3 months of age revealed female offspring from ClockΔ19+MEL mutant dams had significantly reduced area under the curve following glucose administration (-25%), although no differences were found at 12 months of age. There was no effect of maternal genotype on intraperitoneal insulin tolerance at 3 or 12 months of age for either sex. These results demonstrate that foetal growth within a genetically disrupted circadian environment during gestation has no effect on pregnancy success, and only marginal impacts upon the long-term metabolic health of offs

Topics: Animals; Body Composition; Circadian Clocks; Circadian Rhythm; CLOCK Proteins; Female; Gene Expression Regulation, Developmental; Genotype; Glucose Intolerance; Insulin Resistance; Leptin; Male; Mice; Pregnancy; Pregnancy Outcome; Prenatal Exposure Delayed Effects

Kisspeptin regulates reproduction via signaling through the receptor, Kiss1r, in GnRH neurons. However, both kisspeptin and Kiss1r are produced in several peripheral tissues, and recent studies have highlighted a role for kisspeptin signaling in metabolism and glucose homeostasis. We recently reported that Kiss1r knockout (KO) mice display a sexually dimorphic metabolic phenotype, with KO females displaying obesity, impaired metabolism, and glucose intolerance at 4-5 months of age. However, it remains unclear when this metabolic phenotype first emerges in development, or which aspects of the pleiotropic phenotype underlie the metabolic defects and which are secondary to the obesity. Here, we studied Kiss1r KO females at different ages, including several weeks before the emergence of body weight (BW) differences and later when obesity is present. We determined that at young adult ages (6 wk old), KO females already exhibit altered adiposity, leptin levels, metabolism, and energy expenditure, despite having normal BWs at this time. In contrast, food intake, water intake, and glucose tolerance are normal at young ages and only show impairments at older adult ages, suggesting that these impairments may be secondary to earlier alterations in metabolism and adiposity. We also demonstrate that, in addition to BW, all other facets of the adult metabolic phenotype persist even when gonadal sex steroids are similar between genotypes. Collectively, these data highlight the developmental emergence of a metabolic phenotype induced by disrupted kisspeptin signaling and reveal that multiple, but not all, aspects of this phenotype are already disrupted before detectable changes in BW.

Topics: Adiposity; Animals; Body Composition; Body Weight; Eating; Energy Metabolism; Female; Glucose Intolerance; Glucose Tolerance Test; Leptin; Male; Mice; Mice, Knockout; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Signal Transduction

Very few systematic studies are done during the onset and progression of metabolic syndrome in suitable animal models. In this paper we present the effect of High-Fat Simple Carbohydrate (HFSC) feed on the metabolic hormones in C57BL/6J mice to understand the sequence of events leading to impairment of glucose homeostasis.. One-month-old male C57BL/6J mice were fed with control (C group) and HFSC (T group) feed (n = 30 each) respectively for five months. The glucose tolerance was studied by Oral Glucose Tolerance Test (OGTT) whereas serum insulin and leptin were quantified using ELISA kits, and serum cortisol was quantified using CLIA kits.. Insulin resistance index and HOMA-IR levels were higher in the mice of group T as compared to age-matched mice of group C within one month and significantly higher after and five months of feeding. The total area under the glucose tolerance test curve (AUC) and the insulin curve (AUC ins) was found to significantly increase in the mice of T group as compared to the mice of C group as early as two months of feeding and was elevated after 5 months post feeding. Comparison of the Matsuda index revealed that pancreatic beta cell function was significantly lower in mice of T group as compared to mice of C group by five months of feeding. Leptin levels fluctuated during the 1st-4th month and by the 5th month significant hyperleptinaemia was detected. There was no significant change in cortisol levels in mice of group T as compared to mice of group C after five months of feeding.. HFSC feed induces insulin resistance by the first month and progressively impairs glucose tolerance, resulting in hyperleptinaemia by the fifth month in male C57BL/6J mice. (Endokrynol Pol 2016; 67 (6): 592-598).

Topics: Animals; Diet, Carbohydrate Loading; Diet, High-Fat; Glucose Intolerance; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Up-Regulation

Metabolic syndrome (MetS) is considered as a proinflammatory and prothrombotic state with atherogenic risk factors including dyslipidemia, obesity and glucose intolerance. Oxidative stress is a unifying basis of several disorders including diabetes mellitus (DM) and MetS. We therefore designed this cross-sectional study to investigate the potential interaction among iron metabolism, inflammation and endothelial plexus in MetS and DM patients.. A total of 62 patients [median age 54 (23-76) years; male/female 16/46] and 18 healthy controls [median age 38 (30-64) years; male/female 6/12] were included in the study. Patient population was classified as MetS (n = 30) and DM (n = 32).. Leukocyte count (p = 0.002) and osteopontin (OPN) levels (p = 0.008) were significantly higher, while C-reactive protein (CRP) (p = 0.056) and IL-6 (p = 0.059) represented a relative increase in the patient group. Leptin, endothelin 1 (ET1), hepcidin, nitric oxide synthase (NOS), erythrocyte sedimentation rate (ESR), iron, transferrin saturation (TS) and ferritin levels were not significantly different between the patient and control groups. Endothelin 1 was found to be higher in the DM group compared to MetS group (p = 0.15, p = 0.049). Leukocyte count, leptin, hepcidin, OPN, NOS, IL-6, ESR, CRP, iron, TS and ferritin levels were not different between DM and MetS groups. A positive correlation was demonstrated between leptin and OPN (p = 0.001, r = 0.360), ferritin and hepcidin (p < 0.01, r = 0.633), IL-6 and CRP (p = 0.023, r = 0.319), leptin and NOS (p = 0.005, r = 0.309) and OPN and NOS (p < 0.001, r = 0.803). There was a negative correlation between hepcidin and NOS (p = 0.009, r = -0.289). When the study cohort was divided into two particular groups based on median ferritin and hepcidin levels, hepcidin (p = 0.002), ALT (p = 0.001) and LDL (p = 0.049) levels were higher in the high-ferritin group. Nitric oxide synthase levels (p = 0.033) were lower, whereas ferritin levels (p = 0.004) were higher in the high-hepcidin group.. Mechanisms involved in the vicious circle of MetS including inflammation, endothelial vasculature and iron metabolism remain to be elucidated. The role of iron metabolism in this complex interaction should be confirmed with further studies.

Topics: Adult; Aged; C-Reactive Protein; Cross-Sectional Studies; Diabetes Mellitus; Endothelium, Vascular; Female; Ferritins; Glucose Intolerance; Hepcidins; Humans; Inflammation; Interleukin-6; Iron; Leptin; Male; Metabolic Syndrome; Middle Aged; Oxidative Stress; Young Adult

Diabetes is a growing health care issue, and prediabetes has been established as a risk factor for type 2 diabetes. Prediabetes is characterized by deregulated glucose control, and elucidating pathways which govern this process is critical. We have identified the wild-type (WT) p53-inducible phosphatase (WIP1) phosphatase as a regulator of glucose homeostasis. Initial characterization of insulin signaling in WIP1 knockout (WIP1(KO)) murine embryo fibroblasts demonstrated reduced insulin-mediated Ak mouse transforming activation. In order to assess the role of WIP1 in glucose homeostasis, we performed metabolic analysis on mice on a low-fat chow diet (LFD) and high fat diet (HFD). We observed increased expression of proinflammatory cytokines in WIP1(KO) murine embryo fibroblasts, and WIP1(KO) mice fed a LFD and a HFD. WIP1(KO) mice exhibited glucose intolerance and insulin intolerance on a LFD and HFD. However, the effects of WIP1 deficiency cause different metabolic defects in mice on a LFD and a HFD. WIP1(KO) mice on a LFD develop hepatic insulin resistance, whereas this is not observed in HFD-fed mice. Mouse body weights and food consumption increase slightly over time in LFD-fed WT and WIP1(KO) mice. Leptin levels are increased in LFD-fed WIP1(KO) mice, compared with WT. In contrast, HFD-fed WIP1(KO) mice are resistant to HFD-induced obesity, have decreased levels of food consumption, and decreased leptin levels compared with HFD-WT mice. WIP1 has been shown to regulate the nuclear factor kappa-light-chain-enhancer of activated B cells pathway, loss of which leads to increased inflammation. We propose that this increased inflammation triggers insulin resistance in WIP1(KO) mice on LFD and HFD.

Topics: Animals; Cells, Cultured; Diabetes Mellitus, Type 2; Diet, Fat-Restricted; Diet, High-Fat; Dietary Fats; Fibroblasts; Genetic Predisposition to Disease; Glucose; Glucose Intolerance; Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); Insulin; Insulin Resistance; Interleukin-6; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Phosphoprotein Phosphatases; Prediabetic State; Primary Cell Culture; Protein Phosphatase 2C; Signal Transduction; Tumor Necrosis Factor-alpha

Reduced GH levels have been associated with improved glucose metabolism and increased longevity despite obesity in multiple mouse lines. However, one mouse line, the GH receptor antagonist (GHA) transgenic mouse, defies this trend because it has reduced GH action and increased adiposity, but glucose metabolism and life span are similar to controls. Slight differences in glucose metabolism and adiposity profiles can become exaggerated on a high-fat (HF) diet. Thus, in this study, male and female GHA and wild-type (WT) mice in a C57BL/6 background were placed on HF and low-fat (LF) diets for 11 weeks, starting at 10 weeks of age, to assess how GHA mice respond to additional metabolic stress of HF feeding. On a HF diet, all mice showed significant weight gain, although GHA gained weight more dramatically than WT mice, with males gaining more than females. Most of this weight gain was due to an increase in fat mass with WT mice increasing primarily in the white adipose tissue perigonadal depots, whereas GHA mice gained in both the sc and perigonadal white adipose tissue regions. Notably, GHA mice were somewhat protected from detrimental glucose metabolism changes on a HF diet because they had only modest increases in serum glucose levels, remained glucose tolerant, and did not develop hyperinsulinemia. Sex differences were observed in many measures with males reacting more dramatically to both a reduction in GH action and HF diet. In conclusion, our findings show that GHA mice, which are already obese, are susceptible to further adipose tissue expansion with HF feeding while remaining resilient to alterations in glucose homeostasis.

Topics: Adipocytes; Adiposity; Animals; Body Weight; Cattle; Diet, High-Fat; Disease Models, Animal; Eating; Female; Glucose; Glucose Intolerance; Hyperinsulinism; Insulin; Leptin; Liver; Male; Mice, Inbred C57BL; Mice, Transgenic; Obesity; Receptors, Somatotropin; Triglycerides; Weight Gain

Maternal under- or over-nutrition not only alters neonatal body mass but also increases the risk of metabolic disorders in adulthood. Little is known about how maternal dietary protein affects offspring fitness in wild rodents. The present study was conducted to test the hypothesis that maternal dietary protein supplement has a long-term beneficial effect on offspring fitness in Brandt's vole (Lasiopodomys brandtii), a herbivorous rodent model. The vole dams were fed either a control (18% protein) or high-protein (36% protein) diet throughout pregnancy and lactation. After weaning, all offspring received a control diet till 14 weeks old. Energetic parameters, serum leptin concentration and glucose tolerance were measured. The adult offspring were fed high-fat diet for 8 weeks, and body weight and food intake were measured. No difference was observed in litter size, litter mass or pup mass before weaning. Maternal protein supplement increased body mass and the mass of reproductive organ but decreased digestibility and fat deposition and alleviated HFD-induced obesity especially in the males. Glucose tolerance was elevated in the offspring from maternal protein supplement, especially in the females. The accelerated growth may be associated with high serum leptin concentration at weaning, a state of leptin resistance, and the low digestibility may predispose obesity resistance especially in male offspring from maternal high-protein diet. These data demonstrate that maternal protein supplement confers the long-term sex-specific beneficial consequences of accelerated growth and improved obesity resistance and glucose tolerance of their offspring.

Topics: Animals; Arvicolinae; Body Composition; Body Weight; Diet, High-Fat; Dietary Proteins; Dietary Supplements; Eating; Female; Glucose Intolerance; Lactation; Leptin; Male; Obesity; Pregnancy; Pregnancy, Animal

Recent studies demonstrate that epigenetic changes under malnutrition in utero might play important roles in transgenerational links with metabolic diseases. We have previously shown that exposure to a high-fat diet (HFD) in utero may cause a metabolic syndrome-like phenomenon through epigenetic modifications of Adiponectin and Leptin genes. Because an association of obesity between mother and offspring endured in multiple generations, we examined whether HFD exposure in utero might affect the metabolic status of female offspring through multigenerational epigenetic changes of Adiponectin and Leptin genes and whether a normal diet in utero for multiple generations might abolish such epigenetic changes after exposure to a HFD in utero using ICR mice. We observed that the effect of maternal HFD on offspring over multiple generations in metabolic syndrome-like phenomenon such as weight and fat mass gain, glucose intolerance, hypertriglyceridemia, abnormal adiponectin and leptin levels, and hypertension, were accumulated with expression and epigenetic changes in Adiponectin and Leptin genes. A normal diet in utero in the subsequent generations after HFD exposure in utero diminished, and a normal diet in utero for 3 generations completely abolished, the effect of HFD in utero on weight and fat mass gain, insulin resistance, serum triglyceride, adiponectin, and leptin levels, with epigenetic changes of Adiponectin and Leptin genes. Exposure to a HFD in utero might affect glucose and lipid metabolism of female offspring through epigenetic modifications to Adiponectin and Leptin genes for multiple generations. Obesogenic and diabetogenic traits were abolished after a maternal normal diet for 3 generations.

Topics: Adiponectin; Animals; Blood Glucose; Body Weight; Diet, High-Fat; Epigenesis, Genetic; Female; Gene Expression; Glucose Intolerance; Glucose Tolerance Test; Hypertriglyceridemia; Insulin; Insulin Resistance; Leptin; Metabolic Syndrome; Mice; Mice, Inbred ICR; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Real-Time Polymerase Chain Reaction; RNA, Messenger; Triglycerides

Adipose tissue (AT) distribution is a major determinant of mortality and morbidity in obesity. In mice, intra-abdominal transplantation of subcutaneous AT (SAT) protects against glucose intolerance and insulin resistance (IR), but the underlying mechanisms are not well understood.. We investigated changes in adipokines, tissue-specific glucose uptake, gene expression and systemic inflammation in male C57BL6/J mice implanted intra-abdominally with either inguinal SAT or epididymal visceral AT (VAT) and fed a high-fat diet (HFD) for up to 17 weeks.. Glucose tolerance was improved in mice receiving SAT after 6 weeks, and this was not attributable to differences in adiposity, tissue-specific glucose uptake, or plasma leptin or adiponectin concentrations. Instead, SAT transplantation prevented HFD-induced hepatic triacylglycerol accumulation and normalised the expression of hepatic gluconeogenic enzymes. Grafted fat displayed a significant increase in glucose uptake and unexpectedly, an induction of skeletal muscle-specific gene expression. Mice receiving subcutaneous fat also displayed a marked reduction in the plasma concentrations of several proinflammatory cytokines (TNF-α, IL-17, IL-12p70, monocyte chemoattractant protein-1 [MCP-1] and macrophage inflammatory protein-1β [ΜIP-1β]), compared with sham-operated mice. Plasma IL-17 and MIP-1β concentrations were reduced from as early as 4 weeks after transplantation, and differences in plasma TNF-α and IL-17 concentrations predicted glucose tolerance and insulinaemia in the entire cohort of mice (n = 40). In contrast, mice receiving visceral fat transplants were glucose intolerant, with increased hepatic triacylglycerol content and elevated plasma IL-6 concentrations.. Intra-abdominal transplantation of subcutaneous fat reverses HFD-induced glucose intolerance, hepatic triacylglycerol accumulation and systemic inflammation in mice.

Topics: Adipocytes; Adiponectin; Adiposity; Animals; Body Composition; Cytokines; Diet, High-Fat; Eating; Gluconeogenesis; Glucose; Glucose Intolerance; Inflammation; Insulin; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Subcutaneous Fat; Triglycerides

Metabolic syndrome and T2D produce significant health and economic issues. Many available animal models have monogenic leptin pathway mutations that are absent in the human population. Development of the ZDSD rat model was undertaken to produce a model that expresses polygenic obesity and diabetes with an intact leptin pathway. A lean ZDF rat with the propensity for beta-cell failure was crossed with a polygenetically obese Crl:CD (SD) rat. Offspring were selectively inbred for obesity and diabetes for >30 generations. In the current study, ZDSD rats were followed for 6 months; routine clinical metabolic endpoints were included throughout the study. In the prediabetic metabolic syndrome phase, ZDSD rats exhibited obesity with increased body fat, hyperglycemia, insulin resistance, dyslipidemia, glucose intolerance, and elevated HbA1c. As disease progressed to overt diabetes, ZDSD rats demonstrated elevated glucose levels, abnormal oral glucose tolerance, increases in HbA1c levels, reductions in body weight, increased insulin resistance with decreasing insulin levels, and dyslipidemia. The ZDSD rat develops prediabetic metabolic syndrome and T2D in a manner that mirrors the development of metabolic syndrome and T2D in humans. ZDSD rats will provide a novel, translational animal model for the study of human metabolic diseases and for the development of new therapies.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Disease Models, Animal; Glucose Intolerance; Insulin; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Obesity; Rats; Signal Transduction

The exact mechanism of ethanol's effects on glucose tolerance has not been well determined. The present study focuses for the first time on hypoxia and low-grade inflammation in adipose tissue (AT). In the in vivo experiments, twenty-four male Wistar rats were randomly allocated into control and ethanol feeding groups. Ethanol-treated rats received edible ethanol once a day at a total dosage of 5 g/kg per d, and the controls received distilled water. Ethanol volumes were adjusted every week. At the end of 8 weeks, we carried out an oral glucose tolerance test. Blood and AT were collected for measuring hypoxia-inducible factor-1α (HIF-1α), GLUT1, TNF-α, IL-6, leptin and vascular endothelial growth factor (VEGF). In the in vitro experiments, differentiated OP9 adipocytes were incubated with 100 mm of ethanol for 48 h; the media and cells were then collected for measuring HIF-1α, GLUT1, TNF-α and IL-6. The results showed that long-term ethanol consumption impaired glucose tolerance in rats. Ethanol consumption had little influence on body weight, but both epididymal and perirenal AT were markedly enlarged in the ethanol-treated rats as compared to the controls. Visceral adipose tissue (VAT) had accumulated, and the protein levels of HIF-1α and GLUT1, the indicators of hypoxia in rat epididymal AT and OP9 adipocytes, were elevated. Secondary to the AT hypoxia, the levels of inflammation-related adipokines, such as TNF-α, IL-6, leptin and VEGF, were increased. Based on these findings, we conclude that VAT hypoxia and low-grade inflammation might be a new mechanism in the treatment of ethanol-related diabetes.

Topics: Adipocytes; Adipose Tissue; Animals; Cell Hypoxia; Cell Line; Diabetes Mellitus, Type 2; Epididymis; Ethanol; Glucose Intolerance; Glucose Tolerance Test; Glucose Transporter Type 1; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Insulin Resistance; Interleukin-6; Intra-Abdominal Fat; Leptin; Lipid Metabolism; Male; Mice; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

The aims of this study were: (1) to assess the association of adiponectin, leptin and interleukin-6 (IL-6) with incidence of type 2 diabetes (T2DM) in Asian Indian men with impaired glucose tolerance (IGT) and (2) to evaluate the additional contribution of these with the well-established glycaemic marker HbA1c.. This is an ancillary analyses of a nested case-control study derived from a prospective, prevention trial in India. All the participants had IGT at baseline. For this subanalysis a total of 147 (T2DM: 71; nondiabetic: 76) participants were selected based on the final glycemic outcomes. Association of these selected adipokines with T2DM were assessed using logistic regression analyses. Clinical usefulness of adding adipokine markers with HbA1c on prediction of T2DM was assessed using the area under the curve (AUC) of the receiver operating characteristics.. Baseline levels of adiponectin were lower and the levels of IL-6 were higher in T2DM cases when compared with non-diabetic cases (P<0.05). Levels of leptin were similar in both groups. In fully adjusted models, adiponectin (odds ratio (OR): 0.55 [95%CI: 0.33-0.91]; P=0.019) and IL-6 (OR: 2.27 [95%CI: 1.40-3.691]; P=0.001) were associated with diabetes. Addition of adiponectin to HbA1c improved the AUC (ΔAUC: 0.0619; P=0.0251), whereas addition of IL-6 did not improve the predictive power of HbA1c alone.. Adiponectin and IL-6 are independently associated with incident diabetes. However, they are unlikely to serve as simple tools to predict future risk of diabetes but may have a role in understanding the pathogenesis.

Topics: Adiponectin; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Glucose Intolerance; Glycated Hemoglobin; Humans; Incidence; India; Interleukin-6; Leptin; Male; Middle Aged; Prospective Studies

Leptin receptor, which is encoded by the diabetes (db) gene and is highly expressed in the choroid plexus, regulatesenergy homeostasis, the balance between food intake and energy expenditure, fertility and bone mass. Here, using CRISPR/Cas9 technology, we created the leptin receptor knockout rat. Homozygous leptin receptor null rats are characterized by obesity, hyperphagia, hyperglycemia, glucose intolerance, hyperinsulinemia and dyslipidemia. Due to long-term poor glycemic control, the leptin receptor knockout rats also develop some diabetic complications such as pancreatic, hepatic and renal lesions. In addition, the leptin receptor knockout rats show a significant decrease in bone volume and bone mineral density of the femur compared with their wild-type littermates. Our model has rescued some deficiency of the existing rodent models, such as the transient hyperglycemia of db/db mice in the C57BL/6J genetic background and the delayed onset of glucose intolerance in the Zucker rats, and it is proven to be a useful animal model for biomedical and pharmacological research on obesity and diabetes.

Topics: Animals; Blood Glucose; Bone Density; Clustered Regularly Interspaced Short Palindromic Repeats; Dyslipidemias; Femur; Gene Knockout Techniques; Glucose Intolerance; Homeostasis; Hyperglycemia; Hyperphagia; Leptin; Models, Animal; Obesity; Rats; Rats, Sprague-Dawley; Receptors, Leptin

Research on the characteristics and mechanisms of diabetes in Tibetans is scant. Especially, there is no study on the relationship between osteocalcin and glucose metabolism. The objective of this study was to investigate the associations of serum total osteocalcin (tOC) and undercarboxylated osteocalcin (ucOC) with glucose and lipid metabolism in Chinese indigenous Tibetans with different degrees of glucose tolerance.. In this study, 160 middle-aged Tibetan men were involved, including 46 subjects with normal glucose tolerance (NGT), 52 subjects with impaired glucose regulation (IGR) and 62 subjects with type 2 diabetes. The homeostasis model assessment (HOMA) parameters, including HOMA-IR and HOMA-B, were used to estimate insulin resistance and β-cell function, respectively. Adiponectin, leptin, testosterone, 1,25-dihydroxyvitamin D, tOC and ucOC were measured using ELISA kits.. After adjustment for age and body mass index, plasma tOC level was correlated negatively with fasting and 30-min post-OGTT glucose, HOMA-IR, leptin and testosterone; plasma ucOC level was correlated negatively with 30-min post-OGTT glucose, total cholesterol and 1,25-dihydroxyvitamin D; ucOC : tOC was correlated positively with leptin. The negative association between HOMA-IR and tOC remained significant after correcting for adiponectin; however, the association disappeared after correcting for leptin. HOMA-IR was correlated negatively with age, adiponectin and tOC, and positively with total cholesterol, triglyceride and leptin. Stepwise linear regression analysis revealed that total cholesterol, leptin and adiponectin were independent predictors for HOMA-IR in all subjects.. Our data support a link between osteocalcin and glucose metabolism in middle-aged Tibetan men. The improved glucose tolerance exerted by tOC may be related to improved insulin sensitivity rather than improved β-cell function.

Topics: Adiponectin; Adult; Blood Glucose; Calcitriol; Cohort Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Down-Regulation; Glucose Intolerance; Hospitals, University; Humans; Insulin Resistance; Leptin; Lipids; Male; Middle Aged; Osteocalcin; Protein Processing, Post-Translational; Testosterone; Tibet

Estrogens are known to play a role in modulating metabolic processes within the body. The Aromatase knockout (ArKO) mice have been shown to harbor factors of Metabolic syndrome with central adiposity, hyperinsulinemia and male-specific hepatic steatosis. To determine the effects of estrogen ablation and subsequent replacement in males on whole body glucose metabolism, three- and six-month-old male ArKO mice were subjected to whole body glucose, insulin and pyruvate tolerance tests and analyzed for ensuing metabolic changes in liver, adipose tissue, and skeletal muscle. Estrogen-deficient male ArKO mice showed increased gonadal adiposity which was significantly reduced upon 17β-estradiol (E2) treatment. Concurrently, elevated ArKO serum leptin levels were significantly reduced upon E2 treatment and lowered serum adiponectin levels were restored to wild type levels. Three-month-old male ArKO mice were hyperglycemic, and both glucose and pyruvate intolerant. These phenotypes continued through to 6 months of age, highlighting a loss of glycemic control. ArKO livers displayed changes in gluconeogenic enzyme expression, and in insulin signaling pathways upon E2 treatment. Liver triglycerides were increased in the ArKO males only after 6 months of age, which could be reversed by E2 treatment. No differences were observed in insulin-stimulated ex vivo muscle glucose uptake nor changes in ArKO adipose tissue and muscle insulin signaling pathways. Therefore, we conclude that male ArKO mice develop hepatic glucose intolerance by the age of 3 months which precedes the sex-specific development of hepatic steatosis. This can be reversed upon the administration of exogenous E2.

Topics: Adiponectin; Adipose Tissue; Animals; Aromatase; Blood Glucose; Body Weight; Estrogens; Gluconeogenesis; Glucose Intolerance; Insulin; Insulin Resistance; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscles; Organ Size; Phosphorylation; Pyruvic Acid; Real-Time Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Triglycerides

Adiponectin, an adipocyte-derived hormone, regulates glucose and lipid metabolism. It is also antiinflammatory. During obesity, adiponectin levels and sensitivity are reduced. Whereas the action of adiponectin in the periphery is well established the neuroendocrine role of adiponectin is largely unknown. To address this we analyzed the expression of adiponectin and the 2 adiponectin receptors (AdipoR1 and AdipoR2) in response to fasting and to diet-induced and genetic obesity. We also investigated the acute impact of adiponectin on central regulation of glucose homeostasis. Adiponectin (1 μg) was injected intracerebroventricularly (ICV), and glucose tolerance tests were performed in dietary and genetic obese mice. Finally, the influence of ICV adiponectin administration on central signaling cascades regulating glucose homeostasis and on markers of hypothalamic inflammation was assessed. Gene expression of adiponectin was down-regulated whereas AdipoR1 was up-regulated in the arcuate nucleus of fasted mice. High-fat (HF) feeding increased AdipoR1 and AdipoR2 gene expression in this region. In mice on a HF diet and in leptin-deficient mice acute ICV adiponectin improved glucose tolerance 60 minutes after injection, whereas normoglycemia in control mice was unaffected. ICV adiponectin increased pAKT, decreased phospho-AMP-activated protein kinase, and did not change phospho-signal transducer and activator of transcription 3 immunoreactivity. In HF-fed mice, ICV adiponectin reversed parameters of hypothalamic inflammation and insulin resistance as determined by the number of phospho-glycogen synthase kinase 3 β(Ser9) and phospho-c-Jun N-terminal kinase (Thr183/Tyr185) immunoreactive cells in the arcuate nucleus and ventromedial hypothalamus. This study demonstrates that the insulin-sensitizing properties of adiponectin are at least partially based on a neuroendocrine mechanism that involves centrally synthesized adiponectin.

Topics: Adiponectin; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arcuate Nucleus of Hypothalamus; Diet, High-Fat; Glucose Intolerance; Hypoglycemic Agents; Injections, Intraventricular; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Nerve Tissue Proteins; Neurons; Obesity; Receptors, Adiponectin; Signal Transduction; Ventromedial Hypothalamic Nucleus

The fundamental questions of what represents a macronutritionally balanced diet and how this maintains health and longevity remain unanswered. Here, the Geometric Framework, a state-space nutritional modeling method, was used to measure interactive effects of dietary energy, protein, fat, and carbohydrate on food intake, cardiometabolic phenotype, and longevity in mice fed one of 25 diets ad libitum. Food intake was regulated primarily by protein and carbohydrate content. Longevity and health were optimized when protein was replaced with carbohydrate to limit compensatory feeding for protein and suppress protein intake. These consequences are associated with hepatic mammalian target of rapamycin (mTOR) activation and mitochondrial function and, in turn, related to circulating branched-chain amino acids and glucose. Calorie restriction achieved by high-protein diets or dietary dilution had no beneficial effects on lifespan. The results suggest that longevity can be extended in ad libitum-fed animals by manipulating the ratio of macronutrients to inhibit mTOR activation.

Topics: Aging; Amino Acids, Branched-Chain; Animals; Blood Pressure; Body Composition; Cardiovascular Physiological Phenomena; Diet; Energy Intake; Glucose; Glucose Intolerance; Insulin; Kaplan-Meier Estimate; Leptin; Liver; Longevity; Male; Mice; Mice, Inbred C57BL; Phosphorylation; TOR Serine-Threonine Kinases

This study sought to determine the role of white adipose tissue (WAT) metabolism in the prevention of insulin resistance (IR) by physical training (PT).. Male C57BL/6J mice were assigned into groups CHOW-SED (chow diet, sedentary; n=15), CHOW-TR (chow diet, trained; n=18), CAF-SED (cafeteria diet, sedentary; n=15) and CAF-TR (cafeteria diet, trained; n=18). PT consisted of running sessions of 60 min at 60% of maximal speed conducted five days per week for eight weeks.. PT prevented body weight and fat mass accretion in trained groups and prevented hyperglycemia, hyperinsulinemia, glucose intolerance and IR in the CAF-TR. The CAF-SED group presented higher leptin and free fatty acid and lower adiponectin serum levels compared with other groups. Lipolytic activity (in mmol/10(6) adipose cells) stimulated by isoproterenol increased in CHOW-TR (16347±3005), CAF-SED (18110±3788) and CAF-TR (15837±2845) compared with CHOW-SED (8377±2284). The CAF-SED group reduced FAS activity compared with CHOW-SED and CHOW-TR, reduced citrate synthase activity and increased DGAT2 content compared with other groups. Both trained groups reduced G6PDH activity and increased the expression of p-AMPK (Thr172) compared with sedentary groups. CAF-SED group had lower levels of AMPK, p-AMPK (Thr172), ACC and p-ACC (Ser79) compared with other groups.. The prevention of IR by PT is mediated by adaptations in WAT metabolism by improving lipolysis, preventing an increase in enzymes responsible for fatty acid esterification and by activating enzymes that improve fat oxidation instead of fat storage.

Topics: Adipocytes; Adiponectin; Adipose Tissue, White; Adiposity; Animals; Fatty Acids, Nonesterified; Glucose Intolerance; Hyperglycemia; Hyperinsulinism; Insulin Resistance; Isoproterenol; Leptin; Lipolysis; Male; Mice; Mice, Inbred C57BL; Oxidation-Reduction; Physical Conditioning, Animal; Physical Exertion; Weight Gain

Hyperprolactinemia occurs during gestation and lactation with marked hyperphagia associated with leptin resistance. Prolactin (PRL) induces the expression of orexigenic neuropeptide Y (NPY) in hypothalamic dorsomedial nucleus (DMH) leading to hyperphagia. Along this line prolactin receptor deficient (PRLR-/-) mice are resistant to obesity under high fat diet due to increased energy expenditure. As these mice have an altered food intake, our objective was to test whether leptin is responsible for these characteristics. PRLR-/- male mice and control littermates were injected subcutaneously every other day with 12 mg/kg pegylated superactive mouse leptin antagonist (PEG-SMLA) for 3 weeks. We tested the effect of PEG-SMLA on body weight, food intake and metabolic parameters. The antagonist led to a rapid increase in body weight (20%) but increased adipose mass in PEG-SMLA treated mice was less pronounced in PRLR-/- than in WT mice. Food intake of PEG-SMLA-injected animals increased during the first week period of the experiment but then declined to a similar level of the control animals during the second week. Interestingly, PRLR-/- mice were found to have the same bone volume than those of control mice although PEG-SMLA increased bone mass by 7% in both strains. In addition, PEG-SMLA led to insulin resistance and glucose intolerance as well as an altered lipid profile in treated mice. Altogether, these results suggest that PRLR-/- mice respond to leptin antagonist similarly to the control mice, indicating no interaction between the actions of the two hormones.

Topics: Adiposity; Animals; Bone and Bones; Glucose Intolerance; Glucose Tolerance Test; Insulin Resistance; Leptin; Male; Mice; Mice, Knockout; Polyethylene Glycols; Receptors, Prolactin; Trabecular Meshwork; Weight Gain

Estrogen is thought to aid maintenance of insulin sensitivity potentially through modulation of a counter-regulatory mechanism that interferes with the contribution of adaptive and innate immune systems to visceral fat deposition. We evaluated the impact of estrogen on long-term high fat diet (HFD) intake in B- and T-cell deficient and immunocompetent animals comparatively.. A total of 16 BALB and 16 SCID mice, 8 of each sex and strain, were randomized to receive low fat diet, 4.1% fat or HFD, 35% fat, such that there was a group of both each sex and each strain receiving each diet. Biweekly levels of adiponectin, leptin and insulin levels were assessed and a glucose tolerance test (GTT) was performed after 13 weeks.. Unlike their male counterparts, HFD-fed SCID females neither gained weight, nor became insulin resistant. Meanwhile, in the HFD-fed BALB groups both males and females gained weight similarly, but remarkable sexual dimorphism was nonetheless observed. The females had notable higher adiponectin levels as compared to males (10-60 μg/mL vs. 6-10 μg/mL respectively) causing the adiponectin-to-leptin (A/L) ratio to reach 80 one week after HFD initiation. The A/L dropped to 10, still higher than males, by week 13, but dropped to 2 by the end of the study in agreement with inverse insulin trends. None of the HFD-fed female groups developed insulin resistance (IR) by week 13, while all male counterparts had. Similar results were observed in the HFD-fed SCID groups whereby the females did not develop IR and had a higher A/L; however, adiponectin levels were comparable between groups (5-11 μg/mL).. The present study provides lacking evidence indicating that estrogen may be sufficient to prevent weight gain and development of glucose intolerance in high-fat fed B- and T-cell deficient mice.

Topics: Adiponectin; Animals; B-Lymphocytes; Diet, High-Fat; Disease Models, Animal; Female; Glucose Intolerance; Insulin; Insulin Resistance; Leptin; Male; Mice, Inbred BALB C; Mice, SCID; Random Allocation; Sex Factors; T-Lymphocytes; Time Factors; Weight Gain

Patients with adult growth hormone deficiency exhibit visceral fat accumulation, which gives rise to a cluster of metabolic disorders such as impaired glucose tolerance and dyslipidemia. Plasma growth hormone levels are lower in obese patients with metabolic syndrome than in healthy subjects. Here we examined the hypothesis that exogenous growth hormone administration regulates function of adipose tissue to improve glucose tolerance in diet-induced obese mice. Twelve-week-old obese male C57BL/6 J mice received bovine growth hormone daily for 6 weeks. In epididymal fat, growth hormone treatment antagonized diet-induced changes in the gene expression of adiponectin, leptin, and monocyte chemoattractant protein-1, and significantly increased the gene expression of interleukin-10 and CD206. Growth hormone also suppressed the accumulation of oxidative stress marker, thiobarbituric acid-reactive substances, in the epididymal fat and enhanced the gene expression of anti-oxidant enzymes. Moreover, growth hormone significantly restored glucose tolerance in obese mice. In cultured 3T3-L1 adipocytes, growth hormone prevented the decline in adiponectin gene expression in the presence of hydrogen peroxide. These results suggest that growth hormone administration ameliorates glucose intolerance in obese mice presumably by decreasing adipose mass, oxidative stress, and chronic inflammation in the visceral fat.

Topics: Adiponectin; Adipose Tissue; Animals; Blood Glucose; Cattle; Glucose Intolerance; Growth Hormone; Humans; Interleukin-10; Lectins, C-Type; Leptin; Male; Mannose Receptor; Mannose-Binding Lectins; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Oxidative Stress; Receptors, Cell Surface

Obesity rates continue to rise throughout the world. Recent evidence has suggested that environmental factors contribute to altered energy balance regulation. However, the role of epigenetic modifications to the central control of energy homeostasis remains unknown. To investigate the role of DNA methylation in the regulation of energy balance, we investigated the role of the de novo DNA methyltransferase, Dnmt3a, in Single-minded 1 (Sim1) cells, including neurons in the paraventricular nucleus of the hypothalamus (PVH). Dnmt3a expression levels were decreased in the PVH of high-fat-fed mice. Mice lacking Dnmt3a specifically in the Sim1 neurons, which are expressed in the forebrain, including PVH, became obese with increased amounts of abdominal and subcutaneous fat. The mice were also found to have hyperphagia, decreased energy expenditure, and glucose intolerance with increased serum insulin and leptin. Furthermore, these mice developed hyper-LDL cholesterolemia when fed a high-fat diet. Gene expression profiling and DNA methylation analysis revealed that the expression of tyrosine hydroxylase and galanin were highly upregulated in the PVH of Sim1-specific Dnmt3a deletion mice. DNA methylation levels of the tyrosine hydroxylase promoter were decreased in the PVH of the deletion mice. These results suggest that Dnmt3a in the PVH is necessary for the normal control of body weight and energy homeostasis and that tyrosine hydroxylase is a putative target of Dnmt3a in the PVH. These results provide evidence for a role for Dnmt3a in the PVH to link environmental conditions to altered energy homeostasis.

Topics: Adipose Tissue; Animals; Basic Helix-Loop-Helix Transcription Factors; Cholesterol, LDL; Diet, High-Fat; DNA (Cytosine-5-)-Methyltransferases; DNA Methylation; DNA Methyltransferase 3A; Energy Metabolism; Female; Galanin; Gene Expression Profiling; Glucose Intolerance; Homeostasis; Hyperphagia; Insulin; Leptin; Male; Mice; Mice, Knockout; Neurons; Obesity; Paraventricular Hypothalamic Nucleus; Repressor Proteins; Tyrosine 3-Monooxygenase; Up-Regulation

We have generated a novel monoclonal antibody targeting human FGFR1c (R1c mAb) that caused profound body weight and body fat loss in diet-induced obese mice due to decreased food intake (with energy expenditure unaltered), in turn improving glucose control. R1c mAb also caused weight loss in leptin-deficient ob/ob mice, leptin receptor-mutant db/db mice, and in mice lacking either the melanocortin 4 receptor or the melanin-concentrating hormone receptor 1. In addition, R1c mAb did not change hypothalamic mRNA expression levels of Agrp, Cart, Pomc, Npy, Crh, Mch, or Orexin, suggesting that R1c mAb could cause food intake inhibition and body weight loss via other mechanisms in the brain. Interestingly, peripherally administered R1c mAb accumulated in the median eminence, adjacent arcuate nucleus and in the circumventricular organs where it activated the early response gene c-Fos. As a plausible mechanism and coinciding with the initiation of food intake suppression, R1c mAb induced hypothalamic expression levels of the cytokines Monocyte chemoattractant protein 1 and 3 and ERK1/2 and p70 S6 kinase 1 activation.

Topics: Animals; Antibodies, Monoclonal; Arcuate Nucleus of Hypothalamus; Chemokine CCL2; Chemokine CCL7; Circumventricular Organs; Eating; Energy Metabolism; Female; Gene Expression Regulation; Glucose Intolerance; Humans; Hypothalamus; Leptin; Mice; Mice, Knockout; Mice, Obese; Mitogen-Activated Protein Kinases; Obesity; Receptor, Fibroblast Growth Factor, Type 1; Receptor, Melanocortin, Type 4; Receptors, Somatostatin; Ribosomal Protein S6 Kinases, 70-kDa; Serum Response Factor; Signal Transduction

Glucolipotoxicity, which is exerted by free fatty acids (FFA) and prolonged hyperglycemia, is implicated in pancreatic β-cell failure in diabetes. Pattern recognition receptors such as receptor for advanced glycation end products (RAGE) and toll-like receptors 2 and 4 could mediate danger signals in β-cells. We examined whether RAGE contributes to β-cell failure in a type 2 diabetes mouse model. Pancreatic islets were isolated from ob/ob, db/db, diet-induced obesity (DIO), RAGE-null (RAGE(-/-) ), and RAGE(+/+) wild-type (WT) control mice and dispersed into single cells for flow cytometry. RAGE expression was detected in insulin-positive β-cells of ob/ob and db/db mice, but not of WT, DIO, or RAGE(-/-) mice: thus, inadequate leptin receptor signaling and RAGE expression may be linked. Compared with RAGE(+/+) db/db mice, RAGE(-/-) db/db mice showed higher β-cell number and mass with less apoptosis as well as glucose tolerance with higher insulin secretion without any differences in serum levels of FFA and adiponectin. Palmitate or oleate pretreatment combined with a leptin antagonist induced RAGE expression, AGE-elicited apoptosis, and impaired glucose-stimulated insulin secretion by advanced glycation end products (AGE) in MIN6 cells. FFA elevation with concomitant AGE formation during prolonged hyperglycemia could cause β-cell damage through insufficient leptin action and subsequent RAGE induction in type 2 diabetes.

Topics: Adiponectin; Animals; Apoptosis; Blood Glucose; Cell Line; Cell Proliferation; Diabetes Mellitus, Type 2; Diet, High-Fat; Fatty Acids, Nonesterified; Gene Expression; Glucose Intolerance; Glycation End Products, Advanced; Insulin; Insulin-Secreting Cells; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Receptors, Leptin

The peel of the native Brazilian fruit jaboticaba is rich in anthocyanins, which are known for their anti-obesity effects in animal models. The aim of the present study was to evaluate the effects of freeze-dried jaboticaba peel powder (FDJPP) on a number of metabolic parameters in a model of diet-induced obesity. Mice (n 8 per group) were initially fed on a high-fat diet (HFD, 35% w/w) for 4 weeks and then switched to a HFD supplemented with FDJPP (1, 2 or 4% w/w) for an additional 6 weeks. Energy intake, weight loss, glucose tolerance, insulin resistance and lipid profile were determined, and the results were evaluated using ANOVA and Tukey’s tests. The FDJPP exerted no protective effect on HFD-induced weight gain, hyperleptinaemia and glucose intolerance. However, the supplementation was effective to reduce insulin resistance, as evidenced in the insulin tolerance test, and subsequently confirmed by improved signal transduction through the insulin receptor/insulin receptor substrate-1/Akt/forkhead box protein pathway and by the attenuation of HFD-induced inflammation in the liver, verified by lower expressions of IL-1b and IL-6 and decreased phosphorylated IkB-a protein levels in all jaboticaba-treated mice. These results suggest that FDJPP may exert a protective role against obesity-associated insulin resistance.

Topics: Analysis of Variance; Animals; Anthocyanins; Anti-Obesity Agents; Diet, High-Fat; Dietary Supplements; Fruit; Glucose Intolerance; Inflammation; Insulin; Insulin Resistance; Leptin; Liver; Male; Mice; Mice, Inbred Strains; Myrtaceae; Obesity; Phytotherapy; Plant Preparations; Powders; Receptor, Insulin; Signal Transduction; Weight Gain

Maternal high-fat (HF) diet can alter offspring metabolism via perinatal developmental programming. This study tests the hypothesis that maternal HF diet also induces perinatal programming of offspring bone mass and strength. We compared skeletal acquisition in pups from C57Bl/6J mice fed HF or normal diet from preconception through lactation. Three-week-old male and female pups from HF (HF-N) and normal mothers (N-N) were weaned onto normal diet. Outcomes at 14 and 26 weeks of age included body mass, body composition, whole-body bone mineral content (WBBMC) via peripheral dual-energy X-ray absorptiometry, femoral cortical and trabecular architecture via microcomputed tomography, and glucose tolerance. Female HF-N had normal body mass and glucose tolerance, with lower body fat (%) but higher serum leptin at 14 weeks vs. N-N (P<0.05 for both). WBBMC was 12% lower at 14 weeks and 5% lower at 26 weeks, but trabecular bone volume fraction was 20% higher at 14 weeks in female HF-N vs. N-N (P<0.05 for all). Male HF-N had normal body mass and mildly impaired glucose tolerance, with lower body fat (%) at 14 weeks and lower serum leptin at 26 weeks vs. N-N (P<0.05 for both). Serum insulin was higher at 14 weeks and lower at 26 weeks in HF-N vs. N-N (P<0.05). Trabecular BV/TV was 34% higher and cortical bone area was 6% higher at 14 weeks vs. N-N (P<0.05 for both). These data suggest that maternal HF diet has complex effects on offspring bone, supporting the hypothesis that maternal diet alters postnatal skeletal homeostasis.

Topics: Animals; Bone and Bones; Bone Density; Bone Development; Diet, High-Fat; Female; Fetal Development; Glucose Intolerance; Lactation; Leptin; Male; Maternal Nutritional Physiological Phenomena; Mice; Mice, Inbred C57BL; Minerals; Overweight; Pregnancy; Pregnancy Complications; Radiography; Severity of Illness Index; Sex Characteristics

Most Swedish studies show stable diabetes prevalence despite increasing obesity, but glucose levels may shift upwards below the diagnostic threshold for diabetes. Our aim was to explore trends in glucose distribution in northern Sweden; whether these trends were uniformly distributed throughout the spectrum of glucose concentrations; and to relate trends to traditional risk factors and the obesity-related adipokine leptin.. The project consisted of four cross-sectional surveys between 1990 and 2009, with 7069 participants aged 25-64 years. The overall participation rate was 74.4%. Trend analyses of glucose concentrations along the entire distribution and linear regression in relation to survey years and risk markers were used.. Fasting and post-load glucose increased in women (both P < 0.001) and post-load glucose in men (P = 0.004). The increase was seen in most deciles of glucose concentrations. The prevalence of impaired glucose tolerance doubled in women to 14.5% and tripled in men to 10.1% (both P = 0.004). The prevalence of impaired fasting glucose rose in women from 4.5 to 7.7% (P < 0.001). The prevalence of diabetes was unchanged-6.4% in 2009. In men, leptin, together with traditional risk factors, explained 7.8 and 10.8% of the variance in fasting (P = 0.008) and post-load (P < 0.001) glucose, respectively.. Increasing fasting and post-load glucose concentrations were seen in most deciles of the glucose distribution, indicating a shift in the entire population. Leptin was significantly associated with fasting and post-load glucose in men.

Topics: Adult; Biomarkers; Blood Glucose; Cohort Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Fasting; Female; Glucose Intolerance; Glucose Tolerance Test; Health Surveys; Health Transition; Humans; Leptin; Male; Middle Aged; Models, Biological; Prediabetic State; Prevalence; Risk Factors; Sex Factors; Sweden

Dietary supplement may potentially help to fight obesity and other metabolic disorders such as insulin-resistance and low-grade inflammation. The present study aimed to test whether supplementation with Agaricus blazei murill (ABM) extract could have an effect on diet-induced obesity in rats.. Wistar rats were fed with control diet (CD) or high-fat diet (HF) and either with or without supplemented ABM for 20 weeks.. HF diet-induced body weight gain and increased fat mass compared to CD. In addition HF-fed rats developed hyperleptinemia and insulinemia as well as insulin resistance and glucose intolerance. In HF-fed rats, visceral adipose tissue also expressed biomarkers of inflammation. ABM supplementation in HF rats had a protective effect against body weight gain and all study related disorders. This was not due to decreased food intake which remained significantly higher in HF rats whether supplemented with ABM or not compared to control. There was also no change in gut microbiota composition in HF supplemented with ABM. Interestingly, ABM supplementation induced an increase in both energy expenditure and locomotor activity which could partially explain its protective effect against diet-induced obesity. In addition a decrease in pancreatic lipase activity is also observed in jejunum of ABM-treated rats suggesting a decrease in lipid absorption.. Taken together these data highlight a role for ABM to prevent body weight gain and related disorders in peripheral targets independently of effect in food intake in central nervous system.

Topics: Agaricus; Animals; Biomarkers; Blood Glucose; Body Composition; Calorimetry, Indirect; Diet, High-Fat; Dietary Fats; Dietary Supplements; Energy Metabolism; Gastrointestinal Tract; Glucose Intolerance; Inflammation; Insulin; Insulin Resistance; Intra-Abdominal Fat; Leptin; Lipase; Male; Microbiota; Obesity; Probiotics; Rats; Rats, Wistar; Subcutaneous Fat, Abdominal; Weight Gain

Previous studies have shown markedly lower birth weight among infants of South Asian origin compared with those of White European origin. Whether such differences mask greater adiposity in South Asian infants and whether they persist across generations in contemporary UK populations is unclear. Our aim was to compare birth weight, skinfold thickness and cord leptin between Pakistani and White British infants and to investigate the explanatory factors, including parental and grandparental birthplace.. We examined the differences in birth weight and skinfold thickness between 4649 Pakistani and 4055 White British infants born at term in the same UK maternity unit and compared cord leptin in a subgroup of 775 Pakistani and 612 White British infants.. Pakistani infants were lighter (adjusted mean difference -234 g 95% CI -258 to -210) and were smaller in both subscapular and triceps skinfold measurements. The differences for subscapular and triceps skinfold thickness (mean z-score difference -0.27 95% CI -0.34 to -0.20 and -0.23 95% CI -0.30 to -0.16, respectively) were smaller than the difference in birth weight (mean z-score difference -0.52 95% CI -0.58 to -0.47) and attenuated to the null with adjustment for birth weight (0.03 95% CI -0.03 to 0.09 and -0.01 95% CI -0.08 to 0.05, respectively). Cord leptin concentration (indicator of fat mass) was similar in Pakistani and White British infants without adjustment for birth weight, but with adjustment became 30% higher (95% CI 17% to 44%) among Pakistani infants compared with White British infants. The magnitudes of difference did not differ by generation.. Despite being markedly lighter, Pakistani infants had similar skinfold thicknesses and greater total fat mass, as indicated by cord leptin, for a given birth weight than White British infants. Any efforts to reduce ethnic inequalities in birth weight need to consider differences in adiposity and the possibility that increasing birth weight in South Asian infants might inadvertently worsen health by increasing relative adiposity.

Topics: Adipose Tissue; Adult; Birth Weight; Body Mass Index; Diabetes, Gestational; Female; Fetal Blood; Gestational Age; Glucose Intolerance; Hospitals, Maternity; Humans; Infant, Newborn; Leptin; Pakistan; Pre-Eclampsia; Pregnancy; Pregnant Women; Prospective Studies; Regression Analysis; Skinfold Thickness; Surveys and Questionnaires; United Kingdom; White People

Type 2 Diabetes is a global health burden and based on current estimates will become an even larger problem in the future. Developing new strategies to prevent and treat diabetes is a scientific challenge of high priority. The stomach hormone ghrelin has been associated with playing a role in the regulation of glucose homeostasis. However, its precise mechanism and impact on whole glucose metabolism remains to be elucidated. This study aims to clarify the role of the two ghrelin isoforms acyl- and desacyl ghrelin in regulating glucose homeostasis. Therefore ghrelin activating enzyme Ghrelin-O-acyltransferase (GOAT) was ablated in leptin-deficient ob/ob mice to study whether specific acyl ghrelin deficiency or desacyl ghrelin abundance modifies glucose tolerance on a massively obese background. As targeted deletion of acyl ghrelin does not improve glucose homeostasis in our GOAT-ob/ob mouse model we conclude that neither acyl ghrelin nor the increased ratio of desacyl/acyl ghrelin is crucial for controlling glucose homeostasis in the here presented model of massive obesity induced by leptin deficiency.

Topics: Acylation; Acyltransferases; Adiposity; Animals; Body Weight; Female; Gene Knockout Techniques; Ghrelin; Glucose; Glucose Intolerance; Homeostasis; Leptin; Male; Membrane Proteins; Mice; Mice, Knockout; Mice, Obese; Obesity; Phenotype; Protein Processing, Post-Translational

Synthetic glucocorticoids (sGCs) are administered to women threatening preterm labor. We have shown multigenerational endocrine and metabolic effects of fetal sGC exposure. We hypothesized that sGC exposure would alter the second filial generation (F2) offspring neonatal leptin peak that controls development of appetitive behavior with metabolic consequences.. F0 nulliparous ewes were bred to a single ram. Beginning at day 103 of gestation (term 150 days), dexamethasone (DEX) ewes received 4 injections of 2 mg DEX intramuscularly, 12 hours apart. Control ewes received saline. Ewes lambed naturally. At 22 months of age, F1 offspring were mated to produce F2 offspring. At 10 months of age, F2 female offspring were placed on an ad libitum feeding challenge for 12 weeks.. DEX F2 female offspring did not show a postnatal leptin peak and their plasma cortisol concentration was elevated in the first days of life. During the feeding challenge, DEX F2 offspring consumed 10% more feed and gained 20% more weight compared with control F2 offspring. At the end of the feeding challenge, DEX F2 offspring had greater adiposity compared with control F2 offspring. F2 sGC offspring showed impaired insulin secretion in response to an intravenous glucose tolerance test.. sGC administration to F0 mothers eliminates the neonatal leptin peak in F2 female offspring potentially by inhibition caused by elevated cortisol in the DEX F2 offspring. F2 offspring showed increased appetite, weight gain, and adiposity during an ad libitum feeding challenge accompanied by decreased insulin response to an intravenous glucose tolerance test.

Topics: Adiposity; Animals; Appetite; Dexamethasone; Feeding Behavior; Female; Glucocorticoids; Glucose; Glucose Intolerance; Glucose Tolerance Test; Hydrocortisone; Leptin; Pregnancy; Prenatal Exposure Delayed Effects; Sheep; Weight Gain

Oral salmon calcitonin (sCT) has demonstrated clinical efficacy in treating osteoporosis in postmenopausal women. The postmenopausal state is also associated with obesity-related insulin resistance (IR) and type 2 diabetes. The aim of this study was to investigate the preventive effects of oral sCT on energy and glucose homeostasis in high-fat diet (HFD)- and ovariectomy (OVX)-induced obese rats. Furthermore, the weight-regulatory and gluco-regulatory effects of short-term oral sCT intervention on HFD-induced obese rats were explored.. For prevention, female rats exposed to HFD with or without OVX were treated with oral sCT for 5 weeks. As intervention, HFD-induced obese male rats were treated with oral sCT for 4 days. Body weight, food intake, and plasma glucose, insulin, and leptin levels were measured, and the clinical homeostasis model assessment for insulin resistance (HOMA-IR) index was calculated. In addition, oral glucose tolerance was evaluated in the systemic and portal circulations.. For prevention, oral sCT reduced body weight by ∼16% to 19% (P < 0.001), reduced plasma insulin and leptin by ∼50%, and improved impaired fasting glycemia (P < 0.05) concomitantly with amelioration of IR (HOMA-IR; P < 0.01) in HFD- and OVX-induced obesity. Furthermore, oral sCT significantly reduced the incremental area under the curve for plasma glucose and insulin by ∼40% and ∼70%, respectively, during glucose tolerance testing. As intervention in HFD-induced obese rats, oral sCT reduced body weight, fasting glycemia, and insulinemia in conjunction with HOMA-IR (P < 0.001). Finally, oral sCT alleviated glucose intolerance predominantly in the portal circulation.. Oral sCT treatment displays weight-regulatory and glucoregulatory efficacy in HFD- and OVX-induced obese rats, indicating the clinical usefulness of oral sCT in postmenopausal obesity-related IR and type 2 diabetes.

Topics: Animals; Blood Glucose; Body Weight; Calcitonin; Diabetes Mellitus, Type 2; Diet, High-Fat; Fasting; Female; Glucose Intolerance; Insulin; Insulin Resistance; Leptin; Male; Obesity; Ovariectomy; Rats; Rats, Sprague-Dawley

Bariatric surgeries are hypothesized to produce weight loss and improve diabetes control by multiple mechanisms including gastric restriction and lower gut stimulation; the relative importance of these mechanisms remains poorly understood. We compared the effects of a typical foregut procedure, sleeve gastrectomy, (SG) with a primarily hindgut surgery, ileal transposition (IT), alone and together (SGIT), or sham manipulations, on food intake, body weight, gut hormones, glucose tolerance, and key markers of glucose homeostasis in peripheral tissues of adult male Sprague-Dawley rats (450-550 g, n = 7-9/group). SG, IT, and SGIT surgeries produced transient reduction in food intake and weight gain; the effects of SG and IT on intake and body weight were nonadditive. SG, IT, and SGIT surgeries resulted in increased tissue expression and plasma concentrations of the lower gut hormones glucagon-like peptide-1 and peptide YY and decreased plasma glucose-dependent insulinotropic peptide, insulin, and leptin concentrations. Despite transient effects on intake and weight gain, the SG, IT, and SGIT surgeries produced a significant improvement in glucose tolerance. In support of glycemic improvements, the protein abundance of key markers of glucose metabolism (e.g., GLUT4, PKA, IRS-1) in muscle and adipose tissue were increased, whereas the expression of key gluconeogenic enzyme in liver (G-6-Pase) were decreased following the surgeries. Therefore, our data suggest that enhanced lower gut stimulation following SG, IT, and SGIT surgeries leads to transient reduction in food intake and weight gain together with enhanced secretion of lower gut hormones and improved glucose clearance by peripheral tissues.

Topics: Adipose Tissue, White; Animals; Bariatric Surgery; Biomarkers; Carbohydrate Metabolism; Energy Intake; Gastrectomy; Gastrointestinal Hormones; Glucose; Glucose Intolerance; Ileum; Insulin; Insulin Secretion; Intestinal Mucosa; Leptin; Liver; Male; Muscle, Skeletal; Random Allocation; Rats; Rats, Sprague-Dawley; Vitamin K; Weight Gain

Emerging evidence has demonstrated that saturated fatty acids prime pro-IL-1β production and inflammasome-mediated IL-1β activation is critical in obesity-associated insulin resistance (IR). Nonetheless, IL-1 receptor I-deficient (IL-1RI(-/-)) mice develop mature-onset obesity despite consuming a low-fat diet (LFD). With this apparent contradiction, the present study evaluated whether IL-1RI(-/-) mice were protected against long-term (6 mo) high-fat diet (HFD)-induced IR. Male wild-type and IL-1RI(-/-) mice were fed LFD or HFD for 3 or 6 mo, and glucose and insulin tolerance tests were performed. Adipose insulin sensitivity, cytokine profiles, and adipocyte morphology were assessed. The adipogenic potential of stromal vascular fraction was determined. Hepatic lipid accumulation and insulin sensitivity were characterized. IL-1RI(-/-) mice developed glucose intolerance and IR after 6 mo HFD compared with 3 mo HFD, coincident with enhanced weight gain, hyperinsulinemia, and hyperleptinemia. The aggravated IR phenotype was associated with loss of adipose functionality, switch from adipocyte hyperplasia to hypertrophy and hepatosteatosis. Induction of adipogenic genes was reduced in IL-1RI(-/-) preadipocytes after 6 mo HFD compared with 3 mo HFD. Obese LFD-IL-1RI(-/-) mice exhibited preserved metabolic health. IL-1RI(-/-) mice develop glucose intolerance and IR after 6 mo HFD intervention. While mature-onset obesity is evident in LFD-IL-1RI(-/-) mice, the additional metabolic insult of HFD was required to drive adipose inflammation and systemic IR. These findings indicate an important interaction between dietary fat and IL-1, relevant to optimal metabolic health.

Topics: Adipose Tissue; Adiposity; Animals; Diet, High-Fat; Dietary Fats; Fatty Liver; Glucose Intolerance; Glucose Tolerance Test; Inflammation; Insulin; Insulin Resistance; Leptin; Male; Mice; Mice, Knockout; Receptors, Interleukin-1 Type I

Perfluorooctane sulfonate (PFOS), which belongs to the degradation product of many perfluorinated compounds, is on the list of persistent organic pollutants (POPs) and is currently detected in both wildlife and humans. The consequence of gestational and lactational exposure to PFOS on prediabetes effect in offspring was investigated in rats in the present study. Maternal rats were treated with vehicle, 0.5 mg/kg/day or 1.5 mg/kg/day PFOS respectively from gestation day 0 to postnatal day 21. The glucose and lipid metabolism effects were investigated on the offspring in adulthood. The gestational and lactational exposure to PFOS led to low body weight from birth to weaning, and evoked signs of a prediabetic state, with elevated fasting serum insulin and leptin level, impaired glucose tolerance, though the fasting serum glucose and glycosylated serum protein level were normal. Abnormal lipid homeostasis was also observed by the phenomenon of hepatic steatosis and increased gonadal fat pad weight. However, the circulating serum level of fasting triglyceride and cholesterol level were no different from controls. Our results suggested that developmental exposure to PFOS may contribute to glucose and lipid metabolic disorder in adulthood.

Topics: Adipose Tissue; Alkanesulfonic Acids; Animals; Animals, Newborn; Environmental Pollutants; Fatty Liver; Female; Fluorocarbons; Glucose; Glucose Intolerance; Homeostasis; Insulin; Lactation; Leptin; Lipid Metabolism; Male; Maternal Exposure; Prediabetic State; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Triglycerides; Weight Gain

Air pollutants have been associated with increased diabetes in humans. We hypothesized that ozone would impair glucose homeostasis by altering insulin signaling and/or endoplasmic reticular (ER) stress in young and aged rats. One, 4, 12, and 24 month old Brown Norway (BN) rats were exposed to air or ozone, 0.25 or 1.0 ppm, 6 h/day for 2 days (acute) or 2 d/week for 13 weeks (subchronic). Additionally, 4 month old rats were exposed to air or 1.0 ppm ozone, 6 h/day for 1 or 2 days (time-course). Glucose tolerance tests (GTT) were performed immediately after exposure. Serum and tissue biomarkers were analyzed 18 h after final ozone for acute and subchronic studies, and immediately after each day of exposure in the time-course study. Age-related glucose intolerance and increases in metabolic biomarkers were apparent at baseline. Acute ozone caused hyperglycemia and glucose intolerance in rats of all ages. Ozone-induced glucose intolerance was reduced in rats exposed for 13 weeks. Acute, but not subchronic ozone increased α2-macroglobulin, adiponectin and osteopontin. Time-course analysis indicated glucose intolerance at days 1 and 2 (2>1), and a recovery 18 h post ozone. Leptin increased day 1 and epinephrine at all times after ozone. Ozone tended to decrease phosphorylated insulin receptor substrate-1 in liver and adipose tissues. ER stress appeared to be the consequence of ozone induced acute metabolic impairment since transcriptional markers of ER stress increased only after 2 days of ozone. In conclusion, acute ozone exposure induces marked systemic metabolic impairments in BN rats of all ages, likely through sympathetic stimulation.

Topics: Adiponectin; Adipose Tissue; Age Factors; alpha-Macroglobulins; Animals; Biomarkers; Diabetes Mellitus; Endoplasmic Reticulum Stress; Glucose Intolerance; Glucose Tolerance Test; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Leptin; Lipoproteins, HDL; Lipoproteins, IDL; Liver; Male; Metabolic Diseases; Osteopontin; Ozone; Phosphorylation; Rats; Rats, Inbred BN; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Triglycerides

Alcohol use affecting the risk of type 2 diabetes mellitus (T2DM) is poorly identified as well as the role of brain-derived neurotrophic factor (BDNF), ghrelin, and leptin in alcohol dependence with T2DM. We tested the hypothesis that alcohol abstinence affects diabetes-related factors and BDNF, ghrelin, and leptin secretions in alcohol-dependent patients with glucose intolerance.. A total of 64 male alcohol-dependent patients were classified into normal glucose tolerance (NGT), pre-diabetes mellitus (pre-DM), and diabetes mellitus (DM) groups according to a 75-g oral glucose tolerance test (OGTT). All participants got alcohol dependence rehabilitation treatment for 30 days, and then we compared changes in BDNF, ghrelin, and leptin between pre- and post-alcohol abstinence.. After alcohol abstinence, both pre-DM and DM groups had significantly decreased levels of fasting glucose. All 3 groups exhibited elevated ghrelin levels and reduced leptin levels, but BDNF levels were significantly increased only in the pre-DM group. The pre-DM group had large increases in BDNF and ghrelin levels compared with those of the NGT group. Moreover, decreases in homeostasis model assessment of insulin resistance (HOMA-IR), fasting glucose, and leptin levels in the DM group were larger than those in the NGT group.. Alcohol abstinence might influence diabetes-related factors of alcohol-dependent patients with glucose intolerance. Further, BDNF, ghrelin, and leptin differently affect this improvement, depending on the stage of DM. In the pre-DM group, elevated BDNF and ghrelin levels are likely to influence insulin sensitivity, insulin resistance, and fasting glucose levels. Further, reduced leptin levels after abstinence might be related to improved glucose kinetics in patients with diabetes.

Topics: Adult; Alcoholism; Biomarkers; Brain-Derived Neurotrophic Factor; Ghrelin; Glucose Intolerance; Humans; Leptin; Male; Middle Aged; Temperance

SCFA are produced in the gut by bacterial fermentation of undigested carbohydrates. Activation of the Gαi-protein-coupled receptor GPR41 by SCFA in β-cells and sympathetic ganglia inhibits insulin secretion and increases sympathetic outflow, respectively. A possible role in stimulating leptin secretion by adipocytes is disputed. In the present study, we investigated energy balance and glucose homoeostasis in GPR41 knockout mice fed on a standard low-fat or a high-fat diet. When fed on the low-fat diet, body fat mass was raised and glucose tolerance was impaired in male but not female knockout mice compared to wild-type mice. Soleus muscle and heart weights were reduced in the male mice, but total body lean mass was unchanged. When fed on the high-fat diet, body fat mass was raised in male but not female GPR41 knockout mice, but by no more in the males than when they were fed on the low-fat diet. Body lean mass and energy expenditure were reduced in male mice but not in female knockout mice. These results suggest that the absence of GPR41 increases body fat content in male mice. Gut-derived SCFA may raise energy expenditure and help to protect against obesity by activating GPR41.

Topics: Adipose Tissue; Animals; Bacteria; Body Composition; Body Fluid Compartments; Diet, Fat-Restricted; Diet, High-Fat; Dietary Fats; Energy Metabolism; Fatty Acids, Volatile; Female; Gastrointestinal Tract; Glucose Intolerance; Heart; Insulin; Insulin Secretion; Leptin; Male; Mice; Mice, Knockout; Muscle, Skeletal; Obesity; Organ Size; Receptors, G-Protein-Coupled; Sex Factors

Rats given sugar-sweetened drinks can develop glucose intolerance, insulin resistance and dyslipidaemia. The aim of this study was to investigate whether such metabolic disruptions and also possible weight gain induced by chronic sucrose consumption could be attenuated by low-volume exercise.. Using a 2 × 2 factorial design, rats were given free access for 57 days to either a 10% sucrose solution (Suc and SucEx) or water only (Con and ConEx), while exercise rats (SucEx and ConEx) received 20-min treadmill training every 3 days. Caloric intake and body weight were measured throughout this dietary intervention. Oral glucose tolerance tests were performed on days 29 and 54. Plasma insulin, triglycerides and leptin were also measured, together with post-mortem measures of retroperitoneal fat pads and liver triglycerides.. In groups given sucrose, exercise reduced calorie consumption, reduced weight gain and decreased leptin relative to non-exercised controls. Exercise was found to improve glucose tolerance and insulin action at day 29, but not day 54.. Low-volume exercise can be effective in preventing weight gain in sucrose-fed rats, probably via reduction of subcutaneous fat, but prevention of the glucose intolerance and dyslipidaemia produced by sucrose consumption may be transient.

Topics: Animals; Blood Glucose; Energy Intake; Glucose Intolerance; Glucose Tolerance Test; Insulin; Insulin Resistance; Intra-Abdominal Fat; Leptin; Liver; Male; Obesity; Physical Conditioning, Animal; Rats; Rats, Wistar; Sedentary Behavior; Sucrose; Triglycerides; Weight Gain

Although several researches have demonstrated that rooibos extract has hypoglycemic effect, the role of aspalathin, a main polyphenol in the extract, remains unclear. Our aims were to find specific mechanisms for anti-diabetic action of aspalathin employing a rat skeletal muscle-derived cell line (L6 myocytes) and a rat-derived pancreatic β-cell line (RIN-5F cells) and to investigate its effect in type 2 diabetic model ob/ob mice.. We investigated in vitro the effect of aspalathin on the glucose metabolism through the studies on molecular mechanisms of glucose uptake using cultured L6 myotubes. We also measured the antioxidative ability of aspalathin against reactive oxygen species (ROS) generated by artificial advanced glycation end product (AGE) in RIN-5F cells. In vivo, ob/ob mice were fed 0.1 % aspalathin-containing diet for 5 weeks, and the effect of aspalathin on fasting blood glucose level, glucose intolerance, and hepatic gene expression was studied.. Aspalathin dose dependently increased glucose uptake by L6 myotubes and promoted AMP-activated protein kinase (AMPK) phosphorylation. Aspalathin enhanced GLUT4 translocation to plasma membrane in L6 myoblasts and myotubes. In RIN-5F cells, aspalathin suppressed AGE-induced rises in ROS. In vivo, aspalathin significantly suppressed the increase in fasting blood glucose levels and improved glucose intolerance. Furthermore, aspalathin decreased expression of hepatic genes related to gluconeogenesis and lipogenesis.. Hypoglycemic effect of aspalathin is related to increased GLUT4 translocation to plasma membrane via AMPK activation. In addition, aspalathin reduces the gene expression of hepatic enzymes related to glucose production and lipogenesis. These results strongly suggest that aspalathin has anti-diabetic potential.

Topics: Adiponectin; AMP-Activated Protein Kinases; Animals; Blood Glucose; Body Weight; Cell Line; Chalcones; Cholesterol; Diabetes Mellitus, Experimental; Gluconeogenesis; Glucose Intolerance; Glucose Transporter Type 4; Glycogenolysis; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Leptin; Lipogenesis; Mice; Mice, Obese; Muscle Fibers, Skeletal; Muscle, Skeletal; Phosphorylation; Rats; Reactive Oxygen Species

Poor nutrition during the perinatal period is associated with an increased risk for metabolic syndrome in adulthood. Taurine (TAU) regulates β-cell function and glucose homeo-stasis. Here, we assessed the effects of TAU supplementation upon adiposity and glucose control in malnourished mice fed a high-fat diet (HFD).. Weaned male C57BL/6J mice were fed a control (14% protein - C) or a protein-restricted (6% protein - R) diet for 6 weeks. Afterwards, mice received or not an HFD for 8 weeks (CH and RH). Half of the HFDmice were supplemented with 5% TAU after weaning (CHT and RHT). Protein restriction led to typical malnutrition features. HFD increased body weight, adiposity, and led to hyperleptinemia, hyperphagia, glucose intolerance, and higher liver glucose output in RH and CH groups. Fasted R mice showed higher plasma adiponectin levels and increased phosphorylation of the AMP-activated protein kinase (p-AMPK) in the liver. These parameters were reduced in RH mice and increased p-AMPK persisted in RHT. TAU prevented obesity and improved glucose tolerance only in CHT, but liver glucose control was ameliorated in both supplemented groups. Better CHT liver glucose control was linked to increased Akt (thymoma viral proto-oncogene/protein kinase B) phosphorylation.. Malnourished mice fed an HFD developed obesity, glucose intolerance, and increased liver glucose output. TAU preserved only normal liver glucose control in RHT mice, an effect associated with increased liver p-AMPK content.

Topics: Adiponectin; Adiposity; Amino Acids; AMP-Activated Protein Kinases; Animals; Blood Glucose; Body Weight; Diet, High-Fat; Dietary Supplements; Glucose Intolerance; Leptin; Liver; Male; Malnutrition; Mice; Mice, Inbred C57BL; Phosphorylation; Proto-Oncogene Proteins c-akt; Taurine

Consumption of a high-fat (HF) diet results in insulin resistance and glucose intolerance. Weight loss is often recommended to reverse these metabolic alterations and the use of a high-protein (HP), low-carbohydrate diet is encouraged. In lean rats, consumption of a HP diet improves glycemic control. However, it is unknown whether this diet has a similar effectiveness in rodents with impaired glucose tolerance. Rats were fed a HF or a chow (CH) diet for 6 weeks and then switched to a HP diet or a CH or pair-fed (PF) to the amount of kcals consumed per day by the HP group. Following the diet switch, body weight gain was attenuated as compared to HF rats, and similar between HP, CH, and PF rats. Despite similar weight progression, HP and PF rats had a significant decrease in body fat after 2 weeks, as compared to HF rats. In contrast, CH rats did not show this effect. Glucose tolerance was attenuated more quickly in HP rats than in CH or PF rats. These results indicate that a HP diet may be more effective than a balanced diet for improving glycemic control in overweight individuals.

Topics: Adipose Tissue; Animals; Body Weight; Diet, Carbohydrate-Restricted; Diet, High-Fat; Dietary Proteins; Energy Intake; Energy Metabolism; Enzyme-Linked Immunosorbent Assay; Glucose Intolerance; Glucose Tolerance Test; Insulin; Leptin; Male; Radioimmunoassay; Rats; Rats, Long-Evans; Weight Loss

Obesity increases the risk of diabetes. The dysregulation of estrogen metabolism has been associated with the susceptibility to obesity and diabetes. Here, we explore the role estrogen plays in sex differences in obesity and glucose metabolism, specifically adipocyte biology.. We randomized C57BL/6 J male, non-ovariectomized female, ovariectomized female, and ovariectomized female mice supplemented with 17β estradiol to receive a calorie-restricted, low- or a high-fat diet (15 mice per group). We measured weight gained, calories consumed, percent body fat, abdominal adipose tissue, adipocyte size, lipogenic and adipogenic gene expression, and glucose tolerance.. Male mice had a higher susceptibility to obesity than intact female mice. However, removal of the ovaries in female mice eliminated the protection to obesity and estrogen supplementation restored this protection. Male and ovariectomized female mice gained weight predominately in the form of abdominal adipose tissue possibly due to an increase in adipocyte size. Moreover, for mice consuming the high-fat diet, male and ovariectomized female mice had significantly higher levels of leptin mRNA and lower hormone-sensitive lipase mRNA relative to intact female mice and ovariectomized female mice supplemented with estrogen. Additionally, estrogen had a strong inhibitory effect on key adipogenic genes in non-ovariectomized female and ovx-female mice supplemented with estrogen. Finally, we show that male and ovariectomized female mice consuming the high-fat diet had a higher incidence of glucose intolerance.. Estrogen protects female mice from obesity and impaired glucose tolerance possibly by modulating the expression of genes regulating adipogenesis, lipogenesis, and lipolysis.

Topics: Abdominal Fat; Adipogenesis; Adiposity; Animals; Body Composition; Caloric Restriction; Diet, Fat-Restricted; Diet, High-Fat; Dietary Supplements; Estradiol; Estrogens; Female; Gene Expression Regulation; Glucose Intolerance; Insulin; Leptin; Lipogenesis; Lipolysis; Male; Mice; Mice, Inbred C57BL; Obesity; Ovariectomy; Resistin; Sex Factors; Sterol Esterase

Environmental factors such as a high-fat diet contribute to type 2 diabetes and obesity. This study examined glycemia, insulin sensitivity, and β-cell function after switching from a high-fat diet to a low-fat diet in mice.. C57BL/6J mice were fed a high-fat diet or low-fat diet for 18 months, after which mice on the high-fat diet either maintained this diet or switched to a low-fat diet for 4 weeks. Body weight and glucose and insulin responses to intraperitoneal glucose were determined. Insulin secretion (insulinogenic index: the 10-minute insulin response divided by the 10-minute glucose level) and insulin sensitivity (1 divided by basal insulin) were determined.. After 18 months on a high-fat diet, mice had glucose intolerance, marked hyperinsulinemia, and increased body weight compared to mice on a low-fat diet (P < 0.001). Switching from a high-fat diet to low-fat diet normalized glucose tolerance, reduced but not normalized body weight (P < 0.001), increased insulin secretion (248 ± 39 vs 141 ± 46 pmol/mmol; P = 0.028) and improved but not normalized insulin sensitivity (3.2 ± 0.1 vs 1.0 ± 0.1 [pmol/L]; P = 0.012).. Switching from a high-fat diet to low-fat diet normalizes glucose tolerance and improves but not normalizes insulin secretion and insulin sensitivity. These effects are more pronounced than the reduced body weight.

Topics: Animals; Blood Glucose; Body Weight; Diet, Fat-Restricted; Diet, High-Fat; Fatty Acids, Nonesterified; Female; Glucose Intolerance; Glucose Tolerance Test; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Leptin; Mice; Mice, Inbred C57BL; Recovery of Function; Time Factors

Adipose tissue secretes a variety of bioactive signaling molecules, termed adipokines, which regulate numerous biological functions including appetite, energy balance, glucose homeostasis, and inflammation. Chemerin is a novel adipokine that regulates adipocyte differentiation and metabolism by binding to and activating the G protein-coupled receptor, chemokine like receptor-1 (CMKLR1). In the present study, we investigated the impact of CMKLR1 deficiency on adipose development, glucose homeostasis, and inflammation in vivo. Herein we report that regardless of diet (low or high fat), CMKLR1(-/-) mice had lower food consumption, total body mass, and percent body fat compared with wild-type controls. CMKLR1(-/-) mice also exhibited decreased hepatic and white adipose tissue TNFα and IL-6 mRNA levels coincident with decreased hepatic dendritic cell infiltration, decreased adipose CD3+ T cells, and increased adipose natural killer cells. CMKLR1(-/-) mice were glucose intolerant compared with wild-type mice, and this was associated with decreased glucose stimulated insulin secretion as well as decreased skeletal muscle and white adipose tissue glucose uptake. Collectively these data provide compelling evidence that CMKLR1 influences adipose tissue development, inflammation, and glucose homeostasis and may contribute to the metabolic derangement characteristic of obesity and obesity-related diseases.

Topics: Adiponectin; Adipose Tissue, White; Adiposity; Animals; Blood Glucose; Body Weight; Cytokines; Dietary Fats; Eating; Gene Expression Regulation; Glucaric Acid; Glucose Intolerance; Insulin; Insulin Resistance; Leptin; Liver; Mice; Mice, Knockout; Receptors, Chemokine; Receptors, G-Protein-Coupled

Exercise has beneficial effects on human health, including protection against metabolic disorders such as diabetes. However, the cellular mechanisms underlying these effects are incompletely understood. The lysosomal degradation pathway, autophagy, is an intracellular recycling system that functions during basal conditions in organelle and protein quality control. During stress, increased levels of autophagy permit cells to adapt to changing nutritional and energy demands through protein catabolism. Moreover, in animal models, autophagy protects against diseases such as cancer, neurodegenerative disorders, infections, inflammatory diseases, ageing and insulin resistance. Here we show that acute exercise induces autophagy in skeletal and cardiac muscle of fed mice. To investigate the role of exercise-mediated autophagy in vivo, we generated mutant mice that show normal levels of basal autophagy but are deficient in stimulus (exercise- or starvation)-induced autophagy. These mice (termed BCL2 AAA mice) contain knock-in mutations in BCL2 phosphorylation sites (Thr69Ala, Ser70Ala and Ser84Ala) that prevent stimulus-induced disruption of the BCL2-beclin-1 complex and autophagy activation. BCL2 AAA mice show decreased endurance and altered glucose metabolism during acute exercise, as well as impaired chronic exercise-mediated protection against high-fat-diet-induced glucose intolerance. Thus, exercise induces autophagy, BCL2 is a crucial regulator of exercise- (and starvation)-induced autophagy in vivo, and autophagy induction may contribute to the beneficial metabolic effects of exercise.

Topics: Adiponectin; Animals; Apoptosis Regulatory Proteins; Autophagy; Beclin-1; Cells, Cultured; Dietary Fats; Food Deprivation; Gene Knock-In Techniques; Glucose; Glucose Intolerance; Glucose Tolerance Test; Homeostasis; Leptin; Male; Mice; Mice, Transgenic; Muscle, Skeletal; Mutation; Myocardium; Phosphorylation; Physical Conditioning, Animal; Physical Endurance; Physical Exertion; Protein Binding; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Running

Farnesoid X receptor (FXR) is known to play important regulatory roles in bile acid, lipid, and carbohydrate metabolism. Aged (>12 months old) Fxr(-/-) mice also develop spontaneous liver carcinomas. In this report, we used three mouse models to investigate the role of FXR deficiency in obesity. As compared with low-density lipoprotein receptor (Ldlr) knockout (Ldlr(-/-)) mice, the Ldlr(-/-)Fxr(-/-) double-knockout mice were highly resistant to diet-induced obesity, which was associated with increased expression of genes involved in energy metabolism in the skeletal muscle and brown adipose tissue. Such a striking effect of FXR deficiency on obesity on an Ldlr(-/-) background led us to investigate whether FXR deficiency alone is sufficient to affect obesity. As compared with wild-type mice, Fxr(-/-) mice showed resistance to diet-induced weight gain. Interestingly, only female Fxr(-/-) mice showed significant resistance to diet-induced obesity, which was accompanied by increased energy expenditure in these mice. Finally, we determined the effect of FXR deficiency on obesity in a genetically obese and diabetic mouse model. We generated ob(-/-)Fxr(-/-) mice that were deficient in both Leptin and Fxr. On a chow diet, ob(-/-)Fxr(-/-) mice gained less body weight and had reduced body fat mass as compared with ob/ob mice. In addition, we observed liver carcinomas in 43% of young (<11 months old) Ob(-/-)Fxr(-/-) mice. Together these data indicate that loss of FXR prevents diet-induced or genetic obesity and accelerates liver carcinogenesis under diabetic conditions.

Topics: Adipose Tissue, Brown; Adiposity; Animals; Carcinoma; Cell Transformation, Neoplastic; Diet, High-Fat; Dietary Fats; Energy Metabolism; Female; Gene Knockout Techniques; Glucose Intolerance; Intestinal Absorption; Leptin; Liver; Liver Neoplasms; Male; Mice; Mice, Knockout; Mice, Obese; Muscle, Skeletal; Obesity; Receptors, Cytoplasmic and Nuclear; Sex Factors; Weight Gain

Consumption of high levels of fructose in humans and animals leads to metabolic and cardiovascular dysfunction. There are questions as to the role of the autonomic changes in the time course of fructose-induced dysfunction. C57/BL male mice were given tap water or fructose water (100 g/l) to drink for up to 2 mo. Groups were control (C), 15-day fructose (F15), and 60-day fructose (F60). Light-dark patterns of arterial pressure (AP) and heart rate (HR), and their respective variabilities were measured. Plasma glucose, lipids, insulin, leptin, resistin, adiponectin, and glucose tolerance were quantified. Fructose increased systolic AP (SAP) at 15 and 60 days during both light (F15: 123 ± 2 and F60: 118 ± 2 mmHg) and dark periods (F15: 136 ± 4 and F60: 136 ± 5 mmHg) compared with controls (light: 111 ± 2 and dark: 117 ± 2 mmHg). SAP variance (VAR) and the low-frequency component (LF) were increased in F15 (>60% and >80%) and F60 (>170% and >140%) compared with C. Cardiac sympatho-vagal balance was enhanced, while baroreflex function was attenuated in fructose groups. Metabolic parameters were unchanged in F15. However, F60 showed significant increases in plasma glucose (26%), cholesterol (44%), triglycerides (22%), insulin (95%), and leptin (63%), as well as glucose intolerance. LF of SAP was positively correlated with SAP. Plasma leptin was correlated with triglycerides, insulin, and glucose tolerance. Results show that increased sympathetic modulation of vessels and heart preceded metabolic dysfunction in fructose-consuming mice. Data suggest that changes in autonomic modulation may be an initiating mechanism underlying the cluster of symptoms associated with cardiometabolic disease.

Topics: Animals; Baroreflex; Blood Glucose; Blood Pressure; Body Weight; Disease Models, Animal; Fructose; Glucose Intolerance; Heart Rate; Insulin; Insulin Resistance; Leptin; Lipids; Male; Mice; Sympathetic Nervous System

Renin-angiotensin system blockade improves glucose intolerance and insulin resistance, which contribute to the development of metabolic syndrome. However, the contribution of impaired insulin secretion to the pathogenesis of metabolic syndrome is not well defined. To assess the contributions of angiotensin receptor type 1 (AT₁) activation and high glucose intake on pancreatic function and their effects on insulin signaling in skeletal muscle and adipose tissue, an oral glucose tolerance test (oGTT) was performed in five groups (n = 10/group) of rats: 1) lean strain-control 2) obese Otsuka Long-Evans Tokushima Fatty (OLETF), 3) OLETF + angiotensin receptor blocker (ARB; 10 mg/kg · d olmesartan for 6 wk; OLETF ARB), 4) OLETF + 5% glucose water (HG) for 6 wk (OLETF HG), and 5) OLETF + HG + ARB (OLETF HG/ARB). The glucose response to the oGTT increased 58% in OLETF compared with lean-strain control, whereas glucose supplementation increased it an additional 26%. Blockade of angiotensin receptor reduced the oGTT response 19% in the ARB-treated groups and increased pancreatic insulin secretion 64 and 113% in OLETF ARB and OLETF HG/ARB, respectively. ARB treatment in OLETF ARB and OLETF HG/ARB did not have an effect on insulin signaling proteins in skeletal muscle; however, it reduced pancreatic AT₁ protein expression 20 and 27%, increased pancreatic glucagon-like peptide-1 (GLP-1) receptor protein expression 41 and 88%, respectively, and increased fasting plasma GLP-1 approximately 2.5-fold in OLETF ARB. The results suggest that improvement of glucose intolerance is independent of an improvement in muscle insulin signaling, but rather by improved glucose-stimulated insulin secretion associated with decreased pancreatic AT₁ activation and increased GLP-1 signaling.

Topics: Adipose Tissue; Angiotensin II Type 1 Receptor Blockers; Animals; Blood Pressure; Dietary Supplements; Disease Models, Animal; Glucagon-Like Peptide-1 Receptor; Glucose; Glucose Intolerance; Insulin; Leptin; Male; Metabolic Syndrome; Muscle, Skeletal; Pancreas; Rats; Rats, Inbred OLETF; Rats, Inbred Strains; Receptor, Angiotensin, Type 1; Receptors, Glucagon; Triglycerides

Serotonin reuptake transporter (SERT) is a key regulator of serotonin neurotransmission and a major target of antidepressants. Antidepressants, such as selectively serotonin reuptake inhibitors (SSRIs), that block SERT function are known to affect food intake and body weight. Here, we provide genetic evidence that food intake and metabolism are regulated by separable mechanisms of SERT function. SERT-deficient mice ate less during both normal diet and high fat diet feeding. The reduced food intake was accompanied with markedly elevated plasma leptin levels. Despite reduced food intake, SERT-deficient mice exhibited glucose intolerance and insulin resistance, and progressively developed obesity and hepatic steatosis. Several lines of evidence indicate that the metabolic deficits of SERT-deficient mice are attributable to reduced insulin-sensitivity in peripheral tissues. First, SERT-deficient mice exhibited beta-cell hyperplasia and islet-mass expansion. Second, biochemical analyses revealed constitutively elevated JNK activity and diminished insulin-induced AKT activation in the liver of SERT-deficient mice. SERT-deficient mice exhibited hyper-JNK activity and hyperinsulinemia prior to the development of obesity. Third, enhancing AKT signaling by PTEN deficiency corrected glucose tolerance in SERT-deficient mice. These findings have potential implications for designing selective SERT drugs for weight control and the treatment of metabolic syndromes.

Topics: Animals; Body Weight; Eating; Enzyme Activation; Fatty Liver; Glucose Intolerance; Hypertrophy; Insulin; Insulin Resistance; Islets of Langerhans; JNK Mitogen-Activated Protein Kinases; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscles; Mutation; Obesity; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Serotonin Plasma Membrane Transport Proteins

Targeted deletion of S6 kinase (S6K) 1 in mice leads to higher energy expenditure and improved glucose metabolism. However, the molecular mechanisms controlling these effects remain to be fully elucidated. Here, we analyze the potential role of dietary lipids in regulating the mTORC1/S6K system. Analysis of S6K phosphorylation in vivo and in vitro showed that dietary lipids activate S6K, and this effect is not dependent upon amino acids. Comparison of male mice lacking S6K1 and 2 (S6K-dko) with wt controls showed that S6K-dko mice are protected against obesity and glucose intolerance induced by a high-fat diet. S6K-dko mice fed a high-fat diet had increased energy expenditure, improved glucose tolerance, lower fat mass gain, and changes in markers of lipid metabolism. Importantly, however, these metabolic phenotypes were dependent upon dietary lipids, with no such effects observed in S6K-dko mice fed a fat-free diet. These changes appear to be mediated via modulation of cellular metabolism in skeletal muscle, as shown by the expression of genes involved in energy metabolism. Taken together, our results suggest that the metabolic functions of S6K in vivo play a key role as a molecular interface connecting dietary lipids to the endogenous control of energy metabolism.

Topics: Amino Acids, Branched-Chain; Animals; Cell Line; Cholesterol; Diet, High-Fat; Dietary Fats; Enzyme Activation; Fatty Acids; Fatty Acids, Nonesterified; Female; Gene Deletion; Glucose Intolerance; Leptin; Lipid Metabolism; Male; Mice; Mice, Knockout; Muscle, Skeletal; Obesity; Phenotype; Ribosomal Protein S6 Kinases; Triglycerides

Topics: Ghrelin; Glucose Intolerance; Humans; Leptin; Sleep Apnea, Obstructive

Irs2-mediated insulin/IGF1 signaling in the CNS modulates energy balance and glucose homeostasis; however, the site for Irs2 function is unknown. The hormone leptin mediates energy balance by acting on leptin receptor (LepR-b)-expressing neurons. To determine whether LepR-b neurons mediate the metabolic actions of Irs2 in the brain, we utilized Lepr(cre) together with Irs2(L/L) to ablate Irs2 expression in LepR-b neurons (Lepr(ΔIrs2)). Lepr(ΔIrs2) mice developed obesity, glucose intolerance, and insulin resistance. Leptin action was not altered in young Lepr(ΔIrs2) mice, although insulin-stimulated FoxO1 nuclear exclusion was reduced in Lepr(ΔIrs2) mice. Indeed, deletion of Foxo1 from LepR-b neurons in Lepr(ΔIrs2) mice normalized energy balance, glucose homeostasis, and arcuate nucleus gene expression. Thus, Irs2 signaling in LepR-b neurons plays a crucial role in metabolic sensing and regulation. While not required for leptin action, Irs2 suppresses FoxO1 signaling in LepR-b neurons to promote energy balance and metabolism.

Topics: Animals; Brain; Cytoskeletal Proteins; Energy Metabolism; Female; Forkhead Box Protein O1; Forkhead Transcription Factors; Gene Expression; Glucose; Glucose Intolerance; Homeostasis; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Leptin; Male; Mice; Mice, Transgenic; Nerve Tissue Proteins; Neurons; Obesity; Receptors, Leptin; Signal Transduction

This study measured the serum concentrations of resistin and adiponectin in Chinese subjects with impaired glucose tolerance (IGT) and investigated their association with insulin resistance, metabolic parameters and circulating inflammatory markers.. A total of 124 subjects participated in the study (44 with IGT and 80 with normal glucose tolerance [NGT]). Fasting serum concentrations of lipids, glucose, insulin and adipocytokines (resistin, adiponectin, leptin, tumour necrosis factor-α [TNF-α], interleukin-6 and C-reactive protein) were measured.. Serum resistin concentrations were similar in the IGT and NGT groups but were significantly higher in overweight/ obese IGT subjects than in those of normal weight. Serum adiponectin concentrations were significantly lower in the IGT group than in the NGT group. In the IGT group, resistin was positively correlated with age, body mass index and TNF-α, and adiponectin was correlated positively with high-density lipoprotein cholesterol and negatively with TNF-α and waist/hip ratio.. Circulating resistin is unlikely to be a major mediator of glucose tolerance in humans but it may have an inflammatory role in IGT. The data support the theory that circulating adiponectin has an anti-inflammatory and anti-insulin resistance function.

Topics: Adiponectin; Blood Glucose; Blood Pressure; Body Mass Index; C-Reactive Protein; China; Cholesterol, HDL; Female; Glucose; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Interleukin-6; Leptin; Male; Middle Aged; Obesity; Resistin; Tumor Necrosis Factor-alpha

Topics: Adiposity; Birth Weight; Body Weight; Female; Glucose Intolerance; Humans; Leptin; Lipids; Pregnancy

The delivery of excess maternal nutrients to the fetus is known to increase the risk of macrosomia, even among infants of women without gestational diabetes mellitus. With the current obesity epidemic, maternal adiposity and its associated effects on circulating adipokines and inflammatory proteins may now have a greater impact on fetal growth. We sought to evaluate the independent effects of maternal glycemia, lipids, obesity, adipokines and inflammation on infant birth weight.. We included 472 women who underwent an oral glucose tolerance test in late pregnancy and were found not to have gestational diabetes; 104 (22.0%) had gestational impaired glucose tolerance. We also measured fasting levels of insulin, low-and high-density lipoprotein cholesterol, triglycerides, leptin, adiponectin and C-reactive protein. Obstetric outcomes were assessed at delivery.. The mean birth weight was 3481 g (standard deviation 493 g); 68 of the infants were large for gestational age. On multiple linear regression analysis, positive determinants of birth weight were length of gestation, male infant, weight gain during pregnancy up to the time of the oral glucose tolerance test, body mass index (BMI) before pregnancy and impaired glucose tolerance in pregnancy. Leptin, adiponectin and C-reactive protein levels were each negatively associated with birth weight. On logistic regression analysis, the significant metabolic predictors of having a large-for-gestational-age infant were BMI before pregnancy (odds ratio [OR] 1.16, 95% confidence interval [CI] 1.05-1.27, per 1 kg/m(2) increase), weight gain during pregnancy up to the time of the oral glucose tolerance test (OR 1.12, 95% CI 1.05-1.19, per 1 kg increase) and leptin level (OR 0.50, 95% CI 0.30-0.82, per 1 standard deviation change).. Among women without gestational diabetes, maternal adiposity and leptin levels were the strongest metabolic determinants of having a large-for-gestational-age infant rather than glucose intolerance and lipid levels.

Topics: Adipokines; Adiposity; Adult; Birth Weight; Body Mass Index; Body Weight; C-Reactive Protein; Female; Fetal Macrosomia; Glucose Intolerance; Humans; Leptin; Lipids; Logistic Models; Mothers; Pregnancy

Maternal high-fat (HF) diet throughout gestation and suckling has long-term consequences on the offspring's metabolic phenotype. Here we determine the relative contribution of pre- or postnatal maternal HF diet on offspring's metabolic phenotype. Pregnant Sprague-Dawley rats were maintained on normal chow or HF diet throughout gestation and suckling. All litters were cross-fostered to chow or HF dams on postnatal day (PND)1, resulting in four groups. Body weight, body composition, and glucose tolerance were measured at weaning and in adulthood. Leptin sensitivity was assessed by signal transducer and activator of transcription (STAT)3 activation on PND10 and PND21. Pups cross-fostered to HF dams gained more body weight than chow pups by PND7 and persisted until weaning. Postnatal HF pups had greater adiposity, higher plasma leptin concentration, impaired glucose tolerance, and reduced phosphorylated STAT3 in response to leptin in the arcuate nucleus at weaning. After weaning, male offspring cross-fostered to HF dams were hyperphagic and maintained greater body weight than postnatal chow pups. Postnatal HF diet during suckling continued to impair glucose tolerance in male and female offspring in adulthood. Maternal HF diet during suckling has a greater influence in determining offspring's metabolic phenotype than prenatal HF diet exposure and could provide insight regarding optimal perinatal nutrition for mothers and children.

Topics: Adiposity; Animals; Animals, Suckling; Arcuate Nucleus of Hypothalamus; Diet, High-Fat; Disease Susceptibility; Female; Glucose Intolerance; Lactation; Leptin; Lipid Metabolism; Male; Maternal Nutritional Physiological Phenomena; Milk; Obesity; Phosphorylation; Pregnancy; Protein Processing, Post-Translational; Rats; Rats, Sprague-Dawley; Sex Characteristics; STAT3 Transcription Factor

GSK3β (glycogen synthase kinase 3β) is a ubiquitous kinase that plays a key role in multiple intracellular signalling pathways, and increased GSK3β activity is implicated in disorders ranging from cancer to Alzheimer's disease. In the present study, we provide the first evidence of increased hypothalamic signalling via GSK3β in leptin-deficient Lep(ob/ob) mice and show that intracerebroventricular injection of a GSK3β inhibitor acutely improves glucose tolerance in these mice. The beneficial effect of the GSK3β inhibitor was dependent on hypothalamic signalling via PI3K (phosphoinositide 3-kinase), a key intracellular mediator of both leptin and insulin action. Conversely, neuron-specific overexpression of GSK3β in the mediobasal hypothalamus exacerbated the hyperphagia, obesity and impairment of glucose tolerance induced by a high-fat diet, while having little effect in controls fed standard chow. These results demonstrate that increased hypothalamic GSK3β signalling contributes to deleterious effects of leptin deficiency and exacerbates high-fat diet-induced weight gain and glucose intolerance.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Base Sequence; Diet, High-Fat; DNA Primers; Eating; Glucose; Glucose Intolerance; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Hypothalamus; Leptin; Male; Mice; Mice, Knockout; Obesity; Signal Transduction; Weight Gain

Selenium (Se) is an essential trace element used for biosynthesis of selenoproteins and is acquired either through diet or cellular recycling mechanisms. Selenocysteine lyase (Scly) is the enzyme that supplies Se for selenoprotein biosynthesis via decomposition of the amino acid selenocysteine (Sec). Knockout (KO) of Scly in a mouse affected hepatic glucose and lipid homeostasis. Mice lacking Scly and raised on an Se-adequate diet exhibit hyperinsulinemia, hyperleptinemia, glucose intolerance, and hepatic steatosis, with increased hepatic oxidative stress, but maintain selenoprotein levels and circulating Se status. Insulin challenge of Scly KO mice results in attenuated Akt phosphorylation but does not decrease phosphorylation levels of AMP kinase alpha (AMPKα). Upon dietary Se restriction, Scly KO animals develop several characteristics of metabolic syndrome, such as obesity, fatty liver, and hypercholesterolemia, with aggravated hyperleptinemia, hyperinsulinemia, and glucose intolerance. Hepatic glutathione peroxidase 1 (GPx1) and selenoprotein S (SelS) production and circulating selenoprotein P (Sepp1) levels are significantly diminished. Scly disruption increases the levels of insulin-signaling inhibitor PTP1B. Our results suggest a dependence of glucose and lipid homeostasis on Scly activity. These findings connect Se and energy metabolism and demonstrate for the first time a unique physiological role of Scly in an animal model.

Topics: AMP-Activated Protein Kinases; Animals; Fatty Liver; Glucose Intolerance; Glutathione Peroxidase; Glutathione Peroxidase GPX1; Hypercholesterolemia; Hyperinsulinism; Leptin; Lyases; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Oxidative Stress; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Proto-Oncogene Proteins c-akt; Selenium; Selenoproteins

Several previous studies have investigated circulating levels of the adipokine leptin in relation to gestational diabetes mellitus (GDM). However, these studies have yielded markedly conflicting results, including increased, decreased, and unchanged leptin levels in women with GDM as compared with their peers.. We sought to evaluate the metabolic determinants of serum leptin in a well-characterized cohort reflecting the full spectrum of glucose intolerance in pregnancy.. Metabolic characterization, including oral glucose tolerance test (OGTT) and measurement of serum leptin, insulin, lipids, adiponectin, and C-reactive protein, was performed in 817 pregnant women. The OGTT identified 198 women with GDM, 142 with gestational impaired glucose tolerance, and 477 with normal glucose tolerance.. Median leptin (ng/ml) did not differ between the normal glucose tolerance (33.7), gestational impaired glucose tolerance (36.3), and GDM (36.4) groups (P = 0.085). On univariate correlation analysis, leptin was most strongly associated with prepregnancy body mass index (BMI) (r = 0.54, P < 0.0001), fasting insulin (r = 0.60, P < 0.0001), and C-reactive protein (r = 0.38, P < 0.0001) but only weakly associated with area under the glucose curve (AUC(glucose)) on the OGTT (r = 0.10, P = 0.0066). On multiple linear regression analysis, the strongest independent determinant of leptin was prepregnancy BMI (t = 11.55, P < 0.0001), whereas AUC(glucose) was not a significant predictor (t = -0.95, P = 0.34). Furthermore, although its respective associations with fasting insulin, triglycerides, and adiponectin varied across tertiles of prepregnancy BMI, leptin was not significantly associated with AUC(glucose) in any BMI tertile.. Pregravid BMI, rather than gestational glucose tolerance, is the primary determinant of serum leptin concentration in pregnancy.

Topics: Adiponectin; Adult; Blood Glucose; Body Weight; C-Reactive Protein; Diabetes, Gestational; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Leptin; Lipids; Pregnancy

Anti-obesity effects of onion extract were determined in obesity and diabetes-prone Zucker diabetic fatty rats by measuring the efficacy of markers concerned with diabetes and obesity. Body and adipose tissue weights in 5% of onion extract-fed group were found to be significantly lower than the control group without onion extract. Fasting blood glucose and HOMA-IR levels were also improved, although the serum insulin and leptin levels did not show any remarkable difference. Serum triglyceride and free fatty acid levels in both the 3% and 5%-fed group were found to be reduced compared to the control group. Additionally the feeding of the onion extract increased the glucose tolerance. These results suggest that dietary onion extract is beneficial for improving diabetes by decreasing lipid levels. We also examined differentiation ability of rat white preadipocyte cells using the onion extract and its sulfur-containing components. Cycloalliin, S-methyl-L-cysteine, S-propyl-L-cysteine sulfoxide, dimethyl trisulfide, especially S-methyl-L-cysteine sulfoxide were reported to be effective in inhibiting formation of oil drop in the cells, suggesting that these compounds may be involved in the anti-obesity effect of the onion extract.

Topics: Adipocytes; Adipogenesis; Adipose Tissue; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Cell Line; Diabetes Mellitus; Fatty Acids, Nonesterified; Glucose Intolerance; Hypolipidemic Agents; Insulin; Insulin Resistance; Leptin; Male; Obesity; Onions; Phytotherapy; Plant Extracts; Rats; Rats, Zucker; Triglycerides

To determine the extent to which known prenatal and perinatal predictors of childhood obesity also predict weight gain in early infancy.. We studied 690 infants participating in the prospective cohort Project Viva. We measured length and weight at birth and at 6 months. Using multivariable linear regression, we examined relationships of selected maternal and infant factors with change in weight-for-length z-score (WFL-z) from 0 to 6 months.. Mean (standard deviation) change in WFL-z from 0 to 6 months was 0.23 (1.11), which translates to 4500 grams gained from birth to 6 months of life in an infant with average birth weight and length. After adjustment for confounding variables and birth weight-for-gestational age z-score (-0.28 [95% confidence interval, -0.37, -0.19] per unit), cord blood leptin (-0.40 [95%confidence interval, -0.61, -0.19] per 10 ng/mL), and gestational diabetes -0.50 [95%confidence interval, -0.88, -0.11] versus normal glucose tolerance)were each associated with slower gain in WFL-z from 0 to 6 months.. Higher neonatal leptin and gestational diabetes predicted slower weight gain in the first 6 months of life. The hormonal milieu of the intrauterine environment may determine growth patterns in early infancy and thus later obesity.

Topics: Biomarkers; Blood Glucose; Body Height; Body Mass Index; Child Development; Cohort Studies; Confidence Intervals; Diabetes, Gestational; Female; Fetal Blood; Follow-Up Studies; Gestational Age; Glucose Intolerance; Glucose Tolerance Test; Humans; Infant; Infant, Newborn; Leptin; Male; Multivariate Analysis; Odds Ratio; Predictive Value of Tests; Pregnancy; Prospective Studies; Regression Analysis; Sensitivity and Specificity; Time Factors; Weight Gain

The "portal hypothesis" proposes that the liver is directly exposed to free fatty acids and cytokines increasingly released from visceral fat tissue into the portal vein of obese subjects, thus rendering visceral fat accumulation particularly hazardous for the development of hepatic insulin resistance and type 2 diabetes. In the present study, we used a fat transplantation paradigm to (artificially) increase intra-abdominal fat mass to test the hypothesis that venous drainage of fat tissue determines its impact on glucose homeostasis.. Epididymal fat pads of C57Bl6/J donor mice were transplanted into littermates, either to the parietal peritoneum (caval/systemic venous drainage) or, by using a novel approach, to the mesenterium, which confers portal venous drainage.. Only mice receiving the portal drained fat transplant developed impaired glucose tolerance and hepatic insulin resistance. mRNA expression of proinflammatory cytokines was increased in both portally and systemically transplanted fat pads. However, portal vein (but not systemic) plasma levels of interleukin (IL)-6 were elevated only in mice receiving a portal fat transplant. Intriguingly, mice receiving portal drained transplants from IL-6 knockout mice showed normal glucose tolerance.. These results demonstrate that the metabolic fate of intra-abdominal fat tissue transplantation is determined by the delivery of inflammatory cytokines to the liver specifically via the portal system, providing direct evidence in support of the portal hypothesis.

Topics: Adiponectin; Adipose Tissue; Animals; Blood Glucose; Cytokines; DNA Primers; Epididymis; Fatty Acids, Nonesterified; Glucose Clamp Technique; Glucose Intolerance; Hyperinsulinism; Inflammation; Insulin; Insulin Resistance; Interleukin-6; Intra-Abdominal Fat; Leptin; Male; Mesentery; Mice; Mice, Inbred C57BL; Mice, Knockout; Peritoneum; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Messenger

The prevalence of metabolic syndrome including central obesity, insulin resistance, impaired glucose tolerance, hypertension, and dyslipidemia is increasing. Development of adequate therapy for metabolic syndrome requires an animal model that mimics the human disease state. Therefore, we have characterized the metabolic, cardiovascular, hepatic, renal, and pancreatic changes in male Wistar rats (8-9 weeks old) fed on a high-carbohydrate, high-fat diet including condensed milk (39.5%), beef tallow (20%), and fructose (17.5%) together with 25% fructose in drinking water; control rats were fed a cornstarch diet. During 16 weeks on this diet, rats showed progressive increases in body weight, energy intake, abdominal fat deposition, and abdominal circumference along with impaired glucose tolerance, dyslipidemia, hyperinsulinemia, and increased plasma leptin and malondialdehyde concentrations. Cardiovascular signs included increased systolic blood pressure and endothelial dysfunction together with inflammation, fibrosis, hypertrophy, increased stiffness, and delayed repolarization in the left ventricle of the heart. The liver showed increased wet weight, fat deposition, inflammation, and fibrosis with increased plasma activity of liver enzymes. The kidneys showed inflammation and fibrosis, whereas the pancreas showed increased islet size. In comparison with other models of diabetes and obesity, this diet-induced model more closely mimics the changes observed in human metabolic syndrome.

Topics: Abdominal Fat; Animals; Body Weight; Diabetes Mellitus, Experimental; Dietary Carbohydrates; Dietary Fats; Energy Intake; Fructose; Glucose Intolerance; Humans; Hypertension; Inflammation; Insulin Resistance; Leptin; Liver; Male; Metabolic Syndrome; Obesity; Random Allocation; Rats; Rats, Wistar; Ventricular Remodeling

Women, but not men, show an association between fructose consumption and an increased risk of Type 2 diabetes mellitus. As rats are considered a model for human fructose metabolism, we sought to determine whether such a gender-related difference is present in Sprague-Dawley rats and to analyze the molecular mechanism behind. Male and female Sprague-Dawley rats had free access to water or to a 10% w/v fructose solution for 14 days. Plasma analytes, liver triglycerides and enzyme activities and the expression of enzymes and transcription factors related to fatty acid metabolism, insulin signaling and glucose tolerance were determined. Fructose-fed rats had hypertriglyceridemia, steatosis and reduced fatty acid oxidation activity, although the metabolic pattern of fructose-fed female rats was different to that observed for male rats. Fructose-fed female, but not male rats, showed no change in plasma leptin; they had hyperinsulinemia, an altered glucose tolerance test and less liver insulin receptor substrate-2. Further, only fructose-fed female rats had increased adenosine 5'-monophosphate (AMP)-activated protein kinase activity, resulting in a decreased expression of hepatic nuclear factor 4 and sterol response element binding protein 1. These differences were related to the fact that liver expression of the enzyme fructokinase, controlling fructose metabolism, was markedly induced by fructose ingestion in female, but not in male rats, resulting in a significant increase in the AMP/adenosine 5'-triphosphate (ATP) ratio and, thus, AMP-activated protein kinase activation, in female rats only. The difference in fructokinase induction could explain the higher metabolic burden produced by fructose ingestion in the livers of female Sprague-Dawley rats.

Topics: Adenosine Monophosphate; Adenosine Triphosphate; Adiponectin; AMP-Activated Protein Kinases; Animals; Blood Glucose; Blotting, Western; Female; Fructokinases; Fructose; Glucose Intolerance; Glucose Tolerance Test; Hypertriglyceridemia; Insulin; Insulin Receptor Substrate Proteins; Leptin; Lipid Metabolism; Liver; Male; Rats; Rats, Sprague-Dawley; Sex Factors; Signal Transduction; Sterol Regulatory Element Binding Protein 1; Transcription Factors; Triglycerides

The aim of the study was to assess the association between visceral and subcutaneous fat with glucose intolerance, adipocytokines, inflammatory markers and carotid IMT in Asian Indians.. Subjects with NGT (n=85), IGT (n=49) and T2DM (n=93) were randomly selected from CURES. Total abdominal, visceral and subcutaneous fat were measured using Helical CT scan. Adiponectin, hs-CRP, TNF-alpha, oxidized LDL, visfatin and leptin and IMT and insulin resistance were assessed.. Total abdominal fat (p=0.041) and the visceral fat (p=0.039) but not subcutaneous fat progressively increased from NGT, IGT and T2DM subjects. With increasing quartiles of visceral fat, there was a significant increase in insulin resistance (p=0.040); significant decrease in adiponectin (p=0.043) and increase in TNF-alpha (p=0.028), hs-CRP (p=0.043), OX-LDL (p=0.034) and visfatin (p=0.040), and carotid IMT (p=0.047) was observed.. Visceral fat levels increased with increasing glucose intolerance and are associated with decreased levels of adiponectin and increased levels of hs-CRP, TNF-alpha, oxidized LDL, visfatin, HOMA-IR and IMT.

Topics: Abdominal Fat; Adipokines; Adiponectin; Adiposity; Adult; Asian People; Biomarkers; Blood Glucose; C-Reactive Protein; Causality; Diabetes Mellitus, Type 2; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; India; Inflammation; Insulin Resistance; Intra-Abdominal Fat; Leptin; Lipoproteins, LDL; Male; Nicotinamide Phosphoribosyltransferase; Subcutaneous Fat; Tumor Necrosis Factor-alpha

Obesity is a growing epidemic characterized by excess fat storage in adipocytes. Although lipoprotein receptors play important roles in lipid uptake, their role in controlling food intake and obesity is not known. Here we show that the lipoprotein receptor LRP1 regulates leptin signaling and energy homeostasis. Conditional deletion of the Lrp1 gene in the brain resulted in an obese phenotype characterized by increased food intake, decreased energy consumption, and decreased leptin signaling. LRP1 directly binds to leptin and the leptin receptor complex and is required for leptin receptor phosphorylation and Stat3 activation. We further showed that deletion of the Lrp1 gene specifically in the hypothalamus by Cre lentivirus injection is sufficient to trigger accelerated weight gain. Together, our results demonstrate that the lipoprotein receptor LRP1, which is critical in lipid metabolism, also regulates food intake and energy homeostasis in the adult central nervous system.

Topics: Agouti-Related Protein; Animals; Appetite Regulation; Brain; Cell Line; Energy Metabolism; Female; Glucose Intolerance; Homeostasis; Hyperlipidemias; Hypothalamus; Insulin Resistance; Leptin; Lipid Metabolism; Low Density Lipoprotein Receptor-Related Protein-1; Male; Mice; Mice, Knockout; Neuropeptide Y; Obesity; Receptors, LDL; Tumor Suppressor Proteins; Up-Regulation

We aimed to examine whether circulating levels of osteocalcin, bone formation marker secreted from osteoblast, are changed in glucose-intolerant subjects without taking glucose lowering agent, because bone metabolism is reportedly related to glucose metabolism in animal and human studies. According to 75 g oral glucose tolerance test (75 g-OGTT), all subjects (47.6 ± 10.2 years of age; 45 men and 10 women) were divided into three categories: normal glucose tolerance (NGT, n = 39), prediabetes (PDM, n = 11) that included impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), and diabetes (T2DM, n = 5). Serum osteocalcin levels were increased in T2DM as compared to NGT. In all the participants, simple regression analysis model revealed positive correlation of osteocalcin with plasma glucose at 120 min, G(120), on 75 g-OGTT, negative with both creatinine and Ln(CRP), but not significantly with fasting plasma glucose. Osteocalcin and leptin were independent variables for G(120) (P = 0.026 and 0.035, respectively). In multinomial logistic analysis leptin (PDM vs. NGT: P = 0.02 Odds ratio (OR) of 1.05, 95% confidence intervals, 1.007-1.084) and osteocalcin (T2DM vs. NGT: P = 0.038, OR 10.8, 1.13-102.4) were independently associated. We conclude that circulating osteocalcin and leptin are related to glucose intolerant state.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Leptin; Male; Middle Aged; Osteocalcin

We have previously demonstrated that running-wheel access normalizes the food intake and body weight of Otsuka Long-Evens Tokushima Fatty (OLETF) rats. Following 6 wk of running-wheel access beginning at 8 wk of age, the body weight of OLETF rats remains reduced, demonstrating a lasting effect on their phenotype. In contrast, access to a high-fat diet exacerbates the hyperphagia and obesity of OLETF rats. To determine whether diet modulates the long-term effects of exercise, we examined the effects of high-fat diet on food intake and body weight in OLETF rats that had prior access to running wheels for 4 wk. We found that 4 wk of running exercise significantly decreased food intake and body weight of OLETF rats. Consistent with prior results, 4 wk of exercise also produced long-lasting effects on food intake and body weight in OLETF rats fed a regular chow. When running wheels were relocked, OLETF rats stabilized at lower levels of body weight than sedentary OLETF rats. However, access to a high-fat diet offset these effects. When OLETF rats were switched to a high-fat diet following wheel relocking, they significantly increased food intake and body weight, so that they reached levels similar to those of sedentary OLETF rats fed a high-fat diet. Gene expression determination of hypothalamic neuropeptides revealed changes that appeared to be appropriate responses to the effects of diet and running exercise. Together, these results demonstrate that high-fat diet modulates the long-lasting effects of exercise on food intake and body weight in OLETF rats.

Topics: Adipose Tissue; Agouti-Related Protein; Animals; Body Weight; Corticotropin-Releasing Hormone; Diabetes Mellitus, Type 2; Dietary Fats; Disease Models, Animal; Eating; Glucose Intolerance; Hypothalamus; Leptin; Male; Physical Conditioning, Animal; Pro-Opiomelanocortin; Rats; Rats, Inbred OLETF; Time Factors

Maternal serum leptin concentrations have been suggested as a key factor in programming growth patterns and protecting against adult metabolic disease in human offspring. However, the role of maternal leptin in the development of wild rodent offspring is not clear. We tested the hypothesis that maternal hyperleptinemia in lactating Brandt's voles (Lasiopodomys brandtii) can protect their offspring from the risks of high-fat-diet-induced-obesity and insulin resistance. Lactating voles were supplemented with murine leptin (0.64 μg g(-1 ) day(-1)) or phosphate-buffered saline (control) on days 10-17 of lactation (peak lactation). At 12 weeks of age, the female and male offspring of the two maternal groups were randomly assigned to two groups each and fed either a high-fat diet (41% of gross energy as fat) or a control diet (14% of gross energy as fat) until the age of 23 weeks. Body mass, food intake, glucose tolerance and resting metabolic rate were determined in the four offspring groups. After animals were sacrificed, organ masses and adipose tissue distribution, and serum leptin and insulin concentrations were measured. Offspring of leptin-treated mothers showed no significant differences in body mass, energy intake or energy expenditure, body composition, glucose tolerance or serum leptin and insulin concentrations from offspring of control mothers. The high-fat diet induced increases in body mass (by 23% in female and 17% in male offspring) and reduced glucose tolerance in both female and male offspring, indicative of the emergence of insulin resistance, even though digestible energy intake of the male offspring decreased on the high-fat diet. These results indicate that maternal hyperleptinemia during peak lactation in Brandt's voles did not protect against diet-induced obesity or glucose intolerance in their offspring.

Topics: Animals; Arvicolinae; Basal Metabolism; Body Composition; Body Weight; Dietary Fats; Eating; Energy Intake; Female; Glucose Intolerance; Lactation; Leptin; Male; Mice; Obesity

Plasma leptin and adiponectin, and membrane phospholipid fatty acid composition are implicated into the mechanism of insulin resistance but no clear pattern has emerged. Hence, this study examined these variables in subjects presenting to the diabetic clinic for a diagnostic glucose tolerance test.. Body composition, glucose, glycated hemoglobin, insulin, leptin, adiponectin, and red cell and plasma phospholipid fatty acids were assessed from 42 normal and 28 impaired glucose tolerant subjects. Insulin sensitivity was determined by homeostatic model assessment.. The plasma phosphatidylcholine fatty acid composition of the impaired glucose tolerant subjects was similar to that of normal subjects. However, the impaired glucose tolerant subjects had significantly lower linoleic (P<0.05), eicosapentaenoic (P<0.05) and docosahexaenoic (P<0.01) acids in the red cell phosphatidylcholine and phosphatidylethanolamine compared with the normal subjects. Moreover, red cell phosphatidylcholine docosahexaenoic acid correlated positively with adiponectin (r=0.290, P<0.05) but negatively with leptin (r=-0.252, P<0.05), insulin (r=-0.335, P<0.01) and insulin resistance (r=-0.322, P<0.01). Plasma triglycerides, leptin and glucose combined predicted about 60% of variation in insulin level whereas insulin was the only component that predicted the membrane fatty acids.. We postulate that membrane phospholipids fatty acids have an indirect role in determining insulin concentration but insulin has a major role in determining membrane fatty acid composition.

Topics: Adipokines; Adiponectin; Adult; Blood Glucose; Cell Membrane; Docosahexaenoic Acids; Erythrocytes; Fatty Acids; Fatty Acids, Omega-3; Female; Glucose Intolerance; Glycerophospholipids; Humans; Insulin; Insulin Resistance; Leptin; Linoleic Acid; Male; Middle Aged; Triglycerides

This study investigated the effects of indole-3-carbinol (I3C), a cruciferous vegetable derivative, on obesity and its associated factors in high-fat-diet-induced obese (DIO) mice.. Eighteen male C57BL/6 mice were randomly assigned to one of three groups: basal, high fat (HF), and HF + 5 mg/kg of I3C intraperitoneally (HFI). After 12 wk of treatment, obesity-associated factors, including body weight, organ weight, serum concentrations of glucose, triacylglycerol, insulin, and adipokines, and macrophage accumulation and lipid metabolism-associated factors in epididymal adipose tissue were measured.. Body weight and epididymal adipose tissue weight were greater (P < 0.01), and adipocytes were larger in the HF group than in the basal and HFI groups. Compared with the HF group, the HFI group had improved glucose tolerance, a higher serum adiponectin concentration, lower serum glucose, triacylglycerol, insulin, and leptin concentrations, and less F4/80 expression in epididymal adipose tissue (P < 0.001). Furthermore, I3C treatment decreased acetyl coenzyme A carboxylase mRNA expression (P < 0.05) and increased peroxisome proliferator-activated receptor-γ protein expression (P < 0.05) in epididymal adipose tissue of DIO mice.. The I3C treatment decreased body weight and fat accumulation and infiltrated macrophages in epididymal adipose tissue of DIO mice, and these reductions were associated with improved glucose tolerance and with modulated expression of adipokines and lipogenic-associated gene products, including acetyl coenzyme A carboxylase and peroxisome proliferator-activated receptor-γ.

Topics: Acetyl-CoA Carboxylase; Adiponectin; Adipose Tissue; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Brassicaceae; Dietary Fats; Glucose Intolerance; Indoles; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Organ Size; Phytotherapy; Plant Extracts; PPAR gamma; RNA, Messenger; Triglycerides

Women with gestational diabetes mellitus (GDM) have an enhanced cardiovascular risk factor profile at 3-months postpartum and an elevated risk of future cardiovascular disease, as compared to their peers. Recently, it has emerged that even mild dysglycemia on antepartum oral glucose tolerance test (OGTT) predicts an increased risk of future cardiovascular disease, although it is not known whether there exists an identifiable high-risk subgroup within this patient population. Since gestational impaired glucose tolerance (GIGT) due to isolated hyperglycemia at 1-h during the OGTT (1-h GIGT) bears metabolic similarity to GDM, we hypothesized that, like GDM, 1-h GIGT may predict a high-risk postpartum cardiovascular phenotype.. In this prospective cohort study, 485 women underwent antepartum OGTT, followed by cardiovascular risk factor assessment at 3-months postpartum. The antepartum OGTT identified 4 gestational glucose tolerance groups: GDM (n = 137); 1-h GIGT (n = 39); GIGT at 2- or 3-h (2/3-h GIGT)(n = 50); and normal glucose tolerance (NGT)(n = 259). After adjustment for age, ethnicity, breastfeeding and waist circumference, mean levels of the following cardiovascular risk factors progressively increased from NGT to 2/3-h GIGT to 1-h GIGT to GDM: LDL cholesterol (p = 0.0026); total cholesterol:HDL (p = 0.0030); apolipoprotein B (p = 0.004); apolipoprotein B:apolipoprotein A1 (p = 0.026); leptin (p = 0.018); and C-reactive protein (p = 0.011).. Amongst women without GDM, 1-h GIGT predicts an enhanced postpartum cardiovascular risk factor profile. It thus emerges, that amongst young women with mild dysglycemia in pregnancy, those with 1-h GIGT may comprise an unrecognized patient population at risk for future cardiovascular disease.

Topics: Adult; Apolipoproteins B; C-Reactive Protein; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Diabetes, Gestational; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Hyperglycemia; Leptin; Postpartum Period; Pregnancy; Prospective Studies; Risk Factors

Although acute leptin administration in the hypothalamus decreases food intake and increases peripheral energy metabolism, the peripheral actions of central chronic leptin administration are less understood. In this study, we investigated what effects chronic (7 d) intracerebroventricular (ICV) administration of leptin has on energy metabolism and insulin sensitivity in diet-induced obese mice. C57/BL mice were fed a low-fat diet (LFD; 10% total calories) or high-fat diet (HFD; 60% total calories) for 8 wk after which leptin was administered ICV for 7 consecutive days. Mice fed a HFD showed signs of insulin resistance, as evidenced by an impaired glucose tolerance test. Chronic leptin treatment resulted in a decrease in food intake and body weight and normalization of glucose clearance but no improvement in insulin sensitivity. Chronic ICV leptin increased hypothalamic signal transducer and activator of transcription-3 and AMP-activated protein kinase phosphorylation but did not change hypothalamic malonyl CoA levels in HFD fed and LFD-fed mice. In the gastrocnemius muscles, the levels of malonyl CoA in both leptin-treated groups were lower than their respective control groups, suggesting an increase in fatty acid oxidation. However, only in the muscles of ICV leptin-treated LFD mice was there a decrease in lipid metabolites including diacylglycerol, triacylglycerol, and ceramide. Our results suggest that chronic ICV leptin decreases food consumption and body weight via a mechanism different from acute ICV leptin administration. Although chronic ICV leptin treatment in HFD mice improves glucose tolerance, this occurs independent of changes in insulin sensitivity in the muscles of HFD mice.

Topics: Adenylate Kinase; Animals; Body Weight; Diet, High-Fat; Eating; Energy Intake; Glucose Intolerance; Hypothalamus; Insulin; Leptin; Malonyl Coenzyme A; Mice; Mice, Obese; Muscle, Skeletal; STAT3 Transcription Factor

To investigate deep and comprehensive analysis of gut microbial communities and biological parameters after prebiotic administration in obese and diabetic mice.. Genetic (ob/ob) or diet-induced obese and diabetic mice were chronically fed with prebiotic-enriched diet or with a control diet. Extensive gut microbiota analyses, including quantitative PCR, pyrosequencing of the 16S rRNA, and phylogenetic microarrays, were performed in ob/ob mice. The impact of gut microbiota modulation on leptin sensitivity was investigated in diet-induced leptin-resistant mice. Metabolic parameters, gene expression, glucose homeostasis, and enteroendocrine-related L-cell function were documented in both models.. In ob/ob mice, prebiotic feeding decreased Firmicutes and increased Bacteroidetes phyla, but also changed 102 distinct taxa, 16 of which displayed a >10-fold change in abundance. In addition, prebiotics improved glucose tolerance, increased L-cell number and associated parameters (intestinal proglucagon mRNA expression and plasma glucagon-like peptide-1 levels), and reduced fat-mass development, oxidative stress, and low-grade inflammation. In high fat-fed mice, prebiotic treatment improved leptin sensitivity as well as metabolic parameters.. We conclude that specific gut microbiota modulation improves glucose homeostasis, leptin sensitivity, and target enteroendocrine cell activity in obese and diabetic mice. By profiling the gut microbiota, we identified a catalog of putative bacterial targets that may affect host metabolism in obesity and diabetes.

Topics: Animals; Cecum; Colon; Diabetes Mellitus, Type 2; Dietary Fats; Enteroendocrine Cells; Gene Expression Regulation; Glucagon-Like Peptide 1; Glucose Intolerance; Gram-Negative Bacteria; Gram-Positive Bacteria; Hyperglycemia; Hyperlipidemias; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Molecular Typing; Obesity; Prebiotics; Proglucagon; RNA, Messenger

Understanding the etiologic mechanisms underlying impaired glucose tolerance in obstructive sleep apnea (OSA) would assist development of therapies against this comorbidity. We hypothesized that in patients with OSA impaired glucose tolerance (IGT) would be associated with elevated levels of hormones associated with appetite regulation (leptin, ghrelin, neuropeptide Y [NPY] and peptide tyrosine-tyrosine [PYY]).. We studied 68 OSA patients (mean AHI 22 events/h) and 37 age and weight matched healthy controls recruited by advertisement. All participants received a standardized evening meal, attended polysomnography and an oral glucose tolerance test (OGTT) on waking. Hormones were measured in blood taken before sleep (22:30) and at the start of the OGTT.. Impaired glucose tolerance was present in 54% of patients and 32% of controls (p = 0.05). The only differences between groups was that leptin was significantly higher at 22:30 in OSA patients compared to controls (9.6 ng/L vs 7.9 ng/L, p = 0.05). OSA patients had marginally elevated plasma NPY levels at 22:30 (56.6 [52, 67] pmol/L vs 51.1[47.3, 61] pmol/L; p = 0.04). No differences in ghrelin, PYY or NPY were observed between patients with IGT and those without. However OSA patients with IGT had significantly higher value of leptin at both 22:30 (10.9 [7.7, 15.9] ng/mL vs 7.4 [5.6, 12.3] ng/mL, p = 0.02) and 07:00 (11.6 [7.6, 16.2] ng/mL vs 6.9 [5.4, 12.6] ng/mL, p = 0.024) than those without. In multivariate analysis the only major association of leptin was body mass index.. Clinically significant abnormalities of appetite regulating hormones are not present in OSA. Appetite regulating hormones did not differ in OSA patients with and without impaired glucose tolerance.

Topics: Blood Glucose; Dipeptides; Ghrelin; Glucose Intolerance; Glucose Tolerance Test; Humans; Leptin; Middle Aged; Neuropeptide Y; Risk Factors; Sleep Apnea, Obstructive

Maternal smoking leads to intrauterine undernutrition and is associated with low birthweight and higher risk of offspring obesity. Intrauterine smoke exposure (SE) may alter neuroendocrine mediators regulating energy homeostasis as chemicals in cigarette smoke can reach the fetus. Maternal high-fat diet (HFD) consumption causes fetal overnutrition; however, combined effects of HFD and SE are unknown. Thus we investigated the impact of combined maternal HFD and SE on adiposity and energy metabolism in offspring.. Female Balb/c mice had SE (2 cigarettes/day, 5 days/week) or were sham exposed for 5 weeks before mating. Half of each group was fed HFD (33% fat) versus chow as control. The same treatment continued throughout gestation and lactation. Female offspring were fed chow after weaning and sacrificed at 12 weeks.. Birthweights were similar across maternal groups. Faster growth was evident in pups from SE and/or HFD dams before weaning. At 12 weeks, offspring from HFD-fed dams were significantly heavier than those from chow-fed dams (chow-sham 17.6±0.3 g; chow-SE 17.8±0.2 g; HFD-sham 18.7±0.3 g; HFD-SE 18.8±0.4 g, P<0.05 maternal diet effect); fat mass was significantly greater in offspring from chow+SE, HFD+SE and HFD+sham dams. Both maternal HFD and SE affected brain lactate transport. Glucose intolerance and impaired brain response to insulin were observed in SE offspring, and this was aggravated by maternal HFD consumption.. While maternal HFD led to increased body weight in offspring, maternal SE independently programmed adverse health outcomes in offspring. A smoke free environment and healthy diet during pregnancy is desirable to optimize offspring health.

Topics: Adiposity; Animals; Blotting, Western; Body Weight; Brain; Carnitine O-Palmitoyltransferase; Diet, High-Fat; Female; Glucose Intolerance; Insulin; Leptin; Lipase; Maternal Exposure; Maternal Nutritional Physiological Phenomena; Mice; Mice, Inbred BALB C; Monocarboxylic Acid Transporters; Muscle Proteins; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Real-Time Polymerase Chain Reaction; RNA, Messenger; Smoking; Tumor Necrosis Factor-alpha

Dominant 'yellow' mutation at the mouse agouti locus (A(y)) results in obesity. Pregnancy and lactation are characterized by large energy demand. The aim of this study was to investigate whether obesity would develop in pregnant and suckling A(y) mice.. Body weight and food intake in pregnancy, lactation, and after weaning, plasma leptin, insulin, corticosterone and blood glucose concentrations on days 7, 13 and 18 of pregnancy, days 1, 10, 21 and 80 postpartum, glucose and insulin tolerance on pregnancy days 7 and 18 were measured in C57Bl/6J mice of a/a (normal metabolism) and A(y)/a genotypes. The same parameters were also measured in age-matched virgin females.. Virgin A(y)/a females exhibited hyperphagia, enhanced body weight, glucose intolerance and normal blood parameters at the mating age. With age, they developed obesity, hyperleptinaemia, hyperinsulinaemia and hyperglycaemia. Obesity did not develop in mated A(y)/a mice; during suckling, they had equal food intake and body weight as a/a mice. During pregnancy, glucose tolerance was enhanced in A(y)/a mice and became equal in both genotypes. In both genotypes, concentrations of hormones increased, and glucose decreased from pregnancy day 7 to day 18 and returned to normal values after parturition. A(y)/a mice did not differ from a/a in corticosterone, insulin and glucose levels during pregnancy and lactation, in leptin levels during suckling; however, A(y)/a mice had two times higher leptin levels than a/a during pregnancy. After weaning, A(y)/a mice began to eat and weigh more than a/a exhibiting normal metabolic parameters for 50 days.. Pregnancy and lactation retard obesity and diabetes development in A(y) mice.

Topics: Age Factors; Animals; Blood Glucose; Body Weight; Breast Feeding; Corticosterone; Diabetes Mellitus; Female; Glucose Intolerance; Insulin Resistance; Lactation; Leptin; Mice; Mice, Inbred C57BL; Obesity; Pregnancy

Obesity-induced inflammation contributes to the development of obesity-related metabolic disorders such as insulin resistance, type 2 diabetes, fatty liver disease, and cardiovascular disease. In this study, we investigated whether dietary capsaicin can reduce obesity-induced inflammation and metabolic disorders such as insulin resistance and hepatic steatosis. Male C57BL/6 obese mice fed a high-fat diet for 10 weeks received a supplement of 0.015% capsaicin for a further 10 weeks and were compared with unsupplemented controls. Glucose intolerance was estimated by glucose tolerance tests. Transcripts of adipocytokine genes and the corresponding proteins were measured by reverse transcription-PCR and enzyme-linked immunosorbent assay, and macrophage numbers were determined by flow cytometric analysis. Transient receptor potential vanilloid type-1 (TRPV-1), peroxisome proliferator-activated receptor (PPAR)-alpha, and PPARgamma coactivator-1alpha (PGC-1alpha) mRNAs were also measured by RT-PCR, and PPARalpha luciferase assays were performed. Dietary capsaicin lowered fasting glucose, insulin, leptin levels, and markedly reduced the impairment of glucose tolerance in obese mice. Levels of tumor necrosis factor-alpha (TNFalpha), monocyte chemoattractant protein-1 (MCP-1), and interleukin (IL)-6 mRNAs and proteins in adipose tissue and liver decreased markedly, as did macrophage infiltration, hepatic triglycerides, and TRPV-1 expression in adipose tissue. At the same time, the mRNA/protein of adiponectin in the adipose tissue and PPARalpha/PGC-1alpha mRNA in the liver increased. Moreover, luciferase assays revealed that capsaicin is capable of binding PPARalpha. Our data suggest that dietary capsaicin may reduce obesity-induced glucose intolerance by not only suppressing inflammatory responses but also enhancing fatty acid oxidation in adipose tissue and/or liver, both of which are important peripheral tissues affecting insulin resistance. The effects of capsaicin in adipose tissue and liver are related to its dual action on PPARalpha and TRPV-1 expression/activation.

Topics: Adiponectin; Adipose Tissue; Animals; Anti-Inflammatory Agents; Blood Glucose; Capsaicin; Dietary Fats; Dietary Supplements; Disease Models, Animal; Fatty Liver; Flow Cytometry; Gene Expression; Glucose Intolerance; Hypoglycemic Agents; Inflammation; Insulin; Insulin Resistance; Leptin; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; PPAR alpha; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Triglycerides; TRPV Cation Channels

The C57BL/6J (B6/J) male mouse represents a standard for diet-induced obesity (DIO) and is unique in expressing a loss-of-function nicotinamide nucleotide transhydrogenase (Nnt) gene. This mutation was associated with a marked reduction in glucose-stimulated insulin secretion from B6/J islets in vitro and moderately impaired glucose clearance in vivo. To assess the contribution of this Nnt mutation, we compared DIO responsiveness of Nnt-mutant B6/J males to Nnt wild-type C57BL/6NJ (B6/NJ) males over a 14-week period of feeding a high-fat (60% of calories) diet. Initial mean body weights at 6 weeks did not distinguish the substrains and both substrains were DIO-sensitive. However, B6/J males outgained the B6/NJ males, with a significant 3 g higher mean body weight at 20 weeks accompanied by significant increases in both lean and fat mass. Mean nonfasting serum glucose over time was also significantly higher in B6/J males, as was impairment of glucose tolerance assessed at 8 and 20 weeks of age. Serum leptin, but not insulin, was significantly higher in B6/J males over time. Potential contributions of the wild-type Nnt gene were demonstrable on a lower fat diet (10% of calories) where a significantly greater weight gain over time by B6/NJ males was correlated with a significantly higher serum insulin. In conclusion, DIO developed in response to 60% fat feeding regardless of Nnt allele status. Contribution of the B6/J-unique Nnt mutation was most evident in response to 10% fat feeding that resulted in reduced serum insulin and weight gain compared to B6/NJ males.

Topics: Adipose Tissue; Animals; Blood Glucose; Body Fluid Compartments; Body Weight; Diet; Dietary Fats; Glucose Intolerance; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mutation; NADP Transhydrogenases; Obesity; Weight Gain

Sustained fructose consumption has been shown to induce insulin resistance and glucose intolerance, in part, by promoting oxidative stress. Alpha-lipoic acid (LA) is an antioxidant with insulin-sensitizing activity. The effect of sustained fructose consumption (20% of energy) on the development of T2DM and the effects of daily LA supplementation in fructose-fed University of California, Davis-Type 2 diabetes mellitus (UCD-T2DM) rats, a model of polygenic obese T2DM, was investigated. At 2 mo of age, animals were divided into three groups: control, fructose, and fructose + LA (80 mg LA.kg body wt(-1).day(-1)). One subset was followed until diabetes onset, while another subset was euthanized at 4 mo of age for tissue collection. Monthly fasted blood samples were collected, and an intravenous glucose tolerance test (IVGTT) was performed. Fructose feeding accelerated diabetes onset by 2.6 +/- 0.5 mo compared with control (P < 0.01), without affecting body weight. LA supplementation delayed diabetes onset in fructose-fed animals by 1.0 +/- 0.7 mo (P < 0.05). Fructose consumption lowered the GSH/GSSG ratio, while LA attenuated the fructose-induced decrease of oxidative capacity. Insulin sensitivity, as assessed by IVGTT, decreased in both fructose-fed and fructose + LA-supplemented rats. However, glucose excursions in fructose-fed LA-supplemented animals were normalized to those of control via increased glucose-stimulated insulin secretion. Fasting plasma triglycerides were twofold higher in fructose-fed compared with control animals at 4 mo, and triglyceride exposure during IVGTT was increased in both the fructose and fructose + LA groups compared with control. In conclusion, dietary fructose accelerates the onset of T2DM in UCD-T2DM rats, and LA ameliorates the effects of fructose by improving glucose homeostasis, possibly by preserving beta-cell function.

Topics: Adiponectin; Animal Feed; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Dietary Fats; Dyslipidemias; Energy Metabolism; Fructose; Glucose Intolerance; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Intercellular Adhesion Molecule-1; Kaplan-Meier Estimate; Leptin; Male; Oxidative Stress; Rats; Rats, Sprague-Dawley; Rats, Zucker; Thioctic Acid; Tocopherols; Triglycerides

Our objectives were to analyse carbohydrate metabolism in a series of ALS patients and to examine potential association with parameters of lipid metabolism and clinical features. Glucose tolerance was assessed by the oral glucose tolerance test in 21 non-diabetic ALS patients and compared with 21 age- and sex-matched normal subjects. Lipids and lactate/pyruvate ratio, levels of pro-inflammatory cytokines (tumour necrosis factor-alpha and interleukin-6) and adipocytokines (leptin and adiponectin) were also measured in ALS patients. Mann-Whitney U-tests analysed continuous data and Fisher's exact tests assessed categorical data. Blood glucose determined 120 min after the glucose bolus was significantly higher in patients with ALS (7.41 mmol/l+/-1.68) compared to controls (6.05+/-1.44, p=0.006). ALS patients with impaired glucose tolerance (IGT) according to WHO criteria (n=7, 33%) were more likely to have elevated free fatty acids (FFA) levels compared to patients with normal glucose tolerance (0.77 nmol/l+/-0.30 vs. 0.57+/-0.19, p=0.04). IGT was not associated with disease duration or severity. In conclusion, patients with ALS show abnormal glucose tolerance that could be associated with increased FFA levels, a key determinant of insulin resistance. The origin of glucose homeostasis abnormalities in ALS may be multifactorial and deserves further investigation.

Topics: Adiponectin; Adolescent; Adult; Aged; Amyotrophic Lateral Sclerosis; Blood Glucose; Fatty Acids, Nonesterified; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin; Interleukin-6; Lactic Acid; Leptin; Male; Middle Aged; Pyruvic Acid; Tumor Necrosis Factor-alpha; Young Adult

The class I(A) phosphatidylinsositol 3-kinases (PI3Ks) form a critical node in the insulin metabolic pathway; however, the precise roles of the different isoforms of this enzyme remain elusive. Using tissue-specific gene inactivation, we demonstrate that p110alpha catalytic subunit of PI3K is a key mediator of insulin metabolic actions in the liver. Thus, deletion of p110alpha in liver results in markedly blunted insulin signaling with decreased generation of PIP(3) and loss of insulin activation of Akt, defects that could not be rescued by overexpression of p110beta. As a result, mice with hepatic knockout of p110alpha display reduced insulin sensitivity, impaired glucose tolerance, and increased gluconeogenesis, hypolipidemia, and hyperleptinemia. The diabetic syndrome induced by loss of p110alpha in liver did not respond to metformin treatment. Together, these data indicate that the p110alpha isoform of PI3K plays a fundamental role in insulin signaling and control of hepatic glucose and lipid metabolism.

Topics: Animals; Blood Glucose; Class I Phosphatidylinositol 3-Kinases; Diabetes Mellitus; Down-Regulation; Energy Metabolism; Glucose Intolerance; Insulin; Leptin; Lipids; Liver; Metformin; Mice; Mice, Knockout; Phosphatidylinositol 3-Kinases; Phosphatidylinositol Phosphates; Proto-Oncogene Proteins c-akt; Signal Transduction

Numerous clinical and experimental studies have linked stress to changes in risk factors associated with the development of physiological syndromes, including metabolic disorders. How different mediators of the stress response, such as corticosterone (CORT), influence these changes in risk remains unclear. Although CORT has beneficial short-term effects, long-term CORT exposure can result in damage to the physiological systems it protects acutely. Disruption of this important physiologic signal is observed in numerous disparate disorders, ranging from depression to Cushing's syndrome. Thus, understanding the effects of chronic high CORT on metabolism and physiology is of key importance. We explored the effects of 4-wk exposure to CORT dissolved in the drinking water on the physiology and behavior of male mice. We used this approach as a noninvasive way of altering plasma CORT levels while retaining some integrity in the diurnal rhythm present in normal animals. This approach has advantages over methods involving constant CORT pellets, CORT injections, or adrenalectomy. We found that high doses of CORT (100 microg/ml) result in rapid and dramatic increases in weight gain, increased adiposity, elevated plasma leptin, insulin and triglyceride levels, hyperphagia, and decreased home-cage locomotion. A lower dose of CORT (25 microg/ml) resulted in an intermediate phenotype in some of these measures but had no effect on others. We propose that the physiological changes observed in the high-CORT animals approximate changes observed in individuals suffering from the metabolic syndrome, and that they potentially serve as a model for hypercortisolemia and stress-related obesity.

Topics: Adipose Tissue, White; Adiposity; Adrenal Glands; Animals; Atrophy; Chemical Phenomena; Corticosterone; Disease Models, Animal; Dose-Response Relationship, Drug; Endocrine System; Glucose Intolerance; Hyperphagia; Insulin; Leptin; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Motor Activity; Thymus Gland; Triglycerides; Weight Gain

The goals of this study were to examine the influence of maternal type 1 diabetes during pregnancy on offspring adiposity and glucose tolerance at age 7 years and to assess whether metabolic factors at birth (neonatal leptin and insulin) predict adverse outcomes.. We examined 100 offspring of mothers with type 1 diabetes (OT1DM) and 45 offspring of control mothers. Mothers had previously been recruited during pregnancy, and, where possible, birth weight, umbilical cord insulin, and leptin were measured. Children were classed as overweight and obese using age-specific reference ranges.. OT1DM had similar height (control, 1.25 +/- 0. 06 m; OT1DM, 1.24 +/- 0.06 m; P = 0.81) but were heavier (control, 25.5 +/- 3.8 kg; OT1DM, 27.1 +/- 5.7 kg; P = 0.048) and had an increased BMI (control, 16.4 kg/m(2); OT1DM, 17.4 +/- 2.6 kg/m(2), P = 0.005). Waist circumference (control, 56.0 +/- 3.7 cm; OT1DM, 58 +/- 6.8 cm; P = 0.02) and sum of skinfolds were increased (control, 37.5 +/- 17.0 mm [n = 42]; OT1DM, 46.1 +/- 24.2 mm [n = 91]; P = 0.02), and there was a marked increase in the prevalence of overweight and obese children (OT1DM, 22% overweight and 12% obese; control, 0% overweight and 7% obese; chi(2) P = 0.001). Glucose tolerance was not different compared with that in control subjects. BMI at age 7 years correlated with cord leptin (OT1DM, r = 0.25; n = 61, P = 0.047), weakly with adjusted birth weight (r = 0.19; P = 0.06) and hematocrit (r = 0.25; n = 50, P = 0.07), but not cord insulin (OT1DM, r = -0.08; P = 0.54).. OT1DM are at increased risk of overweight and obesity in childhood. This risk appears to relate, in part, to fetal leptin and hematocrit but not insulin.

Topics: Adipose Tissue; Birth Weight; Child; Diabetes Mellitus, Type 1; Female; Fetal Blood; Fetus; Follow-Up Studies; Glucose Intolerance; Hematocrit; Humans; Infant, Newborn; Insulin; Leptin; Mothers; Obesity; Predictive Value of Tests; Pregnancy; Prenatal Exposure Delayed Effects; Prevalence; Risk Factors

The pathogenic role of oxidative stress has already been proven both in energy homeostasis and bone metabolism. The effects of +22348C>T (RS769217) polymorphism of catalase (EC 1.11.1.6, hydrogenperoxid-hydrogenperoxid oxidoreduktase) gene were investigated on glucose disposal and bone mineral density in groups of healthy (n = 24) and glucose intolerant (n = 27) females and healthy (n = 64) and glucose intolerant (n = 26) males. Glucose intolerant groups included IFG, IGT and non-treated type 2 diabetic patients. There were no differences in allele frequencies between the genders and groups in this transdanubian Hungarian population. The effects of CAT gene polymorphisms on glucose metabolism and bone status were gender specific. Females with mutant CAT (CT+TT) gene had better HOMA-IR (CC: 2.95+/-1.8 versus CT+TT: 2.06+/-0.9, p<0.05), but bone density did not differ between the CC and CT+TT haplotypes. The homozygote TT females had significantly better whole body glucose disposal. (M-1 mg/kg/min: CC: 9,43+/-4,4 versus TT: 13,23+/-1,6mg/kg body weight/min, p<0.05). The appearance of T allel among males caused lower femur density (CC: 1,11+/-0,17 versus CT+TT: 1,03+/-0,16, p<0.05 g/cm 2 ) and better HOMA-IR (CC: 2.42+/-2.3 versus CT+TT: 1.50+/-0.2, p<0.05), with no change in whole body glucose disposal. Osteocalcin - which has been proven to be the connection between energy homeostasis and bone metabolism - had identical serum levels in both haplotypes, but the significant correlation between muscle tissue glucose utilization and osteocalcin levels (r = +0.4424, p<0.05, n = 23) disappeared in the presence of T allele. Multiple correlation showed significant connection between leptin/adiponectin and femur BMD in CC female group, and between leptin/adiponectin and lumbar BMD in CC male group. The correlations disappeared with the appearance of T allele. Our results differ from the data obtained in Korean postmenopausal women and stress the need of population/ethnic specific replication of genetic data.

Topics: Adiponectin; Adult; Biomarkers; Bone Density; Case-Control Studies; Catalase; Energy Metabolism; Female; Femur; Gene Frequency; Glucose; Glucose Intolerance; Haplotypes; Homozygote; Humans; Hungary; Leptin; Male; Menopause; Middle Aged; Muscle, Skeletal; Osteocalcin; Polymorphism, Genetic; Sex Factors

In an acute treatment experiment, metformin (150, 300 mg/kg, per os (p.o.)) markedly reduced the consumption of a high-fat diet (HFD) (45 kcal% fat-containing diet) for 2 h after the HFD was given to the fasted male C57BL/6J (B6) mice. In addition, metformin at a higher dose increased plasma active glucagon-like peptide-1 (GLP-1) levels at 1 h after the HFD was given. On the other hand, pioglitazone (12 mg/kg, p.o.) slightly increased the food intake but did not affect active GLP-1 levels when given at 6 and 12 mg/kg, p.o. In a long-team experiment for 9 weeks, metformin treatment (0.25, 0.5% in the HFD) resulted in reduction of body weight gain and HFD intake. When wet weights of various body fat pads of each mouse were measured at 9 weeks after treatment, metformin markedly decreased these weights. However, pioglitazone treatment (0.01, 0.02% in the HFD) did not have obvious effects on these parameters. Oral glucose tolerance test was carried out after 20-h fasting at 4 weeks post-treatment. Whereas metformin treatment (0.25, 0.5%) markedly improved glucose intolerance, pioglitazone treatment (0.02%) slightly improved this parameter. At 9 weeks, both metformin and pioglitazone markedly improved hyperglycemia and hyperinsulinemia. Metformin treatment also improved hyperleptinemia, whereas pioglitazone was ineffective. These results indicate that metformin reduces body weight gain and improves glucose intolerance in HFD-induced obese diabetic B6 mice.

Topics: Animals; Blood Glucose; Body Weight; Dietary Fats; Energy Intake; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Hyperglycemia; Hyperinsulinism; Hypoglycemic Agents; Insulin; Leptin; Male; Metformin; Mice; Mice, Inbred C57BL; Obesity; Pioglitazone; Thiazolidinediones; Weight Gain

Obesity and metabolic syndrome result from excess calorie intake and genetic predisposition and are mechanistically linked to type II diabetes and accelerated body aging; abnormal nutrient and insulin signaling participate in this pathologic process, yet the underlying molecular mechanisms are incompletely understood. Mice lacking the p66 kDa isoform of the Shc adaptor molecule live longer and are leaner than wild-type animals, suggesting that this molecule may have a role in metabolic derangement and premature senescence by overnutrition. We found that p66 deficiency exerts a modest but significant protective effect on fat accumulation and premature death in lepOb/Ob mice, an established genetic model of obesity and insulin resistance; strikingly, however, p66 inactivation improved glucose tolerance in these animals, without affecting (hyper)insulinaemia and independent of body weight. Protection from insulin resistance was cell autonomous, because isolated p66KO preadipocytes were relatively resistant to insulin desensitization by free fatty acids in vitro. Biochemical studies revealed that p66shc promotes the signal-inhibitory phosphorylation of the major insulin transducer IRS-1, by bridging IRS-1 and the mTOR effector p70S6 kinase, a molecule previously linked to obesity-induced insulin resistance. Importantly, IRS-1 was strongly up-regulated in the adipose tissue of p66KO lepOb/Ob mice, confirming that effects of p66 on tissue responsiveness to insulin are largely mediated by this molecule. Taken together, these findings identify p66shc as a major mediator of insulin resistance by excess nutrients, and by extension, as a potential molecular target against the spreading epidemic of obesity and type II diabetes.

Topics: 3T3-L1 Cells; Adipocytes; Adipose Tissue; Animals; Cells, Cultured; Flow Cytometry; Glucose Intolerance; Hyperinsulinism; Hypoglycemic Agents; Immunoblotting; Insulin; Insulin Resistance; Leptin; Longevity; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Knockout; Mice, Obese; Obesity; Phosphorylation; Ribosomal Protein S6 Kinases, 70-kDa; RNA Interference; Shc Signaling Adaptor Proteins; Src Homology 2 Domain-Containing, Transforming Protein 1

To verify whether the leptin gene epigenetic (DNA methylation) profile is altered in the offspring of mothers with gestational impaired glucose tolerance (IGT).. Placental tissues and maternal and cord blood samples were obtained from 48 women at term including 23 subjects with gestational IGT. Leptin DNA methylation, gene expression levels, and circulating concentration were measured using the Sequenom EpiTYPER system, quantitative real-time RT-PCR, and enzyme-linked immunosorbent assay, respectively. IGT was assessed after a 75-g oral glucose tolerance test (OGTT) at 24-28 weeks of gestation.. We have shown that placental leptin gene DNA methylation levels were correlated with glucose levels (2-h post-OGTT) in women with IGT (fetal side: ρ=-0.44, P≤0.05; maternal side: ρ=0.53, P≤0.01) and with decreased leptin gene expression (n=48; ρ≥-0.30, P≤0.05) in the whole cohort. Placental leptin mRNA levels accounted for 16% of the variance in maternal circulating leptin concentration (P<0.05).. IGT during pregnancy was associated with leptin gene DNA methylation adaptations with potential functional impacts. These epigenetic changes provide novel mechanisms that could contribute to explaining the detrimental health effects associated with fetal programming, such as long-term increased risk of developing obesity and type 2 diabetes.

Topics: Adult; DNA Methylation; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Leptin; Pregnancy; Reverse Transcriptase Polymerase Chain Reaction

HIV protease inhibitors acutely block glucose transporters (GLUTs) in vitro, and this may contribute to altered glucose homeostasis in vivo. However, several GLUT-independent mechanisms have been postulated. To determine the contribution of GLUT blockade to protease inhibitor-mediated glucose dysregulation, the effects of ritonavir were investigated in mice lacking the insulin-sensitive glucose transporter GLUT4 (G4KO). G4KO and control C57BL/6J mice were administered ritonavir or vehicle at the start of an intraperitoneal glucose tolerance test and during hyperinsulinemic-euglycemic clamps. G4KO mice exhibited elevated fasting blood glucose compared with C57BL/6J mice. Ritonavir impaired glucose tolerance in control mice but did not exacerbate glucose intolerance in G4KO mice. Similarly, ritonavir reduced peripheral insulin sensitivity in control mice but not in G4KO mice. Serum insulin levels were reduced in vivo in ritonavir-treated mice. Ritonavir reduced serum leptin levels in C57BL/6J mice but had no effect on serum adiponectin. No change in these adipokines was observed following ritonavir treatment of G4KO mice. These data confirm that a primary effect of ritonavir on peripheral glucose disposal is mediated through direct inhibition of GLUT4 activity in vivo. The ability of GLUT4 blockade to contribute to derangements in the other molecular pathways that influence insulin sensitivity remains to be determined.

Topics: Adipokines; Adipose Tissue; Animals; Blood Glucose; Cells, Cultured; Enzyme-Linked Immunosorbent Assay; Female; Glucose Intolerance; Glucose Tolerance Test; Glucose Transporter Type 4; HIV Protease Inhibitors; Insulin; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Skeletal; Ritonavir

The link between obesity and insulin resistance largely accounts for the pathogenesis of metabolic syndrome and diabetes mellitus, in which adipokine expression plays a key role. Puerarin, a major active isoflavone extracted from the traditional Chinese medicine Radix Puerariae, has been studied for its comprehensive biological actions. However, its effect on high-fat diet (HFD)-induced insulin resistance and adipokine expression in rat has not been well investigated. In the present study, male Sprague-Dawley rats were fed on a normal control diet (NCD) or HFD for 6 weeks, followed by administration of puerarin (100 and 200 mg/kg) for up to 8 weeks. Compared to NCD, HFD feeding for 6 weeks led to increased body weight gain and impaired glucose/insulin tolerance manifested by oral glucose/intraperitoneal insulin tolerance tests in rats. These exacerbations prolonged through HFD feeding, but were effectively reversed by puerarin administration. Enzyme-linked immunosorbent assay demonstrated that, serum levels of leptin and resistin, but not that of adiponectin, were markedly augmented by HFD and retarded by puerarin treatment. Real-time reverse transcription polymerase chain reaction results showed that, in agreement with the circulating levels, mRNA expression of leptin and resistin in epididymal white adipose tissue was modified by HFD and improved by puerarin in the same pattern. Collectively, we revealed that puerarin could improve body weight gain, glucose/insulin intolerance and adipokine expression in HFD-induced insulin resistant rats, indicating its potential value for treatment of metabolic syndrome.

Topics: Adipokines; Adiponectin; Adipose Tissue, White; Animals; Anti-Obesity Agents; Dietary Fats; Dose-Response Relationship, Drug; Glucose Intolerance; Insulin Resistance; Isoflavones; Leptin; Male; Metabolic Syndrome; Obesity; Random Allocation; Rats; Rats, Sprague-Dawley; Resistin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

The liver plays a critical role in integrating and controlling glucose metabolism. Thus, it is important that the liver receive and react to signals from other tissues regarding the nutrient status of the body. Leptin, which is produced and secreted from adipose tissue, is a hormone that relays information regarding the status of adipose depots to other parts of the body. Leptin has a profound influence on glucose metabolism, so we sought to determine if leptin may exert this effect in part through the liver.. To explore this possibility, we created mice that have disrupted hepatic leptin signaling using a Cre-lox approach and then investigated aspects of glucose metabolism in these animals.. The loss of hepatic leptin signaling did not alter body weight, body composition, or blood glucose levels in the mild fasting or random-fed state. However, mice with ablated hepatic leptin signaling had increased lipid accumulation in the liver. Further, as male mice aged or were fed a high-fat diet, the loss of hepatic leptin signaling protected the mice from glucose intolerance. Moreover, the mice displayed increased liver insulin sensitivity and a trend toward enhanced glucose-stimulated plasma insulin levels. Consistent with increased insulin sensitivity, mice with ablated hepatic leptin signaling had increased insulin-stimulated phosphorylation of Akt in the liver.. These data reveal that unlike a complete deficiency of leptin action, which results in impaired glucose homeostasis, disruption of leptin action in the liver alone increases hepatic insulin sensitivity and protects against age- and diet-related glucose intolerance. Thus, leptin appears to act as a negative regulator of insulin action in the liver.

Topics: Aging; Animals; Diabetes Mellitus, Type 2; Female; Glucose; Glucose Clamp Technique; Glucose Intolerance; Glucose Tolerance Test; Insulin; Insulin Secretion; Insulin-Secreting Cells; Leptin; Liver; Male; Mice; Mice, Transgenic; Obesity; Polymerase Chain Reaction; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction

Altered adipokine serum concentrations early reflect impaired adipose tissue function in obese patients with type 2 diabetes (T2D). It is not entirely clear whether these adipokine alterations are already present in prediabetic states and so far there is no comprehensive adipokine panel available. Therefore, the aim of this study was to assess distinct adipokine profiles in patients with normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or T2D.. Based on 75 g oral glucose tolerance tests, 124 individuals were divided into groups of IFG (n = 35), IGT (n = 45), or NGT (n = 43). Furthermore, 56 subjects with T2D were included. Serum concentrations of adiponectin, chemerin, fetuin-A, leptin, interleukin (IL)-6, retinol-binding protein 4 (RBP4), monocyte chemoattractant protein (MCP)-1, vaspin, progranulin, and soluble leptin receptor (sOBR) were measured by ELISAs.. Chemerin, progranulin, fetuin-A, and RBP4, IL-6, adiponectin and leptin serum concentrations were differentially regulated among the four investigated groups but only circulating chemerin was significantly different in patients with IGT compared to those with IFG. Compared to T2D the IFG subjects had higher serum chemerin, progranulin, fetuin-A and RBP4 levels which was not detectable in the comparison of the T2D and IGT group.. Alterations in adipokine serum concentrations are already detectable in prediabetic states, mainly for chemerin, and may reflect adipose tissue dysfunction as an early pathogenetic event in T2D development. In addition, distinct adipokine serum patterns in individuals with IFG and IGT suggest a specific role of adipose tissue in the pathogenesis of these prediabetic states.

Topics: Adipokines; Adiponectin; Adult; Aged; Aged, 80 and over; alpha-2-HS-Glycoprotein; Blood Glucose; Blood Proteins; Body Mass Index; Chemokine CCL2; Chemokines; Diabetes Mellitus, Type 2; Fasting; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Intercellular Signaling Peptides and Proteins; Interleukin-6; Leptin; Male; Middle Aged; Progranulins; Receptors, Leptin; Retinol-Binding Proteins, Plasma; Serpins; Young Adult

Progranulin is an important molecule in inflammatory response. Chronic inflammation is frequently associated with central obesity and associated disturbances; however, the role of circulating progranulin in human obesity, type 2 diabetes, and dyslipidemia is unknown.. For the measurement of progranulin serum concentrations, we developed an enzyme-linked immunosorbent assay (ELISA). Using this ELISA, we assessed circulating progranulin in a cross-sectional study of 209 subjects with a wide range of obesity, body fat distribution, insulin sensitivity, and glucose tolerance and in 60 individuals with normal (NGT) or impaired (IGT) glucose tolerance or type 2 diabetes before and after a 4-week physical training program. Progranulin mRNA and protein expression was measured in paired samples of omental and subcutaneous adipose tissue (adipocytes and cells of the stromal vascular fraction) from 55 lean or obese individuals. Measurement of Erk activation and chemotactic activity induced by progranulin in vitro was performed using THP-1-based cell migration assays.. Progranulin serum concentrations were significantly higher in individuals with type 2 diabetes compared with NGT and in obese subjects with predominant visceral fat accumulation. Circulating progranulin significantly correlates with BMI, macrophage infiltration in omental adipose tissue, C-reactive protein (CRP) serum concentrations, A1C values, and total cholesterol. Multivariable linear regression analyses revealed CRP levels as the strongest independent predictor of circulating progranulin. The extent of in vitro progranulin-mediated chemotaxis is similar to that of monocyte chemoattractant protein-1 but independent of Galpha. Moreover, in type 2 diabetes, but not in IGT and NGT individuals, physical training for 4 weeks resulted in significantly decreased circulating progranulin levels.. Elevated progranulin serum concentrations are associated with visceral obesity, elevated plasma glucose, and dyslipidemia. We identified progranulin as a novel marker of chronic inflammation in obesity and type 2 diabetes that closely reflects omental adipose tissue macrophage infiltration. Physical training significantly reduces elevated circulating progranulin in patients with type 2 diabetes.

Topics: Adiponectin; Adipose Tissue; Adult; Cohort Studies; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Glucose Intolerance; Humans; Inflammation; Intercellular Signaling Peptides and Proteins; Leptin; Lipids; Macrophages; Male; Middle Aged; Obesity; Omentum; Progranulins; Reference Values; RNA, Messenger

We have currently studied the changes induced by administration of a fructose-rich diet (FRD) to normal rats in the mass and the endocrine function of abdominal (omental) adipose tissue (AAT). Rats were fed ad libitum a standard commercial chow and tap water, either alone (control diet, CD) or containing fructose (10%, w/vol) (FRD). Three weeks after treatment, circulating metabolic markers and leptin release from adipocytes of AAT were measured. Plasma free fatty acids (FFAs), leptin, adiponectin, and plasminogen activator inhibitor-1 (PAI-1) levels were significantly higher in FRD than in CD rats. AAT mass was greater in FRD than in CD rats and their adipocytes were larger, they secreted more leptin and showed impaired insulin sensitivity. While leptin mRNA expression increased in AAT from FRD rats, gene expression of insulin receptor substrate, IRS1 and IRS2 was significantly reduced. Our study demonstrates that administration of a FRD significantly affects insulin sensitivity and several AAT endocrine/metabolic functions. These alterations could be part of a network of interacting abnormalities triggered by FRD-induced oxidative stress at the AAT level. In view of the impaired glucose tolerance observed in FRD rats, these alterations could play a key role in both the development of metabolic syndrome (MS) and beta-cell failure.

Topics: Abdominal Fat; Adipocytes; Animals; Biomarkers; Dexamethasone; Diet; Fructose; Gene Expression; Glucose Intolerance; Insulin; Insulin Receptor Substrate Proteins; Leptin; Male; Oxidative Stress; Rats; Rats, Wistar; RNA, Messenger

Oxytocin (Oxt) is secreted both peripherally and centrally and is involved in several functions including parturition, milk let-down reflex, social behavior, and food intake. Recently, it has been shown that mice deficient in Oxt receptor develop late-onset obesity. In this study, we characterized a murin model deficient in Oxt peptide (Oxt(-/-)) to evaluate food intake and body weight, glucose tolerance and insulin tolerance, leptin and adrenaline levels. We found that Oxt(-/-) mice develop late-onset obesity and hyperleptinemia without any alterations in food intake in addition to having a decreased insulin sensitivity and glucose intolerance. The lack of Oxt in our murin model also results in lower adrenalin levels which led us to hypothesize that the metabolic changes observed are associated with a decreased sympathetic nervous tone. It has been shown that Oxt neurons in the paraventricular nucleus (PVN) are a component of a leptin-sensitive signaling circuit between the hypothalamus and caudal brain stem for the regulation of food intake and energy homeostasis. Nevertheless, the lack of Oxt in these mice does not have a direct impact on feeding behavior whose regulation is probably dependent on the complex interplay of several factors. The lack of hyperphagia evident in the Oxt(-/-) mice may, in part, be attributed to the developmental compensation of other satiety factors such as cholecystokinin or bombesin-related peptides which merits further investigation. These findings identify Oxt as an important central regulator of energy homeostasis.

Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Brain Stem; Crosses, Genetic; Energy Intake; Glucose Intolerance; Hypothalamus; Insulin; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Oxytocin; Signal Transduction; Stomach; Sympathetic Nervous System

It is generally accepted that the metabolic effects of leptin are diminished in the obese due to leptin resistance. Hormone resistance may develop if diurnal (including meal-related) changes in hormone levels are disrupted. We sought to describe leptin changes after a 75 g oral glucose tolerance test (OGTT) in women with a prior diagnosis of gestational diabetes mellitus (a high risk group for the metabolic syndrome) compared to that in healthy controls.. In 2000 a retrospective cohort study was performed on women who had been diagnosed with gestational diabetes mellitus (WHO criteria 1985, n = 57) between 1996 and 1998 and on a healthy control female group (n = 36) all of whom had had a prior pregnancy without any diagnosis of diabetes. All the women underwent a standard 75 g OGTT. Serum leptin was measured by radioimmunoassay before and 90 min after the OGTT.. Using multilevel models of change, fasting leptin levels were shown to be associated with body mass index; 10.1% (95% CI 8.1-12.1%) increase per 1 kg/m(2) increase in body mass index), homeostasis model assessment insulin sensitivity; 0.4% (95% CI 0.2-0.7%) decrease per 1% increase in insulin sensitivity); abnormal glucose tolerance (24% decrease, 95% CI 8-37%); and smoking (31% decrease, 95% CI 16-44%). Postload (90 min) leptin levels decreased significantly in women with normal glucose tolerance by 13% (95% CI 8-18%), while no significant change in postload leptin level was apparent in women with abnormal glucose tolerance (3% increase, 95% CI -4% to 29%).. Disturbed leptin changes were found following an OGTT in women with abnormal glucose tolerance that might be either a cause or a consequence of leptin resistance.

Topics: Adult; Body Mass Index; Cohort Studies; Diabetes, Gestational; Female; Follow-Up Studies; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin Resistance; Leptin; Models, Statistical; Pregnancy; Retrospective Studies; Smoking; Time Factors

In mice of normal weight and with diet-induced obesity, a high-fat, low-carbohydrate ketogenic diet (KD) causes weight loss, reduced circulating glucose and lipids, and dramatic changes in hepatic gene expression. Many of the effects of KD are mediated by fibroblast growth factor 21 (FGF21). We tested the effects of KD feeding on ob/ob mice to determine if metabolic effects would occur in obesity secondarily to leptin deficiency. We evaluated the effect of prolonged KD feeding on weight, energy homeostasis, circulating metabolites, glucose homeostasis, and gene expression. Subsequently, we evaluated the effects of leptin and fasting on FGF21 expression in ob/ob mice. KD feeding of ob/ob mice normalized fasting glycemia and substantially reduced insulin and lipid levels in the absence of weight loss. KD feeding was associated with significant increases in lipid oxidative genes and reduced expression of lipid synthetic genes, including stearoyl-coenzyme A desaturase 1, but no change in expression of inflammatory markers. In chow-fed ob/ob mice, FGF21 mRNA was elevated 10-fold compared with wild-type animals, and no increase from this elevated baseline was seen with KD feeding. Administration of leptin to chow-fed ob/ob mice led to a 24-fold induction of FGF21. Fasting also induced hepatic FGF21 in ob/ob mice. Thus, KD feeding improved ob/ob mouse glucose homeostasis without weight loss or altered caloric intake. These data demonstrate that manipulation of dietary macronutrient composition can lead to marked improvements in metabolic profile of leptin-deficient obese mice in the absence of weight loss.

Topics: Animals; Calorimetry, Indirect; Diet, Carbohydrate-Restricted; Diet, Ketogenic; Fibroblast Growth Factors; Glucose Intolerance; Glucose Tolerance Test; Homeostasis; Inflammation Mediators; Insulin Resistance; Interleukin-6; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Real-Time Polymerase Chain Reaction; RNA; Triglycerides; Tumor Necrosis Factor-alpha; Weight Loss

Obesity represents a low-grade inflammatory disease and appears a risk factor for insulin resistance, but little is known on whether this may contribute to the development of autoimmune inflammatory diseases. The aim of this work was to study the early-life diet-induced obesity in Lewis rats which are known to be highly susceptible to autoimmunity.. Obesity was induced by reduced litter size (4 pups per litter) followed by high-fat diet (SHF rats). Control rats (8 pups per litter) were fed with standard diet (CN rats). Oral glucose tolerance test (3 g glucose per kg b.w.) was performed by intra-gastric tube in conscious rats after 12 h fast. Adipocyte size was assessed by light microscope after collagenase digestion. Hypothalamic arcuate (ARC) and paraventricular nuclei (PVN) were isolated by the punching technique. Target mRNAs were quantified by real-time PCR with the use of TaqMan probes and primers. Serum hormones (leptin, ghrelin, adiponectin, visfatin and insulin) were assayed by specific RIAs .. During the experimental period SHF rats had the same body weight gain and caloric intake as CN rats. At the age of 8 weeks SHF rats showed increased epididymal fat mass and adipocyte volume, impaired glucose tolerance, normal basal fasting insulin, visfatin, and ghrelin level, but decreased adiponectin and high leptin level. In the ARC, the SHF rats showed increased expression of mRNA for orexigenic neuropeptide Y (NPY), agouti-related protein (AgRP) and anorexigenic pro-inflammatory cytokine IL-6. In the PVN, the SHF rats showed increased expression of mRNA for anorexigenic melanocortin 4 receptor (MC4R) and IL-6.. Overexpression of orexigenic NPY and AgRP in the ARC indicates leptin resistance in SHF rats. The increased expression of MC4R in PVN points to the activation of melanocortin anorexigenic system which, along with increased hypothalamic IL-6, might prevent the animals from overfeeding. Higher adiposity in these rats results from the high fat-diet composition and not from increased caloric intake. Furthermore, enhanced leptin production appears the main factor indicating the predisposition to autoimmunity in these overfed rats.

Topics: Adipocytes, White; Adiponectin; Adipose Tissue, White; Adiposity; Aging; Agouti-Related Protein; Analysis of Variance; Animals; Appetite Regulation; Arcuate Nucleus of Hypothalamus; Area Under Curve; Body Weight; Cell Size; Dietary Fats; Energy Intake; Feeding Behavior; Gene Expression; Ghrelin; Glucose Intolerance; Insulin; Interleukin-6; Leptin; Litter Size; Male; Neuropeptide Y; Nicotinamide Phosphoribosyltransferase; Obesity; Paraventricular Hypothalamic Nucleus; Rats; Rats, Inbred Lew; Receptor, Melanocortin, Type 4; RNA, Messenger

It has been recently reported that blockade of type 1 cannabinoid (CB1) receptors by specific antagonists or genetic manipulation alleviates dyslipidaemia, hyperglycaemia and insulin resistance in animal models of obesity and type 2 diabetes. However, the precise role of adipokines in the insulin-sensitising effects of the CB1 antagonist rimonabant is not clear.. ob/ob mice were treated with different doses of rimonabant and then subjected to an oral glucose tolerance test. The expression of different adipokines in white adipose tissue was analysed by quantitative real-time PCR.. Rimonabant (30 mg/kg) significantly inhibited body weight and fat pad weight gain (P < 0.05) and improved glucose tolerance. Gene expression analysis indicated that tumour necrosis factor-alpha, visfatin and retinol binding protein-4 were downregulated in the adipose tissue of ob/ob mice treated with rimonabant compared with controls, whereas adiponectin was significantly upregulated.. Rimonabant-mediated alteration of adipokines in white adipose tissues may play a role in improving insulin sensitivity in obese animals.

Topics: Adipokines; Adiponectin; Adipose Tissue; Adipose Tissue, White; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Down-Regulation; Female; Gene Expression; Glucose Intolerance; Glucose Tolerance Test; Insulin; Insulin Resistance; Leptin; Mice; Mice, Knockout; Models, Animal; Nicotinamide Phosphoribosyltransferase; Obesity; Organ Size; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Retinol-Binding Proteins, Plasma; Reverse Transcriptase Polymerase Chain Reaction; Rimonabant; RNA, Messenger; Tumor Necrosis Factor-alpha

Ghrelin, a gastric peptide hormone, has been reported to regulate GH secretion and energy homeostasis. Here, we examined the effect of des-acyl ghrelin driven from the fatty acid-binding protein-4 (FABP4) promoter on adiposity and glucose metabolism. A high level of expression of des-acyl ghrelin (692 +/- 293 fmol/g fat) in adipose tissue was detected in FABP4-ghrelin transgenic mice, but not in wild-type littermates. Circulating des-acyl ghrelin was significantly higher in FABP4-ghrelin transgenic mice (8409 +/- 3390 pm) compared with wild-type mice (513 +/- 58 pm). No significant change was observed for plasma acylated ghrelin and obestatin. Epididymal and perirenal fat masses decreased 35 +/- 9 and 52 +/- 9%, respectively, in FABP4-ghrelin transgenic mice. FABP4-ghrelin transgenic mice are resistant to obesity induced by high-fat diet. Brown fat mass was not affected by overexpression of ghrelin in adipose tissue. Glucose tolerance tests showed glucose levels to be significantly lower in FABP4-ghrelin transgenic mice than in controls after glucose administration. Insulin sensitivity testing showed that FABP4-ghrelin transgenic mice had a 28 +/- 5% greater hypoglycemic response to insulin. Our study demonstrates that overexpression of ghrelin from the FABP4 promoter impairs the development of white adipose tissues, and alters glucose tolerance and insulin sensitivity in mice.

Topics: Adipose Tissue; Adiposity; Animals; Body Weight; Eating; Energy Metabolism; Fatty Acid-Binding Proteins; Ghrelin; Glucose; Glucose Intolerance; Insulin; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Promoter Regions, Genetic

The high-fat diet (HFD)-fed mouse is a model of obesity, impaired glucose tolerance, and insulin resistance. The main objective of this study was to elucidate the molecular mechanisms underlying the antidiabetogenic and weight-lowering effects of 17beta-estradiol (E(2)) in this mouse model. C57BL/6 female mice (8 wk old) were fed on a HFD for 10 mo. E(2), given daily (50 microg/kg s.c.) during the last month of feeding, decreased body weight and markedly improved glucose tolerance and insulin sensitivity. Plasma levels of insulin, leptin, resistin, and adiponectin were decreased. We demonstrated that E(2) treatment decreased the expression of genes encoding resistin and leptin in white adipose tissue (WAT), whereas adiponectin expression was unchanged. Furthermore, in WAT we demonstrated decreased expression levels of sterol regulatory element-binding protein 1c (SREBP1c) and its lipogenic target genes, such as fatty acid synthase and stearoyl-CoA desaturase 1 (SCD1). In the liver, the expression levels of transcription factors such as liver X receptor alpha and SREBP1c were not changed by E(2) treatment, but the expression of the key lipogenic gene SCD1 was reduced. This was accompanied by decreased hepatic triglyceride content. Importantly, E(2) decreased the hepatic expression of glucose-6-phosphatase (G-6-Pase). We conclude that E(2) treatment exerts antidiabetic and antiobesity effects in HFD mice and suggest that this is related to decreased expression of lipogenic genes in WAT and liver and suppression of hepatic expression of G-6-Pase. Decreased plasma levels of resistin probably also play an important role in this context.

Topics: Adipocytes; Adipokines; Adiponectin; Adipose Tissue; Animals; Dietary Fats; Estradiol; Fatty Acids; Female; Gene Expression; Glucose Intolerance; Glucose Tolerance Test; Hypoglycemic Agents; Insulin; Leptin; Liver; Mice; Mice, Inbred C57BL; Obesity; Resistin; Reverse Transcriptase Polymerase Chain Reaction; Transfection; Triglycerides; Weight Loss

Many cytokines have been found to increase the insulin resistance during pregnancy complicated by glucose metabolism disorder. This study aimed to investigate which comes first, the changes of some cytokines or the abnormal glucose metabolism.. This nested case-control study was undertaken from January 2004 to March 2005. Twenty-two women with gestational diabetes mellitus (GDM), 10 with gestational impaired glucose tolerance (GIGT), and 20 healthy pregnant women were chosen from the women who had visited the antenatal clinics and had blood samples prospectively taken and kept during their visit. The levels of tumor necrosis factor-alpha (TNF-alpha), leptin and adiponectin were determined. One-way ANOVA analysis and bivariate correlation analysis were used to assess the laboratory results and their relationship with body mass index (BMI).. Women with GDM have the highest values of TNF-alpha and leptin and the lowest value of adiponectin compared with those with GIGT and the healthy controls (P < 0.01) at 14-20 weeks of gestation. This was also found when these women progressed to 24-32 weeks. The significantly increased levels of TNF-alpha and leptin and the decreased level of adiponectin were found at the different periods of gestation within the same group. Positive correlation was shown between the levels of TNF-alpha and leptin at the two periods of gestation with the BMI at 14-20 weeks, while adiponectin was negatively correlated (P < 0.05).. The concentrations of TNF-alpha, leptin and adiponectin may change before the appearance of the abnormal glucose level during pregnancy. Further studies are required to verify the mechanism of this alteration and whether the three cytokines can be predictors for GDM at an early stage of pregnancy.

Topics: Adiponectin; Case-Control Studies; Diabetes, Gestational; Female; Glucose Intolerance; Humans; Leptin; Pregnancy; Prospective Studies; Tumor Necrosis Factor-alpha

Hearts of NaCl-induced hypertensive-glucose intolerant (HGI) rats develop reduced infarcts after ischemia-reperfusion injury (IRI) than their hypertensive (H) counterparts. Because high intake of saturated fat is a major risk factor for ischemic heart disease, we tested the hypothesis that chronic (18 weeks) consumption of a high saturated fat diet increases susceptibility to IRI, an effect more marked in the HGI rats than in the H rats. The fat-fed H (HFAT) rat displayed significantly higher body weight and plasma leptin content compared to the H, HGI, or fat-fed HGI (HGIFAT) rats which all showed similar values. In contrast, plasma triglyceride concentration was significantly higher in the HGIFAT rat than in the other three groups. Plasma insulin concentration was similar in the two H groups but higher than that of the two HGI groups. Compared to the H rat, the HGI rat was markedly glucose intolerant, with fat feeding causing comparable worsening of glucose intolerance in each group. The HGIFAT rats displayed a reduction in baseline myocardial contractility and relaxation and a higher end-diastolic pressure compared to the other three groups. Infarct size was significantly lower in the HGI rats than in the H rats. Although fat feeding did not affect infarct size of the H rat, it worsened that of the HGIFAT rat thereby abrogating the differential that existed between the H and HGI rats. In conclusion, excess fat feeding impairs myocardial function of HGI rats and increases their susceptibility to IRI. These findings are of relevance to the metabolic syndrome that manifests as a cluster of insulin resistance, dyslipidemia, and systemic hypertension.

Topics: Animals; Blood Glucose; Blood Pressure; Body Weight; Dietary Fats; Disease Models, Animal; Glucose Intolerance; Hypertension; Insulin; Leptin; Male; Metabolic Syndrome; Myocardial Contraction; Myocardial Infarction; Myocardial Reperfusion Injury; Rats; Rats, Inbred WKY; Sodium Chloride, Dietary; Streptozocin; Time Factors; Triglycerides; Ventricular Pressure

Obesity is a central feature of the metabolic syndrome and is associated with increased risk for insulin resistance and typeII diabetes. Here, we investigated the contribution of human apoliproteinE3 and mouse apoliproteinE to the development of diet-induced obesity in response to western-type diet. Our data show that apolipoproteinE contributes to the development of obesity and other related metabolic disorders, and that human apolipoproteinE3 is more potent than mouse apolipoproteinE in promoting obesity in response to western-type diet. Specifically, we found that apolipoproteinE3 knock-in mice fed western-type diet for 24 weeks became obese and developed hyperglycemia, hyperinsulinemia, hyperleptinemia, glucose intolerance and insulin resistance that were more severe than in C57BL/6 mice. In contrast, apolipoproteinE-deficient mice fed western-type diet for the same period were resistant to diet-induced obesity, had normal plasma glucose, leptin and insulin levels, and exhibited normal responses to glucose tolerance and insulin resistance tests. Furthermore, low-density lipoprotein receptor-deficient mice were more sensitive to the development of diet-induced obesity and insulin resistance than apolipoprotein E-deficient mice, but were still more resistant than C57BL/6 mice, raising the possibility that low-density lipoprotein receptor mediates, at least in part, the effects of apolipoproteinE on obesity. Taken together, our findings suggest that, in addition to other previously identified mechanisms of obesity, apolipoproteinE and possibly the chylomicron pathway are also important contributors to the development of obesity and related metabolic dysfunctions in mice.

Topics: Adipose Tissue; Animals; Apolipoprotein E3; Apolipoproteins E; Blood Glucose; Body Composition; Dietary Fats; Female; Glucose Intolerance; Humans; Insulin; Insulin Resistance; Leptin; Lipids; Liver; Mice; Obesity; Receptors, LDL; Triglycerides

To investigate the association between serum adiponectin levels and 2-hour post-75-g oral glucose load glycemia, we conducted 75-g oral glucose tolerance tests in 50 subjects who had been diagnosed as having impaired glucose tolerance (IGT) within the prior 3 years. When adjusted for age, body mass index, and sex, serum adiponectin levels in the IGT and diabetes mellitus groups were significantly lower than those in the normal glucose tolerance and impaired fasting glucose groups (P < .0001). To determine which variables had significant impacts on 2-hour post-oral glucose glycemia, we performed multiple regression analyses. In stepwise analysis, serum adiponectin levels showed the highest F value (F = 6.43), suggesting the adiponectin level to be an independent predictor of 2-hour post-oral glucose glycemia. Thus, our clinical data suggest the involvement of low adiponectin levels in IGT and diabetes mellitus. To further assess this possibility, we prepared mice fed a high-fat diet for 2 months as an IGT model. Afterward, we compared the 2-hour postglucose glycemia in the IGT mice overexpressing recombinant adiponectin with that in control IGT mice. Mice overexpressing adiponectin showed significantly blunted 2-hour postglucose glycemia (5.66 +/- 0.39 mmol/L) as compared with control mice (8.52 +/- 0.67 mmol/L), whereas fasting glycemia was not significantly altered by adiponectin overexpression. Taken together, our results reveal the plasma glucose level in response to a glucose load to be negatively associated with serum adiponectin levels, suggesting low adiponectin levels to be one of the predictors of abnormal glucose homeostasis in IGT.

Topics: Adiponectin; Adult; Aged; Animals; Blood Glucose; Blotting, Western; Female; Glucose; Glucose Intolerance; Glucose Tolerance Test; Humans; Leptin; Male; Mice; Mice, Inbred C57BL; Middle Aged; Regression Analysis; Transfection; Tumor Necrosis Factor-alpha

Despite a better overall tolerance as compared to classical antipsychotics, atypical antipsychotics are not devoid of side-effects, notably metabolic factors (weight gain, alteration of lipid and glucose profile). These side-effects are very troubling concerning long term morbidity and mortality and may also influence compliance towards drugs. The department of psychiatry of the Hospital University Centre has established a guideline on the clinical monitoring of patients receiving atypical antipsychotics, based on recently published consensus, which will be presented here. In addition, recent studies show that weight gain and metabolic alterations induced by this type of medication may be influenced by the genetic background of the patients. Such studies should allow, in the near future, to adapt the treatment for each patient.

Topics: Antidepressive Agents, Second-Generation; Glucose Intolerance; Humans; Leptin; Metabolic Syndrome; Pharmacogenetics; Receptors, Leptin; Weight Gain

High levels of leptin and low adiponectin are associated with Type 2 diabetes mellitus (T2DM) and cardiovascular (CV) disease. We studied the prognostic implications of leptin and adiponectin in patients with acute myocardial infarction (AMI) without previously known Type 2 DM.. One hundred and eighty-one patients were included. Based on an oral glucose tolerance test at hospital discharge (day 4-5), 168 (67% men) had normal or abnormal glucose tolerance (AGT), defined as impaired glucose tolerance or T2DM. Sex- and age-matched healthy persons served as control subjects (n = 185). The associations between fasting serum leptin and adiponectin (day 2) and newly discovered AGT and CV events (CV mortality, non-fatal stroke, reinfarction or severe heart failure) during a median follow-up of 34 months were investigated.. Compared with control subjects, patients of both genders had significantly higher levels of leptin 2 days after an AMI. These levels were higher than those obtained at hospital discharge and 3 months later. Circulating levels of (ln) leptin 2 days after the AMI predicted AGT at discharge (odds ratio 2.03, P = 0.042). Ln leptin at day 2 was the only biochemical variable that significantly predicted CV events both on univariate [hazard ratio (HR) 1.60, P = 0.018] and on multivariate analysis (HR 1.75, P = 0.045). Adiponectin levels did not differ between patients and control subjects and did not relate to AGT or CV events.. Elevated circulating levels of leptin on the first morning after an AMI are associated with the presence of AGT at discharge and with a poorer long-term prognosis.

Topics: Adiponectin; Aged; Blood Glucose; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Leptin; Male; Middle Aged; Myocardial Infarction; Predictive Value of Tests; Prognosis; Reference Values; Risk Factors

We have previously described that neonate rats supplemented with physiological doses of oral leptin during lactation become more protected against overweight in adulthood. The purpose of this study was to characterize further the long-term effects on glucose and leptin homeostasis and on food preferences. Neonate rats were supplemented during lactation with a daily oral dose of leptin or the vehicle. We followed body weight and food intake of animals until the age of 15 months, and measured glucose, insulin, and leptin levels under different feeding conditions: ad libitum feeding, 14-h fasting, and 3-h refeeding after fasting. An oral glucose tolerance test and a leptin resistance test were performed. Food preferences were also measured. Leptin-treated animals were found to have lower body weight in adulthood and to eat fewer calories than their controls. Plasma insulin levels were lower in leptin-treated animals than in their controls under the different feeding conditions, as was the increase in insulin levels after food intake. The homeostatic model assessment for insulin resistance index was significantly lower in leptin-treated animals, and the oral glucose tolerance test also indicated higher insulin sensitivity in leptin-treated animals. In addition, these animals displayed lower plasma leptin levels under the different feeding conditions and were also more responsive to exogenous leptin administration. Leptin-treated animals also showed a lower preference for fat-rich food than their controls. These observations indicate that animals supplemented with physiological doses of oral leptin during lactation were more protected against obesity and metabolic features of the metabolic syndrome.

Topics: Administration, Oral; Animals; Animals, Newborn; Animals, Suckling; Blood Glucose; Body Weight; Female; Food Preferences; Glucose Intolerance; Glucose Tolerance Test; Homeostasis; Insulin Resistance; Lactation; Leptin; Male; Milk; Obesity; Pregnancy; Rats; Rats, Wistar

Keishibukuryogan, one of the traditional herbal formulations, is used clinically to improve blood circulation. In this study, we examined the effects of keishibukuryogan on glucose and lipids metabolism in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of type 2 diabetes. Forty-five-week-old male OLETF rats were divided into three groups: diabetic control rats given a standard chow; diabetic rats given keishibukuryogan (3%, w/w in chow); diabetic rats given pioglitazone (0.01%, w/w in chow). Oral administration of keishibukuryogan produced significant improvement against impaired glucose tolerance. On the other hand, fasting serum glucose and insulin levels, and the homeostasis index of insulin resistance did not change by keishibukuryogan treatment. Against lipid parameters, keishibukuryogan significantly lowered serum total cholesterol and triglyceride levels, and the hepatic total cholesterol level. Keishibukuryogan treatment also significantly reduced the serum leptin level, but it had no effect on the serum adiponectin level. Additionally, keishibukuryogan showed significant effects on epididymal adipose tissue by decreasing the size of fat cells and on skeletal muscle by reducing TNF-alpha protein content. From these results, it was suggested that keishibukuryogan exerts beneficial effects on the features associated with type 2 diabetes.

Topics: Adiponectin; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Drugs, Chinese Herbal; Glucose Intolerance; Glucose Tolerance Test; Homeostasis; Hyperlipidemias; Hypoglycemic Agents; Insulin; Leptin; Lipid Metabolism; Male; Organ Size; Phytotherapy; Pioglitazone; Rats; Rats, Inbred OLETF; Thiazolidinediones; Tumor Necrosis Factor-alpha

Werner syndrome (WS) is an autosomal recessive progeroid syndrome caused by mutations in the Werner (Wrn) gene. WS patients have increased incidence of a number of chronic conditions including insulin resistance and type 2 diabetes. Since ingestion of foods that are high in fat and sugar is associated with increased incidence of diabetes, we examined if Wrn mutations might affect metabolic response to a diabetogenic diet. Four-month-old mice with a null mutation for the Wrn gene were fed a diet consisting of 36% fat (lard), 33% table sugar, and 20% protein plus balanced vitamins and minerals. Wrn null mice had significantly increased body weights, increased serum insulin levels, impaired glucose tolerance, and insulin resistance during 4 months of eating the diabetogenic diet. Diffuse fatty infiltration of the liver and pancreatic islet hyperplasia was characteristic morphological features. These observations suggest that Wrn null mice have impaired glucose homeostasis and fat metabolism, and may be a useful model to investigate metabolic conditions associated with aging.

Topics: Adiposity; Animal Feed; Animals; Body Weight; Diabetes Mellitus; Diet; Glucose Intolerance; Hyperglycemia; Hyperinsulinism; Hypertriglyceridemia; Insulin Resistance; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; RecQ Helicases; Werner Syndrome Helicase

Serum amyloid A (SAA) is a novel link between increased adipose tissue mass and low-grade inflammation in obesity. Little is known about the factors regulating its serum concentration and mRNA levels. We investigated the association between SAA and leptin in obese and normal weight subjects and analyzed the effect of weight reduction on serum SAA concentration and gene expression in adipose tissue of the obese subjects.. Seventy-five obese subjects (60+/-7 years, body mass index (BMI) 32.9+/-2.8 kg/m(2), mean+/-s.d.) with impaired fasting plasma glucose or impaired glucose tolerance and other features of metabolic syndrome, and 11 normal weight control subjects (48+/-9 years, BMI 23.7+/-1.9 kg/m(2)) were studied at the baseline. Twenty-eight obese subjects underwent a 12-week intensive weight reduction program followed by 5 months of weight maintenance. Blood samples and abdominal s.c. adipose tissue biopsies were taken at the baseline and after the follow-up. Gene expression was studied using real-time quantitative PCR.. The gene expressions in women and serum concentrations of leptin and SAA were interrelated independently of body fat mass in the obese subjects (r=0.54, P=0.001; r=0.24, P=0.039 respectively). In multiple linear regression analyses, leptin mRNA explained 38% of the variance in SAA mRNA (P=0.002) in the obese women. Weight loss of at least 5% increased SAA mRNA expression by 48 and 36% in men and women, but serum SAA concentrations did not change.. The association between SAA and leptin suggests an interaction between these two adipokines, which may have implications in inflammatory processes related to obesity and the metabolic syndrome.

Topics: Adipocytes; Adipose Tissue; Aged; Body Weight; Female; Gene Expression; Glucose Intolerance; Humans; Inflammation; Leptin; Male; Metabolic Syndrome; Middle Aged; Obesity; RNA, Messenger; Serum Amyloid A Protein; Weight Loss

Older, obese, and sedentary individuals are at high risk of developing diabetes and cardiovascular disease. Exercise training improves metabolic anomalies associated with such diseases, but the effects of caloric restriction in addition to exercise in such a high-risk group are not known. Changes in body composition and metabolism during a lifestyle intervention were investigated in 23 older, obese men and women (aged 66 +/- 1 yr, body mass index 33.2 +/- 1.4 kg/m(2)) with impaired glucose tolerance. All volunteers undertook 12 wk of aerobic exercise training [5 days/wk for 60 min at 75% maximal oxygen consumption (Vo(2max))] with either normal caloric intake (eucaloric group, 1,901 +/- 277 kcal/day, n = 12) or a reduced-calorie diet (hypocaloric group, 1,307 +/- 70 kcal/day, n = 11), as dictated by nutritional counseling. Body composition (decreased fat mass; maintained fat-free mass), aerobic fitness (Vo(2max)), leptinemia, insulin sensitivity, and intramyocellular lipid accumulation (IMCL) in skeletal muscle improved in both groups (P < 0.05). Improvements in body composition, leptin, and basal fat oxidation were greater in the hypocaloric group. Following the intervention, there was a correlation between the increase in basal fat oxidation and the decrease in IMCL (r = -0.53, P = 0.04). In addition, basal fat oxidation was associated with circulating leptin after (r = 0.65, P = 0.0007) but not before the intervention (r = 0.05, P = 0.84). In conclusion, these data show that exercise training improves resting substrate oxidation and creates a metabolic milieu that appears to promote lipid utilization in skeletal muscle, thus facilitating a reversal of insulin resistance. We also demonstrate that leptin sensitivity is improved but that such a trend may rely on reducing caloric intake in addition to exercise training.

Topics: Adiponectin; Adiposity; Aged; Body Composition; Caloric Restriction; Diet, Reducing; Dietary Fats; Exercise; Female; Glucose Intolerance; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Muscle, Skeletal; Obesity; Oxidation-Reduction; Oxygen Consumption; Physical Fitness; Weight Loss

Chromium has gained popularity as a nutritional supplement for diabetic patients. This study evaluated the effect of chronic administration of a chromium complex of D-phenylalanine (Cr(D-phe)(3)) on glucose and insulin tolerance in obese mice. The study tested the hypothesis that Cr(D-phe)(3) suppresses endoplasmic reticulum (ER) stress and insulin resistance in these animals.. C57BL lean and ob/ob obese mice were randomly divided to orally receive vehicle or Cr(D-phe)(3) (3.8 mug of elemental chromium/kg/day) for 6 months. Insulin sensitivity was evaluated by glucose and insulin tolerance tests. Protein levels of phosphorylated pancreatic ER kinase (PERK), alpha subunit of translation initiation factor 2 (eIF2alpha) and inositol-requiring enzyme-1 (IRE-1), p-c-Jun, and insulin receptor substrate-1 (IRS-1) phosphoserine-307 were assessed by western blotting. In vitro ER stress was induced by treating cultured muscle cells with thapsigargin in the presence or absence of Cr(D-phe)(3).. ob/ob mice showed poor glucose and insulin tolerance compared to the lean controls, which was attenuated by Cr(D-phe)(3). Markers of insulin resistance (phospho-c-Jun and IRS-1 phosphoserine) and ER stress (p-PERK, p-IRE-1, p-eIF2alpha), which were elevated in ob/ob mice, were attenuated following Cr(D-phe)(3) treatment. Chromium treatment was also associated with a reduction in liver triglyceride levels and lipid accumulation. In cultured myotubes, Cr(D-phe)(3) attenuated ER stress induced by thapsigargin.. Oral Cr(D-phe)(3) treatment reduces glucose intolerance, insulin resistance, and hepatic ER stress in obese, insulin-resistant mice.

Topics: Animals; Blood Glucose; Chromium; Diabetes Mellitus, Type 2; Disease Models, Animal; eIF-2 Kinase; Endoplasmic Reticulum; Glucose Intolerance; Insulin; Insulin Resistance; Leptin; Lipids; Liver; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Protein Serine-Threonine Kinases; Thapsigargin; Trace Elements

Obesity is characterized by systemic low-grade inflammation in which adipose tissue, especially the omental depot, is thought to play a key role. We have previously shown that inflammation impairs 3T3-L1 preadipocyte cell line differentiation. To explore whether this interaction also takes place in vivo, the expression of several genes related to inflammation and adipocyte differentiation was assessed in human samples. Paired adipose tissue biopsies (from omental and subcutaneous depots) were obtained from 24 women: 6 lean normoglycemic and 18 obese volunteers with different glycemic states (normoglycemic, glucose-intolerant, or type 2 diabetic). The expression levels of CD14, IL-18, leptin, adiponectin, sterol regulatory element binding transcription factor 1 (SREBP1), peroxisome proliferator-activated receptor gamma (PPARgamma), pre-B-cell colony enhancing factor 1 (PBEF1) (or visfatin), glycerol-3-phosphate dehydrogenase 1 (soluble) (GPD1), lipoprotein lipase (LPL), fatty acid binding protein 4, adipocyte (FABP4), and hypoxia-inducible factor 1alpha were determined by quantitative real-time PCR. CD14 and IL-18 were overexpressed in omental adipose tissue compared with the subcutaneous depot, irrespective of the subject's obesity or diabetes status. A significant decrease of LPL, GPD1, and leptin expression was observed in omental tissue, and an inverse correlation between expression of CD14 and IL-18 and that of PPARgamma, LPL, and FABP4 was observed. The underexpression of omental lipogenic markers was more accentuated in the presence of glucose intolerance. Furthermore, adiponectin and SREBP1 expression was also significantly decreased in omental tissue of type 2 diabetic patients. PBEF1 and HIF1alpha expression remained comparable in all samples. Therefore, in humans, inflammation is increased in the omental depot, as evidenced by CD14 and IL-18 expression. In this localization, the inflammatory state is associated with a decreased expression of lipogenic markers, which is more pronounced in diabetic subjects.

Topics: Adiponectin; Adipose Tissue; Adult; Body Composition; Cytokines; Diabetes Mellitus, Type 2; Fatty Acid-Binding Proteins; Female; Gene Expression Regulation; Glucose Intolerance; Glycerolphosphate Dehydrogenase; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Interleukin-18; Leptin; Lipogenesis; Lipopolysaccharide Receptors; Lipoprotein Lipase; Middle Aged; Nicotinamide Phosphoribosyltransferase; Obesity; Omentum; PPAR gamma; RNA, Messenger; Sterol Regulatory Element Binding Protein 1

Experimentally-induced hyperglycemia by prolonged glucose infusion allows investigation of the effects of sustained stimulation of the pancreatic beta-cell on insulin secretion and sensitivity. Hormonal responses to a meal following prolonged glucose infusions have not been investigated. To determine if a 48-h glucose infusion alters hormonal responses to a test meal as well as food intake and hunger in normal weight individuals, 16 subjects (8 men, 8 women, age 18-30 years, mean BMI=21.7+/-1.6 kg/m2) were infused for 48 h with either saline (50 ml/h) or 15% glucose (200 mg/m2/min). Subjects ingested a 600 kcal mixed nutrient meal 3 h after infusion termination. Blood samples were taken during the 48 h and for 4 h following food ingestion. The 48-h glucose infusion elicited a metabolic profile of a glucose intolerant obese subjects, with increased plasma glucose, insulin and leptin (all P<0.01) and increased HOMA-IR (P<0.001). During meal ingestion, early insulin secretion was increased (P<0.05) but post-prandial glucose (P<0.01) and insulin (P<0.01) excursions were lower following the glucose infusion. Post-prandial plasma triglyceride concentrations were increased after glucose compared with saline. Food intake and hunger ratings were not different between the two conditions. Plasma leptin levels were inversely correlated with hunger (P<0.03) in both conditions and with food intake (P<0.003) during the glucose condition only. Thus, a 48-h glucose infusion does not impair post-prandial hormonal responses, alter food intake or hunger in normal weight subjects. The glucose-induced increases in plasma leptin result in a stronger inverse relationship between plasma leptin and hunger as well as food intake. These data are the first to demonstrate a relationship between leptin and hunger in normal weight, non-calorically restricted human subjects.

Topics: Adolescent; Adult; Analysis of Variance; Blood Glucose; Eating; Female; Food Preferences; Glucose; Glucose Intolerance; Humans; Hunger; Hyperglycemia; Infusions, Intravenous; Insulin; Leptin; Male; Taste

Adult mice carrying a null mutation of the prostanoid receptor EP3R (EP3R(-/-) mice) exhibit increased frequency of feeding during the light cycle of the day and develop an obese phenotype under a normal fat diet fed ad libitum. EP3R(-/-) mice show increased motor activity, which is not sufficient to offset the increased feeding leading to increased body weight. Altered "nocturnal" activity and feeding behavior is present from a very early age and does not seem to require age-dependent factors for the development of obesity. Obesity in EP3R(-/-) mice is characterized by elevated leptin and insulin levels and >20% higher body weight compared with WT littermates. Abdominal and subcutaneous fat and increased liver weight account for the weight increase in EP3R(-/-) mice. These observations expand the roles of prostaglandin E(2) signaling in metabolic regulation beyond the reported stimulation of leptin release from adipose tissue to involve actions mediated by EP3R in the regulation of sleep architecture and feeding behavior. The findings add to the growing literature on links between inflammatory signaling and obesity.

Topics: Adipose Tissue; Aging; Animals; Body Temperature; Body Weight; Circadian Rhythm; Feeding Behavior; Food; Glucose Intolerance; Insulin; Insulin Resistance; Leptin; Male; Mice; Motor Activity; Obesity; Phenotype; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP3 Subtype

Oxidised frying oil (OFO) and fish oil have been shown to be peroxisome proliferator-activated receptor (PPAR)alpha activators and their ingestion results in pleotropic peroxisome proliferator responses in rats. To examine the effect of dietary OFO on adiposity, four groups of weanling Sprague-Dawley rats were fed isoenergetically with, respectively, a low fat basal diet containing 5 g/100 g of fresh soybean oil (LSB) or a high fat diet containing 20 g/100 g of fresh soybean oil (HSB), OFO (HO) or fish oil (HF). The tissue mass, cell size and lipid/DNA ratio in the retroperitoneal fat pad and serum leptin levels were lowest in the HO group (P < 0.05), indicating that dietary OFO has a greater anti-adipogenic action than dietary fish oil. However, a tendency to hyperglycaemia was observed in the HO group (P = 0.0528). To examine the effect of dietary OFO on glucose tolerance, three groups of rats and three groups of mice were fed, respectively, the LSB, HSB or HO diet, and an oral glucose tolerance test was performed. After oral glucose load, the area under the curve for blood glucose (AUCglu) over 2 h was significantly higher, and that for serum insulin (AUCins) over 90 min was significantly lower, in the HO group than in the other two groups (P < 0.05). These results demonstrate that, in rats and mice, a high OFO diet is less adipogenic, but induces glucose intolerance.

Topics: Adipocytes; Adipose Tissue; Animals; Blood Glucose; Body Weight; Cell Size; Cooking; Dietary Fats; DNA; Fish Oils; Glucose Intolerance; Glucose Tolerance Test; Leptin; Lipids; Male; Mice; Mice, Inbred C57BL; Rats; Rats, Sprague-Dawley; Soybean Oil

Epidemiological studies indicate that the risk factors for the development of various cancers are closely associated with metabolic symptoms such as obesity, hyperlipidemia, and insulin resistance caused by the excess consumption of high-calorie diets. However, the mechanisms of tumor growth and metastasis caused by feeding a high-calorie diet have not been clarified yet in tumor-bearing mice. In this study, we examined the effects of a high-fat (HF), a high-sucrose (HS), a high-cholesterol (HC) or a low-fat/low-sucrose (LF/LS) diet on tumor growth and metastasis in tumor-bearing mice. Angiogenic factors such as plasma leptin and monocyte chemoattractant protein-1 (MCP-1) were increased after the implantation of tumors, whereas conversely, an antiangiogenic factor, adiponectin, was reduced after the implantation of tumors in mice fed the HF, the HS, or the HC diet compared to LF/LS diet. Furthermore, we found that vascular endothelial growth factor, hypoxia inducible factor-1alpha and MCP-1 expression levels in tumors of mice fed the HF, the HS, or the HC diet were increased compared to those of mice fed the LF/LS diet. These findings suggest that the acceleration of tumor growth and metastasis by feeding the 3 diets may be due to the increase of angiogenic factors and the reduction of antiangiogenic factors.

Topics: Adiponectin; Animals; Body Weight; Carcinoma, Lewis Lung; Chemokine CCL2; Cholesterol, Dietary; Diet; Dietary Fats; Dietary Sucrose; Disease Progression; Dose-Response Relationship, Drug; Glucose Intolerance; Glucose Tolerance Test; Hyperinsulinism; Hyperlipidemias; Immunohistochemistry; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms, Experimental; Obesity; Random Allocation

Plasma levels of adiponectin are lower in obese and insulin-resistant subjects compared with lean and insulin-sensitive ones. Thiazolidinediones increase plasma adiponectin levels in diabetic subjects, although the mechanism of this increased plasma adiponectin has not been well studied. In the present study, we compared the plasma levels and adipose tissue expression of adiponectin in subjects with normal (NGT) and impaired glucose tolerance (IGT) and also studied the effects of metformin and pioglitazone on plasma and adipose tissue mRNA level of adiponectin in IGT subjects. IGT subjects had lower plasma adiponectin levels compared with NGT subjects, and similarly IGT subjects had lower adiponectin mRNA levels. In contrast, the increased plasma levels of adiponectin in response to pioglitazone were not associated with increased adiponectin expression in adipose tissue. Metformin did not cause any change in plasma or expression levels of adiponectin. Other adipokines were examined, and both pioglitazone and metformin decreased plasma levels of resistin in IGT subjects, and pioglitazone (but not metformin) decreased plasma levels of leptin. These data suggest that pioglitazone increases plasma adiponectin levels by posttranscriptional regulation in contrast to transcriptional regulation of adiponectin in relation to insulin sensitivity in NGT vs. IGT subjects.

Topics: Abdominal Fat; Adiponectin; Adult; Blood Glucose; Female; Gene Expression; Glucose Intolerance; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin; Leptin; Metformin; Middle Aged; Pioglitazone; Resistin; Thiazolidinediones

The prevalence of type 2 diabetes has been rapidly increasing in conjunction with the westernization of diet patterns in Asia. We determined whether the antecedent consumption of traditional Asian-style diets (ADs) deteriorates insulin action, insulin secretion and pancreatic beta-cell mass after subsequent imposition of the diabetogenic challenge of Western-style diets (WDs) in weaning male Sprague-Dawley rats. Rats were provided AD (a low-fat and plant protein diet), WD (a high-fat and animal protein diet) or a control diet (CD) (a low-fat and animal protein diet) for 12 weeks. After 12 weeks, the groups were divided into two subsets; one set of the groups continued to consume their previous diets of WD, AD and CD for another 12 weeks, and the second set was divided into three groups represented by a switch in their designated diets from WD to AD, AD to WD and CD to WD. Whole-body glucose disposal rates and GLUT4 contents in soleus muscles were lower in WD regardless of the antecedent protein sources. The first-phase insulin secretion was higher in the CD group than in the other groups, whereas the second phase was lowered with AD consumption as antecedent and/or present diets. Asian-style diet and AD-WD intake did not compensate for insulin resistance due to the failure of beta-cell expansion via decreased proliferation. These findings suggest that the antecedent consumption of AD possibly accelerates and augments the development of glucose dysregulation via decreased insulin secretion capacity and pancreatic beta-cell mass when the diets switch to WD.

Topics: Animals; Asia; Blood Glucose; Body Weight; Diet; Diet, Fat-Restricted; Dietary Fats; Dietary Proteins; Energy Intake; Fasting; Glucose Clamp Technique; Glucose Intolerance; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Leptin; Male; Plant Proteins; Rats; Rats, Sprague-Dawley; Weaning

Polygenic mouse models for obesity-induced type 2 diabetes (T2D) more accurately reflect the most common manifestations of the human disease. Two inbred mouse strains (NON/Lt and NZO/HlLt) separately contributed T2D susceptibility- conferring quantitative trait loci to F1 males. Although chronic administration of rosiglitazone (Rosi) in diet (50 mg/kg) effectively suppressed F1 diabetes, hepatosteatosis was an undesired side effect. Three recombinant congenic strains (designated RCS1, -2, and -10) developed on the NON/Lt background carry variable numbers of these quantitative trait loci that elicit differential weight gain and male glucose intolerance syndromes of variable severity. We previously showed that RCS1 and -2 mice responded to chronic Rosi therapy without severe steatosis, whereas RCS10 males were moderately sensitive. In contrast, another recombinant congenic strain, RCS8, responded to Rosi therapy with the extreme hepatosteatosis observed in the F1. Longitudinal changes in multiple plasma analytes, including insulin, the adipokines leptin, resistin, and adiponectin, and plasminogen activator inhibitor-1 (PAI-1) allowed profiling of the differential Rosi responses in steatosis-exacerbated F1 and RCS8 males vs. the resistant RCS1 and RCS2 or moderately sensitive RCS10. Of these biomarkers, PAI-1 most effectively predicted adverse drug responses. Unexpectedly, mean resistin concentrations were higher in Rosi-treated RCS8 and RCS10. In summary, longitudinal profiling of multiple plasma analytes identified PAI-1 as a useful biomarker to monitor for differential pharmacogenetic responses to Rosi in these new mouse models of T2D.

Topics: Adiponectin; Analysis of Variance; Animals; Biomarkers; Diabetes Mellitus, Type 2; Disease Models, Animal; Fatty Liver; Female; Glucose Intolerance; Hypoglycemic Agents; Insulin; Leptin; Male; Mice; Mice, Congenic; Mice, Inbred NOD; Mice, Obese; Obesity; Phenotype; Plasminogen Activator Inhibitor 1; Quantitative Trait, Heritable; Recombination, Genetic; Resistin; Rosiglitazone; Species Specificity; Syndrome; Thiazolidinediones

Glucose tolerance progressively declines with age whilst the onset of type two diabetes increases dramatically. Glucose-dependent insulinotropic polypeptide (GIP) potentiates glucose-induced insulin secretion. The present study was designed to assess the insulinotropic effects of a potent long-acting GIP receptor agonist, N-AcGIP(LysPAL37), in aging mice. In older mice, body weights, basal plasma glucose and insulin concentrations were significantly higher than in young mice (P<0.05 to P<0.001). Intraperitoneal injection of glucose alone (18 mmol/kg body weight) revealed a significantly lower (P<0.05) insulin response in older mice, which was accompanied by impaired glucose tolerance (P<0.05). Normal glucose-mediated insulin secretion was restored in N-AcGIP(LysPAL37) treated older mice. However the glycaemic excursion remained significantly impaired in older mice (P<0.05), suggestive of impaired insulin action. Native GIP had a similar overall effect in younger and older mice. These data indicate that N-AcGIP(LysPAL37) is able to counter the age-related deterioration of pancreatic beta cell glucose sensitivity and insulin secretion.

Topics: Aging; Animals; Blood Glucose; Eating; Gastric Inhibitory Polypeptide; Glucose Intolerance; Glucose Tolerance Test; Homeostasis; Insulin; Islets of Langerhans; Leptin; Mice; Mice, Mutant Strains

Weight gain and type 2 diabetes mellitus (DM) are often linked to antipsychotics treatment. The aim of the study is to investigate serum free fatty acids (FFA) levels in schizophrenic patients who received long-term antipsychotics treatment, and to explore the associations between serum FFA and fasting blood glucose, and insulin resistance.. 308 inpatients with schizophrenia who met with the criteria of DSM-IV were recruited into this study, and were divided into four groups: control subjects, single obesity, impaired glucose tolerance (IGT) and type 2 DM according to different body mass index, fasting blood glucose level and 2-hour postprandial blood glucose. Serum FFA was measured with colorimetry. Serum insulin and leptin were measured with radioimmunoassay respectively.. There was a significant elevation in serum FFA levels in schizophrenic patients who received long-term antipsychotics treatment, especially in single obesity, IGT, and DM groups. The elevated serum FFA was remarkably positive correlated with fasting blood glucose and insulin resistance.. The study suggested the elevated serum FFA in schizophrenic patients with long-term antipsychotics treatment affected the blood glucose metabolism, may have played an important role in insulin resistance and type 2 DM, and was also an important trait of metabolic syndromes.

Topics: Adult; Antipsychotic Agents; Blood Glucose; Body Mass Index; Colorimetry; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Glucose Intolerance; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Psychiatric Status Rating Scales; Radioimmunoassay; Regression Analysis; Schizophrenia

Low birthweight (LBW) and rapid postnatal weight gain, or catch-up growth, are independent risk factors for the development of obesity and diabetes during adult life. Individuals who are both small at birth and have postnatal catch-up growth are at the highest risk. We hypothesised that dietary interventions designed to attenuate catch-up growth in LBW subjects may have long-term beneficial consequences.. We used our previously described mouse model of LBW-associated diabetes, created by restricting maternal food intake to 50% during the last week of gestation. Control (C) dams and dams that had been subjected to undernutrition (U) were then provided either chow ad libitum after delivery or 50% food restriction on a per-day basis from delivery until weaning. We designated the resulting four groups control-control (CC), undernutrition-control (UC), control-undernutriton (CU) and undernutrition-undernutrition (UU), indicating the prenatal and postnatal experimental conditions, respectively. Carbohydrate metabolism and adiposity were assessed prospectively in offspring until age 6 months.. Males that were small at birth and exhibited early postnatal catch-up growth developed glucose intolerance and obesity by age 6 months. In contrast, LBW mice without catch-up growth (UU) remained smaller than controls (CC), and glucose intolerance and obesity was prevented. Similarly, mice with normal birthweight that had blunted catch-up growth (CU) were leaner and had better tolerance test than CC mice. Catch-up growth during the first week of life correlated better than birthweight with glucose, fat mass and glucose tolerance up to 6 months of age.. Prevention of early catch-up growth reversed the development of glucose intolerance and obesity in our mouse model of LBW-associated diabetes.

Topics: Diet, Reducing; Energy Intake; Glucose Intolerance; Growth; Humans; Infant; Infant, Low Birth Weight; Infant, Newborn; Insulin; Leptin; Obesity

Prolactin (PRL), best recognized for its lactogenic activity, is also involved in the regulation of metabolic homeostasis in both mammalian and nonmammalian species. Although several mouse models have been used to study the metabolic functions of PRL, a clear-cut consensus has not emerged given the limited and often conflicting data. To clarify the role of PRL in metabolic homeostasis in males and nonlactating females, we used the PRL-deficient mouse. Our objectives were to compare: 1) weight gain, 2) body composition, 3) serum lipid profile, 4) circulating leptin and adiponectin levels, and 5) glucose tolerance in PRL knockout, heterozygous, and wild-type mice maintained on standard chow, high-fat, or low-fat diets. In addition, we compared the lipolytic actions of PRL using adipose tissue explants from mice, rats, and humans. We are reporting that PRL deficiency does not affect the rate of weight gain, body composition, serum lipids, or adiponectin levels in either sex on any diet. Glucose tolerance was slightly impaired in very young PRL knockout male pups but not in adults or in females at any age. Leptin was elevated in male, but not female, PRL knockout mice maintained on a low-fat diet. PRL did not affect lipolysis in adipose tissue explants from mice but significantly inhibited glycerol release from both rat and human adipose explants in a dose-dependent manner. We conclude that PRL deficiency has negligible gross metabolic effects in mice.

Topics: Adiponectin; Adipose Tissue; Animals; Body Composition; Diet, Fat-Restricted; Dietary Fats; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Leptin; Lipids; Lipolysis; Lymphocytes; Male; Metabolism; Mice; Mice, Knockout; Phenotype; Prolactin; Rats; Reverse Transcriptase Polymerase Chain Reaction; Sex Characteristics; Weight Gain

To evaluate the relation between cardiovascular disease (CVD) risk factors and hormone therapy, serum hormone levels, glucose tolerance, and psychosocial and psychological conditions in subjectively healthy obese female subjects.. The study included 606 women, aged 50-64 years, with BMI 30-40 kg/m(2) and no history of cardiovascular or other severe diseases. One group with a CVD risk profile (n = 473) (i.e., cholesterol >7.0 mmol/l, HDL cholesterol <1.2 mmol/l, triglycerides >2.0 mmol/l, systolic or diastolic blood pressure >140/90 mmHg, or waist-to-hip ratio >0.85) was compared with women without such risk (n = 133). Steroid hormones, leptin, insulin, and oral glucose tolerance tests (OGTTs) were analyzed. A subgroup of women with baseline impaired glucose tolerance (IGT) completed a 2.5-year follow-up OGTT.. Fewer obese postmenopausal women with CVD risk had ever used hormone therapy (odds ratio 0.24 [95% CI 0.07-0.75]), after multivariate adjustments. Furthermore, women with CVD risk had a higher testosterone index (1.07 [1.01-1.13]) and more had insulin resistance (1.04 [1.00-1.08]) and IGT (2.92 [1.50-5.69]), while OGTT was similar at follow-up. No differences were observed regarding family history or lifestyle, except that fewer women with CVD risk consumed fruits, boiled vegetables, or whole-grain cereals. More women with CVD risk lived alone (3.26 [1.28-8.31]) and had more mental problems (1.16 [1.05-1.28]).. Previously healthy obese women with a CVD risk profile seemed to have a high risk of diabetes, as well as psychosocial or psychological problems. Hormone therapy was associated with reduced CVD risk. Obesity's growing burden on society makes it more important to further target individuals that are at greatest risk of future health hazards.

Topics: Adult; Cardiovascular Diseases; Cholesterol; Estradiol; Estrogen Replacement Therapy; Family Health; Feeding Behavior; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin; Leptin; Life Style; Multivariate Analysis; Obesity; Occupations; Psychology; Quality of Life; Risk Factors; Testosterone

Topics: Adoptive Transfer; Animals; CD4-CD8 Ratio; CD4-Positive T-Lymphocytes; Cell Transplantation; Fatty Liver; Glucose Intolerance; Glucose Tolerance Test; Hepatitis; Immunity, Innate; Interleukin-10; Killer Cells, Natural; Leptin; Mice; Mice, Obese; Nuclear Magnetic Resonance, Biomolecular; Spleen

Adipokines and ghrelin play role in insulin resistance, the key pathophysiological abnormality in patients with nonalcoholic fatty liver diseases. In the present study, relationship between nonalcoholic steatohepatitis (NASH) and serum adipokine and ghrelin levels was investigated. Thirty seven patients with biopsy-proven NASH and 25 age- and sex-matched controls were enrolled. Ten of NASH patients (27%) had diabetes mellitus (n = 5) or impaired glucose tolerance (n = 5). Body mass index (BMI) was less than 30 kg/m(2) in 67.6% of patients, while in the remaining 32.4% it was more than 30 kg/m(2). Serum adiponectin, leptin, TNF-alpha, and ghrelin were determined. Serum leptin (15.49 +/- 4.84 vs 10.31 +/- 2.53) and TNF-alpha (12.1 +/- 2.7 vs 10.31 +/- 2.56) levels were significantly higher in the NASH group compared to in the control group (P < .001 for each). Nevertheless, adiponectin (11.1 +/- 2.1 vs 17.3 +/- 2.8) and ghrelin (6.46 +/- 1.1 vs 7.8 +/- 1.1) levels were lower in the NASH group than in the control group (P < .001 for each). Serum levels of the adipokines and ghrelin, however, were comparable in the subgroups of patients regardless of whether BMI was < 30 or > 30 or glucose tolerance was impaired or not (P > .05). Additionally, neither adipokines nor ghrelin was correlated with histopathological grade and stage (P > .05). In conclusion; there is a significant relationship between NASH and adipokines and ghrelin independent from BMI and status of the glucose metabolism. These cytokines that appear to have role in the pathogenesis of NASH, however, do not have any effect upon the severity of the histopathology.

Topics: Adiponectin; Adult; Body Mass Index; Case-Control Studies; Diabetes Mellitus; Fatty Liver; Female; Ghrelin; Glucose Intolerance; Hepatitis; Humans; Leptin; Male; Middle Aged; Peptide Hormones; Reference Values; Tumor Necrosis Factor-alpha

Topics: Adiponectin; Arteriosclerosis; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Gene Expression; Glucose Intolerance; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Intercellular Signaling Peptides and Proteins; Leptin; Lipid Metabolism; Pioglitazone; PPAR gamma; Thiazolidinediones; Tumor Necrosis Factor-alpha

To investigate whether maternal serum leptin level can be used as a predictor of gestational diabetes mellitus (GDM) and gestational impaired glucose tolerance (GIGT).. Five hundred and eighty-three pregnant women were screened for GDM by the 50g oral glucose challenge test. At the same time, serum leptin levels were determined by radioimmunoassay, then the relationship between maternal serum leptin level and the incidence of GIGT and GDM was analyzed. According to the screening result, all the pregnant women were divided into three groups, the normal glucose group (NGT group), the gestational impaired glucose tolerance group (GIGT group), and gestational diabetes mellitus group (GDM group). GIGT group and GDM group were named as glucose intolerant group as a whole.. (1) The serum leptin concentration of normal pregnant women ascended gradually from (7.0 +/- 1.8) microg/L in 24 gestational week to (9.4 +/- 2.1) microg/L during 34 - 36 gestational week, and then declined slightly but still maintained high level till delivery. (2) The serum leptin concentration of the glucose intolerant pregnant women ranged from (11.3 +/- 3.1) microg/L to(14.5 +/- 4.3) microg/L, and showed no difference among different gestational weeks (P > 0.05). (3) Serum leptin level of glucose intolerant women was (12.5 +/- 3.5) microg/L on average, much higher than that of NGT group, (8.5 +/- 2.6) microg/L (P < 0.05), and this difference remained in any gestational week (P < 0.05). (4) Most of the GDM clustered in the higher leptin level groups and 66.7% GDM had a serum leptin level higher than 14.0 microg/L. Moreover, 64.7% of women whose serum leptin level was above 17.0 microg/L had different degree of glucose intolerance. Serum leptin level positively correlated with the incidence of GIGT and GDM.. Serum leptin level is correlated with glucose tolerance during pregnancy. Its abnormal increase during pregnancy might have a predictive value for GDM and GIGT.

Topics: Adult; Blood Glucose; Diabetes, Gestational; Female; Glucose Intolerance; Humans; Leptin; Pregnancy; Prenatal Diagnosis

We describe the generation and characterization of the first inducible 'fatless' model system, the FAT-ATTAC mouse (fat apoptosis through targeted activation of caspase 8). This transgenic mouse develops identically to wild-type littermates. Apoptosis of adipocytes can be induced at any developmental stage by administration of a FK1012 analog leading to the dimerization of a membrane-bound, adipocyte-specific caspase 8-FKBP fusion protein. Within 2 weeks of dimerizer administration, FAT-ATTAC mice show near-knockout levels of circulating adipokines and markedly reduced levels of adipose tissue. FAT-ATTAC mice are glucose intolerant, have diminished basal and endotoxin-stimulated systemic inflammation, are less responsive to glucose-stimulated insulin secretion and show increased food intake independent of the effects of leptin. Most importantly, we show that functional adipocytes can be recovered upon cessation of treatment, allowing the study of adipogenesis in vivo, as well as a detailed examination of the importance of the adipocyte in the regulation of multiple physiological functions and pathological states.

Topics: Adipocytes; Adipose Tissue; Animals; Apoptosis; Caspase 8; Caspases; Dimerization; Eating; Enzyme Activation; Glucose Intolerance; Inflammation; Insulin; Insulin Secretion; Leptin; Lipodystrophy; Lipopolysaccharides; Mice; Mice, Transgenic; Recombinant Fusion Proteins; Tacrolimus; Tacrolimus Binding Proteins

Leptin augments glucose and lipid metabolism independent of its effect on satiety. Administration of leptin in rodents increases skeletal muscle beta-oxidation by activating AMP-activated protein kinase (AMPK). We previously reported that, as hyperleptinemic as obese human subjects, transgenic skinny mice overexpressing leptin in liver (LepTg) exhibit enhanced insulin sensitivity and lipid clearance. To assess skeletal muscle AMPK activity in leptin-sensitive and -insensitive states, we examined phosphorylation of AMPK and its target, acetyl CoA carboxylase (ACC), in muscles from LepTg under dietary modification. Here we show that phosphorylation of AMPK and ACC are chronically augmented in LepTg soleus muscle, with a concomitant increase in the AMP-to-ATP ratio and a significant decrease in tissue triglyceride content. Despite preexisting hyperleptinemia, high-fat diet (HFD)-fed LepTg develop obesity, insulin-resistance, and hyperlipidemia. In parallel, elevated soleus AMPK and ACC phosphorylation in regular diet-fed LepTg is attenuated, and tissue triglyceride content is increased in those given HFD. Of note, substitution of HFD with regular diet causes a robust recovery of soleus AMPK and ACC phosphorylation in LepTg, with a higher rate of body weight reduction and a regain of insulin sensitivity. In conclusion, soleus AMPK and ACC phosphorylation in LepTg changes in parallel with its insulin sensitivity under dietary modification, suggesting a close association between skeletal muscle AMPK activity and sensitivity to leptin.

Topics: Acetyl-CoA Carboxylase; Adenosine Monophosphate; Adenosine Triphosphate; AMP-Activated Protein Kinases; Animals; Carrier Proteins; Diet; Dietary Fats; Glucose Intolerance; Hyperlipidemias; Insulin Resistance; Ion Channels; Leptin; Liver; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondrial Proteins; Multienzyme Complexes; Muscle, Skeletal; Obesity; Phosphorylation; Protein Serine-Threonine Kinases; RNA, Messenger; Stearoyl-CoA Desaturase; Triglycerides; Uncoupling Protein 1; Weight Loss

Nonalcoholic steatohepatitis is prevalent among obese individuals with excessive caloric intake, insulin resistance, and type II diabetes. However, no animal models exist that recapitulate this important association. This study produced and characterized steatohepatitis (SH) caused by intragastric overfeeding in mice. C57BL/6, tumor necrosis factor (TNF) type I receptor-deficient, and genetically matched wild type mice were fed via an implanted gastrostomy tube a high-fat diet for 9 weeks in the increasing amount up to 85% in excess of the standard intake. Animals were examined for weight gain, insulin sensitivity, and histology and biochemistry of liver and white adipose tissue (WAT). Overfed C57BL/6 mice progressively became obese, with 71% larger final body weights. They had increased visceral WAT, hyperglycemia, hyperinsulinemia, hyperleptinemia, glucose intolerance, and insulin resistance. Of these mice, 46% developed SH with increased plasma alanine aminotransferase (121 +/- 27 vs. 13 +/- 1 U/L), neutrophilic infiltration, and sinusoidal and pericellular fibrosis. Obese WAT showed increased TNFalpha and leptin expression and reciprocally reduced adiponectin expression. The expression of lipogenic transcription factors (SREBP-1c, PPARgamma, LXRalpha) was increased, whereas that of a lipolytic nuclear factor PPARalpha was reduced in SH. SH was associated with reduced cytochrome P450 (Cyp)2e1 but increased Cyp4a. TNF type I receptor deficiency did not prevent obesity and SH. In conclusion, forced overfeeding with a high-fat diet in mice induces obesity, insulin resistance, and SH in the absence of TNF signaling or Cyp2e1 induction.

Topics: Alanine Transaminase; Animals; Cytochrome P-450 CYP2E1; Cytochrome P-450 CYP4A; Dietary Fats; Disease Models, Animal; Eating; Fatty Liver; Gastrostomy; Glucose Intolerance; Insulin Resistance; Leptin; Liver Cirrhosis; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophils; Obesity; PPAR alpha; Receptors, Tumor Necrosis Factor, Type I; Tumor Necrosis Factor-alpha

Age-related obesity is associated with impaired hypothalamic pro-opiomelanocortin (Pomc) gene expression. We assessed whether overproduction of POMC in the hypothalamus ameliorates age-related obesity in rats.. Recombinant adeno-associated virus (rAAV) encoding Pomc (rAAV-Pomc) or control vector was delivered bilaterally into the basomedial hypothalamus of aged obese rats with coordinates targeting the arcuate nucleus. Energy balance, glucose metabolism, brown adipose tissue thermogenesis and mRNA levels of hypothalamic neuropeptides and melanocortin receptors were assessed.. Forty-two days after Pomc gene delivery, hypothalamic Pomc expression increased 12-fold while agouti-related protein and neuropeptide Y mRNA levels remained unchanged. Using a punch technique, we detected the highest Pomc RNA level in the arcuate nucleus. Pomc overexpression reduced food consumption from day 10 after vector injection, but this anorexic effect abated by day 30. In contrast, there was a steady decrease in body weight without apparent attenuation. Pomc gene delivery decreased visceral adiposity and induced uncoupling protein 1 in brown adipose tissue in aged rats. Serum NEFA and triglyceride levels were also diminished by rAAV-Pomc treatment. Improved glucose metabolism and insulin sensitivity were observed on day 36 but not day 20 after Pomc gene delivery. The expression of hypothalamic melanocortin 3 and 4 receptor decreased by 17% and 25%, respectively in rAAV-Pomc rats.. This study demonstrates that targeted Pomc gene therapy in the hypothalamus reduces body weight and visceral adiposity, and improves glucose and fat metabolism in aged obese rats. Thus long-term activation of the central melanocortin system may be a viable strategy to combat age-related obesity and diabetes.

Topics: Adipose Tissue, Brown; Aging; Agouti-Related Protein; Animals; Body Weight; Cholesterol; Dependovirus; Eating; Fatty Acids, Nonesterified; Genetic Therapy; Genetic Vectors; Glucose; Glucose Intolerance; Glucose Tolerance Test; Hypothalamus; Intercellular Signaling Peptides and Proteins; Leptin; Male; Neuropeptide Y; Obesity; Peptide Hormones; Pro-Opiomelanocortin; Rats; Rats, Inbred F344; Receptor, Melanocortin, Type 3; Receptor, Melanocortin, Type 4; Triglycerides

The pathophysiology of TallyHo mouse, a recently established animal model for type 2 diabetes mellitus, was analyzed at prediabetic state to examine the inherent defects which contribute to the development of diabetes. At 4 weeks of age, the TallyHo mice already revealed glucose intolerance while their peripheral tissues exhibited normal insulin sensitivity. On the other hand, decreased plasma insulin concentration was observed with little differences in pancreatic insulin contents, indicating the impaired insulin secretion. Such defect, however, was not found in the isolated islets, which suggests a role of endocrine factor in impaired insulin secretion of TallyHo mice. Treatment of leptin inhibited the glucose-stimulated insulin secretion from the isolated islets of TallyHo mice, while in vivo administration of anti-leptin antibody lowered plasma glucose concentration with increased insulin level in TallyHo mice. Expression of glucokinase mRNA was decreased both in whole pancreas and leptin treated islets of TallyHo mice compared with whole pancreas in C57BL/6 mice and untreated islets of TallyHo mice, respectively. These results suggest that elevated plasma leptin can, through the inhibition of insulin secretion, induce glucose intolerance in TallyHo mice.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Glucokinase; Glucose Intolerance; Insulin; Insulin Secretion; Islets of Langerhans; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Pancreas; Prediabetic State; Receptors, Cell Surface; Receptors, Leptin

Overexpression of the rate-limiting enzyme for hexosamine synthesis (glutamine:fructose-6-phosphate amidotransferase) in muscle and adipose tissue of transgenic mice was previously shown to result in insulin resistance and hyperleptinemia. Explanted muscle from transgenic mice was not insulin resistant in vitro, suggesting that muscle insulin resistance could be mediated by soluble factors from fat tissue. To dissect the relative contributions of muscle and fat to hexosamine-induced insulin resistance, we overexpressed glutamine:fructose-6-phosphate amidotransferase 2.5-fold, specifically in fat under control of the aP2 promoter. Fasting glucose, insulin, and triglycerides were unchanged in the transgenic mice; leptin and beta-hydroxybutyrate levels were 91% and 29% higher, respectively. Fasted transgenic mice have mild glucose intolerance and skeletal muscle insulin resistance in vivo. In fasting transgenic mice, glucose disposal rates with hyperinsulinemia were decreased 27% in females and 10% in males. Uptake of 2-deoxy-D-glucose into muscle was diminished by 45% in female and 21% in male transgenics. Serum adiponectin was also lower in the fasted transgenics, by 37% in females and 22% in males. TNF alpha and resistin mRNA levels in adipose tissue were not altered in the fasted transgenics; levels of mRNA for leptin were increased and peroxisome proliferator-activated receptor gamma decreased. To further explore the relationship between adiponectin and insulin sensitivity, we examined mice that have been refed for 6 h after a 24-h fast. Refeeding wild-type mice resulted in decreased serum adiponectin and increased leptin. In transgenic mice, however, the regulation of these hormones by refeeding was lost for adiponectin and diminished for leptin. Refed transgenic female and male mice no longer exhibited decreased serum adiponectin in the refed state, and they were no longer insulin resistant as by lower or unchanged insulin and glucose levels. We conclude that increased hexosamine levels in fat, mimicking excess nutrient delivery, are sufficient to cause insulin resistance in skeletal muscle. Changes in serum adiponectin correlate with the insulin resistance of the transgenic animals.

Topics: 3-Hydroxybutyric Acid; Adiponectin; Adipose Tissue; Animals; Blood Glucose; Deoxyglucose; Fasting; Female; Food; Gene Expression; Glucose Intolerance; Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing); Hexosamines; Humans; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Muscle, Skeletal; Proteins; Receptors, Cytoplasmic and Nuclear; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Transcription Factors; Triglycerides

Our primary objective was to evaluate changes in energy expenditure and body composition in women with normal glucose tolerance (NGT) and gestational diabetes mellitus (GDM). A secondary objective was to examine the relationship between maternal leptin and nutrient metabolism. Fifteen obese women, eight with NGT and seven with GDM, were evaluated before conception (P), at 12-14 wk (E), and at 34-36 wk (L). Energy expenditure and glucose and fat metabolism were measured using indirect calorimetry. Basal hepatic glucose production was measured using [6,6-2H2]glucose and insulin sensitivity by euglycemic clamp. There was a significant increase (6.6 kg, P = 0.0001) in fat mass from P to L. There was a 30% (P = 0.0001) increase in basal O2 consumption (VO2, ml/min). There were no significant changes in carbohydrate oxidation during fasting or storage from P to L. There was, however, a significant (P = 0.0001) 150% increase in basal fat oxidation (mg/min) from P to L. Under hyperinsulinemic conditions, there were similar 25% increases in VO2 (P = 0.0001) from P to L in both groups. Because of the significant increases in insulin resistance from P to L, there was a significant (P = 0.0001) decrease in carbohydrate oxidation and storage. There was a net change from lipogenesis to lipolysis, i.e., fat oxidation (30-40 mg/min, P = 0.0001) from P to L. Serum leptin concentrations had a significant positive correlation with fat oxidation at E (r = 0.76, P = 0.005) and L (r = 0.72, P = 0.009). Pregnancy in obese women is associated with significant increases in fat mass and basal metabolic rate and an increased reliance on lipids both in the basal state and during the clamp. These modifications are similar in women with NGT and GDM. The increased reliance on fat metabolism is accompanied by a concomitant decrease in carbohydrate metabolism during hyperinsulinemia. The increase in fat oxidation may be related to increased maternal serum leptin.

Topics: Adult; Body Composition; Diabetes, Gestational; Energy Metabolism; Female; Glucose; Glucose Intolerance; Humans; Insulin; Leptin; Lipid Metabolism; Longitudinal Studies; Obesity; Osmolar Concentration; Oxidation-Reduction; Pregnancy; Pregnancy Complications; Prospective Studies

Impaired insulin secretion and insulin resistance are thought to be two major causes of type 2 diabetes mellitus. There are two kinds of diabetic model mice: one is a K(ATP) channel knockout (Kir6.2KO) mouse which is defective in glucose-induced insulin secretion, and the other is a transgenic mouse expressing the tyrosine kinase-deficient (dominant-negative form of) human insulin receptor (hIR(KM)TG), and which has insulin resistance in muscle and fat. However, all of these mice have no evidence of overt diabetes. To determine if the double mutant Kir6.2KO/hIR(KM)TG mice would have diabetes, we generated mutant mice by crossbreeding, which would show both impaired glucose-induced insulin secretion and insulin resistance in muscle and fat. We report here that: 1) blood glucose levels of randomly fed and 6 h fasted double mutant (Kir6.2KO/hIR(KM)TG) mice were comparable with those of wild type mice; 2) in intraperitoneal glucose tolerance test (ipGTT), Kir6.2KO/hIR(KM)TG mice had an impaired glucose tolerance; and 3) during ipGTT, insulin secretion was not induced in either Kir6.2KO/hIR(KM)TG or Kir6.2KO mice, while the hIR(KM)TG mice showed a more prolonged insulin secretion than did wild type mice; 4) hyperinsulinemic euglycemic clamp test revealed that Kir6.2KO, Kir6.2KO/hIR(KM)TG and hIR(KM)TG mice, showed decreased whole-body glucose disposal compared with wild type mice; 5) Kir6.2KO, but not Kir6.2KO/hIR(KM)TG mice had some obesity and hyperleptinemia compared with wild type mice. Thus, the defects in glucose-induced insulin secretion (Kir6.2KO) and an insulin resistance in muscle and fat (hIR(KM)TG) were not sufficient to lead to overt diabetes.

Topics: Adipose Tissue; Animals; Blood Glucose; Enzyme Activation; Epididymis; Fasting; Genes, Dominant; Genotype; Glucose; Glucose Clamp Technique; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Leptin; Liver; Male; Mice; Mice, Knockout; Mice, Transgenic; Organ Size; Postprandial Period; Potassium Channels, Inwardly Rectifying; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Receptor, Insulin

We evaluated the effects of E2F1 on glucose homeostasis using E2F1(-/-) mice. E2F1(-/-) mice show an overall reduction in pancreatic size as the result of impaired postnatal pancreatic growth. Furthermore, these animals have dysfunctional beta cells, linked to impaired PDX-1 activity. Because of the disproportionate small pancreas and dysfunctional islets, E2F1(-/-) mice secrete insufficient amounts of insulin in response to a glucose load, resulting in glucose intolerance. Despite this glucose intolerance, E2F1(-/-) mice do not develop overt diabetes mellitus because they have insulin hypersensitivity, which is secondary to a diminished adipose tissue mass and altered adipocytokine levels, which compensates for the defect in insulin secretion. These data demonstrate that factors controlling cell proliferation, such as E2F1, determine pancreatic growth and function, subsequently affecting metabolic homeostasis.

Topics: Adaptor Proteins, Signal Transducing; Adipocytes; Animals; Apoptosis; Blood Glucose; Carrier Proteins; Cell Division; Gene Expression Regulation; Glucose; Glucose Intolerance; Homeodomain Proteins; Homeostasis; Insulin; Insulin Secretion; Islets of Langerhans; Leptin; Male; Mice; Mice, Knockout; Muscle, Smooth; Pancreas; RNA-Binding Proteins; Time Factors; Trans-Activators

There is growing evidence that prenatal adversities could be implicated in foetal programming of adult chronic diseases. Since maternal stress is known to disturb the foetal glucocorticoid environment, we examined the consequences of prenatal stress on foetal growth, on glucose-insulin metabolism and on feeding behaviour in the aged male rat. In foetuses at term, maternal stress reduced body, adrenal and pancreas weight as well as plasma corticosterone and glucose levels. In aged male rats (24 months of age), prenatal stress induced hyperglycaemia and glucose intolerance and decreased basal leptin levels. Moreover, after a fasting period, they showed an increased food intake. These data suggest that maternal stress induces a long-lasting disturbance in feeding behaviour and dysfunctions related to type 2 diabetes mellitus. This programming could be linked to the early restricted foetal growth and to the adverse glucocorticoid environment in utero.

Topics: Adrenal Glands; Aging; Animals; Birth Weight; Blood Glucose; Corticosterone; Feeding Behavior; Female; Fetal Growth Retardation; Glucose Intolerance; Leptin; Male; Organ Size; Pancreas; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Stress, Psychological

Leptin and its receptors are known to play a role in glucose metabolism. We succeeded in cloning human Ob-R cDNA and revealed 7 single nucleotide polymorphisms (SNPs) (Lys109Arg, Arg223Gln, Ser343Ser, Ser492Thr, Lys656Asn, Ala976Asp, and Pro1019Pro) in the coding region of Ob-Rb. Although these 7 SNPs were not associated with an obese phenotype, several studies have reported that some of them were associated with impaired glucose metabolism. To clarify whether the Arg223Gln and A3057G (Pro1019Pro) polymorphisms influence glucose metabolism in Japanese, 696 Japanese men were genotyped. Individually, the Arg223Gln and the A3057G polymorphisms were not associated with the glucose metabolic parameters. No associations were found between haplotype and clinical parameters. However, in 327 subjects with normal glucose tolerance (NGT), the subjects with Arg/Gln or Gln/Gln + A/A haplotype showed significantly higher serum insulin levels and homeostasis model assessment (HOMA) index than those with Arg/Arg + A/A haplotype and Arg/Gln or Gln/Gln + A/G or G/G haplotype. The subjects with Arg/Gln or Gln/Gln + A/A haplotype showed a significantly lower fasting glucose to insulin (GI) ratio than those with Arg/Arg + A/A haplotype. These results suggest that the Ob-R gene may serve as a modifier gene for insulin resistance in Japanese men.

Topics: Blood Glucose; Blood Pressure; Body Composition; Body Mass Index; Diabetes Mellitus; Gene Frequency; Glucose Intolerance; Glucose Tolerance Test; Glycated Hemoglobin; Haplotypes; Humans; Insulin Resistance; Japan; Leptin; Lipid Metabolism; Male; Middle Aged; Polymorphism, Single Nucleotide; Prospective Studies; Receptors, Cell Surface; Receptors, Leptin

Dysregulation of the adipoinsular axis in male obese Zucker diabetic fatty (ZDF; fa/fa) rats, a model of type 2 diabetes, results in chronic hyperinsulinemia and increased de novo lipogenesis in islets, leading to beta-cell failure and diabetes. Diazoxide (DZ; 150 mg/kg.d), an inhibitor of insulin secretion, was administered to prediabetic ZDF animals for 8 wk as a strategy for prevention of diabetes. DZ reduced food intake (P < 0.02) and rate of weight gain only in ZDF rats (P < 0.01). Plasma insulin response to glucose load was attenuated in DZ-Zucker lean rats (ZL; P < 0.01), whereas DZ-ZDF had higher insulin response to glucose than controls (P < 0.001). DZ improved hemoglobin A1c (P < 0.001) and glucose tolerance in ZDF (P < 0.001), but deteriorated hemoglobin A1c in ZL rats (P < 0.02) despite normal tolerance in the fasted state. DZ lowered plasma leptin (P < 0.001), free fatty acid, and triglyceride (P < 0.001) levels, but increased adiponectin levels (P < 0.02) only in ZDF rats. DZ enhanced beta3-adrenoreceptor mRNA (P < 0.005) and adenylate cyclase activity (P < 0.01) in adipose tissue from ZDF rats only, whereas it enhanced islet beta3- adrenergic receptor mRNA (P < 0.005) but paradoxically decreased islet adenylate cyclase activity (P < 0.005) in these animals. Islet fatty acid synthase mRNA (P < 0.03), acyl coenzyme A carboxylase mRNA (P < 0.01), uncoupling protein-2 mRNA (P < 0.01), and triglyceride content (P < 0.005) were only decreased in DZ-ZDF rats, whereas islet insulin mRNA and insulin content were increased in DZ-ZDF (P < 0.01) and DZ-ZL rats (P < 0.03). DZ-induced beta-cell rest improved the lipid profile, enhanced the metabolic efficiency of insulin, and prevented beta-cell dysfunction and diabetes in diabetes-prone animals. This therapeutic strategy may be beneficial in preventing beta-cell failure and progression to diabetes in humans.

Topics: Adenylyl Cyclases; Adiponectin; Adipose Tissue; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Diazoxide; Eating; Fasting; Glucose Intolerance; Glycated Hemoglobin; Hypoglycemic Agents; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Islets of Langerhans; Leptin; Male; Obesity; Rats; Rats, Zucker; Receptors, Adrenergic, beta-3; RNA, Messenger; Triglycerides

A carboxypeptidase E (CPE) knockout (KO) mouse was generated by deletion of exons 4 and 5 from the CPE gene, and its phenotype was characterized. KO mice became obese by 10-12 wk of age and reached 60-80 g by 40 wk. At this age, body fat content was more than double that in the wild-type (WT) controls. The null animals consumed more food overall, were less physically active during the light phase of the light-dark cycle, and burned fewer calories as fat than WT littermates. Fasting levels of glucose and insulin-like immunoreactivity in plasma were elevated in both male and female KO mice at approximately 20 wk; males recovered fully and females partially from this state by 32 wk. At this time, insulin-like immunoreactivity in the plasma, identified as proinsulin, was 50-100 times higher than that of the WT animals. The KO mice showed impaired glucose clearance and were insulin resistant. High levels of leptin and no circulating fully processed cocaine- and amphetamine-related transcript, a peptide that is responsive to leptin-induced feedback inhibition of feeding, were found in serum. The KO mice were subfertile and showed deficits in GnRH processing in the hypothalamus. Behavioral analyses revealed that KO animals showed diminished reactivity to stimuli and had reduced muscle strength and coordination, as well as visual placing and toe-pinch reflexes. These data demonstrate that CPE KO mice display a wide range of neural and endocrine abnormalities and suggest that CPE may have additional physiological roles beyond those ascribed to peptide processing and sorting of prohormones in cells.

Topics: Adipose Tissue; Animals; Behavior, Animal; Body Size; Body Weight; Calorimetry, Indirect; Carboxypeptidase H; Chromatography, High Pressure Liquid; Drinking; Eating; Endocrine System Diseases; Female; Fertility; Glucose Intolerance; Insulin Resistance; Leptin; Male; Mice; Mice, Knockout; Nerve Tissue Proteins; Obesity; Phenotype; Proinsulin

We previously demonstrated that insulin receptor substrate 2 (Irs2) KO mice develop diabetes associated with hepatic insulin resistance, lack of compensatory beta cell hyperplasia, and leptin resistance. To more precisely determine the roles of Irs2 in beta cells and the hypothalamus, we generated beta cell-specific Irs2 KO and hypothalamus-specific Irs2 knockdown (betaHT-IRS2) mice. Expression of Irs2 mRNA was reduced by approximately 90% in pancreatic islets and was markedly reduced in the arcuate nucleus of the hypothalamus. By contrast, Irs2 expression in liver, muscle, and adipose tissue of betaHT-IRS2 mice was indistinguishable from that of control mice. The betaHT-IRS2 mice displayed obesity and leptin resistance. At 4 weeks of age, the betaHT-IRS2 mice showed normal insulin sensitivity, but at 8 and 12 weeks, they were insulin resistant with progressive obesity. Despite their normal insulin sensitivity at 8 weeks with caloric restriction, the betaHT-IRS2 mice exhibited glucose intolerance and impaired glucose-induced insulin secretion. beta Cell mass and beta cell proliferation in the betaHT-IRS2 mice were reduced significantly at 8 and 12 weeks but not at 10 days. Insulin secretion, normalized by cell number per islet, was significantly increased at high glucose concentrations in the betaHT-IRS2 mice. We conclude that, in beta cells and the hypothalamus, Irs2 is crucially involved in the regulation of beta cell mass and leptin sensitivity.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Blood Glucose; Body Weight; Caloric Restriction; Cell Division; Diet; Female; Glucose Intolerance; Hyperlipidemias; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Intracellular Signaling Peptides and Proteins; Islets of Langerhans; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Phosphoproteins; RNA, Messenger; Signal Transduction; Tissue Distribution; Transcription Factors

We examined the effect of a high-fat diet on the diabetes-related traits of the Japanese Fancy mouse 1 (JF1), MSM, and C57BL/6J (B6J) mice. MSM and JF1 mice were derived from Mus musculus molossinus. B6J is a commonly used laboratory strain, with the vast majority of genome segments derived from Mus musculus domesticus and Mus musculus musculus, and is susceptible to high-fat diet-induced type 2 diabetes. None of the strains showed symptoms of diabetes or obesity when fed a laboratory chow diet. Under a high-fat diet, JF1 mice developed impaired glucose tolerance, hyperglycemia, hyperinsulinemia, and obesity. B6J mice fed a high-fat diet mildly developed these diabetes-related traits compared to JF1 mice fed a high-fat diet. JF1 mice fed a high-fat diet were classified as having type 2 diabetes and were susceptible to high-fat diet-induced diabetes and obesity. On the other hand, MSM mice were resistant to high-fat diet-induced diabetes. These results indicate that the JF1 strain, with its unique genetic origin, is a useful new animal model of high-fat diet-induced diabetes and obesity. Further investigations using JF1 mice will help to clarify the role of the high-fat diet on human diabetes and obesity.

Topics: Animals; Blood Glucose; Body Mass Index; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dietary Fats; Disease Models, Animal; Eating; Genetic Predisposition to Disease; Glucose Intolerance; Hyperglycemia; Insulin; Leptin; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Obesity; Organ Size; Triglycerides

High-fat diet and intrauterine growth retardation may predispose to obesity, insulin resistance, and type 2 diabetes. Because prenatal ethanol (ETOH) exposure causes intrauterine growth retardation, we investigated its interactions with postnatal high-fat diet on glucose tolerance and adipocyte-derived hormones in the rat offspring. High-fat-fed offspring had increased adiposity, serum leptin, and muscle uncoupling protein-3, but decreased adiponectin mRNA, compared with corresponding chow-fed groups. ETOH-exposed offspring had normal adiponectin, but increased resistin mRNA and protein, compared with controls, regardless of postnatal diet. Skeletal muscle glucose transporter-4 content was decreased after both ETOH exposure and high-fat feeding. Glycemic and insulin responses to an ip glucose challenge were equally increased in non-ETOH-exposed high-fat-fed offspring and in ETOH-exposed chow-fed offspring, with additive effects of ETOH and high-fat diet. Pancreatic insulin content was elevated only in non-ETOH-exposed high-fat-fed offspring. The data suggest that high-fat diet worsens glucose intolerance in offspring of rats exposed to ETOH. Prenatal ETOH exposure and postnatal high-fat diet might cause insulin resistance through separate mechanisms, involving resistin and adiponectin, respectively.

Topics: Adiponectin; Adipose Tissue; Animals; Body Weight; Carrier Proteins; Central Nervous System Depressants; Dietary Fats; Eating; Ethanol; Fatty Acids, Nonesterified; Female; Gene Expression; Glucose Intolerance; Glucose Transporter Type 4; Hormones, Ectopic; Hyperinsulinism; Insulin; Intercellular Signaling Peptides and Proteins; Ion Channels; Leptin; Mitochondrial Proteins; Monosaccharide Transport Proteins; Muscle Proteins; Muscle, Skeletal; Nerve Growth Factor; Organ Size; Pancreas; Pregnancy; Prenatal Exposure Delayed Effects; Proteins; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, Leptin; Resistin; Uncoupling Protein 3

Hepatocyte retinoid X receptor (RXR)alpha-deficient mice and wild-type mice were fed either a regular or a high-saturated-fat diet for 12 wk to study the functional role of hepatocyte RXRalpha in fatty acid and carbohydrate metabolism. Food intake was significantly reduced in hepatocyte RXRalpha-deficient mice when either diet was used. The amount of food intake was negatively associated with serum leptin level. Although mutant mice ate less, body weight and fat content were significantly higher in mutant than wild-type mice. Examination of the expression of peroxisome proliferator-activated receptor-alpha target genes indicated that the peroxisome proliferator-activated receptor-alpha-mediated pathway was compromised in the mutant mice, which, in turn, might affect fatty-acid metabolism and result in increased body weight and fat content. Although mutant mice were obese, they demonstrated the same degree of insulin sensitivity and the same level of serum insulin as the wild-type mice. However, these mutant mice have improved glucose tolerance. To explore a mechanism that may be responsible for the improved glucose tolerance, serum IGF-I level was examined. Serum IGF-1 level was significantly increased in mutant mice compared with wild-type mice. Taken together, hepatocyte RXRalpha deficiency increases leptin level and reduces food intake. Those mice also develop obesity, with an unexpected improvement of glucose tolerance. The result also suggests that an increase in serum IGF-I level might be one of the mechanisms leading to improved glucose tolerance in hepatocyte RXRalpha-deficient mice.

Topics: Animals; Body Weight; Dietary Fats; Eating; Glucose Intolerance; Hepatocytes; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Obese; Receptors, Retinoic Acid; Retinoid X Receptors; Transcription Factors

Women with previous gestational diabetes (pGDM) are frequently insulin-resistant, which could relate to intramyocellular lipid content (IMCL). IMCL were measured with (1)H nuclear magnetic resonance spectroscopy in soleus (IMCL-S) and tibialis-anterior muscles (IMCL-T) of 39 pGDM (32 +/- 2 years, waist-to-hip ratio 0.81 +/- 0.01) and 22 women with normal glucose tolerance (NGT; 31 +/- 1 years, 0.76 +/- 0.02) at 4-6 months after delivery. Body fat mass (BFM) was assessed from bioimpedance analysis, insulin sensitivity index (S(I)), and glucose effectiveness (S(G)) from insulin-modified frequently sampled glucose tolerance tests. pGDM exhibited 45% increased BFM, 35% reduced S(I) and S(G) (P < 0.05), and 40% (P < 0.05) and 55% (P < 0.005) higher IMCL-S and IMCL-T, respectively. IMCL related to body fat (BFM P < 0.005, leptin P < 0.03), but only IMCL-T correlated (P < 0.03) with S(I) and glucose tolerance index independent of BMI. Insulin-resistant pGDM (n = 17) had higher IMCL-S (+66%) and IMCL-T (+86%) than NGT and insulin-sensitive pGDM (+28%). IMCL were also higher (P < 0.005, P = 0.05) in insulin-sensitive pGDM requiring insulin treatment during pregnancy and inversely related to the gestational week of GDM diagnosis. Thus, IMCL-T reflects insulin sensitivity, whereas IMCL-S relates to obesity. IMCL could serve as an additional parameter of increased diabetes risk because it identifies insulin-resistant pGDM and those who were diagnosed earlier and/or required insulin during pregnancy.

Topics: Adult; Blood Glucose; Body Constitution; Body Mass Index; Diabetes, Gestational; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin Resistance; Leptin; Lipid Metabolism; Lipids; Magnetic Resonance Imaging; Muscle, Skeletal; Pregnancy; Receptors, Cell Surface; Receptors, Leptin; Regression Analysis

Low birth weight in humans predisposes to obesity, cardiovascular diseases, and type 2 diabetes in adult life. Alcohol exposure during pregnancy has been associated with fetal growth restriction. We investigated the effects of prenatal exposure to alcohol on glucose metabolism later in the offspring. Female Sprague Dawley rats were given ethanol (ETOH), 4 g/kg/day by gavage throughout pregnancy. Compared with controls, newborn ETOH rats had decreased body size (5.1 +/- 0.1 v 6.3 +/- 0.1 g, P <.001), plasma insulin (0.44 +/- 0.4 v 0.67 +/- 0.1 ng/mL, P <.05), and leptin mRNA (P <.05), but they had normal beta-cell mass and elevated adipose resistin mRNA and plasma glucose (5.0 +/- 0.5 v 3.6 +/- 0.3 mmol/L, P <.01). Food intake was decreased in ETOH rats during the fourth week of life, and body weight remained decreased compared with controls until a catch-up growth occurred by 7 weeks of life. At 13 weeks of age, body weight and beta-cell mass of ETOH offspring were normal, but plasma glucose and insulin after a glucose challenge were increased compared with controls (P <.05). Adipose leptin and hypothalamic Ob-R mRNA were not different from controls, but resistin was increased (P <.05), and muscle GLUT4 content was decreased (P <.05) in ETOH offspring compared with controls. The data suggest that prenatal alcohol exposure impairs glucose tolerance in the offspring by both inducing insulin resistance and beta-cell dysfunction. The prevailing mechanism in 3-month-old rat offspring appears to be insulin resistance, manifested by glucose intolerance and decreased GLUT4 despite hyperinsulinemia.

Topics: Animals; Body Weight; Central Nervous System Depressants; Eating; Ethanol; Female; Fetal Growth Retardation; Glucose Intolerance; Glucose Transporter Type 4; Hormones, Ectopic; Insulin; Leptin; Monosaccharide Transport Proteins; Muscle Proteins; Nerve Growth Factor; Pancreas; Pregnancy; Prenatal Exposure Delayed Effects; Proteins; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, Leptin; Resistin

The p90 ribosomal S6 kinase 2 (RSK2) is a serine/threonine kinase with high expression levels in adipose tissue. Numerous in vitro studies show that RSK2 is activated by a broad number of cellular stimuli and suggest that RSK2 is involved in the regulation of a variety of cellular processes. However, the physiological role of RSK2 still remains elusive. We therefore generated rsk2 knockout (KO) mice to better understand the function of RSK2 in vivo. Birth weights of RSK2 KO mice are normal, but the body weight is reduced with age, as compared with wild-type littermates. We found that the difference in body weight was largely caused by a specific loss of white adipose tissue that is accompanied by reduced serum levels of the adipocyte-derived peptide, leptin. KO mice also have impaired glucose tolerance and elevated fasting insulin and glucose levels that are restored following administration of low amounts of leptin, which do not affect food intake. We conclude that RSK2 plays a novel and an important role in regulation of adipose mass in mice and speculate that the reduction in fat tissue may negatively affect insulin sensitivity, as observed in human lipodystrophy, through reduced levels of adipocyte-derived factors, such as leptin.

Topics: Adipose Tissue; Aging; Animals; Blood Glucose; Body Weight; Dietary Fats; Glucose Intolerance; Insulin; Insulin Resistance; Leptin; Lipodystrophy; MAP Kinase Signaling System; Mice; Mice, Knockout; Ribosomal Protein S6 Kinases, 90-kDa

Obstructive sleep apnoea, a syndrome that leads to recurrent intermittent hypoxia, is associated with insulin resistance in obese individuals, but the mechanisms underlying this association remain unknown. We utilized a mouse model to examine the effects of intermittent hypoxia on insulin resistance in lean C57BL/6J mice and leptin-deficient obese (C57BL/6J-Lepob) mice. In lean mice, exposure to intermittent hypoxia for 5 days (short term) resulted in a decrease in fasting blood glucose levels (from 173 +/- 11 mg dl-1 on day 0 to 138 +/- 10 mg dl-1 on day 5, P < 0.01), improvement in glucose tolerance without a change in serum insulin levels and an increase in serum leptin levels in comparison with control (2.6 +/- 0.3 vs. 1.7 +/- 0.2 ng ml-1, P < 0.05). Microarray mRNA analysis of adipose tissue revealed that leptin was the only upregulated gene affecting glucose uptake. In obese mice, short-term intermittent hypoxia led to a decrease in blood glucose levels accompanied by a 607 +/- 136 % (P < 0.01) increase in serum insulin levels. This increase in insulin secretion after 5 days of intermittent hypoxia was completely abolished by prior leptin infusion. Obese mice exposed to intermittent hypoxia for 12 weeks (long term) developed a time-dependent increase in fasting serum insulin levels (from 3.6 +/- 1.1 ng ml-1 at baseline to 9.8 +/- 1.8 ng ml-1 at week 12, P < 0.001) and worsening glucose tolerance, consistent with an increase in insulin resistance. We conclude that the increase in insulin resistance in response to intermittent hypoxia is dependent on the disruption of leptin pathways.

Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Fasting; Gene Expression; Glucose Intolerance; Hypoxia; Insulin; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity

In healthy individuals, peripheral insulin resistance evoked by dietary saturated lipid can be accompanied by increased insulin secretion such that glucose tolerance is maintained. Substitution of long-chain omega-3 fatty acids for a small percentage of dietary saturated fat prevents insulin resistance in response to high-saturated fat feeding. We substituted a small amount (7%) of dietary lipid with long-chain omega-3 fatty acids during 4 wk of high-saturated fat feeding to investigate the relationship between amelioration of insulin resistance and glucose-stimulated insulin secretion (GSIS). We demonstrate that, despite dietary delivery of saturated fat throughout, this manipulation prevents high-saturated fat feeding-induced insulin resistance with respect to peripheral glucose disposal and reverses insulin hypersecretion in response to glucose in vivo. Effects of long-chain omega-3 fatty acid enrichment to lower GSIS were also observed in perifused islets suggesting a direct effect on islet function. However, long-chain omega-3 fatty acid enrichment led to hepatic insulin resistance with respect to suppression of glucose output and impaired glucose tolerance in vivo. Our data demonstrate that the insulin response to glucose is suppressed to a greater extent than whole-body insulin sensitivity is enhanced by enrichment of a high-saturated fat diet with long-chain omega-3 fatty acids. Additionally, reduced GSIS despite glucose intolerance suggests that either long-chain omega-3 fatty acids directly impair the beta-cell response to saturated fat such that insulin secretion cannot be augmented to normalize glucose tolerance or beta-cell compensatory hypersecretion represents a response to insulin resistance at the level of peripheral glucose disposal but not endogenous glucose production.

Topics: Animals; Dietary Fats; Fatty Acids, Omega-3; Female; Fish Oils; Glucose; Glucose Clamp Technique; Glucose Intolerance; Glycogen; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Leptin; Liver; Phenotype; Rats; Rats, Wistar; Triglycerides

Histamine has been referred to as an anorexic factor that decreases appetite and fat accumulation and affects feeding behavior. Tuberomammillary histaminergic neurons have been implicated in central mediation of peripheral metabolic signals such as leptin, and centrally released histamine inhibits ob gene expression. Here we have characterized the metabolic phenotype of mice that completely lack the ability to produce histamine because of targeted disruption of the key enzyme in histamine biosynthesis (histidine decarboxylase, HDC). Histochemical analyses confirmed the lack of HDC mRNA, histamine immunoreactivity, and histaminergic innervation throughout the brain of gene knockout mouse. Aged histamine-deficient (HDC-/-) mice are characterized by visceral adiposity, increased amount of brown adipose tissue, impaired glucose tolerance, hyperinsulinemia, and hyperleptinemia. Histamine-deficient animals are not hyperphagic but gain more weight and are calorically more efficient than wild-type controls. These metabolic changes presumably are due to the impaired regulatory loop between leptin and hypothalamic histamine that results in orexigenic dominance through decreased energy expenditure, attenuated ability to induce uncoupling protein-1 mRNA in the brown adipose tissue and defect in mobilizing energy stores. Our results further support the role of histamine in regulation of energy homeostasis.

Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Blood Glucose; Body Weight; Brain; Carrier Proteins; Energy Metabolism; Glucose Intolerance; Histamine; Histidine; Histidine Decarboxylase; Hormones; Insulin; Insulin Secretion; Ion Channels; Leptin; Male; Membrane Proteins; Mice; Mice, Knockout; Mitochondrial Proteins; Neurons; RNA, Messenger; Uncoupling Protein 1; Viscera

Leptin and tumor necrosis factor (TNF)-alpha are associated with insulin resistance and cardiovascular disease. In vitro studies suggested that these effects may be mediated via overproduction of monocyte chemoattracting protein (MCP)-1/CCL2, which is a chemokine involved in the pathogenesis of atherosclerosis.. In this study, fasting plasma leptin, soluble TNF-alpha receptor 2 (TNF-alpha-R2), and MCP-1/CCL2 concentrations were measured in 207 middle-aged women (age 61 +/- 12 years, BMI 30.1 +/- 6.6 kg/m(2)), including 53 patients with type 2 diabetes, 42 with impaired glucose tolerance, and 112 with normal glucose tolerance, to assess cross-sectionally their relationship with markers of atherosclerosis and, longitudinally over 7 years, whether their circulating levels were associated with cardiovascular disease (CVD) mortality.. At baseline, leptin and TNF-alpha-R2 were not different among groups; meanwhile, MCP-1/CCL2 was increased in type 2 diabetes (P < 0.05). All showed significant associations with biochemical risk markers of atherosclerosis. In a univariate analysis, age, fasting insulin, leptin, and MCP-1/CCL2 were associated with CVD mortality at 7 years. When a multivariate analysis was performed, only age, leptin, and insulin retained an independent association with CVD mortality, with leptin showing a protective effect (hazard ratio 0.88; P < 0.02).. In middle-aged women, MCP-1/CCL2, leptin, and TNF-alpha-R2 were all related to biochemical risk markers of atherosclerosis. MCP-1/CCL2 concentration was the only one to be increased in type 2 diabetes with respect to nondiabetic women and the only one to be associated with increased risk of CVD mortality after a 7-year follow-up period in the univariate analysis. In the multivariate analysis, neither MCP-1/CCL2 nor TNF-alpha-R2 was associated with CVD mortality, and inspection of the data showed that leptin, in both the univariate and multivariate analysis, was associated with a protective effect.

Topics: Aged; Blood Glucose; Cardiovascular Diseases; Chemokine CCL2; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Fasting; Female; Glucose Intolerance; Humans; Leptin; Middle Aged; Multivariate Analysis; Risk Factors; Tumor Necrosis Factor-alpha

Topics: Animals; C-Reactive Protein; Coronary Disease; Diabetes Mellitus; Glucose Intolerance; Humans; Hypertension; Inflammation; Leptin; Lipoproteins, HDL; Matrix Metalloproteinase 9; Metabolic Syndrome; Mice; Mice, Knockout; Obesity; Oxidative Stress; Phosphatidylcholine-Sterol O-Acyltransferase; Receptors, LDL; Risk Factors; Smoking

Insulin signaling in adipose tissue plays an important role in lipid storage and regulation of glucose homeostasis. Using the Cre-loxP system, we created mice with fat-specific disruption of the insulin receptor gene (FIRKO mice). These mice have low fat mass, loss of the normal relationship between plasma leptin and body weight, and are protected against age-related and hypothalamic lesion-induced obesity, and obesity-related glucose intolerance. FIRKO mice also exhibit polarization of adipocytes into populations of large and small cells, which differ in expression of fatty acid synthase, C/EBP alpha, and SREBP-1. Thus, insulin signaling in adipocytes is critical for development of obesity and its associated metabolic abnormalities, and abrogation of insulin signaling in fat unmasks a heterogeneity in adipocyte response in terms of gene expression and triglyceride storage.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Animals; Aurothioglucose; Body Weight; CCAAT-Enhancer-Binding Proteins; Cell Size; Diabetes Mellitus, Type 2; DNA-Binding Proteins; Energy Metabolism; Female; Glucose; Glucose Intolerance; Glucose Transporter Type 1; Glucose Transporter Type 4; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Male; Mice; Mice, Knockout; Monosaccharide Transport Proteins; Muscle Proteins; Obesity; Proteins; Receptor, Insulin; Sterol Regulatory Element Binding Protein 1; Transcription Factors; Ventromedial Hypothalamic Nucleus

In this study, the ob/ob mouse model was used to investigate epidemiological evidence linking fish intake to relative reduction in incidence of Type 2 diabetes mellitus and glucose. We have investigated, in comparison to low and high fat diets, the effect of a fish oil diet on basal and stimulated plasma glucose and insulin levels in male and female ob/ob mice. Mice were fed for 12 months with a saturated fat diet containing 25% lard, with a low fat diet containing 5% soybean oil, with a polyunsaturated fat diet containing 25% safflower seed oil (n-6) or with polyunsaturated fat diet containing 23% fish oil (n-3). Total body weight increased to approximately 100 g at the end of the experiment, with the highest increase in the order of lard > safflower oil > fish oil > soybean oil diet. Intercurrent deaths were found especially in the fish oil diet group. Compared to the other diet groups, plasma insulin levels of the fish oil diet group were significantly increased 3 months after the start of the diet and remained higher for another 3 months. Thereafter, the level declined to those of the other diet groups. Glucose-tolerance tests at 3, 6, 8 and 10 months showed a tendency of more efficient tissue glucose uptake in the fish oil group compared to the other groups, which was in accordance with a higher plasma insulin levels. At 12 months, microscopy revealed an increased severity of hepatic brown pigment accumulation and extramedullary haematopoiesis in the spleen of mice fed with fish oil. We conclude that fish oil diet in ob/ob mice reduced the body weight gain and increased the glucose-induced insulin secretion. Fish oil diet also increased intercurrent mortality. However, a consistent course of death could not be established using morphological parameters.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dietary Fats, Unsaturated; Fatty Acids, Omega-3; Female; Fish Oils; Glucose Intolerance; Glucose Tolerance Test; Insulin; Insulin Resistance; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Spleen

It remains unclear whether adiposity plays an important role in glucose intolerance independently of insulin resistance. We investigated whether adiposity and insulin resistance had distinct roles in glucose intolerance in rats. We examined glucose tolerance and insulin resistance using ventromedial hypothalamic (VMH)-lesioned rats in the dynamic and the static phases of obesity (2 and 14 weeks after lesioning, respectively). Rats were fed either normal chow or a fructose-enriched diet (60% of total calories). The intravenous glucose tolerance test (IVGTT) was performed by bolus injection of glucose solution (1 g/kg) and blood sampling after 0, 5 10, 30, and 60 minutes. Insulin resistance was evaluated from the steady-state plasma glucose (SSPG) value during continuous infusion of glucose, insulin, and somatostatin. SSPG was not increased in VMH-lesioned rats in the dynamic phase of obesity, but increased markedly in the static phase. The area under the glucose curve (glucose AUC) during IVGTT was increased in VMH-lesioned rats in the static phase, but not in the dynamic phase, when compared with their sham-operated counterparts. A fructose-enriched diet for 2 or 14 weeks increased SSPG values to a similar extent in both sham-operated and VMH-lesioned rats without inducing excess adiposity, but glucose intolerance was only developed in the obese rats. The plasma leptin level, an excellent indicator of adiposity, was significantly related to the glucose AUC independently of the insulin level. Insulin resistance or increased adiposity alone is not sufficient to impair glucose tolerance, but increased adiposity plays an important role in the development of glucose intolerance in an insulin-resistant state.

Topics: Animals; Area Under Curve; Blood Glucose; Body Weight; Dietary Supplements; Disease Models, Animal; Eating; Fatty Acids, Nonesterified; Female; Fructose; Glucose Intolerance; Glucose Tolerance Test; Insulin; Insulin Resistance; Leptin; Obesity; Rats; Triglycerides; Ventromedial Hypothalamic Nucleus

Historically, insulin resistance during pregnancy has been ascribed to increased production of placental hormones and cortisol. The purpose of this study was to test this hypothesis by correlating the longitudinal changes in insulin sensitivity during pregnancy with changes in placental hormones, cortisol, leptin, and tumor necrosis factor (TNF)-alpha. Insulin resistance was assessed in 15 women (5 with gestational diabetes mellitus [GDM] and 10 with normal glucose tolerance) using the euglycemic-hyperinsulinemic clamp procedure, before pregnancy (pregravid) and during early (12-14 weeks) and late (34-36 weeks) gestation. Body composition, plasma TNF-alpha, leptin, cortisol, and reproductive hormones (human chorionic gonadotropin, estradiol, progesterone, human placental lactogen, and prolactin) were measured in conjunction with the clamps. Placental TNF-alpha was measured in vitro using dually perfused human placental cotyledon from five additional subjects. Compared with pregravid, insulin resistance was evident during late pregnancy in all women (12.4 +/- 1.2 vs. 8.1 +/- 0.8 10(-2) mg. kg(-1) fat-free mass. min(-1). microU(-1). ml(-1)). TNF-alpha, leptin, cortisol, all reproductive hormones, and fat mass were increased in late pregnancy (P < 0.001). In vitro, most of the placental TNF-alpha (94%) was released into the maternal circulation; 6% was released to the fetal side. During late pregnancy, TNF-alpha was inversely correlated with insulin sensitivity (r = -0.69, P < 0.006). Furthermore, among all of the hormonal changes measured in this study, the change in TNF-alpha from pregravid to late pregnancy was the only significant predictor of the change in insulin sensitivity (r = -0.60, P < 0.02). The placental reproductive hormones and cortisol did not correlate with insulin sensitivity in late pregnancy. Multivariate stepwise regression analysis revealed that TNF-alpha was the most significant independent predictor of insulin sensitivity (r = -0.67, P < 0.0001), even after adjustment for fat mass by covariance (r = 0.46, P < 0.01). These observations challenge the view that the classical reproductive hormones are the primary mediators of change in insulin sensitivity during gestation and provide the basis for including TNF-alpha in a new paradigm to explain insulin resistance in pregnancy.

Topics: Adult; Blood Glucose; Body Composition; Chorionic Gonadotropin; Diabetes, Gestational; Female; Gestational Age; Glucose Clamp Technique; Glucose Intolerance; Humans; Hydrocortisone; Infusions, Intravenous; Insulin; Insulin Resistance; Leptin; Placenta; Placental Lactogen; Predictive Value of Tests; Pregnancy; Prolactin; Reference Values; Regression Analysis; Tumor Necrosis Factor-alpha

To investigate the relationship between insulin resistance and plasma concentrations of free fatty acids (FFAs), leptin, and potential agonists of the insulin receptor substrate (IRS) system, including tumor necrosis factor-alpha (TNF-alpha), IGF-I, growth hormone (GH), and angiotensin II in individuals with impaired glucose tolerance (IGT).. Because glucose toxicity per se leads to insulin resistance, the determination of the primary metabolic alterations leading to insulin resistance is best accomplished in individuals who are at an increased risk to develop type 2 diabetes. Therefore, 48 subjects with IGT and insulin resistance (IR), characterized by hyperinsulinemic-euglycemic clamps, were compared with 52 healthy insulin-sensitive (IS) control subjects with respect to the relationship between the plasma levels of TNF-alpha, IGF-I, GH, angiotensin II, FFA, leptin, and insulin resistance.. Between the IR and the IS groups, there were no significant differences in the plasma concentrations of TNF-alpha, GH, angiotensin II, IGF-I, and leptin. However, plasma FFA levels were significantly elevated in the IR group compared with the IS group after matching for BMI.. The plasma concentrations of FFA, but not TNF-alpha, IGF-I, GH, and angiotensin II, are elevated in patients at an early stage of insulin resistance, suggesting that FFAs, but not the other modulators of the IRS system, may be a primary metabolic abnormality leading to insulin resistance.

Topics: Adult; Angiotensin II; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Glucose Clamp Technique; Glucose Intolerance; Glucose Tolerance Test; Human Growth Hormone; Humans; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Male; Middle Aged; Obesity; Risk Factors; Tumor Necrosis Factor-alpha

To investigate whether the peripheral blood mtDNA (pb-mtDNA) content is decreased and linked to insulin resistance in the offspring of type 2 diabetic patients.. A total of 82 offspring of type 2 diabetic patients and 52 age-, sex-, and BMI-matched normal subjects from the Mokdong, Korea, population were selected for this study by stratified, randomized sampling. Of the offspring of diabetic patients, 52 had normal glucose tolerance (NGT), 21 had impaired glucose tolerance (IGT), and 9 had newly diagnosed type 2 diabetes. The pb-mtDNA content was measured by real-time polymerase chain reaction with a mitochondria-specific fluorescent probe, normalized by a nuclear DNA, 285 rRNA gene. The associations between pb-mtDNA content and several parameters of insulin resistance were studied.. The pb-mtDNA contents tended to be lower in the 82 offspring of type 2 diabetic patients (1,084.7 +/- 62.6 vs. 1,304.0 +/- 99.2 in the offspring and control subjects, respectively, P = 0.051) and was significantly lower in the combined NGT and IGT offspring group (NGT+IGT, 1,068.0 +/- 67.8, P < 0.05) than in the control subjects. In NGT+IGT offspring, the pb-mtDNA content was significantly correlated with logarithmically transformed insulin sensitivity (r = 0.253, P < 0.05) and was the main predictor of insulin sensitivity.. Quantitative mtDNA status might be a hereditary factor associated with type 2 diabetes and could serve as an indicator for insulin sensitivity.

Topics: Adipose Tissue; Adult; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; DNA, Mitochondrial; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion; Korea; Leptin; Male; Nuclear Family; Reference Values

Gestational diabetes mellitus (GDM) results from an interaction between susceptibility genes and the diabetogenic effects of pregnancy. During pregnancy, mice heterozygous for the lepin receptor (db/+) gain more weight, are glucose intolerant, and produce macrosomic fetuses compared with wild-type (+/+) mothers, suggesting that an alteration in leptin action may play a role in GDM and fetal overgrowth. To investigate whether leptin administration or pair-feeding can reduce adiposity and thereby prevent GDM and neonatal overgrowth, we examined energy balance, glucose and insulin tolerance, and fetal growth in pregnant db/+ and +/+ mice treated with recombinant human leptin-IgG during late pregnancy. Leptin reduced food intake and adiposity in pregnant db/+ mice to levels similar to pregnant +/+ mice and significantly reduced maternal weight gain. Maternal glucose levels were markedly lower during glucose and insulin challenge tests in leptin-treated db/+ mice relative to db/+ and pair-fed controls. Despite reduced energy intake and improved glucose tolerance, leptin administration did not reduce fetal overgrowth in offspring from db/+ mothers. Fetal and placental leptin levels were 1.3- to 1.5-fold higher in offspring from db/+ mothers and remained unchanged with leptin administration, whereas leptin treatment in +/+ mothers or pair-feeding decreased placental leptin concentration and reduced fetal birth weight. Our results provide evidence that leptin administration during late gestation can reduce adiposity and improve glucose tolerance in the db/+ mouse model of spontaneous GDM. However, fetal and placenta leptin levels are higher in db/+ mothers and are subject to reduced negative feedback in response to leptin treatment. These data suggest that alterations in placenta leptin may contribute to the regulation of fetal growth independently of maternal glucose levels.

Topics: Animals; Carrier Proteins; Diabetes, Gestational; Embryonic and Fetal Development; Female; Fetus; Glucose Intolerance; Heterozygote; Humans; Insulin; Leptin; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Placenta; Pregnancy; Pregnancy Complications; Receptors, Cell Surface; Receptors, Leptin; Recombinant Proteins; Signal Transduction

A longitudinal, clinical intervention study with bariatric surgery was done to investigate the relationship between leptin levels, BMI, and insulin during weight loss across a range of glucose tolerance from normal to diabetes.. 43 morbidly obese patients (BMI: 42-75 kg/m2) undergoing vertical banded gastroplasty Roux-en-Y gastric bypass (VBG-RGB), were divided into 3 groups: 21 normal (NGT), 12 impaired glucose tolerance (IGT) and 10 type 2 diabetes (DM). Leptin, insulin, glucose, lipids and uric acid were measured at baseline and 2, 4, 6, and 12 months following surgery.. BMI fell from 54.1 +/- 9.1 to 34.6 +/- 6.3 kg/m2, similarly in all groups. Leptin decreased from 73.9 +/- 8.7 to 16.9 +/- 10.2 ng/ml and was strongly correlated with BMI during 1-year follow-up (r = 0.78; p < 0.001). Linear univariate analysis for repeated evaluation showed a positive correlation between leptin and glucose, triglycerides, uric acid, and insulin. Multivariate regression analysis indicated that BMI was independently correlated with the decrease in leptin (p < 0.001), accounting for 66% of the variance in leptin levels during weight loss. These results were found in the NGT and IGT groups. In the DM group, a small additional influence in leptin levels was attributed to glucose decrease.. A strong link between leptin and BMI was found after surgery. BMI was the main determinant of the decrease of leptin. In these patients submitted to bariatric surgery, ranging from normal glucose tolerance to diabetes, changes in insulin levels and metabolic parameters, except for glucose in the DM group, did not appear to be correlated with changes in leptin levels.

Topics: Adult; Blood Glucose; Body Mass Index; Diabetes Mellitus; Female; Gastric Bypass; Glucose Intolerance; Humans; Insulin; Leptin; Longitudinal Studies; Male; Middle Aged; Obesity, Morbid; Regression Analysis; Weight Loss

Increases in ventromedial hypothalamic (VMH) norepinephrine (NE) levels and/or activities have been observed in a variety of animal models of the obese insulin-resistant condition. This study examined the metabolic effects of chronic NE infusion (25 nmol/h) into the unilateral VMH of normal rats. Within 4 days, VMH NE infusion significantly increased plasma insulin (140%), glucagon (45%), leptin (300%), triglyceride (100%), abdominal fat pad weight (50%), and white adipocyte lipogenic (100%) and lipolytic (100%) activities relative to vehicle-infused rats. Furthermore, isolated islet insulin secretory response to glucose (15 mM) within 4 days of such treatment was increased over twofold (P < 0.05). Among treated animals, fat stores continued to increase over time and plateaued at approximately 2 wk (3-fold increase), remaining elevated to the end of the study (5 wk). By week 4 of treatment, NE infusion induced glucose intolerance as evidenced by a 32% increase in plasma glucose total area under the glucose tolerance test curve (P < 0.01). Whole body fat oxidation rate measured after 5 wk of infusion was significantly increased among treated animals as evidenced by a reduced respiratory quotient (0.87 +/- 0.01) relative to controls (0. 90 +/- 0.01). VMH NE infusion induced hyperphagia (30%) only during the first week and did not affect body weight over the 5-wk period. Increases in VMH NE activity that are common among obese insulin-resistant animal models can cause the development of this obese glucose-intolerant (metabolic) syndrome.

Topics: Adipose Tissue; Animals; Carbohydrate Metabolism; Endocrine Glands; Female; Glucose Intolerance; Hormones; Injections; Isoproterenol; Leptin; Lipid Metabolism; Lipolysis; Norepinephrine; Obesity; Rats; Rats, Sprague-Dawley; Reference Values; Syndrome; Time Factors; Ventromedial Hypothalamic Nucleus

A direct relationship between body mass index (BMI), visceral adipose tissue, insulin levels and growth hormone-binding protein (GHBP) activity has consistently been reported. It was recently described that GHBP directly depends on serum leptin levels. Since leptin co-varies with insulin secretion and/or sensitivity, we aimed to study the influence of these variables on plasma GHBP activity.. In order to isolate the effects of obesity per se from those of insulin secretion, three groups of subjects were prospectively studied: 14 lean, 10 obese and nine obese subjects with glucose intolerance.. The percentage of body fat was measured through bioelectric impedance. Insulin sensitivity and secretion were determined through a frequently sampled intravenous glucose tolerance test with minimal model analysis. Serum leptin was measured by radioimmunoassay. GHBP activity was determined by the high performance liquid chromatography-gel filtration method.. Plasma GHBP activity was found to correlate with BMI (r = 0. 65, P < 0.0001), fat mass (r = 0.51, P = 0.003), waist circumference (r = 0.64, P < 0.0001), waist-to-hip ratio (r = 0.42, P = 0.01), insulin sensitivity (SI, r = - 0.61, P = 0.0001), insulin secretion (expressed as the acute insulin response to intravenous glucose, AIRg) (r = 0.48, P = 0.006) and leptin concentration (r = 0.49, P = 0.004). The associations with SI (r = - 0.42, P = 0.02) and AIRg (r = 0.38, P = 0.03) persisted even after controlling for fat mass. Since insulin secretion and insulin sensitivity usually covary in glucose tolerant subjects (an increased insulin secretion is necessary to compensate a decreased insulin sensitivity), we constructed a multiple linear regression to predict GHBP activity. In this model, SI (P = 0.005), AIRg (P = 0.02) and SD score-leptin (P = 0.03) independently contributed to 34, 10 and 8% of the variability in serum GHBP activity.. Our results suggest that plasma GHBP activity is simultaneouslly influenced by insulin secretion and sensitivity and leptin. Perhaps leptin, through increased insulin secretion, might induce GHBP/GH secretion, explaining the normal to high insulin-like growth factor (IGF)-I levels found in overnutrition.

Topics: Adult; Body Constitution; Carrier Proteins; Chromatography, Gel; Chromatography, High Pressure Liquid; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Leptin; Linear Models; Male; Obesity; Prospective Studies

Plasma leptin has been shown to correlate positively with many indices of obesity, as well as insulin resistance. For a given body weight, the levels are higher in women than in men, but the reasons for this difference are not clear. Insulin has been shown to stimulate leptin production by adipose tissue in vivo and in vitro. Previous studies have reported that leptin levels are similar in diabetic and nondiabetic individuals. However, these studies were not performed in newly diagnosed diabetics, and other variables (such as gender) could have confounded the results. Therefore, the goal of the present cross-sectional study is to examine the effect of metabolic variables (such as glucose and insulin) on plasma leptin concentrations in men and women separately. We measured leptin levels in 48 subjects (17 with newly diagnosed type 2 diabetes mellitus, 13 with impaired glucose tolerance [IGT], and 18 normal individuals). The 3 groups were well matched for gender, age, and body mass index (BMI). When adjusted for the BMI and gender, a statistically significant gender-related difference in mean plasma leptin was observed across the 3 glucose tolerance subgroups (P < .03 by analysis of covariance [ANCOVA]). More specifically, plasma leptin levels were, on average, 44% lower in women with diabetes or IGT versus normal women (P < .02). No such between-group difference was observed in the men. In univariate analysis in the same female subgroup, plasma leptin correlated positively with fasting insulin (rs = +.43, P < .06) and negatively with 2-hour post-75-g glucose load plasma glucose concentration (rs = -.54, P < .02). In a multiple regression model controlling for the BMI in the female subgroup, circulating insulin and glucose concentrations 2 hours after the 75-g glucose load were good predictors of fasting plasma leptin (r = +.38, P = .02 and r = -.70, P < .001, respectively). Leptin levels in women appear to be influenced independently and to an important degree by ambient plasma glucose and plasma insulin concentrations. These findings suggest that the synthesis of leptin by adipose tissue is more susceptible to in vivo regulation by insulin and glucose in women than in men. Plasma leptin concentrations were also lower in women with IGT or type 2 diabetes versus normal women, suggesting that fasting and/or postprandial hyperglycemia interferes with the stimulatory effect of plasma insulin on the synthesis of leptin by adipose tissue in women only.

Topics: Adipose Tissue; Adult; Aged; Blood Glucose; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Fasting; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Leptin; Male; Middle Aged; Multivariate Analysis; Predictive Value of Tests; Regression Analysis; Sex Factors

To assess the independent and joint effects of the components of the metabolic syndrome, including leptin, which is a recently proposed addition to this syndrome, in predicting the cumulative incidence of impaired glucose tolerance (IGT) and diabetes among individuals with normal glucose tolerance.. This prospective study involved 2,605 residents of Mauritius with normal glucose tolerance who were followed for 5 years for IGT or diabetes onset in relation to total and regional adiposity (BMI, waist-to-hip ratio [WHR]), fasting and 2-h 75-g oral glucose load glucose and insulin, total and HDL cholesterol, blood pressure, serum uric acid, triglyceride, and leptin levels.. A multivariate logistic regression model adjusted for age, sex, ethnicity, and diabetes family history showed a significantly higher linear increase in risk of IGT and diabetes in association with the following variables only: fasting glucose (odds ratio 1.89 [95% CI 1.51-2.34]), 2-h glucose (1.68 [1.50-1.88]), WHR (1.30 [1.10-1.52]), BMI (1.04 [1.00-1.08]), and serum uric acid (1.37 [1.20-1.57]). However, a nonlinear increase was seen with serum triglyceride and plasma leptin concentrations. No risk factors resulted in joint effects that were greater than expected from combining individual effects.. Metabolic syndrome features independently predict a higher risk of diabetes or IGT in normoglycemic subjects but in combination confer no higher-than-expected risk of these outcomes. At higher concentrations of triglycerides and leptin, risk plateaus and even declines slightly.

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Ethnicity; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Hyperlipidemias; Hypertension; Insulin; Leptin; Longitudinal Studies; Male; Mauritius; Middle Aged; Multivariate Analysis; Prospective Studies; Racial Groups; Regression Analysis; Risk Factors; Syndrome; Time Factors

Studies, comparing several disease-prone and disease-resistant rat strains to elucidate the extent and severity of syndromes resembling human diseases are lacking. Therefore we studied the inbred rat strains BB/OK, BN/Crl, LEW/K and WKY/Crl in comparison with SHR/Mol and WOKW/K rats as models of metabolic syndrome.. Body weight and body mass index (BMI) were measured in 12 males of each strain at 14 weeks. In addition blood glucose, serum triglycerides, cholesterol, insulin and leptin were determined at 12, 13 and 14 weeks of age.. In contrast to SHR animals, WOKW rats develop a severe metabolic syndrome including obesity, hyperleptinemia, hyperinsulinemia and dyslipidemia.. We conclude that; (i) the choice of disease-resistant inbred rat strains as 'healthy controls' for a disease-prone strain has to be carefully evaluated; (ii) in comparison with SHR, WOKW rats develop most if not all facets of the metabolic syndrome described in human and (iii) as with the human disease the syndrome in rats is polygenic.

Topics: Animals; Blood Glucose; Body Mass Index; Body Weight; Cholesterol; Glucose Intolerance; Hyperlipidemias; Hypertension; Insulin; Insulin Resistance; Leptin; Male; Obesity; Quality Control; Rats; Rats, Inbred BB; Rats, Inbred BN; Rats, Inbred Lew; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Wistar; Triglycerides

Impaired glucose tolerance (IGT) is frequently associated with an increased fat mass and an altered fat distribution. The adipocyte derived hormone, leptin has been shown to interact with insulin at various levels and may be intimately involved in this process. However, only limited data concerning the interaction of insulin, glucose tolerance and leptin are available and no data exist on the potential influence of bound vs. free circulating leptin. We therefore studied free and bound leptin in 136 patients (77 males, 59 females) with IGT, in relation to plasma glucose, insulin, proinsulin and C-peptide levels as well as serum free and bound leptin concentrations during an oral glucose tolerance test (oGTT). The expected positive relation of free serum leptin levels with body mass index (BMI) was found. Free leptin concentrations were higher in women than in men. Analysis in tertiles revealed a significant relation between free leptin (16-58, 60-160, and 169-932 pmol/l) and mean fasting insulin levels (65, 93, and 100 pmol/l). This relationship remained significant in a multiple regression analysis with BMI and gender as covariates. Similar independent relationships to leptin serum levels were observed for HbA1c and plasma C peptide levels and the proinsulin/insulin ratio but not for plasma glucose and proinsulin levels. These data suggest a fine tuning of leptin by small changes in circulating insulin levels observed in impaired glucose tolerance.

Topics: Blood Glucose; Body Constitution; Body Mass Index; C-Peptide; Female; Glucose Intolerance; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Insulin; Insulin Secretion; Leptin; Male; Middle Aged; Proinsulin; Proteins; Sex Characteristics

We asked whether the likelihood for mice of the C57BL/6J strain to develop glucose intolerance when fed a high-fat diet is related to the increase in circulating levels of leptin or free fatty acids (FFA). We therefore administered a high-fat diet (58% fat) or a control diet (11% fat) for 1.5 years. NMRI mice were used as a more glucose-tolerant control group. After a high-fat diet, the area under the glucose curve following an intraperitoneal glucose challenge (1 g/kg) increased more markedly in C57BL/6J mice (by 42+/-8%) than in NMRI mice (by 21+/-3%, P = 0.007). Plasma levels of insulin, leptin and FFA increased in both strains of mice, whereas plasma glucose levels were elevated after the high-fat diet only in C57BL/6J mice. The slope of the relationship between body weight and plasma leptin was higher in C57BL/6J mice than in NMRI mice. suggesting leptin insensitivity. Circulating leptin correlated to circulating insulin in both strains of mice, whereas plasma FFA correlated to plasma insulin in NMRI mice but not in C57BL/6J mice. These correlations remained significant after adjustment for body weight. The results show that elevated leptin and FFA levels evolve after high-fat feeding in mice, in conjunction with evolvement of glucose intolerance and hyperglycemia.

Topics: Animals; Body Weight; Dietary Fats; Fatty Acids, Nonesterified; Glucose Intolerance; Hyperglycemia; Insulin; Insulin Resistance; Leptin; Mice; Mice, Inbred C57BL; Proteins

Leptin, the obese (ob) gene product, is thought to be a lipostatic hormone that contributes to body weight regulation through modulating feeding behavior and/or energy expenditure. The determinants of plasma leptin concentration were evaluated in 267 subjects (106 with normal glucose tolerance, 102 with impaired glucose tolerance, and 59 with noninsulin-dependent diabetes). Fasting plasma leptin levels ranged from 1.8-79.6 ng/mL (geometric mean, 12.4), were higher in the obese subjects, and were not related to glucose tolerance. Women had approximately 40% higher leptin levels than men at any level of adiposity. After controlling for body fat, postmenopausal women had still higher leptin levels than men of similar age, and their levels were not different from those in younger women. Multiple regression analysis showed that adiposity, gender, and insulinemia were significant determinants of leptin concentration, explaining 42%, 28%, and 2% of its variance, respectively. Neither age nor the waist/hip ratio was significantly related to leptin concentration. Thus, our data indicate that gender is a major determinant of the plasma leptin concentration. This sex difference is not apparently explained by sex hormones or body fat distribution. Leptin's sexual dimorphism suggests that women may be resistant to its putative lipostatic actions and that it may have a reproductive function.

Topics: Adipose Tissue; Adult; Body Composition; Fasting; Female; Glucose Intolerance; Humans; Insulin; Leptin; Male; Middle Aged; Obesity; Osmolar Concentration; Proteins; Reference Values; Sex Characteristics

It has been suggested that insulin could regulate the secretion of leptin, the ob gene product, but the findings have been contradictory. Therefore, we studied the association between leptin and insulin secretion and insulin sensitivity in impaired glucose tolerance (IGT).. 39 obese subjects (17 men, 22 women, body mass index (BMI) 30.6 +/- 0.6 kg/m2, age 54 +/- 1 y, mean +/- s.e.m.) with IGT.. Leptin, insulin sensitivity and first-phase insulin response (frequently sampled intravenous glucose tolerance test), anthropometry, infrared densitometric assay.. Leptin correlated with BMI (r = 0.36, P = 0.022), fat percent (r = 0.74, P < 0.001) and fat mass (r = 0.53, P < 0.001). After adjustment for sex and fat mass, leptin showed no significant linear correlation with fasting insulin, insulin sensitivity or first-phase insulin response.. In obese IGT subjects fat mass is the main correlate of serum leptin concentration. First-phase insulin response or the degree of insulin resistance are not associated with leptin in IGT.

Topics: Cohort Studies; Fasting; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Leptin; Male; Middle Aged; Obesity; Proteins

Ovarian hyperandrogenism can be associated with insulin resistance, hyperinsulinemia, glucose intolerance, and obesity. High levels of the lipostatic hormone, leptin, have also been reported in this condition. The purpose of the present study was to examine the effect of an oral contraceptive (OC) of low androgenicity containing desogestrel on glucose tolerance in hyperandrogenic women and the impact of changes in androgenic/estrogenic status on leptin concentrations. Sixteen nondiabetic hyperandrogenic women, aged 29 +/- 1 yr with a body mass index (BMI) of 36.8 +/- 1.8 kg/m2, underwent an oral glucose tolerance test before and after 6 months of therapy with the OC. Free testosterone decreased and sex hormone-binding globulin increased after therapy (P < 0.001). Glucose tolerance deteriorated significantly, and two women developed diabetes. Body weight, BMI, and leptin did not change significantly. Leptin correlated with BMI before (r = 0.56; P = 0.02) and after (r = 0.51; P = 0.04) treatment, but not with glucose, insulin, total and free testosterone, or sex hormone-binding globulin before or after treatment. In conclusion, 1) glucose tolerance should be monitored in hyperandrogenic women using OC, even those of low androgenicity; and 2) changes in androgenic/estrogenic status had no effect on the leptin concentration, suggesting that its sexual dimorphism is not related to sex steroids.. Ovarian hyperandrogenism can be associated with insulin resistance, hyperinsulinemia, and glucose intolerance--all of which, in turn, have been linked to high levels of the lipostatic hormone, leptin. This study investigated the effect of an oral contraceptive (OC) containing a progestin of low androgenicity on glucose tolerance and insulinemia in hyperandrogenic women and the impact of changes in androgenic/estrogenic status on plasma leptin levels. 16 nondiabetic hyperandrogenic US women (mean age, 29 years) with a mean body mass index of 36.8 kg/sq. m underwent oral glucose tolerance testing before and after 6 months of treatment with an OC containing 30 mcg of ethinyl estradiol and 150 mcg of desogestrel. Treatment was associated with significant decreases in free testosterone and increased sex hormone-binding globulin (p 0.001). Glucose tolerance deteriorated moderately but significantly. After 6 months of treatment, 5 women had normal glucose tolerance, 9 had impaired glucose tolerance, and 2 developed non-insulin-dependent diabetes mellitus. There were no significant changes in serum insulin concentrations, body weight, body mass index, or leptin, but leptin levels were highly correlated with body mass index both before and after treatment. The data suggest that the sexual dimorphism of leptin is not caused by differences in sex hormones. Even when OCs containing low androgenic progestins are prescribed, women at high risk for diabetes should receive regular glucose tolerance tests.

Topics: Adult; Body Mass Index; Contraceptives, Oral; Desogestrel; Estradiol; Estrone; Female; Glucose Intolerance; Humans; Hyperandrogenism; Insulin; Leptin; Osmolar Concentration; Proteins; Reference Values

It has previously been demonstrated that plasma leptin correlates to body fat content. Increased body fat content is accompanied by low insulin sensitivity, which is compensated with increased insulin secretion. We therefore studied whether plasma levels of leptin also correlate to insulin secretion and sensitivity in humans. Therefore, we examined insulin sensitivity by the euglycemic-hyperinsulinemic clamp technique and measured the insulin response to intravenous arginine (5 g) at fasting and 14 mmol/l glucose in postmenopausal women. Percent body fat content was determined with impedance measurements. Log plasma leptin significantly correlated to percent body fat (r = 0.84, P < 0.001). In women with normal glucose tolerance (n = 36), partial correlation studies controlling for body fat content revealed significant correlations between log plasma leptin and fasting insulin levels (r = 0.39, P = 0.029), the insulin response to arginine at both glucose levels (r = 0.38 and r = 0.37, P < 0.036 for both), and the glucose potentiation of arginine-stimulated insulin secretion (r = 0.40, P = 0.025). In contrast, in women with impaired glucose tolerance (n = 17), these correlations were not significant. Plasma leptin did not correlate with insulin sensitivity independently of body fat content. To study whether the correlation between leptin and insulin would be explained by insulin stimulating leptin secretion, we examined plasma leptin during hyperinsulinemic conditions (689 +/- 41 pmol/l), under both euglycemia (5.0 mmol/l, n = 10) and hypoglycemia (2.5 mmol/l, n = 7). However, under both these conditions, plasma leptin was unaltered. In conclusion, plasma leptin 1) reflects body fat content and 2) correlates to insulin secretion independently of percent body fat in postmenopausal women with normal glucose tolerance.

Topics: Adipose Tissue; Arginine; Biomarkers; Blood Glucose; Fasting; Female; Glucose Clamp Technique; Glucose Intolerance; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Leptin; Middle Aged; Obesity; Postmenopause; Proteins; Reference Values