leptin and Disease-Models--Animal

Type II diabetes mellitus (T2DM) is one of the most prevalent diseases in the world, associated with diabetic foot ulcers and impaired wound healing. There is an ongoing need for interventions effective in treating these two problems. Pre-clinical studies in this field rely on adequate animal models. However, producing such a model is near-impossible given the complex and multifactorial pathogenesis of T2DM. A leptin-deficient murine model was developed in 1959 and relies on either dysfunctional leptin (ob/ob) or a leptin receptor (db/db). Though monogenic, this model has been used in hundreds of studies, including diabetic wound healing research. In this study, we systematically summarize data from over one hundred studies, which described the mechanisms underlying wound healing impairment in this model. We briefly review the wound healing dynamics, growth factors' dysregulation, angiogenesis, inflammation, the function of leptin and insulin, the role of advanced glycation end-products, extracellular matrix abnormalities, stem cells' dysregulation, and the role of non-coding RNAs. Some studies investigated novel chronic diabetes wound models, based on a leptin-deficient murine model, which was also described. We also discussed the interventions studied in vivo, which passed into human clinical trials. It is our hope that this review will help plan future research.

Topics: Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Leptin; Mice; Mice, Inbred Strains; Wound Healing

Adipose tissue secretes various peptides, including leptin. This hormone acts through the leptin receptor (Ob-R), which is expressed ubiquitously on the surface of various cells, including breast cancer cells and immune cells. Increasing evidence points to an interaction between the tumor microenvironment, tumor cells, and the immune system. Leptin plays an important role in breast cancer tumorigenesis and may be implicated in activation of the immune system. While breast cancer cannot be considered an immunogenic cancer, the triple-negative subtype is an exception. Specific immune cells - tumor infiltrating lymphocytes - are involved in the immune response and act as predictive and prognostic factors in certain breast cancer subtypes. The aim of this article is to review the interaction between adipose tissue, through the expression of leptin and its receptor, and the adaptive immune system in breast cancer.

Topics: Adipose Tissue; Animals; Breast; Breast Neoplasms; Carcinogenesis; Disease Models, Animal; Female; Humans; Immunity, Cellular; Leptin; Lymphocytes, Tumor-Infiltrating; Mice, Transgenic; Receptors, Leptin; T-Lymphocytes, Cytotoxic; Tumor Microenvironment

Obesity, a global challenge, is a complex disorder linked to various diseases. Different kinds of treatments are currently used to treat or control this pandemic. Despite their positive effects on controlling obesity, they still have limitations and side effects including digestive problems, difficulties of daily infusion of some drugs, surgical complications, and weight regain. All these issues cause these conventional methods not to have desirable efficacy. In this regard, brown adipose tissue (BAT) transplantation as a new investigational treatment is proposed, which has beneficial effects with no documented side effect in studies up to now.. This systematic review protocol was registered in the International Prospective Register of Systematic Reviews (Registration Number: CRD42018110045). The systematical search was conducted on Web of Science, Scopus, PubMed, Embase, and ProQuest databases. The quality assessments in the included studies and data gathering were conducted independently by two authors. The main variables were anthropometric indices including body weight, levels of leptin, IGF-1, glucagon, adiponectin, fasting blood glucose, and UCP-1.. Following the search in mentioned databases, ten articles were entered into this systematic review. In most studies, weight gain and white adipocyte size were reduced in the BAT transplant group. It seems that the transplantation leads to the regeneration of healthy adipose tissue by activating the endogenous BAT.. Since BAT transplantation is one of the possible future treatments of obesity, many studies are conducted to evaluate the outcomes and related procedures precisely, so it can finally step into clinical application.

Topics: Adiponectin; Adipose Tissue, Brown; Animals; Blood Glucose; Disease Models, Animal; Female; Leptin; Male; Mice; Mice, Obese; Obesity

The present study aimed to assess the prevalence of symptoms of anxiety and depression among health professionals in the three most affected regions in Cameroon.. The study was a descriptive cross-sectional type. Participants were health care professionals working in the three chosen regions of Cameroon. The non_probability convinient sample technique and that of the snowball were valued via a web questionnaire. The non-exhaustive sample size was 292. The diagnosis of anxiety and depression was made by the HAD (Hospital Anxiety and Depression scale).. Les auteurs rapportent que le secteur médical est classé à un plus grand risque de contracter le COVID-19 et de le propager potentiellement à d’autres. Le nombre sans cesse croissant de cas confirmés et suspects, la pression dans les soins, l’épuisement des équipements de protection individuelle et le manque de médicaments spécifiques peuvent contribuer à un vécu anxio-dépressif significatif. La présente étude s’est donnée pour ambition d’évaluer la prévalence des symptômes de l’anxiété et de la dépression chez les professionnels de santé dans les trois Régions les plus concernées au Cameroun.. Le choix des trois Régions du Cameroun se justifie non seulement par le fait qu’elles totalisent 95,8 % des cas de coronavirus au pays depuis le début de la pandémie, mais aussi parce qu’elles disposent de plus de la moitié des personnels de santé (56 %). Il s’agit d’une étude transversale, descriptive et analytique. Les participants sont des professionnels de la santé en service dans les Régions du Centre, Littoral et de l’Ouest du Cameroun. La méthode d’échantillonnage non probabiliste de convenance couplée à celle de boule de neige via un web questionnaire a été adoptée. La collecte des données a duré du 5 au 19 avril 2020, intervalle de temps après lequel on n’avait plus eu de répondants. À la fin de cette période, la taille de l’échantillon non exhaustive était de 292 professionnels. Le diagnostic de l’état anxio-dépressive était posé via l’échelle de HAD (Hospital Anxiety and Depression scale). Dans le HAD, chaque réponse cotée évalue de manière semi-quantitative l’intensité du symptôme au cours de la semaine écoulée. Un score total est obtenu ainsi que des scores aux deux sous-échelles : le score maximal est de 42 pour l’échelle globale et de 21 pour chacune des sous-échelles. Le coefficient alpha de Cronbach est de 0,70 pour la dépression et de 0,74 pour l’anxiété. Certains auteurs après plusieurs travaux ont proposé qu’une note inférieure ou égale à 7 indique une absence d’anxiété ou de dépression ; celle comprise entre 8 et 10 suggère une anxiété ou une dépression faible à bénigne ; entre 11 et 14, pour une anxiété ou une dépression modérée ; enfin, une note comprise entre 15 et 21 est révélatrice d’une anxiété sévère. Le logiciel Excel 2013 et Epi Info version 7.2.2.6 ont été utilisés pour les traitements statistiques. Les liens entre les variables ont été considérées significatifs pour une valeur de. L’amélioration des conditions de travail et notamment la fourniture d’équipement de protection, la mise en place des cellules spéciales d’écoute pour le personnel de santé pourraient être proposées.. Taken together with satisfactory selectivity index (SI) values, the acetone and methanol extracts of. During a mean follow-up period of 25.6 ± 13.9 months, 38 (18.4%) VAs and 78 (37.7%) end-stage events occurred. Big ET-1 was positively correlated with NYHA class (. In primary prevention ICD indication patients, plasma big ET-1 levels can predict VAs and end-stage events and may facilitate ICD-implantation risk stratification.. Beyond age, cognitive impairment was associated with prior MI/stroke, higher hsCRP, statin use, less education, lower eGFR, BMI and LVEF.. These data demonstrate that even a short period of detraining is harmful for elderly women who regularly participate in a program of strength training, since it impairs physical performance, insulin sensitivity and cholesterol metabolism.. Exposure to PM. Respiratory sinus arrhythmia is reduced after PVI in patients with paroxysmal AF. Our findings suggest that this is related to a decrease in cardiac vagal tone. Whether and how this affects the clinical outcome including exercise capacity need to be determined.. BDNF and leptin were not associated with weight. We found that miR-214-5p exerted a protective role in I/R injured cardiac cells by direct targeting FASLG. The results indicated that the MGO injection reduced all CCl. The hepatoprotective effects of MGO might be due to histopathological suppression and inflammation inhibition in the liver.. OVEO showed moderate antifungal activity, whereas its main components carvacrol and thymol have great application potential as natural fungicides or lead compounds for commercial fungicides in preventing and controlling plant diseases caused by. PF trajectories were mainly related to income, pregestational BMI, birth weight, hospitalisation due to respiratory diseases in childhood, participant's BMI, report of wheezing, medical diagnosis and family history of asthma, gestational exposure to tobacco and current smoking status in adolescence and young adult age.. In chronic pain patients on opioids, administration of certain benzodiazepine sedatives induced a mild respiratory depression but paradoxically reduced sleep apnoea risk and severity by increasing the respiratory arousal threshold.. Quantitative measurements of sensory disturbances using the PainVision. The serum level of 20S-proteasome may be a useful marker for disease activity in AAV.. The electrophysiological data and MD simulations collectively suggest a crucial role of the interactions between the HA helix and S4-S5 linker in the apparent Ca. Invited for the cover of this issue are Vanesa Fernández-Moreira, Nils Metzler-Nolte, M. Concepción Gimeno and co-workers at Universidad de Zaragoza and Ruhr-Universität Bochum. The image depicts the reported bimetallic bioconjugates as planes directing the gold fragment towards the target (lysosomes). Read the full text of the article at 10.1002/chem.202002067.. The optimal CRT pacing configuration changes during dobutamine infusion while LV and RV activation timing does not. Further studies investigating the usefulness of automated dynamic changes to CRT pacing configuration according to physiologic condition may be warranted.

Topics: 3' Untranslated Regions; 5'-Nucleotidase; A549 Cells; Accidental Falls; Acetylcholinesterase; Acrylic Resins; Actinobacillus; Acute Disease; Acute Kidney Injury; Adaptor Proteins, Signal Transducing; Adenosine; Adenosine Triphosphate; Administration, Inhalation; Administration, Oral; Adolescent; Adult; Advance Care Planning; Africa, Northern; Age Factors; Aged; Aged, 80 and over; Air Pollutants; Air Pollution; Air Pollution, Indoor; Albendazole; Aluminum Oxide; Anastomosis, Surgical; Ancylostoma; Ancylostomiasis; Androstadienes; Angiogenesis Inhibitors; Angiotensin II; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antibodies, Bispecific; Antibodies, Viral; Anticoagulants; Antihypertensive Agents; Antinematodal Agents; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antiporters; Antiviral Agents; Apoptosis; Aptamers, Nucleotide; Aromatase Inhibitors; Asian People; Astrocytes; Atrial Fibrillation; 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The triad of obesity, metabolic syndrome (MetS), Type 2 diabetes mellitus (T2DM) and advancing age are currently global societal problems that are expected to grow over the coming decades. This triad is associated with multiple end-organ complications of diabetic vasculopathy (maco-microvessel disease), neuropathy, retinopathy, nephropathy, cardiomyopathy, cognopathy encephalopathy and/or late-onset Alzheimer's disease. Further, obesity, MetS, T2DM and their complications are associated with economical and individual family burdens. This review with original data focuses on the white adipose tissue-derived adipokine/hormone leptin and how its deficient signaling is associated with brain remodeling in hyperphagic, obese, or hyperglycemic female mice. Specifically, the ultrastructural remodeling of the capillary neurovascular unit, brain endothelial cells (BECs) and their endothelial glycocalyx (ecGCx), the blood-brain barrier (BBB), the ventricular ependymal cells, choroid plexus, blood-cerebrospinal fluid barrier (BCSFB), and tanycytes are examined in female mice with impaired leptin signaling from either dysfunction of the leptin receptor (DIO and

Topics: Animals; Blood-Brain Barrier; Brain; Diabetes Mellitus, Type 2; Disease Models, Animal; Humans; Leptin; Mice, Obese; Obesity; Signal Transduction

Natural killer cells (NK cells) are a crucial constituent of the innate immune system as they mediate immunity against viruses, bacteria, parasites, and most importantly, tumor cells. The exact mechanism of how the innate immune system and specifically NK cells interact with cancer cells is complex and is yet to be understood. Several factors that constitute the tumor microenvironment (TME) such as hypoxia and TGF-

Topics: Adipokines; Adipose Tissue; Animals; Breast Neoplasms; Cytokines; Disease Models, Animal; Female; Humans; Immunity, Innate; Immunotherapy; Killer Cells, Natural; Leptin; Lymphocyte Activation; Obesity; Resistin; Tumor Microenvironment

Infertility is somewhat more prevalent in men who are obese. They are also reported to have low sperm concentration, higher fraction of spermatozoa that look morphologically abnormal, higher DNA fragmentation index and evidence of oxidative stress. The precise cause for this remains uncertain. Leptin levels in serum and percentage body fat correlate positively, and obese men therefore usually have elevated serum leptin levels. Although leptin is important for normal reproductive function, but when present in excess, leptin could seriously affect reproductive function in men. Reports on the findings of sperm parameters in obese men, particularly those who are subfertile or infertile, seem to be similar to those reported from studies on normal-weight rats treated with leptin. Collectively, the observations reported in human and experimental animal studies point to leptin as a possible link between infertility and obesity. Herein, we review some findings on sperm function in obese subfertile or infertile men and those from animal studies following leptin treatment, and discuss the possible link between leptin and reproductive dysfunction in obese men. The large amounts of leptin secreted by the adipose tissue and its higher circulating levels could indeed be responsible for the higher prevalence of infertility in obese men.

Topics: Animals; Disease Models, Animal; Humans; Infertility, Male; Leptin; Male; Obesity; Prevalence; Rats; Sperm Count; Sperm Motility

To review the latest reports of the contributions of the endothelial mineralocorticoid receptor to endothelial dysfunction and hypertension to begin to determine the clinical potential for this pathway for hypertension treatment.. Endothelial mineralocorticoid receptor expression is sex-specifically increased in female mice and humans compared with males. Moreover, the expression of endothelial mineralocorticoid receptors is increased by endothelial progesterone receptor activation and naturally occurring fluctuations in progesterone levels (estrous, pregnancy) predict endothelial mineralocorticoid receptor expression levels in female mice. These data follow many previous reports that have indicated that endothelial mineralocorticoid receptor deletion is protective in the development of obesity- and diabetes-associated endothelial dysfunction in female mouse models. These studies have more recently been followed up by reports indicating that both intact endothelial mineralocorticoid receptor and progesterone receptor expression are required for obesity-associated, leptin-mediated endothelial dysfunction in female mice. In addition, the intra-endothelial signaling pathway for endothelial mineralocorticoid receptors to induce dysfunction requires the intact expression of α-epithelial sodium channels (αENaC) in endothelial cells in females. Endothelial mineralocorticoid receptors are sex-specifically upregulated in the vasculature of females, a sex difference which is driven by endothelial progesterone receptor activation, and increased activity of these endothelial mineralocorticoid receptors is a crucial mediator of endothelial dysfunction, and potentially hypertension, in obese female experimental models.

Topics: Aldosterone; Animals; Disease Models, Animal; Endothelial Cells; Endothelium, Vascular; Epithelial Sodium Channels; Female; Humans; Hypertension; Leptin; Male; Mice; Mineralocorticoid Receptor Antagonists; Obesity; Receptors, Mineralocorticoid; Receptors, Progesterone; Sex Factors; Vascular Diseases

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in the elderly population. Numerous epidemiological and experimental studies have demonstrated that patients who suffer from obesity or type 2 diabetes mellitus have a higher risk of cognitive dysfunction and AD. Several recent studies demonstrated that food intake-lowering (anorexigenic) peptides have the potential to improve metabolic disorders and that they may also potentially be useful in the treatment of neurodegenerative diseases. In this review, the neuroprotective effects of anorexigenic peptides of both peripheral and central origins are discussed. Moreover, the role of leptin as a key modulator of energy homeostasis is discussed in relation to its interaction with anorexigenic peptides and their analogs in AD-like pathology. Although there is no perfect experimental model of human AD pathology, animal studies have already proven that anorexigenic peptides exhibit neuroprotective properties. This phenomenon is extremely important for the potential development of new drugs in view of the aging of the human population and of the significantly increasing incidence of AD.

Topics: Alzheimer Disease; Animals; Appetite Depressants; Disease Models, Animal; Energy Metabolism; Homeostasis; Humans; Leptin; Neuroprotective Agents; Oligopeptides; Pyrrolidonecarboxylic Acid

Multiple sclerosis (MS) is a multifactorial, inflammatory, and neurodegenerative disease of the central nervous system, where environmental factors interact with genetic susceptibility. The role of diet on MS has not been comprehensively elucidated; therefore, through an extensive search of relevant literature, this review reports the most significant evidence regarding nutrition as a possible co-factor influencing the inflammatory cascade by acting on both its molecular pathways and gut microbiota. Since nutritional status and dietary habits in MS patients have not been extensively reported, the lack of a scientific-based consensus on dietary recommendation in MS could encourage many patients to experiment alternative dietetic regimens, increasing the risk of malnutrition. This work investigates the health implications of an unbalanced diet in MS, and collects recent findings on nutrients of great interest among MS patients and physicians. The aim of this review is to elucidate the role of an accurate nutritional counseling in MS to move toward a multidisciplinary management of the disease and to encourage future studies demonstrating the role of a healthy diet on the onset and course of MS.

Topics: Animals; Antioxidants; Body Composition; Complementary Therapies; Diet; Disease Models, Animal; Dysbiosis; Fatty Acids; Fatty Acids, Unsaturated; Humans; Inflammation; Leptin; Lipopolysaccharides; Malnutrition; Micronutrients; Multiple Sclerosis; Nutritional Status; Obesity; Osteoporosis; Randomized Controlled Trials as Topic; Recommended Dietary Allowances; Risk Factors; Vitamin D

　The antihyperglycemic activities of extracts of boiogito (BOT) and bofutsushosan (BTS) were investigated in streptozotocin-induced (STZ)-diabetic mice. BOT extract containing Stephania tetrandra S. MOORE root (stephania), has more potent antihyperglycemic activity than BOT extract containing sinomenium stem (sinomenium). Extracts of stephania and astragalus root (astragalus) exert combined effects in the antihyperglycemic and insulinotropic activities of BOT extract. Fangchinoline, but not tetrandrine, in stephania plays a role in its activity. Formononetin in astragalus potentiates the actions of fangchinoline. Tetrandrine has antiangiogenic effects on choroidal vessels in STZ-diabetic rats, which are associated with the inhibition of tumor necrosis factor (TNF)-α-induced nuclear factor (NF)-κB activation. BTS extract has shown antihyperglycemic and insulinotropic activities whereas gardenia fruit (gardenia) extract in BTS has antihyperglycemic, but not insulinotropic, activity in the diabetic mice. Gardenia extract decreased the HOMA-IR level and increased insulin-stimulated 2-deoxyglucose (2-DG) uptake to skeletal muscle. The effects of gardenia extract on 2-DG uptake were associated with the upregulation of glucose transporter type 4 and Akt phosphorylation. Gardenia extract was also shown to have antihyperglycemic and insulinotropic actions in high-fat diet (HFD)-fed and STZ-diabetic mice. In addition, gardenia extract decreased the production of TNF-α and leptin, and increased the production of adiponectin in the visceral adipose tissues. In the early administration period, BTS extract increased mRNA expression levels of leptin, adiponectin, and UCP1 in brown adipose tissues in HFD-fed obese mice. With a longer duration of administration, BTS extract improved insulin resistance and subsequently reduced serum leptin and triglyceride levels in parallel with visceral adipose tissue volume and size.

Topics: Animals; Deoxyglucose; Diabetes Mellitus, Experimental; Disease Models, Animal; Drugs, Chinese Herbal; Gardenia; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Mice; Muscle, Skeletal; NF-kappa B; Obesity; Phytotherapy; Stephania; Streptozocin; Tumor Necrosis Factor-alpha

Intrauterine growth restriction (IUGR) has been identified as a risk factor for adult chronic kidney disease (CKD), including hypertension (HTN). Accelerated postnatal catch-up growth superimposed to IUGR has been shown to further increase the risk of CKD and HTN. Although the impact of excessive postnatal growth without previous IUGR is less clear, excessive postnatal overfeeding in experimental animals shows a strong impact on the risk of CKD and HTN in adulthood. On the other hand, food restriction in the postnatal period seems to have a protective effect on CKD programming. All these effects are mediated at least partially by the activation of the renin-angiotensin system, leptin and neuropeptide Y (NPY) signaling and profibrotic pathways. Early nutrition, especially in the postnatal period has a significant impact on the risk of CKD and HTN at adulthood and should receive specific attention in the prevention of CKD and HTN.

Topics: Animals; Child Development; Disease Models, Animal; Fetal Growth Retardation; Humans; Hypertension; Infant Nutritional Physiological Phenomena; Infant, Low Birth Weight; Infant, Newborn; Leptin; Metabolic Networks and Pathways; Neuropeptide Y; Nutritional Status; Renal Insufficiency, Chronic; Renin-Angiotensin System

Leptin, produced and secreted by white adipose tissue, plays a critical role in regulating body weight, food intake, and energy metabolism. Recently, several studies have identified an underlying role for leptin in regulation of mood and cognition via regulation of synaptic changes in the brain that have been associated with antidepressant-like actions. Brain neural plasticity occurs in response to a range of intrinsic and extrinsic stimuli, including those that may mediate the effects of antidepressants. Neural plasticity theories of depression are thought to explain multiple aspects of depression and the effects of antidepressants. It is also well documented that leptin has effects on neural plasticity. This review summarizes the recent literature on the role of leptin in neural plasticity in order to elaborate the possible mechanism of leptin's antidepressant-like effects. Recent findings provide new insights into the underlying mechanisms of neural plasticity in depression. Leptin may influence these mechanisms and consequently constitute a possible target for novel therapeutic approaches to the treatment of depression.

Topics: Animals; Antidepressive Agents; Brain-Derived Neurotrophic Factor; Depression; Disease Models, Animal; Female; Hippocampus; Humans; Hypothalamus; Leptin; Long-Term Potentiation; Long-Term Synaptic Depression; Male; Mice; Molecular Targeted Therapy; Neurogenesis; Rats

Leptin is a peptide hormone produced mainly in white adipose tissue. It is known to regulate energy homeostasis, inflammation, metabolism, and sympathetic nerve activity. Increasing evidence suggests it has a role in ventilatory function and upper airway obstruction. Leptin levels correlate positively with measurements of adiposity and can potentially provide important insights into the pathophysiology of diseases associated with obesity. Obesity is a strong risk factor for obstructive sleep apnea, a disease characterized by periodic upper airway occlusion during sleep. The neuromuscular activity that maintains upper airway patency during sleep and the anatomy of upper airway are key factors involved in its pathogenesis. Experimental studies using animal models of a low leptin state such as leptin deficiency have shown that leptin regulates sleep architecture, upper airway patency, ventilatory function, and hypercapnic ventilatory response. However, findings from human studies do not consistently support the data from the animal models. The effect of leptin on the pathophysiology of obstructive sleep apnea is being investigated, but the results of studies have been confounded by leptin's diurnal variation and the short-term effects of feeding, adiposity, age, and sex. Improved study design and methods of assessing functional leptin levels, specifically their central versus peripheral effects, will improve understanding of the role of leptin in sleep apnea.

Topics: Animals; Biomarkers; Disease Models, Animal; Humans; Leptin; Mice; Obesity; Rats; Sleep; Sleep Apnea, Obstructive

The incidence of obesity is rapidly escalating and has reached epidemic proportions. In all species, including rodents, humans, and sheep, there is large variation in the degree of weight gain across individuals in response to an obesogenic environment. This individual variation is, at least in part, determined by innate differences in energy expenditure, of which adaptive thermogenesis is a key component. The hypothalamus is essential to the control of body weight and adiposity. Appetite-regulating peptides within the hypothalamus exert reciprocal effects on food intake and energy expenditure, such that neuropeptides that stimulate food intake inhibit thermogenesis and vice versa. This review discusses the role of the hypothalamic neuropeptides in determining innate predisposition to obesity in 3 animal models being obesity-prone and obesity-resistant rodents, genetically lean and obese sheep, and animals selected for high/low cortisol responsiveness. In rodents, leptin resistance is a primary feature of the propensity to become obese. This contrasts that of larger mammals, such as sheep, where altered susceptibility to obesity manifests within the melanocortin and/or orexin pathways. This review highlights fundamental species differences within the hypothalamus that lead to altered susceptibility to weight gain and increased propensity to become obese.

Topics: Animals; Disease Models, Animal; Energy Metabolism; Humans; Hypothalamus; Leptin; Melanocortins; Models, Biological; Obesity; Orexins; Species Specificity; Thermogenesis

There is accumulating evidence from epidemiological studies that changes in body weight are associated with Alzheimer's disease (AD) from mid-life obesity increasing the risk of developing AD to weight loss occurring at the earliest stages of AD. Therefore, factors that regulate body weight are likely to influence the development and progression of AD. The adipocyte-derived hormone leptin has emerged as a major regulator of body weight mainly by activating hypothalamic neural circuits. Leptin also has several pleotropic effects including regulating cognitive function and having neuroprotective effects, suggesting a potential link between leptin and AD. Here, we will examine the relationship between leptin and AD by reviewing the recent evidence from cellular and animal models to human studies. We present a model where leptin has a bidirectional role in AD. Not only can alterations in leptin levels and function worsen cognitive decline and progression of AD pathology, but AD pathology, in of itself, can disrupt leptin signaling, which together would lead to a downward spiral of progressive neurodegeneration and worsening body weight and systemic metabolic deficits. Collectively, these studies serve as a framework to highlight the importance of understanding the molecular mechanisms underlying the body weight and systemic metabolic deficits in AD, which has the potential to open new avenues that may ultimately lead to novel therapeutic targets and diagnostic tools.

Topics: Alzheimer Disease; Animals; Body Weight; Disease Models, Animal; Humans; Leptin; Neuroprotective Agents; Translational Research, Biomedical

Obesity and its major comorbidities, including type 2 diabetes mellitus, nonalcoholic fatty liver disease (NAFLD), obesity cardiomyopathy, and certain cancers, have caused life expectancy in the United States to decline in recent years. Obesity is the increased accumulation of triglycerides (TG), which are synthesized from glycerol and long-chain fatty acids (LCFA) throughout the body. LCFA enter adipocytes, hepatocytes, and cardiomyocytes via specific, facilitated transport processes. Metabolism of increased cellular TG content in obesity may lead to comorbidities such as NAFLD and cardiomyopathy. Better understanding of LCFA transport processes may lead to successful treatment of obesity and NAFLD.

Topics: Animals; Disease Models, Animal; Fatty Acids; Humans; Insulin Resistance; Leptin; Non-alcoholic Fatty Liver Disease; Obesity; Peptide Hormones; Triglycerides

The risk of hypertension is increased by intrauterine growth restriction (IUGR) and preterm birth. In the search for modifiable etiologies for this life-threatening cardiovascular morbidity, a number of pathways have been investigated, including excessive glucocorticoid exposure, nutritional deficiency and aberration in sex hormone levels. As a neurotrophic hormone that is intimately involved in the cardiovascular regulation and whose levels are influenced by glucocorticoids, nutritional status and sex hormones, leptin has emerged as a putative etiologic and thus a therapeutic agent. As a product of maternal and late fetal adipocytes and the placenta, circulating leptin typically surges late in gestation and declines after delivery until the infant consumes sufficient leptin-containing breast milk or accrues sufficient leptin-secreting adipose tissue to reestablish the circulating levels. The leptin deficiency seen in IUGR infants is a multifactorial manifestation of placental insufficiency, exaggerated glucocorticoid exposure and fetal adipose deficit. The preterm infant suffers from the same cascade of events, including separation from the placenta, antenatal steroid exposure and persistently underdeveloped adipose depots. Preterm infants remain leptin deficient beyond term gestation, rendering them susceptible to neurodevelopmental impairment and subsequent cardiovascular dysregulation. This pathologic pathway is efficiently modeled by placing neonatal mice into atypically large litters, thereby recapitulating the perinatal growth restriction-adult hypertension phenotype. In this model, neonatal leptin supplementation restores the physiologic leptin surge, attenuates the leptin-triggered sympathetic activation in adulthood and prevents leptin- or stress-evoked hypertension. Further pathway interrogation and clinical translation are needed to fully test the therapeutic potential of perinatal leptin supplementation.

Topics: Adiposity; Adult; Animals; Animals, Newborn; Disease Models, Animal; Female; Fetal Growth Retardation; Hormone Replacement Therapy; Humans; Hypertension; Hypothalamus; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Leptin; Male; Mice; Nerve Tissue Proteins; Neurodevelopmental Disorders; Pregnancy; Receptors, Leptin; Recombinant Proteins; Signal Transduction

Multiple Sclerosis (MS) is an autoimmune disorder of the Central Nervous System that has been associated with several environmental factors, such as diet and obesity. The possible link between MS and obesity has become more interesting in recent years since the discovery of the remarkable properties of adipose tissue. Once MS is initiated, obesity can contribute to increased disease severity by negatively influencing disease progress and treatment response, but, also, obesity in early life is highly relevant as a susceptibility factor and causally related risk for late MS development. The aim of this review was to discuss recent evidence about the link between obesity, as a chronic inflammatory state, and the pathogenesis of MS as a chronic autoimmune and inflammatory disease. First, we describe the main cells involved in MS pathogenesis, both from neural tissue and from the immune system, and including a new participant, the adipocyte, focusing on their roles in MS. Second, we concentrate on the role of several adipokines that are able to participate in the mediation of the immune response in MS and on the possible cross talk between the latter. Finally, we explore recent therapy that involves the transplantation of adipocyte precursor cells for the treatment of MS.

Topics: Adipocytes; Adipokines; Adiponectin; Adipose Tissue; Animals; Astrocytes; Autoimmune Diseases; CD8-Positive T-Lymphocytes; Complement Factor D; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Humans; Immune System; Inflammation; Interleukin-17; Leptin; Mesenchymal Stem Cells; Mice; Microglia; Multiple Sclerosis; Nicotinamide Phosphoribosyltransferase; Obesity; Oligodendroglia; Prevalence; Resistin; Risk; Th1 Cells; Th2 Cells

Obesity is a growing health risk with few successful treatment options and fewer still that target both obesity and obesity-associated comorbidities. Despite ongoing scientific efforts, the most effective treatment option to date was not developed from basic research but by surgeons observing outcomes in the clinic. Bariatric surgery is the most successful treatment for significant weight loss, resolution of type 2 diabetes and the prevention of future weight gain. Recent work with animal models has shed considerable light on the molecular underpinnings of the potent effects of these 'metabolic' surgical procedures. Here we review data from animal models and how these studies have evolved our understanding of the critical signalling systems that mediate the effects of bariatric surgery. These insights could lead to alternative therapies able to accomplish effects similar to bariatric surgery in a less invasive manner.

Topics: Animals; Disease Models, Animal; Energy Intake; Energy Metabolism; Feeding Behavior; Gastrectomy; Gastric Bypass; Homeostasis; Leptin; Lipids; Mice; Obesity; Paracrine Communication; Peptide Hormones; Rats; Weight Loss

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality, affecting both developed and developing countries. Whilst it is well recognized that our risk of CVD can be determined by the interaction between our genetics and lifestyle, this only partly explains the variability at the population level. Based on these well-known risk factors, for many years, intervention and primary prevention strategies have focused on modifying lifestyle factors in adulthood. However, research shows that our risk of CVD can be pre-determined by our early life environment and this area of research is known as the Developmental Origins of Health and Disease. The aim of this review is to evaluate our current understanding of mechanisms underlying the programming of CVD. This article is part of a special issue entitled CV Aging.

Topics: Aging; Animals; Cardiovascular Diseases; Disease Models, Animal; Epigenesis, Genetic; Female; Heart; Humans; Insulin; Kidney; Leptin; Obesity; Oxidative Stress; Pregnancy; Renin-Angiotensin System; Risk Factors; Signal Transduction

Nonalcoholic steatohepatitis (NASH) is the advanced form of nonalcoholic fatty liver disease, which is often accompanied by obese and/or type II diabetes mellitus. Approximately one-third of NASH patients develop hepatic fibrosis. Hepatic stellate cells are the major effector cells during liver fibrogenesis. Advanced liver fibrosis usually proceeds to cirrhosis and even hepatocellular carcinoma, leading to liver failure, portal hypertension and even death. Currently, there are no approved agents for treatment and prevention of liver fibrosis in human beings. Curcumin, the principal curcuminoid of turmeric, has been reported to show antitumor, antioxidant, and anti-inflammatory properties both in in vitro and in vivo systems. Accumulating data shows that curcumin plays a critical role in combating liver fibrogenesis. This review will discuss the inhibitory roles of curcumin and update the underlying mechanisms by which curcumin targets in inhibiting hepatic stellate cell activation.

Topics: Animals; Curcumin; Diabetes Mellitus, Type 2; Disease Models, Animal; Hepatic Stellate Cells; Humans; In Vitro Techniques; Leptin; Lipid Metabolism; Liver Cirrhosis; Oxidative Stress; Signal Transduction

The past 20 years of research on leptin has provided important insights into its role in rheumatoid arthritis (RA). Leptin is one of the different adipokines produced by the adipose tissue that influences the endocrine system, energy homeostasis and the immune response in several ways. Leptin is known to have predominantly pro-inflammatory effects, especially in the setting of chronic inflammation. Animal models of arthritis have illustrated well the participation of leptin in the inflammatory response within the joints. In patients with RA, numerous studies have evaluated the concentrations of leptin in the bloodstream and/or the joint cavity, showing higher levels compared to control populations. Leptin has also been found to correlate with clinical or biological measurements of disease activity of RA. Conversely, the relationship between serum leptin and joint structural damage is less evident. Leptin may also promote the development of atherosclerosis in RA and may contribute to the cardiovascular consequences of the metabolic syndrome that coexists with RA. Indeed, leptin could be a link between inflammation, metabolic risk factors and cardiovascular diseases in RA. Finally, due to abnormal body composition phenotypes with an increased prevalence of obesity in RA, the therapeutic response to traditional DMARDs and/or biological agents may be attenuated. This review discusses the multiple interplays that have been described between leptin and the clinical, radiographic and therapeutic aspects of RA.

Topics: Animals; Arthritis, Rheumatoid; Disease Models, Animal; Humans; Leptin

Energy homeostasis in our body system is maintained by balancing the intake and expenditure of energy. Excessive accumulation of fat by disrupting the balance system causes overweight and obesity, which are increasingly becoming global health concerns. Understanding the pathogenesis of obesity focused on studying the genes related to familial types of obesity. Recently, a rare human genetic disorder, ciliopathy, links the role for genes regulating structure and function of a cellular organelle, the primary cilium, to metabolic disorder, obesity and type II diabetes. Primary cilia are microtubule based hair-like membranous structures, lacking motility and functions such as sensing the environmental cues, and transducing extracellular signals within the cells. Interestingly, the subclass of ciliopathies, such as Bardet-Biedle and Alström syndrome, manifest obesity and type II diabetes in human and mouse model systems. Moreover, studies on genetic mouse model system indicate that more ciliary genes affect energy homeostasis through multiple regulatory steps such as central and peripheral actions of leptin and insulin. In this review, we discuss the latest findings in primary cilia and metabolic disorders, and propose the possible interaction between primary cilia and the leptin and insulin signal pathways which might enhance our understanding of the unambiguous link of a cell's antenna to obesity and type II diabetes.

Topics: Animals; Cilia; Diabetes Mellitus, Type 2; Disease Models, Animal; Energy Metabolism; Homeostasis; Humans; Insulin; Leptin; Metabolic Diseases; Mice; Microtubules; Obesity; Signal Transduction

Osteoarthritis (OA) is the most common cause of musculoskeletal disability and pain in the world. The current drug treatment for OA is symptom relieving, and there is an urgent need for treatments that could retard, prevent or repair cartilage destruction in OA. Obesity is a major risk factor for OA. Traditionally, it has been thought to contribute to the development of OA by increasing the load on weight-bearing joints. However, this appears to be an over-simplification, because obesity is also linked to OA in the hand and finger joints. Recent studies have shown that adipocytokine leptin is a possible link between obesity and OA: Leptin levels in synovial fluid are increased in obese patients, leptin receptor (Ob-R) is expressed in cartilage, and leptin induces the production of matrix metalloproteinases (MMPs), pro-inflammatory mediators and nitric oxide (NO) in chondrocytes. Furthermore, according to the very recent findings, not only leptin levels in the joint but also leptin sensitivity in the cartilage are enhanced in obese OA patients. The findings supporting leptin as a causative link between obesity and OA offer leptin as a potential target to the development of disease-modifying drugs for osteoarthritis (DMOAD), especially for obese patients.

Topics: Animals; Disease Models, Animal; Gene Expression Regulation; Humans; Leptin; Obesity; Osteoarthritis; Receptors, Leptin; Synovial Fluid

Follicle wall rupture and ovum release, i.e., ovulation, has been described as a controlled inflammatory event. The process involves tissue remodeling achieved through leukocyte-mediated proteolysis. In birds, ovulation is the first step in the energy-intensive process of egg formation, yet hens that consume energy in excess of productive requirements experience impaired egg-laying ability. Broiler chickens, selected for rapid lean muscle gain, and coincidentally hyperphagia, develop adult obesity when given free access to feed. Obese broiler hens experience elevated circulating concentrations of insulin and leptin, changes in lipid and lipoprotein metabolism similar to those of human metabolic syndrome, as well as increased systemic inflammation. Overall, the manifestations in poultry are similar to those of women with polycystic ovary syndrome. It was shown recently that, in hens, as in mammals, changes in lipid synthesis and metabolism cause granulosa cell apoptosis and altered immune function and hormone production, further compromising ovarian function. To date, there is insufficient information on the means used by the ovary to direct leukocyte function toward successful ovulation. More information is needed regarding the control of proteolytic actions by leukocytes with regards to the roles of specific enzymes in both ovulation and atresia. The broiler hen has provided unique insight into the interrelations of energy intake, obesity, leukocyte function, and reproduction. Additional work with this model can serve the dual purposes of improving avian reproduction and providing novel insights into polycystic ovary syndrome in women.

Topics: Animals; Body Weight; Chickens; Disease Models, Animal; Energy Intake; Female; Humans; Insulin; Leptin; Mammals; Obesity; Ovary; Oviposition; Polycystic Ovary Syndrome; Reproduction

As the population of the world ages, the prevalence of neurodegenerative disease continues to rise, accompanied by increases in disease burden related to obesity and metabolic disorders. Thus, it will be essential to develop tools for preventing and slowing the progression of these major disease entities. Epidemiologic studies have shown strong associations between obesity, metabolic dysfunction, and neurodegeneration, while animal models have provided insights into the complex relationships between these conditions. Experimentally, the fat-derived hormone leptin has been shown to act as a neuroprotective agent in various animal models of dementia, toxic insults, ischemia/reperfusion, and other neurodegenerative processes. Specifically, leptin minimizes neuronal damage induced by neurotoxins and pro-apoptotic conditions. Leptin has also demonstrated considerable promise in animal models of obesity and metabolic disorders via modulation of glucose homeostasis and energy intake. However, since obesity is known to induce leptin resistance, we hypothesize that resistance to the neuroprotective effects of leptin contributes to the pathogenesis of obesity-associated neurodegenerative diseases. This review aims to explore the literature pertinent to the role of leptin in the protection of neurons from the toxic effects of aging, obesity and metabolic disorders, to investigate the physiological state of leptin resistance and its causes, and to consider how leptin might be employed therapeutically in the prevention and treatment of neurodegenerative disease.

Topics: Alzheimer Disease; Animals; Brain; Disease Models, Animal; Humans; Hypothalamus; Leptin; Mice; Neurons; Neuroprotective Agents; Obesity; Parkinson Disease; Rats

It is well known that hypercholesterolemia can lead to atherosclerosis and coronary heart disease. Adipose tissue represents an active endocrine and metabolic site, which might be involved in the development of chronic disease. Because adipose tissue is a key site for cholesterol metabolism and the presence of hypercholesterolemia has been shown to induce adipocyte cholesterol overload, it is critical to investigate the role of hypercholesterolemia on normal adipose function. Studies in preadipocytes revealed that cholesterol accumulation can impair adipocyte differentiation and maturation by affecting multiple transcription factors. Hypercholesterolemia has been observed to cause adipocyte hypertrophy, adipose tissue inflammation, and disruption of endocrine function in animal studies. Moreover, these effects can also be observed in obesity-independent conditions as confirmed by clinical trials. In humans, hypercholesterolemia disrupts adipose hormone secretion of visfatin, leptin, and adiponectin, adipokines that play a central role in numerous metabolic pathways and regulate basic physiologic responses such as appetite and satiety. Remarkably, treatment with cholesterol-lowering drugs has been shown to restore adipose tissue endocrine function. In this review the role of hypercholesterolemia on adipose tissue differentiation and maturation, as well as on hormone secretion and physiologic outcomes, in obesity and non–obesity conditions is presented.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Adiposity; Animals; Anticholesteremic Agents; Cell Differentiation; Clinical Trials as Topic; Disease Models, Animal; Humans; Hypercholesterolemia; Inflammation; Leptin; Nicotinamide Phosphoribosyltransferase; Obesity

Parabiosis is a chronic preparation that allows exchange of whole blood between two animals. It has been used extensively to test for involvement of circulating factors in feedback regulation of physiological systems. The total blood volume of each animal exchanges approximately ten times each day, therefore, factors that are rapidly cleared from the circulation do not reach equilibrium across the parabiotic union whereas those with a long half-life achieve a uniform concentration and bioactivity in both members of a pair. Involvement of a circulating factor in the regulation of energy balance was first demonstrated when one member of a pair of parabiosed rats became hyperphagic and obese following bilateral lesioning of the ventromedial hypothalamus. The non-lesioned partner stopped eating, lost a large amount of weight and appeared to be responding to a circulating "satiety" factor released by the obese rat. These results were confirmed using different techniques to induce obesity in one member of a pair. Studies with phenotypically similar ob/ob obese and db/db diabetic mice indicated that the obese mouse lacked a circulating signal that regulated energy balance, whereas the diabetic mouse appeared insensitive to such a signal. Positional cloning studies identified leptin as the circulating factor and subsequent parabiosis studies confirmed leptin's ability to exchange effectively between parabionts. These studies also suggest the presence of additional unidentified factors that influence body composition. This article is part of a Special Issue entitled: Animal Models of Disease.

Topics: Animals; Diabetes Mellitus, Experimental; Disease Models, Animal; Energy Metabolism; Humans; Leptin; Mice; Obesity; Parabiosis; Rats

Although obesity is a well-known risk factor for hypertension, the mechanisms by which hypertension develops in obese patients are not entirely clear. Animal models of obesity and their different susceptibilities to develop hypertension have revealed some of the mechanisms linking obesity and hypertension. Adipose tissue is an endocrine organ secreting hormones that impact blood pressure, such as elements of the renin-angiotensin system whose role in hypertension have been established. In addition, the appetite-suppressing adipokine leptin activates the sympathetic nervous system via the melanocortin system, and this activation, especially in the kidney, increases blood pressure. Leptin secretion from adipocytes is increased in most models of obesity due to leptin resistance, although the resistance is often selective to the anorexigenic effect, while the susceptibility to the hypertensive effect remains intact. Understanding the pathways by which obesity contributes to increased blood pressure will hopefully pave the way to and better define the appropriate treatment for obesity-induced hypertension.

Topics: Animals; Blood Pressure; Disease Models, Animal; Humans; Hypertension; Leptin; Obesity; Renin-Angiotensin System

Obesity is a world health problem that increases the risk for developing type 2 diabetes, cardiovascular disease, fatty liver, and some types of cancer. In postmenopausal women, it represents an important risk factor for the development of breast cancer (BC). Leptin is an adipokine that is secreted by fatty tissue, and high leptin levels are observed both in mouse models of obesity and in obese subjects. High levels of leptin promote the proliferation and progression of various types of cancer, including BC. This review provides a general overview of the biology of leptin, important laboratory studies, and animal and clinical models that have provided evidence for an active role of leptin in the proliferation, progression, and survival of mammary tumors. Finally, this review addresses the most recent studies on the use of leptin receptor antagonists as a novel therapeutic treatment for BC.

Topics: Animals; Breast Neoplasms; Disease Models, Animal; Energy Metabolism; Female; Homeostasis; Humans; Leptin; Mice; Molecular Targeted Therapy; Receptors, Leptin; Risk Factors; Signal Transduction

The number of overweight and obese individuals has dramatically increased in the US and other developed nations during the past 30 years. While type II diabetes and cardiovascular disease are well recognized co-morbid conditions associated with obesity, recent reports have demonstrated a greater severity of illness in obese patients due to influenza during the 2009 H1N1 pandemic. Consistent with these reports, diet-induced obesity has been shown to impair anti-viral host defense in murine models of influenza infection. However, the impact of obesity on the risk of community-acquired and nosocomial pneumonia in human patients is not clear. Relatively few studies have evaluated the influence of diet-induced obesity in murine models of bacterial infections of the respiratory tract. Obese leptin deficient humans and leptin and leptin-receptor deficient mice exhibit greater susceptibility to respiratory infections suggesting a requirement for leptin in the pulmonary innate and adaptive immune response to infection. In contrast to these studies, we have observed that obese leptin receptor signaling mutant mice are resistant to pneumococcal pneumonia highlighting the complex interaction between leptin receptor signaling and immune function. Given the increased prevalence of obesity and poor responsiveness of obese individuals to vaccination against influenza, the development of novel immunization strategies for this population is warranted. Additional clinical and animal studies are needed to clarify the relationship between increased adiposity and susceptibility to community-acquired and nosocomial pneumonia.

Topics: Adiposity; Animals; Bacterial Infections; Disease Models, Animal; Humans; Influenza, Human; Leptin; Mice; Obesity; Pneumonia; Receptors, Leptin; Respiratory Tract Infections; Severity of Illness Index; United States

Different lipid fractions in humans have characteristic fatty acid profiles and these are maintained partly through diet and to a lesser extent through endogenous synthesis. The enzyme stearoyl-CoA desaturase (SCD; EC 1.14.99.5) is the rate-limiting enzyme in the synthesis of monounsaturated fatty acids such as palmitoleic acid (16:1 n-7) and oleic acid (18:1 n-9). These are the two most abundant monounsaturated fatty acids in human plasma lipids, membranes and adipose tissue. Although in quantitative terms, the endogenous synthesis of fatty acids in humans is not great in most circumstances, it is becoming increasingly evident that SCD plays important structural and metabolic roles. In addition, 16:1 n-7 has been purported to act as a beneficial 'lipokine' in an animal model. Research in humans has relied on indirect measurements of SCD1 activity and therefore, much of our understanding has come from work on animal models. However, results have been somewhat counterintuitive and confusing, so the purpose of this review is to try to summarise our current understanding of this fascinating enzyme.

Topics: Adipose Tissue; Animals; Diet; Disease Models, Animal; Evolution, Molecular; Female; Genetic Predisposition to Disease; Humans; Insulin; Leptin; Lipogenesis; Liver; Male; Organ Specificity; Rodentia; Stearoyl-CoA Desaturase; Substrate Specificity; Triglycerides

Metabolic syndrome has been described as the association of insulin resistance, hypertension, hyperlipidemia and obesity. Its prevalence increased dramatically, mainly in developed countries. Animal models are essential to understand the pathophysiology of this syndrome. This review presents the murine models of metabolic syndrome the most often used in pharmacological studies. The most common metabolic syndrome models exhibit a non-functional leptin pathway, or metabolic disorders induced by high fat diets. In a first part, and after a short introduction on leptin, its receptor and mechanism of action, we provide a detailed description of each model: SHROB, SHHF, JCR:LA-cp, Zucker, ZDF, Wistar Ottawa Karlsburg W, and Otsuka Long-Evans Tokushima Fatty rats, ob/ob, db/db, agouti yellow and Mc4R KO mice. The second part of this review is dedicated to metabolic syndrome models obtained by high fat feeding.

Topics: Animals; Diet; Disease Models, Animal; Humans; Leptin; Metabolic Syndrome; Receptors, Leptin

Energy deficit in lean or obese animals or humans stimulates appetite, reduces energy expenditure and possibly also decreases physical activity, thereby contributing to weight regain. Often overlooked in weight loss trials for obesity, however, is the effect of energy restriction on neuroendocrine status. Negative energy balance in lean animals and humans consistently inhibits activity of the hypothalamo-pituitary-thyroid, -gonadotropic and -somatotropic axes (or reduces circulating insulin-like growth factor-1 levels), while concomitantly activating the hypothalamo-pituitary-adrenal axis, with emerging evidence of similar changes in overweight and obese people during lifestyle interventions for weight loss. These neuroendocrine changes, which animal studies show may result in part from hypothalamic actions of orexigenic (e.g. neuropeptide Y, agouti-related peptide) and anorexigenic peptides (e.g. alpha-melanocyte-stimulating hormone, and cocaine and amphetamine-related transcript), can adversely affect body composition by promoting the accumulation of adipose tissue (particularly central adiposity) and stimulating the loss of lean body mass and bone. As such, current efforts to maximize loss of excess body fat in obese people may inadvertently be promoting long-term complications such as central obesity and associated health risks, as well as sarcopenia and osteoporosis. Future weight loss trials would benefit from assessment of the effects on body composition and key hormonal regulators of body composition using sensitive techniques.

Topics: Adipose Tissue; Animals; Appetite; Body Composition; Body Weight; Disease Models, Animal; Energy Intake; Energy Metabolism; Fasting; Humans; Hypothalamus; Leptin; Neuropeptides

Polycystic ovary syndrome (PCOS) is the most frequent female endocrine disorder, affecting 5%-10% of women, causing infertility due to dysfunctional follicular maturation and ovulation, distinctive multicystic ovaries and hyperandrogenism, together with metabolic abnormalities including obesity, hyperinsulinism, an increased risk of type 2 diabetes, and cardiovascular disease. The etiology of PCOS is unclear, and decisive clinical studies are limited by ethical and logistic constraints. Consequently treatment is palliative rather than curative and focuses on symptomatic approaches. Hence, a suitable animal model could provide a valuable means with which to study the pathogenesis of the characteristic reproductive and metabolic abnormalities and thereby identify novel and more effective treatments. So far there is no consensus on the best experimental animal model, which should ideally reproduce the key features associated with human PCOS. The prenatally androgenized rhesus monkey displays many characteristics of the human condition, including hyperandrogenism, anovulation, polycystic ovaries, increased adiposity, and insulin insensitivity. However, the high cost of nonhuman primate studies limits the practical utility of these large-animal models. Rodent models, on the other hand, are inexpensive, provide well-characterized and stable genetic backgrounds readily accessible for targeted genetic manipulation, and shorter reproductive life spans and generation times. Recent rodent models display both reproductive and metabolic disturbances associated with human PCOS. This review aimed to evaluate the rodent models reported to identify the advantages and disadvantages of the distinct rodent models used to investigate this complex endocrine disorder.

Topics: Androgens; Animals; Aromatase Inhibitors; Disease Models, Animal; Estrogens; Female; Humans; Leptin; Luteinizing Hormone; Mice; Mutation; Obesity; Plasminogen Activator Inhibitor 1; Polycystic Ovary Syndrome; Progestins; Rats; Receptors, Leptin

To discuss the relationship between adipokines and connective tissue diseases, by putting special emphasis on the potential role of leptin, adiponectin, resistin, and other adipose tissue products in the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus and on possible application of adipokine-targeted therapy in the treatment of these disorders with emphasis on the recent findings.. PubMed literature search complemented by review of bibliographies listed in identified articles.. Most of the data presented by different research groups showed changed levels of leptin, adiponectin, and resistin and occasionally also other adipokines in rheumatoid arthritis and systemic lupus erythematosus. The relationship between the remaining connective tissue diseases and adipokines is less documented.. Plasma levels of adipokines might tell us too little about their role in connective tissue disorders, whereas adipokine effects on synovial tissues might differ from their known metabolic or cardiovascular effects, which implies that some re-appraisal of adipokines role may need to take place. It still remains obscure whether the observed disturbances in various adipokine systems in subjects with connective tissue diseases contribute to their development or only reflect the presence or activity of inflammatory process, which itself is induced by other pro-inflammatory factors.

Topics: Adipokines; Adiponectin; Animals; Arthritis, Rheumatoid; Connective Tissue; Disease Models, Animal; Humans; Leptin; Lupus Erythematosus, Systemic; Resistin

Enhanced susceptibility to infection has long been recognized in children with congenital deficiency of leptin or its receptor. Studies in mice have demonstrated that leptin deficiency affects both the innate and acquired immune systems. Here, we review recent studies that demonstrate the impact on immunity of a common non-synonomous polymorphism of the leptin receptor. In a Bangladesh cohort of children, the presence of two copies of the ancestral Q223 allele was significantly associated with resistance to amebiasis. Children and mice with at least one copy of the leptin receptor 223R mutation were more susceptible to amebic colitis. Leptin signaling in the intestinal epithelium and downstream STAT3 (signal transducer and activator of transcription 3) and SHP2 (Src homology phosphatase 2) signaling were required for protection in the murine model of amebic colitis. Murine models have also implicated leptin in protection from other infections, including Mycobacterium tuberculosis, Klebsiella pneumoniae, and Streptococcus pneumoniae. Thus, the role of leptin signaling in infectious disease and specifically leptin-mediated protection of the intestinal epithelium will be the focus of this review.

Topics: Animals; Child; Disease Models, Animal; Dysentery, Amebic; Genetic Predisposition to Disease; Humans; Immunity, Mucosal; Intestinal Mucosa; Leptin; Mice; Polymorphism, Genetic; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor

Inflammation in the white adipose tissue (WAT) is considered a major player in the development of insulin resistance. The role of macrophages accumulating in the WAT during obesity, promoting WAT inflammation and insulin resistance is well established. In contrast, less is known about the role of lymphocytes. Recent studies have implicated different lymphocyte subsets in WAT inflammation. For instance, cytotoxic CD8(+) T cells infiltrating the WAT may contribute to the recruitment, differentiation and activation of macrophages. On the other hand, a differential role for CD4(+) Th1 and CD4(+) Th2 cells has been suggested. Levels of WAT regulatory T cells decrease during the course of obesity and may represent a crucial factor for the maintenance of insulin sensitivity. Moreover, activation of natural killer T cells, an innate-like T cell population, which recognises lipid antigens, promotes insulin resistance and WAT inflammation. Finally, B cells may infiltrate WAT very early in response to high-fat feeding and worsen glucose metabolism through modulation of T cells and the production of pathogenic antibodies. These interesting new findings however bear controversies and introduce novel, yet unanswered, questions. Here, we review and discuss the impact of the different lymphocyte subsets in obesity-related WAT inflammation and attempt to identify the open questions to be answered by future studies.

Topics: Adipose Tissue, White; Animals; B-Lymphocyte Subsets; Disease Models, Animal; Humans; Inflammation; Leptin; Lymphocytes; Mice; Obesity; T-Lymphocyte Subsets

The focus of this overview is on the animal models of obesity most commonly utilized in research. The models include monogenic models in the leptin pathway, polygenic diet-dependent models, and, in particular for their historical perspective, surgical and chemical models of obesity. However, there are far too many models to consider all of them comprehensively, especially those caused by selective molecular genetic approaches modifying one or more genes in specific populations of cells. Further, the generation and use of inducible transgenic animals (induced knock-out or knock-in) is not covered, even though they often carry significant advantages compared to traditional transgenic animals, e.g., influences of the genetic modification during the development of the animals can be minimized. The number of these animal models is simply too large to be covered in this unit.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Cricetinae; Diet; Disease Models, Animal; Female; Hypothalamus; Leptin; Lipodystrophy; Male; Mesocricetus; Metabolic Diseases; Mice; Mice, Transgenic; Mutation; Obesity; Ovariectomy; Phodopus; Rats; Rats, Transgenic; Receptors, Leptin; Seasons

Leptin, the adipokine produced mainly by the white adipose tissue, plays important roles not only in the regulation of food intake, but also in controlling immunity and inflammation. It has been widely demonstrated that the absence of leptin leads to immune defects in animal and human models, ultimately increasing mortality. Leptin also regulates inflammation by means of actions on its receptor, that is widely spread across different immune cell populations. The molecular mechanisms by which leptin determines its biological actions have also been recently elucidated, and three intracellular pathways have been implicated in leptin actions: JAK-STAT, PI3K, and ERK 1/2. These pathways are closely regulated by intracellular proteins that decrease leptin biological activity. In this review, we discuss the molecular mechanisms by which leptin regulates immunity and inflammation, and associate those mechanisms with chronic inflammatory disorders.

Topics: Adaptive Immunity; Animals; Chronic Disease; Cytokines; Disease Models, Animal; Humans; Immunologic Factors; Inflammation; Inflammation Mediators; Leptin; Receptors, Leptin

Obesity is the most critical factor in the pathology of metabolic syndrome (MetS), and is associated with an increased risk of depression. The imbalance of hormones and neural peptides which are involved in energy regulation are observed in obesity. It becomes evident that these hormones and neural peptides also affect mood. Leptin plays a pivotal role in energy regulation mainly acting in the hypothalamus of the brain. Although obese humans and rodents usually have high circulating levels of leptin, leptin neither reduces food intake nor increases energy expenditure. This paradoxical situation in obesity has been termed "leptin resistance", which is considered to be a central dogma for obesity. Based on these observations, we examined the functional significance of leptin in the regulation of the depressive state in diet-induced obese (DIO) mice. Our recent study demonstrated that DIO mice showed severe depressive behavior without response to the antidepressant effect of leptin, which is, in part, due to the impairment of leptin action in the hippocampus (Yamada, et al., Endocrinology, 2011). MetS and CNS dysfunction might have common pathological bases vulnerable to these disorders. Our future direction is to investigate a new treatment strategy of MetS by analyzing CNS dysfunction associated with obesity.

Topics: Animals; Central Nervous System Diseases; Depression; Disease Models, Animal; Humans; Leptin; Metabolic Syndrome; Obesity

The protein nucleobindin 2 (NUCB2) or NEFA (DNA binding/EF-hand/acidic amino acid rich region) was identified over a decade ago and implicated in intracellular processes. New developments came with the report that post-translational processing of hypothalamic NUCB2 may result in nesfatin-1, nesfatin-2 and nesfatin-3 and convergent studies showing that nesfatin-1 and full length NUCB2 injected in the brain potently inhibit the dark phase food intake in rodents including leptin receptor deficient Zucker rats. Nesfatin-1 also reduces body weight gain, suggesting a role as a new anorexigenic factor and modulator of energy balance. In light of the obesity epidemic and its associated diseases, underlying new mechanisms regulating food intake may be promising targets in the drug treatment of obese patients particularly as the vast majority of them display reduced leptin sensitivity or leptin resistance while nesfatin-1's mechanism of action is leptin independent. Although much progress on the localization of NUCB2/nesfatin-1 in the brain and periphery as well as on the understanding of nesfatin-1's anorexic effect have been achieved during the past three years, several important mechanisms have yet to be unraveled such as the identification of the nesfatin-1 receptor and the regulation of NUCB2 processing and nesfatin-1 release.

Topics: Animals; Appetite Regulation; Body Weight; Calcium-Binding Proteins; Disease Models, Animal; DNA-Binding Proteins; Eating; Energy Intake; Humans; Hypothalamus; Leptin; Nerve Tissue Proteins; Nucleobindins; Obesity; Peptide Hormones; Rats; Satiety Response; Signal Transduction

Experimental and clinical evidence implicates the 2 major adipose tissue cytokines, adiponectin (ADPN) and leptin (LEP), in renal damage. The interpretation of the link between these cytokines and renal outcomes is strictly context-sensitive. Albuminuria is a feature of renal disease in the ADPN null mouse and this alteration can be reversed by supplementing ADPN. Accordingly, in young normoalbuminuric obese individuals low ADPN is associated with higher albumin excretion rate. Conversely, high ADPN is associated with more severe proteinuria in chronic kidney disease patients, possibly underlying a protective response aimed at countering the high renal and cardiovascular risk of high proteinuria. LEP administration ameliorates insulin resistance in insulin-resistant patients with hereditary lipodystrophy--a disease characterized by severe LEP deficiency and renal disease--and the same intervention reverses both, insulin resistance and renal damage in a mouse model of LEP deficiency. However, LEP may exert noxious effects on the kidney (particularly renal fibrosis) if administered in conditions of LEP sufficiency or excess.

Topics: Adiponectin; Animals; Biomarkers; Disease Models, Animal; Humans; Kidney Failure, Chronic; Leptin; Mice; Rats; Risk Factors

Hyperactivity in anorexia nervosa is difficult to control and negatively impacts outcome. Hyperactivity is a key driving force to starvation in an animal model named activity-based anorexia (ABA). Recent research has started unraveling what mechanisms underlie this hyperactivity. Besides a general increase in locomotor activity that may be an expression of foraging behavior and involves frontal brain regions, the increased locomotor activity expressed before food is presented (food anticipatory behavior or FAA) involves hypothalamic neural circuits. Ghrelin plays a role in FAA, whereas decreased leptin signaling is involved in both aspects of increased locomotor activity. We hypothesize that increased ghrelin and decreased leptin signaling drive the activity of dopamine neurons in the ventral tegmental area. In anorexia nervosa patients, this altered activity of the dopamine system may be involved not only in hyperactivity but also in aberrant cognitive processing related to food.

Topics: Analgesics, Opioid; Animals; Anorexia; Disease Models, Animal; Dopamine; Ghrelin; Humans; Hyperkinesis; Leptin; Melanocortins; Neurobiology; Neuropeptide Y

Progress in identification of effective therapies for diabetic nephropathy continues to be limited by the lack of ideal animal models. Here we review the current status of some leading murine models of this disorder.. A consensus statement of the Animals Models of Diabetic Complications Consortium sets forth guidelines and standards for measuring renal function and structural parameters necessary for validating murine models of diabetic nephropathy. Two murine models exploiting endothelial nitric oxide synthase (eNOS) deficiency as a major susceptibility factor for development of diabetic nephropathy are among the very few options for studying features of advanced diabetic nephropathy. Akita and OVE26 mice with mutations that result in Type I diabetes are also useful models of diabetic nephropathy. The recently described BTBR ob/ob (leptin deficient) mouse with Type II diabetes demonstrates key features of early podocyte loss and mesangiolysis characteristic of human diabetic nephropathy.. While there are many murine models of mesangial matrix expansion in the setting of diabetes, few progress to develop advanced diabetic lesions. Mice with eNOS deficiency, OVE26 mice, and the recently described BTBR ob/ob mouse currently appear to be the best murine models of advanced disease. A model that allows testing of interventions that modulate podocyte loss and regeneration, such as the BTBR ob/ob mouse, may be of particular benefit in developing therapeutics for diabetic nephropathy.

Topics: Animals; Calmodulin; Diabetic Nephropathies; Disease Models, Animal; Glomerular Mesangium; Humans; Insulin Resistance; Leptin; Mice; Nitric Oxide Synthase Type III; Receptor, Insulin

Bardet-Biedl Syndrome (BBS) is a rare human hereditary disorder associated with several features including obesity, retinopathy, renal defects, polydactyly, learning disabilities and hypogenitalism. This article discusses the abnormalities accounting for energy imbalance leading to obesity in BBS, with emphasis on the recent evidence pointing to aberrations in hypothalamic action of leptin. Indeed, BBS proteins have emerged as important mediators of leptin receptor trafficking, and loss of BBS genes results in leptin resistance that could be due to abnormal leptin receptor handling in a subset of leptin-responsive neurons. These recent discoveries hold promise for improved clinical management of BBS patients. The relevance of these findings to non-syndromic common obesity is also discussed.

Topics: Animals; Bardet-Biedl Syndrome; Cilia; Disease Models, Animal; Ependyma; Humans; Leptin; Obesity

Cloned in 1994, the ob gene encodes the protein hormone leptin, which is produced and secreted by white adipose tissue. Since its discovery, leptin has been found to have profound effects on behavior, metabolic rate, endocrine axes, and glucose fluxes. Leptin deficiency in mice and humans causes morbid obesity, diabetes, and various neuroendocrine anomalies, and replacement leads to decreased food intake, normalized glucose homeostasis, and increased energy expenditure. Here, we provide an update on the most current understanding of leptin-sensitive neural pathways in terms of both anatomical organization and physiological roles.

Topics: Adaptation, Physiological; Adipose Tissue, White; Animals; Body Weight; Brain; Disease Models, Animal; Energy Metabolism; Feeding Behavior; Glucose; Humans; Hypothalamus; Leptin; Mice; Mice, Obese; Models, Biological; Overnutrition; Pro-Opiomelanocortin; Receptor, Melanocortin, Type 4; Receptors, Leptin; Starvation; Sympathetic Nervous System

Important advances in our understanding of the relationships between adipokines, inflammation and the immune response have been achieved in the past 10 years. White adipose tissue has emerged as a highly dynamic organ that releases a plethora of immune and inflammatory mediators that are involved in numerous diseases, including not only rheumatic diseases such as rheumatoid arthritis, osteoarthritis and systemic lupus erythematosus, but also cardiovascular and metabolic complications that are frequently observed in rheumatic diseases. Our rapidly growing knowledge of adipokine biology is revealing the complexity of these amazing proteins, thereby redefining white adipose tissue as a key element of the inflammatory and immune response in rheumatic diseases. Adipokines exert potent modulatory actions on target tissues and cells involved in rheumatic disease, including cartilage, synovium, bone and various immune cells. In this Review, we describe the most recent advances in adipokine research in the context of rheumatic diseases, focusing primarily on leptin, adiponectin, visfatin and resistin, and also the potential role of newly identified adipokines such as chemerin, lipocalin 2 and serum amyloid A3.

Topics: Adipokines; Adiponectin; Animals; Disease Models, Animal; Humans; Leptin; Rheumatic Diseases

Osteoarthritis (OA), the most common form of arthritis, is associated with joint malfunction and chronic disability in the aged population. It is a multifactorial disorder to which several factors-such as age, sex, trauma, and obesity-contribute significantly. Obesity is one of the most influential but modifiable risk factors because it exerts an increased mechanical stress on the tibiofemoral cartilage. However, the high prevalence of OA in obese individuals in non-weightbearing areas, like finger joints, suggests that the link between being overweight and OA lies with factors other than simple biomechanics. An important correlation has been made between obesity and inflammation. Adipose tissues (and the infrapatellar fat pad) play an important role in this context because they are the major source of cytokines, chemokines, and metabolically active mediators called adipokines (or adipocytokines). These metabolic factors are known to possess catabolic and proinflammatory properties and to orchestrate the pathophysiological processes in OA. This review provides information on the relationship between obesity and OA through biomechanical and biochemical factors and highlights the functions of important obesity-related inflammatory products in the initiation and progression of OA. This information will broaden our thinking in identifying the targets for both prevention and intervention for OA.

Topics: Adiponectin; Adipose Tissue; Animals; Cytokines; Disease Models, Animal; Humans; Inflammation; Inflammation Mediators; Interleukin-1beta; Interleukin-6; Interleukin-8; Leptin; Obesity; Osteoarthritis; Prevalence; Resistin; Risk Factors; Tumor Necrosis Factor-alpha

Obesity has various deleterious effects on health largely associated with metabolic abnormalities including abnormal glucose and lipid homeostasis that are associated with vascular injury and known cardiac, renal, and cerebrovascular complications. Advanced age is also associated with increased adiposity, decreased lean mass, and increased risk for obesity-related diseases. Although many of these obesity- and age-related disease processes have long been subsumed to be secondary to metabolic or vascular dysfunction, increasing evidence indicates that obesity also modulates nonvascular diseases such as Alzheimer's disease (AD) dementia. The link between peripheral obesity and neurodegeneration will be explored, using adipokines and AD as a template. After an introduction to the neuropathology of AD, the relationship between body weight, obesity, and dementia will be reviewed. Then, population-based and experimental studies that address whether leptin modulates brain health and mitigates AD pathways will be explored. These studies will serve as a framework for understanding the role of adipokines in brain health.

Topics: Aging; Alzheimer Disease; Animals; Biomarkers; Body Weight; Brain; Disease Models, Animal; Female; Humans; Leptin; Male; Mice; Models, Neurological; Obesity; Receptors, Leptin; Risk Factors; Signal Transduction

The mechanisms behind the changes in serum triiodothyronine (T(3)), thyroxine (T(4)) and TSH that occur in the non-thyroidal illness syndrome (NTIS) are becoming clearer. Induction of a central hypothyroidism occurs due to a diminution in hypothalamic thyrotropin-releasing hormone. This can be signalled by a decrease in leptin caused by malnutrition and possibly a localised increase in hypothalamic T(3) catalyzed by altered expression of hypothalamic iodothyronine deiodinases D2 and D3. Data from D1 and D2 knockout mice suggest that these enzymes may have little contribution to the low serum T(3) found in acute illness. The decline in serum T(3) and T(4) in models of acute illness precedes the fall in hepatic D1, suggesting that much of the initial fall in these hormones may be attributable to an acute phase response giving rise to a reduction in the thyroid hormone binding capacity of plasma. When measured by reliable methods, changes in serum free T(4) and free T(3) are modest in comparison to the fall seen in total thyroid hormone. Thyroid hormone transporter expression is up-regulated in many models of the NTIS, thus if diminished tissue uptake of hormone occurs in vivo, it is likely to be the result of impaired transporter function caused by diminished intracellular ATP or plasma inhibitors of transporter action. In man, chronic illness leads to an upregulation of thyroid hormone receptor (THR) expression at least in liver and renal failure. In contrast, human and animal models of sepsis and trauma indicate that expression of THRs and their coactivators are decreased in acute illness.

Topics: Animals; Disease Models, Animal; Euthyroid Sick Syndromes; Hormone Replacement Therapy; Humans; Iodide Peroxidase; Leptin; Mice; Mice, Knockout; Receptors, Thyroid Hormone; Thyroid Hormones; Thyrotropin-Releasing Hormone

TOR (target of rapamycin) is a serine-threonine protein kinase that is conserved across a diverse range of species from fungi to mammals. The signaling pathway that is anchored by TOR is also conserved across species. In mammals, mTOR integrates growth factor, amino acid, nutrient and energy sensing signals, and thus plays a major role in cell growth and proliferation, protein synthesis and autophagy. As a result of the pivotal role of mTOR in signaling, the aberrant regulation of mTOR has been implicated in several disease processes, including cancer, diabetes, ocular diseases and neurodegenerative disorders, as well as in lifespan extension. More recently, rapamycin (sirolimus) analogs that antagonize the mTOR signaling pathway have been approved for the treatment of several cancers. This review describes some recent advances in the understanding of mTOR signaling, with an emphasis on the functional consequences of mTOR inhibition and therapeutic intervention strategies.

Topics: Animals; Diabetes Mellitus; Disease Models, Animal; Enzyme Inhibitors; Eye Diseases; Humans; Intracellular Signaling Peptides and Proteins; Leptin; Longevity; Neoplasms; Neurodegenerative Diseases; Protein Serine-Threonine Kinases; Signal Transduction; TOR Serine-Threonine Kinases

In recent years, obesity has been identified as a risk factor for the development of breast cancer in postmenopausal women, and it has been associated with a poor outcome. Many factors appear to be important in the mechanism of this increased risk, including estrogen, estrogen receptors, and the adipokines leptin and adiponectin. Estrogen, a potent mitogen for mammary cells, has long been implicated in the development of mammary tumors. Because adipose-associated aromatase activity increases the conversion of androgen to estrogen, mammary adipose tissue is thought to be an important source of local estrogen production. Leptin, which increases in the circulation in proportion to body fat stores, has been demonstrated in vitro to promote breast cancer cell growth. Animal models have also identified leptin as an important factor for the development of mammary tumors. In contrast to leptin, serum adiponectin concentrations are inversely related to body fat stores, and the addition of adiponectin to human breast cancer cells reduces cell proliferation and enhances apoptosis. This review explores the relationship between these factors and the development of mammary cancer in humans and mouse models.

Topics: Adiponectin; Animals; Breast Neoplasms; Cell Transformation, Neoplastic; Disease Models, Animal; Estrogens; Female; Humans; Leptin; Mice; Obesity; Receptors, Estrogen

This review summarizes key aspects of what has been learned about the physiology of pancreatic islets and leptin deficiency from studies in obese ob/ob mice. ob/ob Mice lack functional leptin. They are grossly overweight and hyperphagic particularly at young ages and develop severe insulin resistance with hyperglycemia and hyperinsulinemia. ob/ob Mice have large pancreatic islets. The beta-cells respond adequately to most stimuli, and ob/ob mice have been used as a rich source of pancreatic islets with high insulin release capacity. ob/ob Mice can perhaps be described as a model for the prediabetic state. The large capacity for islet growth and insulin release makes ob/ob mice a good model for studies on how beta-cells can cope with prolonged functional stress.

Topics: Animals; Disease Models, Animal; Glucose; Hyperglycemia; Incretins; Insulin; Insulin Resistance; Insulin-Secreting Cells; Islets of Langerhans; Leptin; Mice; Mice, Obese; Models, Biological; Oscillometry

The intrauterine environment supports the development and health of offspring. Perturbations to this environment can have detrimental effects on the fetus that have persistent pathological consequences through adolescence and adulthood. The developmental origins of the health and disease concept, also known as the "Barker Hypothesis", has been put forth to describe the increased incidence of chronic disease such as cardiovascular disease and diabetes in humans and animals exposed to a less than ideal intrauterine environment. Maternal infection, poor or excess nutrition, and stressful events can negatively influence the development of different cell types, tissues and organ systems ultimately predisposing the organism to pathological conditions. Although there are a variety of conditions associated to exposure to altered intrauterine environments, the focus of this review will be on the consequences of stress and high fat diet during the pre- and perinatal periods and associated outcomes related to obesity and other metabolic conditions. We further discuss possible neuroendocrine and epigenetic mechanisms responsible for the metabolic programming of offspring. The paper represents an invited review by a symposium, award winner or keynote speaker at the Society for the Study of Ingestive Behavior [SSIB] Annual Meeting in Portland, July 2009.

Topics: Animals; Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Disease Models, Animal; Disease Susceptibility; Energy Metabolism; Environment; Epigenesis, Genetic; Female; Glucocorticoids; Humans; Insulin; Leptin; Male; Pregnancy; Prenatal Exposure Delayed Effects; Sex Factors

Because leptin reduces food intake and body weight, the coexistence of elevated leptin levels with obesity is widely interpreted as evidence of 'leptin resistance.' Indeed, obesity promotes a number of cellular processes that attenuate leptin signaling (referred to here as 'cellular leptin resistance') and amplify the extent of weight gain induced by genetic and environmental factors. As commonly used, however, the term 'leptin resistance' embraces a range of phenomena that are distinct in underlying mechanisms and pathophysiological implications. Moreover, the induction of cellular leptin resistance by obesity complicates efforts to distinguish the mechanisms that predispose to weight gain from those that result from it. We suggest a framework for approaching these issues and important avenues for future investigation.

Topics: Animals; Animals, Genetically Modified; Disease Models, Animal; Drug Resistance; Humans; Leptin; Models, Biological; Obesity; Receptors, Leptin; Signal Transduction

Epidemiological studies have shown a positive relationship between dietary fat intake and obesity. Since rats and mice show a similar relationship, they are considered an appropriate model for studying dietary obesity. The present paper describes the history of using high-fat diets to induce obesity in animals, aims to clarify the consequences of changing the amount and type of dietary fats on weight gain, body composition and adipose tissue cellularity, and explores the contribution of genetics and sex, as well as the biochemical basis and the roles of hormones such as leptin, insulin and ghrelin in animal models of dietary obesity. The major factors that contribute to dietary obesity - hyperphagia, energy density and post-ingestive effects of the dietary fat - are discussed. Other factors that affect dietary obesity including feeding rhythmicity, social factors and stress are highlighted. Finally, we comment on the reversibility of high-fat diet-induced obesity.

Topics: Adipose Tissue; Animals; Body Composition; Dietary Fats; Disease Models, Animal; Energy Intake; Feeding Behavior; Ghrelin; Humans; Hyperphagia; Insulin; Leptin; Obesity; Sex Factors; Social Environment; Stress, Psychological; Weight Gain

The hormones insulin and leptin have been demonstrated to act in the central nervous system (CNS) as regulators of energy homeostasis at medial hypothalamic sites. In a previous review, we described new research demonstrating that, in addition to these direct homeostatic actions at the hypothalamus, CNS circuitry that subserves reward and motivation is also a direct and an indirect target for insulin and leptin action. Specifically, insulin and leptin can decrease food reward behaviors and modulate the function of neurotransmitter systems and neural circuitry that mediate food reward, i.e., midbrain dopamine and opioidergic pathways. Here we summarize new behavioral, systems, and cellular evidence in support of this hypothesis and in the context of research into the homeostatic roles of both hormones in the CNS. We discuss some current issues in the field that should provide additional insight into this hypothetical model. The understanding of neuroendocrine modulation of food reward, as well as food reward modulation by diet and obesity, may point to new directions for therapeutic approaches to overeating or eating disorders.

Topics: Adiposity; Animals; Disease Models, Animal; Dopamine; Eating; Feeding Behavior; Food Preferences; Homeostasis; Humans; Insulin; Leptin; Mesencephalon; Motivation; Neural Pathways; Obesity; Opioid Peptides; Reward; Signal Transduction

Common obesity is a multi-factorial trait, contributed by the "obesogenic" environment of caloric abundance and increasing automation, sedentary lifestyle and an underlying genetic susceptibility. There have been major advances in the past decade in our understanding of the human weight regulation mechanism and pathogenesis of obesity, abetted by discoveries of genetic defects which lead to human obesity.. Reports of genetic mutations causing obesity in humans and murine models were reviewed.. Humans with genetic defects resulting in leptin deficiency, leptin receptor deficiency, proopiomelanocortin deficiency (POMC), and melanocortin 4 receptor (MC4R) deficiency developed severe obesity as the dominant phenotypic feature, though these are rare autosomal recessive conditions, except MC4R deficiency which is inherited in an autosomal co-dominant fashion. Common and rare variants of the POMC and melanocortin 3 receptor genes may be predisposing factors in the development of common obesity. Recent reports of human obesity associated with thyrosine kinase B (TrkB) defect and brain derived neurotrophic factor (BDNF) disruption, coupled with other murine studies, supported the role of BDNF/TrkB as effectors downstream of the melanocortin receptors.. Despite exciting discoveries of single gene mutations resulting in human obesity, most cases of obesity are likely the result of subtle interactions of several related genetic variants with environmental factors which favour the net deposition of calories as fat, culminating in the obese phenotype. The mechanisms of action of these genes in the development of obesity are now being examined, with the aim of eventually discovering a therapeutic intervention for obesity.

Topics: Animals; Body Weight; Disease Models, Animal; Humans; Leptin; Melanocortins; Mice; Mutation; Obesity

Leptin was first characterized as a hormone that plays a central role in the control of body adiposity. A number of studies later revealed several other functions for leptin, including the capacity to modulate immune system activity. Currently, leptin occupies an important position as a unifying mechanism integrating nutritional status and immune function. Here, we will review some of the actions of leptin in the immune system, with special attention to the functions it exerts in the thymus.

Topics: Animals; Disease Models, Animal; Humans; Leptin; Receptors, Leptin; Signal Transduction; Thymus Gland

Epidemiological studies suggest that maternal undernutrition, obesity and diabetes during gestation and lactation can all produce obesity in human offspring. Animal models provide a means of assessing the independent consequences of altering the pre- vs postnatal environments on a variety of metabolic, physiological and neuroendocrine functions, which lead to the development of offspring obesity, diabetes, hypertension and hyperlipidemia. During the gestational period, maternal malnutrition, obesity, type 1 and type 2 diabetes, and psychological and pharmacological stressors can all promote offspring obesity. Normal postnatal nutrition can sometimes reduce the adverse effect of some of these prenatal factors, but may also exacerbate the development of obesity and diabetes in offspring of dams that are malnourished during gestation. The genetic background of the individual is also an important determinant of outcome when the perinatal environment is perturbed. Individuals with an obesity-prone genotype are more likely to be adversely affected by factors such as maternal obesity and high-fat diets. Many perinatal manipulations are associated with reorganization of the central neural pathways which regulate food intake, energy expenditure and storage in ways that enhance the development of obesity and diabetes in offspring. Both leptin and insulin have strong neurotrophic properties so that an excess or an absence of either of them during the perinatal period may underlie some of these adverse developmental changes. As perinatal manipulations can permanently and adversely alter the systems that regulate energy homeostasis, it behooves us to gain a better understanding of the factors during this period that promote the development of offspring obesity as a means of stemming the tide of the emerging worldwide obesity epidemic.

Topics: Animals; Body Weight; Child; Disease Models, Animal; Energy Metabolism; Exercise; Female; Humans; Infant, Newborn; Insulin; Lactation; Leptin; Maternal Nutritional Physiological Phenomena; Mice; Mice, Inbred Strains; Obesity; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Weaning

Emerging evidence points to a critical role for the skeleton in several homeostatic processes, including energy balance. The connection between fuel utilization and skeletal remodeling begins in the bone marrow with lineage allocation of mesenchymal stem cells to adipocytes or osteoblasts. Mature bone cells secrete factors that influence insulin sensitivity, and fat cells synthesize cytokines that regulate osteoblast differentiation; thus, these two pathways are closely linked. The emerging importance of the bone-fat interaction suggests that novel molecules could be used as targets to enhance bone formation and possibly prevent fractures. In this article, we discuss three pathways that could be pharmacologically targeted for the ultimate goal of enhancing bone mass and reducing osteoporotic fracture risk: the leptin, peroxisome proliferator-activated receptor gamma and osteocalcin pathways. Not surprisingly, because of the complex interactions across homeostatic networks, other pathways will probably be activated by this targeting, which could prove to be beneficial or detrimental for the organism. Hence, a more complete picture of energy utilization and skeletal remodeling will be required to bring any potential agents into the future clinical armamentarium.

Topics: Adipose Tissue; Animals; Bone and Bones; Bone Density; Bone Remodeling; Disease Models, Animal; Energy Metabolism; Female; Homeostasis; Humans; Leptin; Male; Mice; Mice, Knockout; Osteocalcin; Osteoporosis; PPAR gamma

We review here our latest results regarding short- and long-term effects of a neonatal maternal deprivation (MD) stress [24h at postnatal day (PND) 9] on diverse psychoneuroimmunoendocrine parameters, pointing out the existence of numerous sexual dimorphisms. Behavioral changes observed in MD animals might be at least in part attributable to neurodevelopmental effects of MD-induced elevated corticosterone levels. Our findings of short-term effects of MD on hippocampal and cerebellar neurons and glial cells appear to support this hypothesis. However, it is important to note that these cellular effects were more marked in males than in females. Moreover, in analyzing the effects of this neonatal stress on the endocannabinoid system (hippocampal endocannabinoid levels and CB1 receptors) we have also found that males were more affected by MD. Since all these sexual dimorphisms were found at an early neonatal age (PND 13), they are attributable to organizational effects of gonadal steroids. We discuss the potential implications of the elevated corticosterone and decreased leptin levels shown by MD animals in their diverse functional alterations, including the above mentioned neural effects as well as the intriguing persistent deficit in their immunological system. We also emphasize the necessity of analyzing the important influence of sex as regards the specific consequences of early life stress.

Topics: Animals; Animals, Newborn; Behavior, Animal; Body Weight; Brain; Cannabinoid Receptor Modulators; Chemotaxis; Corticosterone; Disease Models, Animal; Humans; Leptin; Lymphocyte Activation; Maternal Deprivation; Mental Disorders; Receptors, Cannabinoid; Sex Characteristics; Stress, Psychological

Since the 1980s, a number of bioactive molecules, now known as cardiovascular hormones, have been isolated from the heart and blood vessels, particularly from the subset of vascular endothelial cells. The natriuretic peptide family is the prototype of the cardiovascular hormones. Over the following decade, a variety of hormones and cytokines, now known as adipokines or adipocytokines, have also been isolated from adipose tissue. Leptin is the only adipokine demonstrated to cause an obese phenotype in both animals and humans upon deletion. Thus, the past two decades have seen the identification of two important classes of bioactive molecules secreted by newly recognized endocrine cells, both of which differentiate from mesenchymal stem cells. To assess the physiological and clinical implications of these novel hormones, we have investigated their functions using animal models. We have also developed and analyzed mice overexpressing transgenic forms of these proteins and knockout mice deficient in these and related genes. Here, we demonstrate the current state of the translational research of these novel hormones, the natriuretic peptide family and leptin, and discuss how lessons learned from excellent animal models and rare human diseases can provide a better understanding of common human diseases.

Topics: Animals; Diabetes Mellitus; Disease Models, Animal; Hormones; Humans; Leptin; Lipodystrophy; Mice; Mice, Transgenic; Natriuretic Peptides; Translational Research, Biomedical

The involvement of insulin/IGF-1 signals and leptin signals in spinal ligament cells was investigated using Zucker fatty rats (fa/fa) that carry mutation of the leptin receptor gene (fa) and monosodium glutamate-treated (MSG) rats that present obesity due to destruction of the hypothalamic ventromedial nucleus. Zucker fatty rats (ZFR) , that have a with functional abnormality of leptin receptors are a spontaneous model of ossification of the posterior longitudinal ligament that develops sympathetic nerve hypoactivity. (insulin/IGF-1 signals) IRS-1-positive cells, IRS-1 protein were eminent by detected in the cartilage endplate and the enthesis region in ZFR group. On the other hand, IRS-2-positive cells were slightly less in the ZFR group than in the MSG and control groups. The results suggest that IRS-1-mediated signaling for cell proliferation was enhanced in ZFR, which may explain the ossification of the posterior longitudinal ligament. (Leptin signals) We investigated the effects of leptin on the spinal ligament in ZFR histopathologically and immunohistochemically. Since Ob-R does not play any role due to functional abnormality in ZFR, the direct involvement of leptin in ligament ossification may be slight in ZFR. beta(2)AR expression in the stage preceding ligament ossification was confirmed, suggesting that ossification of the spinal ligament may be inhibited by sympathetic nerve stimulation in ZFR.

Topics: Animals; Disease Models, Animal; Humans; Insulin-Like Growth Factor I; Leptin; Mutation; Ossification of Posterior Longitudinal Ligament; Rats; Rats, Zucker; Receptors, Adrenergic, beta-2; Receptors, Leptin; Signal Transduction; Sodium Glutamate; Sympathetic Nervous System

Leptin, a product of the obesity gene, is a molecule that has received much attention since its cloning in 1994. Initially, most work centered around the effects of leptin on satiety and energy balance. However, in recent years there has been an intense focus on leptin as it relates to the cardiovascular system. Plasma leptin concentration is markedly elevated in obesity and the metabolic syndrome, both of which are associated with increased incidence of cardiovascular pathologies. In many studies, hyperleptinemia has been linked to endothelial dysfunction (a known precursor to atherosclerotic cardiovascular disease) and activation of the sympathetic nervous system. Additionally, recent evidence suggests that leptin released from perivascular adipose tissue may also have deleterious effects on the underlying vasculature, including the coronary circulation. This report reviews pertinent literature on leptin-mediated endothelial dysfunction, leptin-mediated sympathetic activation, and leptin as a significant perivascular adipose-derived factor.

Topics: Animals; Autonomic Nervous System; Cardiovascular Diseases; Cohort Studies; Disease Models, Animal; Endothelium, Vascular; Female; Humans; Leptin; Male; Mice; Obesity; Receptors, Leptin; Risk Assessment; Sensitivity and Specificity

The obesity gene product leptin plays an important role in the physiologic regulation of appetite and energy balance. Plasma leptin levels correlate closely with body fat storage and may respond to changes in energy expenditure. Recent evidence has implicated a direct cardiac regulatory action of leptin in addition to its well-established metabolic properties. Compelling evidence has indicated a link between abnormal leptin levels (hyper- or hypoleptinemia) and cardiac dysfunction. The leptin-deficient ob/ob mice have been used as a model for insulin resistance, obesity, and type 2 diabetes. Leptin replenishment has been shown to restore the depressed cardiac contractile function in ob/ob mice, indicating a permissive role of leptin in cardiac function. The precise role of leptin or leptin deficiency on cardiac health has not been fully elucidated. This article briefly reviews leptin's physiologic role in cardiomyocyte structure and function and how leptin deficiency or disrupted signaling may trigger cardiac functional and morphologic abnormalities.

Topics: Animals; Appetite Regulation; Disease Models, Animal; Energy Metabolism; Heart Function Tests; Leptin; Mice; Mice, Obese; Myocardial Contraction; Myocytes, Cardiac; Receptors, Leptin; Risk Factors; Sensitivity and Specificity; Signal Transduction

Cardiovascular disease caused less than 10% of deaths worldwide at the beginning of the 20th century but accounted for nearly 50% toward its end. Obesity has seen a similarly sharp increase in prevalence and is a major contributing factor to the rise in cardiovascular disease incidence. Mechanisms of obesity-induced heart disease are multifaceted and remain largely unknown, but cardiomyocyte programmed cell death, or apoptosis, seems to play a critical role in their development and progression. The heart maintains a delicate balance between cell proliferation and cell death throughout its lifetime. Even a slight increase in the rate of myocyte apoptosis, as seen in various animal models, has devastating consequences for the heart. This article critically reviews studies conducted in animal models of obesity that have expanded our understanding of the mechanisms of cardiomyocyte apoptosis and their role in various obesity-associated cardiovascular diseases.

Topics: Animals; Apoptosis; Cardiovascular Diseases; Disease Models, Animal; Insulin Resistance; Leptin; Male; Myocytes, Cardiac; Obesity; Rats; Rats, Sprague-Dawley; Rats, Zucker; Risk Factors; Sensitivity and Specificity; Signal Transduction; Survival Rate

It is becoming increasingly apparent that conditions experienced in early life play an important role in the long-term health of individuals. Alterations in development due to impaired, excessive or imbalanced growth, both in utero and during critical periods of relative plasticity beyond birth, can lead to the permanent programming of physiological systems. The regulation of energy balance is one area that is receiving particular attention, as rates of obesity and associated metabolic and cardiovascular disease continue to rise. Over recent decades, much progress has been made toward understanding the way in which metabolic tissues and physiological systems develop, and the impact of early life events and nutrition on these processes. It is apparent within human populations that some individuals are better able to maintain an appropriate body weight in the face of an obesogenic environment. Animal models have been widely used for the investigation of differential susceptibility to diet-induced obesity (DIO) and impaired energy balance regulation, and are shedding light on key pathways that may be involved. Alterations in pathways mediating energy homeostasis, outlined below, are likely candidates for programming effects following disturbed growth in early life.

Topics: Adipose Tissue; Animals; Diet; Disease Models, Animal; Energy Metabolism; Female; Glucocorticoids; Growth; Homeostasis; Humans; Leptin; Metabolic Diseases; Obesity; Overnutrition; Phenotype; Pregnancy

Most laboratory-based research on obesity is carried out in rodents, but there are a number of other interesting models in the animal kingdom that are instructive. This includes domesticated animal species such as pigs and sheep, as well as wild, migrating and hibernating species. Larger animals allow particular experimental manipulations that are not possible in smaller animals and especially useful models have been developed to address issues such as manipulation of fetal development. Although some of the most well-studied models are ruminants, with metabolic control that differs from monogastrics, the general principles of metabolic regulation still pertain. It is possible to obtain much more accurate endocrine profiles in larger animals and this has provided important data in relation to leptin and ghrelin physiology. Genetic models have been created in domesticated animals through selection and these complement those of the laboratory rodent. This short review highlights particular areas of research in domesticated and wild species that expand our knowledge of systems that are important for our understanding of obesity and metabolism.

Topics: Animal Migration; Animals; Birds; Cattle; Disease Models, Animal; Epigenesis, Genetic; Female; Ghrelin; Insulin Resistance; Leptin; Neuropeptide Y; Obesity; Pregnancy; Pregnancy, Animal; Seasons; Sheep; Sus scrofa

An activation of the endocannabinoid system (ECS) in obesity with increased concentrations of endocannabinoids in several tissues and in the circulation is described in this review. This increased availability of endocannabinoids might stimulate cannabinoid receptors in a pathophysiological manner. The successful use of the cannabinoid receptor CB(1) inverse agonists rimonabant and taranabant for weight loss and the treatment of obesity-associated metabolic disorders might well be through blocking this overstimulation of cannabinoid receptors. At present, no single mechanism has been identified that explains the increased bioavailability of endocannabinoids in obesity. Both increased synthesis and decreased degradation appear to operate in a species- and tissue-dependent manner, but many pieces of the puzzle still need to be collected. For example, most data show decreased fatty acid amide hydrolase (FAAH) expression and/or activity as a result of obesity or high-fat intake, but the endocannabinoid predominantly increased in tissues is 2-arachidonoylglycerol (2-AG), which is not degraded by FAAH in vivo. Furthermore, the influence of dietary fatty acids on the synthesis of endocannabinoids needs to be studied in much more detail. Although weight loss does not seem to influence activation of the endocannabinoid system (ECS) in human obesity, suggesting an underlying mechanisms independent of body weight, no such mechanism at the genetic level has yet been identified either. Thus, activation of the ECS is a hallmark of abdominal obesity, and explains the success of pharmacological CB(1) blockade, but serious attempts have to be made to clarify the underlying mechanisms of this activation.

Topics: Adipose Tissue; Animals; Brain; Cannabinoid Receptor Modulators; Diet; Dietary Fats, Unsaturated; Disease Models, Animal; Endocannabinoids; Humans; Leptin; Liver; Obesity; Pancreas; Receptors, Cannabinoid; Weight Loss

Up to 80% of patients with Anorexia Nervosa (AN) demonstrate hyperactivity. Hyperactivity counteracts weight gain during treatment and is associated with poor outcome of the disease. We hypothesized that hyperactivity in AN patients has a neurobiological basis and used an animal model-based translational approach to gain insight in mechanisms underlying this hyperactivity. Previously we and others showed that leptin treatment attenuates hyperactivity in the rat activity-based anorexia (ABA) model. The mechanisms involved in this process are, however, unknown. Here we describe potential downstream effector mechanisms involved in the attenuation of hyperactivity by leptin treatment in ABA rats.

Topics: Animals; Anorexia Nervosa; Disease Models, Animal; Humans; Hyperkinesis; Leptin; Motor Activity

Topics: Animals; Disease Models, Animal; Drug Resistance; Humans; Leptin; Models, Biological; Obesity

Topics: Animals; Disease Models, Animal; Fatty Liver; Humans; Leptin; Liver; Liver Cirrhosis; Mice; Models, Animal; Rats; Receptors, Cell Surface; Receptors, Leptin

Leptin is a multifunctional hormone produced mainly by the adipose tissue and involved in the regulation of food intake and energy balance. In addition, leptin can stimulate mitogenic and angiogenic processes in peripheral organs. Because leptin levels are elevated in obese individuals and excess body weight has been shown to increase breast cancer risk in postmenopausal women, attempts have been made to evaluate whether leptin can promote breast cancer. Data obtained in cell and animal models and analyses of human breast cancer biopsies indeed suggest such an involvement. Furthermore, a recent report clearly shows that targeting leptin signaling may reduce mammary carcinogenesis. Thus, leptin should become a new attractive target in breast cancer.

Topics: Animals; Breast Neoplasms; Cell Transformation, Neoplastic; Disease Models, Animal; Female; Humans; Leptin; Neovascularization, Pathologic; Signal Transduction

The increasing prevalence of the metabolic syndrome in numerous populations throughout the world is currently of major concern, and presents a huge global health problem. The link between low birth weight and the subsequent development of obesity, disrupted glucose homeostasis and hypertension is now well established, and there is extensive evidence supporting these associations in both epidemiological and experimental studies. Alterations in the secretion of, and responses to, the circulating hormones insulin and leptin are likely candidates in terms of disease development. The aim of current research is to define how the central and peripheral pathways in which these signals exert their effects may be disrupted following poor early growth, and how this disruption contributes to the development of metabolic disease. The present review aims to outline the existing evidence whereby alterations in early growth may programme an individual to be at increased risk of the metabolic syndrome. The development of central appetite and expenditure circuits and of peripheral metabolic tissues, are likely to play a key role in the long-term regulation of energy balance.

Topics: Animals; Appetite Regulation; Birth Weight; Disease Models, Animal; Energy Intake; Energy Metabolism; Genetic Predisposition to Disease; Humans; Leptin; Metabolic Syndrome; Nutritional Physiological Phenomena; Obesity; Risk Factors

Atherosclerosis and related forms of cardiovascular disease (CVD) are associated with several genetic and environmental risk factors, including hypercholesterolemia, diabetes mellitus (DM), hypertension, obesity and smoking. Human DM is a multi-system disorder that results from progressive failure of insulin production and insulin resistance. Most diabetic patients die from complications of atherosclerosis and CVD, and DM is also associated with increased risk of restenosis post-angioplasty. Furthermore, the incidence of DM, particularly type 2-DM, is expected to increase significantly during the next decades owing to the unhealthy effects of modern life-style habits (e.g., obesity and lack of physical exercise). Thus, it is of utmost importance to develop novel preventive and therapeutic strategies to reduce the social and health-care burden of CVD and DM. Although a number of physiological alterations thought to promote atherosclerosis have been identified in diabetic patients, the precise molecular mechanisms that link DM and atherosclerosis are largely unknown. Thus, the aim of this review is to discuss current murine models of combined DM and atherosclerosis and to explore how these experimental systems are being utilized to gain mechanistic insights into diabetes-induced neointimal lesion development, as well as their potential use in evaluating the efficacy of new therapies. Our discussion includes models generated by streptozotocin treatment and those resulting from naturally occurring or targeted mutations in the mouse.

Topics: Animals; Atherosclerosis; Constriction, Pathologic; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Models, Animal; Glucose; Insulin; Leptin; Mice; Recurrence; Tunica Intima

This review deals with the question whether resistance to obesity affects resistance to atherosclerosis.. Resistance to diet-induced obesity in inbred mouse strains involves an adequate response to Leptin, the main regulator of the energy balance cycle. Leptin, an adipokine with both central and peripheral targets, regulates food intake and energy expenditure. Adequate response to leptin involves repression of stearoyl-CoA desaturase, activation of Amp-activated protein-kinase and uncoupling proteins, resulting in fatty acid oxidation and energy expenditure. Most of the obesity-resistant strains are also resistant to atherosclerosis, but so far no information concerning the response to the leptin cycle is available in these strains when bred onto a LDLR(-/-) or apoE(-/-) background. Recent studies in mouse strains on an atherosclerosis permissive background have identified genetic links between obesity and atherosclerosis. Moreover, information derived from studies on mice was applied in order to learn about the metabolic effectors in humans and is included in this review.. The data presented in this review provide recent information concerning metabolic pathways that play an important role in the regulation of energy balance, a prerequisite for resistance to obesity. Hopefully they will provide a background for future genetic studies involved in resistance to atherosclerosis.

Topics: Animals; Atherosclerosis; Disease Models, Animal; Energy Metabolism; Genetic Predisposition to Disease; Humans; Leptin; Mice; Mice, Inbred Strains; Mice, Obese; Obesity

The recent rapid increase in the prevalence of obesity across the world is undoubtedly due to changes in diet and lifestyle. However, it is also indisputable that different people react differently to this change in environment and this variation in response is likely to be genetically determined. While for the majority of people this effect is presumed to be polygenic in origin, there is now strong evidence for a small number of genes having a large effect in some families with severe obesity. Studies of these families, coupled with parallel studies in murine models, have provided novel insights into the molecules involved in the regulation of appetite, energy expenditure and nutrient partitioning. We review here the lessons we have learnt from mouse models of obesity, both naturally occurring and artificially generated through targeted gene deletions, and more importantly from human monogenic syndromes of obesity. These have illuminated the critical role in which the central leptin melanocortin pathway plays in the control of mammalian food intake and body weight.

Topics: Animals; Appetite Regulation; Body Weight; Disease Models, Animal; Energy Metabolism; Humans; Leptin; Melanocortins; Mice; Obesity

This review summarizes key aspects of what has been learned about the physiology of leptin deficiency as it can be observed in obese-hyperglycemic ob/ob mice. These mice lack functional leptin. They are grossly overweight and hyperphagic, particularly at young ages, and develop severe insulin resistance. They have been used as a model for obesity and as a rich source of pancreatic islets with high insulin release capacity. The leptin deficiency manifests also with regard to immune function, the cardiovascular system including angiogenesis, supportive tissue function, malignancies, and reproductive function. ob/ob Mice are well suited for studies on the interaction between leptin and insulin, and for studies on initial aspects of metabolic disturbances leading to type-2 diabetes.

Topics: Animals; Disease Models, Animal; Humans; Hyperglycemia; Insulin; Islets of Langerhans; Leptin; Mice; Mice, Obese; Obesity

The metabolic syndrome is an emerging global epidemic characterized by clustering of metabolic abnormalities leading to increased cardiovascular risk: glucose intolerance or type 2 diabetes, dyslipidemia, hypertension, and "central" obesity. Scientists are decoding and piecing together the molecular texture underlying the metabolic syndrome: insulin resistance and dyslipidemia stand out as central pathophysiological events. In this picture, the liver rises as the leading organ in the maintenance of metabolic fitness; it serves as the first relay station for processing dietary information, and encloses the whole biochemical machinery for both glucose and lipid storage and disposal. In addition, the liver is a target of the different endocrine molecules secreted by pancreatic beta-cells and adipose tissue. Evidence collected in animal models supports the central role of the liver in the metabolic syndrome. While specific bereft of insulin sensitivity in skeletal muscle and adipose tissue fails to induce diabetes at certain extent, this is constantly the outcome in case of hepatic insulin resistance. Also, dyslipidemia is currently interpreted as the result of increased flux of free fatty acids to the liver with ensuing misbalance of lipoprotein synthesis and removal. In this review we bring together recent advances in the field of lipid sensing nuclear receptors, adipokines and other molecules responsible for metabolic fitness, and provide a putative coherent frame to conceive the pathophysiology of the metabolic syndrome.

Topics: Adiponectin; Animals; Carbohydrate Metabolism; Disease Models, Animal; Dyslipidemias; Humans; Insulin Resistance; Leptin; Lipid Metabolism; Liver; Metabolic Syndrome; PPAR alpha; PPAR gamma

Obesity is a major health problem. It increases the risk of cardiovascular diseases, 2-type diabetes mellitus, cancers, and premature mortality. Apart from some monogenic forms, it's a polygenic disorder, the result of interaction of genes and environmental factors. Genetic variants of proteins taking part in the regulation of food intake or thermogenesis and tissue mediators produced by the adipose tissue are responsible the genetic components of obesity. Identification of the genetic background of the obesity will help to understand the exact molecular mechanism of the pathogenesis, make possible the prevention, as well as individual therapeutic interventions.

Topics: Animals; Carrier Proteins; Disease Models, Animal; Humans; Ion Channels; Leptin; Membrane Proteins; Mitochondrial Proteins; Obesity; PPAR gamma; Pro-Opiomelanocortin; Proprotein Convertase 1; Receptor, Melanocortin, Type 4; Receptors, Adrenergic, beta-3; Receptors, Cell Surface; Receptors, Leptin; Risk Factors; Uncoupling Protein 1

Recent epidemiology demonstrates higher rate of obesity and metabolic syndrome in offspring with undernutrition in utero. IUGR babies with intrauterine undernutrition grow rapidly to catch up with normal growth course. Leptin is an adipocyte derived satiety factor that regulates food intake and energy expenditure. We demonstrated in mice model with maternal food restriction during pregnancy that premature leptin surge during neonatal catch up growth of the offspring lead them to impaired leptin sensitivity and obesity in adulthood.

Topics: Animals; Disease Models, Animal; Eating; Energy Intake; Female; Fetal Growth Retardation; Humans; Leptin; Malnutrition; Metabolic Syndrome; Obesity; Pregnancy; Pregnancy Complications

Topics: Animals; Animals, Newborn; Animals, Suckling; Disease Models, Animal; Fatty Acids, Unsaturated; Female; Fetal Growth Retardation; Fetal Nutrition Disorders; Humans; Infant, Newborn; Lactation; Leptin; Maternal Nutritional Physiological Phenomena; Pregnancy; Prenatal Nutritional Physiological Phenomena; Rats

The obesity epidemic has focused attention on the endocrine function of adipose tissue. Adipose tissue secretes leptin, cytokines, complement factors, and components of the coagulation cascade, most of which are increased in obesity. In contrast, a strong negative correlation exists between adiponectin and adiposity, insulin sensitivity, diabetes, vascular inflammation, and atherosclerosis. Adiponectin treatment in rodents increases insulin sensitivity and reduces lipids and atherogenesis. Chronic and central adiponectin treatment reduces weight, glucose, and lipids. The insulin-sensitizing action of thiazolidinediones is mediated, in part, through adiponectin. A causal role of adiponectin in diabetes, dyslipidemia, and atherosclerosis has been established in knockout mice. Therefore, adiponectin seems to be a marker of obesity-related diseases and a potential therapeutic target.

Topics: Adipocytes; Adiponectin; Animals; Disease Models, Animal; Energy Metabolism; Homeostasis; Humans; Leptin; Mice; Mice, Knockout; Obesity

Onset expression of Type 2 (NIDDM) diabetes and obesity metabolic syndromes (DOS) are characterized by premature, progressive cytoatrophy and organo-involution induced by dysregulated cellular gluco- and lipo-metabolic cascades. The consequential systemic, interstitial and intracellular hyperlipidemia disrupts normal cytointegrity and metabolic responsivity to the established hypercaloric pericellular environments. The sequential cytostructural, metabolic and endocrine disturbances associated with the development of progressive DOS-associated hypercytolipidemia compromises cellular metabolic response cascades and promotes cytochemical disturbances which culminate with nuclear lipoapoptosis and cytoatrophy. The dramatic alterations in interstitial glucose and lipid (free fatty acids/triglycerides) concentrations are recognized to influence interstitial and cytoplasmic microchemical environments, which markedly alter cellular nutrient diffusion and active trans-membrane flux rates. The progressive exacerbation of interstitial and cytoplasmic lipid imbibition has been demonstrated to be associated with DNA fragmentation by lipo-infiltration into the chromatin matrix, inducing structural disruption and physical dissolution, indexed as nuclear lipoapoptosis. Therapeutic reduction of the severity of hypercytolipidemia-induced structural and cytochemical compromise promotes the restoration of homeostatic metabolic support for normalized cytostructural indices and supportive cellular gluco- and lipo-metabolic cascades. The re-establishment of a homeostatic interstitial microenvironment moderates the severity of cytolipidemic compromise within affected cell types, reduces nuclear lipo-infiltration and DNA lipo-dissolution, resulting in the preservation of cytostructural integrity. Through the therapeutic restoration of extra- and intra-cellular microchemical environments in genetically dysregulated metabolic syndrome models, the coincident cytochemical, endocrine and metabolic disturbances associated with progressive hypercytolipidemia, resulting from the expressed systemic hypercaloric environmental and hepato-pancreatic endometabolic disturbances which characterize Type 2 (NIDDM) diabetes-obesity and metabolic (X) syndromes, may be ameliorated.

Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Diabetes Mellitus, Type 2; Disease Models, Animal; Humans; Hyperlipidemias; Leptin; Mutation; Obesity; Receptors, Cell Surface; Receptors, Leptin; Syndrome

For better understanding the role of each element involved in the physiopathology of obesity and insulin resistance, researchers can use experimental models, which may in controlled manner evaluate the participation of each element on the obesity and insulin resistance and provide information for better understanding the physiopathology and treatment of obesity and insulin resistance. Experimental obesity and insulin resistance can be due to a deficient response to leptin, secondary to hypoleptinemia and/or mutations on leptin receptor, by modifications on insulin receptor, deletion or diminished insulin signal transduction, enhancement of the effects of orexigen peptides and/or diminution of anorexigen peptides actions on hypothalamus, as well as secondary to arterial hypertension, as in the spontaneously hypertension. Obesity and insulin resistance can also be induced by glucocorticoid excess, frutose enriched and cafeteria diet and due to hypothalamus lesions induced by neonatal administration of monossodium glutamate.

Topics: Adipose Tissue; Animals; Diet; Disease Models, Animal; Hypertension; Insulin Resistance; Leptin; Models, Genetic; Models, Immunological; Obesity

Type 2 diabetes is a polygenic disease that can lead to severe complications in multiple tissues. Rodent models have been used widely for investigating the pathophysiology underlying type 2 diabetes and for examining the potential link with obesity, largely due to the limitations of invasive testing and of studying detailed molecular mechanisms in human tissues. Among rodents, the mouse model is especially popular because mice are easy to manipulate genetically, have a short generation time, and are relatively inexpensive. The most commonly used inbred mouse strains are reviewed in addition to several genetically engineered mouse models that have been generated to study type 2 diabetes in the context of obesity, with a focus on insulin, leptin, and peroxisome proliferator-activated receptor (PPAR) signaling pathways.

Topics: Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Glucose; Homeostasis; Humans; Insulin; Leptin; Mice

Topics: Animals; Anti-Obesity Agents; Disease Models, Animal; Energy Metabolism; Humans; Hypothalamic Hormones; Leptin; Melanins; Obesity; Pituitary Hormones; Receptors, Somatostatin

We present the knowledge acquired in the field of the genetics of human obesity. The molecular approach proved to be powerful to define new syndromes associated to obesity. The pivotal role of leptin and melanocortin pathways were recognized but in rare obesity cases. In the commoner form of obesities, a multitude of polymorphisms located in genes and candidate regions participate in an individual susceptibility to weight gain in a permissive environment. The effects are often uncertain and the results not always confirmed. It is now necessary to integrate data of various origins (environment, genotype, expression) to clarify the domain.

Topics: alpha-MSH; Animals; Brain; Disease Models, Animal; DNA; Humans; Leptin; Mice; Mice, Obese; Mutation; Obesity; Polymorphism, Genetic; Receptor, Melanocortin, Type 4

Topics: Amino Acid Sequence; Animals; Disease Models, Animal; Energy Metabolism; Humans; Hypertension; Leptin; Mice; Mice, Obese; Molecular Sequence Data; Mutation; Obesity; Receptors, Cell Surface; Receptors, Leptin; Sympathetic Nervous System

Topics: Animals; Carbon Monoxide; Disease Models, Animal; Hypertension; Insulin Resistance; Leptin; Natriuresis; Nitric Oxide; Nitric Oxide Synthase; Obesity; Oxidative Stress; Rats; Rats, Zucker; Receptors, Cell Surface; Receptors, Dopamine; Receptors, Leptin; Renin-Angiotensin System

Both genetic and environmental aspects are recognized in the obesity field but we are not able to elucidate multiple genes and gene-environment interactions with the present resources and tools used in the study of this complex disease. The purpose of this paper is to present some examples of the knowledge acquired in the field of obesity genetics and the new ongoing tools and developments that aim at studying the contribution of genes to obesity and their response to environmental changes.. In rare cases of monogenic obesities, genetic tools have proved extremely powerful for identifying the genes responsible and for defining new syndromes. However, in common obesity, most studies include the search for genotype-phenotype associations without taking into account the influence of environment (diet, sedentary lifestyle) in the relationship. Among the limitations to this integrated approach, one can cite the difficulty of having large enough samples as well as biocomputing tools that are still in their infancy for accessing the question of multiple interactions with no "a priori hypotheses". This picture will probably change rapidly in the future.. Large databases and DNA and biological sample banks will be available with updated environmental information and precise phenotypes thanks especially to European working groups. The capacity for studying multiple genes at once at the DNA or RNA levels is rapidly growing. Finally, tremendous progress in biocomputing will allow the integration of information from different sources (i.e. environment, phenotype, genotype, gene expression) and thus improve our ability to deal with complexity.

Topics: Adult; Animals; Child; Cohort Studies; Disease Models, Animal; Environment; Female; Forecasting; Gene Expression; Genetic Predisposition to Disease; Genotype; Homeostasis; Humans; Infant; Leptin; Male; Mice; Mutation; Obesity; Phenotype; Polymorphism, Genetic; Receptor, Melanocortin, Type 4; Receptors, Cell Surface; Receptors, Leptin; Risk; Syndrome

A number of epidemiological studies worldwide have demonstrated a relationship between poor early growth and an increased susceptibility to insulin resistance, visceral obesity, type 2 diabetes and other features of the metabolic syndrome in adulthood. However, the mechanistic basis of this relationship and the relative roles of genes and the environment remain a subject of debate. The 'thrifty phenotype' hypothesis proposes that poor fetal nutrition leads to programming of metabolism and an adult phenotype that is adapted to poor but not plentiful nutrition. The maternal reduced-protein rat model has been used to examine the importance of the maternal environment in determining susceptibility to adult disease. Pregnant and lactating rat dams are fed a diet containing 80 g protein/kg as compared with 200 g protein/kg, which leads to growth restriction in utero. Offspring of low-protein dams have increased susceptibility to diabetes, insulin resistance and hypertension when fed a palatable high-fat diet that promotes obesity. Administration of leptin during pregnancy and lactation to these protein-restricted dams produces offspring that have increased metabolic rate and do not become obese or insulin resistant when fed on a high-fat diet. Increased glucocorticoid exposure, particularly during late gestation, has been linked with insulin resistance in adulthood. High levels of fetal glucocorticoids may result from a decreased activity of placental 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 2, which normally protects the fetus from high maternal glucocorticoid levels. Leptin administration to protein-restricted dams inhibits the suppression of 11beta-HSD-2 and may be one mechanism by which the metabolic syndrome is prevented.

Topics: Animals; Disease Models, Animal; Female; Fetal Growth Retardation; Glucose; Humans; Insulin Resistance; Leptin; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Protein Deficiency; Rats

A decrease in the number of functional insulin-producing beta-cells contributes to the pathophysiology of type 2 diabetes. Opinions diverge regarding the relative contribution of a decrease in beta-cell mass versus an intrinsic defect in the secretory machinery. Here we review the evidence that glucose, dyslipidemia, cytokines, leptin, autoimmunity, and some sulfonylureas may contribute to the maladaptation of beta-cells. With respect to these causal factors, we focus on Fas, the ATP-sensitive K+ channel, insulin receptor substrate 2, oxidative stress, nuclear factor-kappaB, endoplasmic reticulum stress, and mitochondrial dysfunction as their respective mechanisms of action. Interestingly, most of these factors are involved in inflammatory processes in addition to playing a role in both the regulation of beta-cell secretory function and cell turnover. Thus, the mechanisms regulating beta-cell proliferation, apoptosis, and function are inseparable processes.

Topics: Animals; Cell Death; Diabetes Mellitus, Type 2; Disease Models, Animal; Dyslipidemias; Humans; Immunity, Innate; Inflammation; Insulin-Secreting Cells; Leptin; Risk Factors

Anovulatory infertility affects a large proportion of reproductive-aged women. Major improvements in successful clinical treatment of this prevalent disorder in women's health have been made possible because of biomedical research employing nonhuman primates. Experiments on female rhesus monkeys were the first to demonstrate that the key hypothalamic neurotransmitter, gonadotropin-releasing hormone, involved in stimulating pituitary gonadotropin synthesis, storage, and release was bioactive only when released in approximately hourly bursts. This breakthrough in understanding gonadotropin regulation enabled identification of hypogonadotropic, apparently normogonadotropic, and hypergonadotropic forms of anovulatory infertility, and development of appropriate stimulatory or inhibitory gonadotropin therapies. Treatments to overcome anovulatory infertility represent one of the major advances in clinical reproductive endocrinology during the last 25 yr. The future promise of nonhuman primate models for human ovulatory dysfunction, however, may be based on an increased understanding of molecular and physiological mechanisms responsible for fetal programming of adult metabolic and reproductive defects and for obesity-related, hyperinsulinemic impairment of oocyte development.

Topics: Animals; Anovulation; Disease Models, Animal; Female; Gonadotropin-Releasing Hormone; Humans; Hyperprolactinemia; Hypothalamus; Infertility, Female; Leptin; Ovarian Diseases; Primates; Stress, Physiological; Time Factors

The last decade witnessed a dramatic increase in knowledge concerning regulation of body weight and obesity. According to recent concepts constancy of body weight is a side product of regulatory events which ensure constant glucose fluxes to the brain. Within these control systems glucocorticoids and melanocortins play a fundamental role at several sites. The melanocortin neurons in the arcuate nucleus of the hypothalamus are important mediators of the feedback effects of leptin and insulin. Glucocorticoid and mineralocorticoid receptors in hippocampal neurons are crucial, as they define the balance between glucose allocation processes and food intake. Thereby, the hippocampal structures determine the setpoint for body weight regulation. A modulation of these brain structures by intranasal administration of melanocortin and inhisulin has been shown to reduce body weight and body fat mass in humans. So the manipulation of weight-regulating centers in the brain opens a novel approach to a pathogenetically based treatment of obesity.

Topics: Administration, Intranasal; alpha-MSH; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Cannabinoids; Disease Models, Animal; Energy Intake; Feedback; Glucocorticoids; Glucose; Hippocampus; Humans; Hypothalamus; Insulin; Leptin; Obesity; Receptors, Glucocorticoid; Receptors, Mineralocorticoid; Weight Loss

Topics: Animals; Chemokine CXCL2; Chemotactic Factors; Disease Models, Animal; Inflammation; Leptin; Mice; Mice, Inbred C57BL; Monokines; Oxidants, Photochemical; Ozone; Respiratory Tract Diseases

Obesity has become a worldwide public health problem affecting millions of people. A disruption of the balance between energy intake and energy expenditure is believed to be the major cause of obesity. Substantial progress has been made in deciphering the pathogenesis of energy homeostasis over the past few years. The fact that obesity is under strong genetic control has been well established. Human monogenic obesity is rare in large populations, the most common form of obesity is considered to be a polygenic disorder arising from the interaction of multiple genetic and environmental factors. Here, we attempt to briefly review the most recent understanding of molecular mechanisms involved in energy homeostasis and adipogenesis. We discuss the advantages and disadvantages of various approaches commonly used in search for susceptibility genes for obesity. The main results from these genetic studies are summarized, with comments made on the most striking or representative findings. Finally, the implications of the recent advances in the understanding of molecular genetic mechanisms of body weight regulation on prevention and therapeutic intervention of obesity will be discussed.

Topics: Adipose Tissue; Animals; Body Mass Index; Body Weight; Disease Models, Animal; Genetic Markers; Homeostasis; Humans; Leptin; Mice; Obesity; Peptides; Phenotype; Temperature

Patients with anorexia nervosa (AN) often show normal to elevated physical activity levels despite severe weight loss and emaciation. This is seemingly in contrast to the loss of energy and fatigue characteristic of other starvation states associated with weight loss. Despite the fact that historical accounts and clinical case studies of AN have regularly commented on the elevated activity levels, the behavior has become only recently the subject of systematic study. Because rodents and other species increase their activity upon food restriction leading to weight loss when given access to an activity wheel--a phenomenon referred to as activity-based anorexia or semi-starvation-induced hyperactivity (SIH)-it has been proposed that the hyperactivity in AN patients may reflect the mobilization of phylogenetically old pathways in individuals predisposed to AN. Exogeneous application of leptin in this animal model of AN has recently been shown to suppress completely the development of SIH. Hypoleptinemia, as a result of the food restriction, may represent the initial trigger for the increased activity levels in AN patients and in food-restricted rats. In the first and second parts of our review, we will summarize the relevant findings pertaining to hyperactivity in AN patients and in the rat model, respectively. We conclude with a synopsis and implications for future research.

Topics: Animals; Anorexia Nervosa; Disease Models, Animal; Exercise; Female; Humans; Hyperkinesis; Leptin; Motor Activity; Rats; Starvation; Weight Loss

Topics: Alcohol Drinking; Alcoholism; Animals; Disease Models, Animal; Ethanol; Humans; Leptin; Motivation; Neuropeptide Y; Neuropeptides; Rats; Substance Withdrawal Syndrome

It has long been known that obesity and insulin resistance are linked. Recently, it has been shown that adipocytes secrete several proteins including tumour necrosis factor-alpha, interleukin-6, resistin, and adiponectin. Since several of these so-called adipocytokines influence insulin sensitivity and glucose metabolism profoundly, they might provide a molecular link between increased adiposity and impaired insulin sensitivity. Thiazolidinediones which decrease insulin resistance and are used in the treatment of Type 2 diabetes seem to mediate part of their insulin-sensitising effects via modulation of adipocytokine expression. Furthermore, hormones such as beta-adrenergic agonists, insulin, glucocorticoids, and growth hormone might impair insulin sensitivity at least in part via up-regulation or down-regulation of adipocytokine synthesis. We summarise the current knowledge on how major adipocyte-secreted proteins are regulated by hormones and drugs influencing insulin sensitivity and discuss its implications for insulin resistance and obesity.

Topics: Adiponectin; Adipose Tissue; Animals; Cytokines; Disease Models, Animal; Hormones, Ectopic; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Interleukin-6; Leptin; Obesity; Proteins; Resistin

Topics: Acute-Phase Proteins; Animals; Brain; Disease Models, Animal; DNA-Binding Proteins; Enzyme Activation; Humans; Hyperphagia; Leptin; Obesity; Phosphatidylinositol 3-Kinases; STAT3 Transcription Factor; Trans-Activators

During the last past years, obesity had become a major public health problem, and new aspects of fat cells biology have been unraveled. First, since the discovery of leptin, the adipocytes has been recognized as true endocrine cells secreting a variety of factors in a regulated manner. The role of these factors on the development of obesity-associated metabolic complications is becoming increasingly clear. Also, the process of fat cell differentiation has been uncovered, leading to the possibility of efficient targeting protein expression in adipose tissue. Finally, lines of transgenic mice have been created, some of which are totally resistant to obesity. These models led to the identification of new potential adipose targets for the treatment of obesity.

Topics: Adipose Tissue; Animals; Cell Differentiation; Disease Models, Animal; Gene Expression Regulation; Humans; Leptin; Mice; Mice, Transgenic; Obesity

The growing number of patients with osteoporosis in our aging population need "anabolic" drugs to stimulate bone growth, improve bone microarchitecture, and accelerate fracture healing. Potent anabolic agents such as parathyroid hormone (PTH) and some of its adenylyl cyclase-stimulating fragments are either on their way, or have just now reached the clinic. This article discusses how PTHs might stimulate bone growth. The controversial bone anabolic activities of the widely used cholesterol-lowering lipophilic statins and how they might stimulate bone growth are also probed. Also, evidence is presented for leptin, a controller of body fat stores and the ovarian cycle. It has the remarkable property of being an anabolic and antianabolic that uses a hypothalamic factor to restrain osteoblast activity but by itself stimulates osteoblasts and inhibits osteoclasts.

Topics: Animals; Bone and Bones; Bone Development; Bone Remodeling; Disease Models, Animal; Drug Therapy, Combination; Fractures, Spontaneous; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Leptin; Osteogenesis; Osteoporosis; Parathyroid Hormone; Prognosis; Risk Assessment

Topics: Animals; Body Composition; Disease Models, Animal; Humans; Hypoventilation; Leptin; Mice; Mice, Obese; Obesity; Respiratory Physiological Phenomena; Sleep Apnea, Obstructive

The inflammatory response is essential in the response to pathogens. TNF-alpha, IL-1 and IL-6 are key mediators of the response. They initiate metabolic changes to provide nutrients for the immune system, from host tissues. These changes include hyperlipidemia and increased gluconeogenesis. Insulin resistance and disordering of lipid metabolism occur in obesity, diabetes mellitus, atherosclerosis. This review examines recent research that links inflammation to insulin insensitivity.. Population studies show a strong association between indices of inflammation, and abnormal lipid and carbohydrate metabolism, obesity and atherosclerosis. TNF-alpha is produced, by cells of the immune system and by adipocytes. It may provide the link between inflammation and insulin sensitivity. TNF-alpha results in insulin insensitivity, indirectly by stimulating stress hormone production and directly by sustained induction of SOCS-3 which decreases insulin-induced insulin receptor substrate 1 (IRS1) tyrosine phosphorylation and its association with the p85, regulatory subunit of phosphatidylinositol-3 kinase; and by negative regulation of PPAR gamma. Adipose tissue produces both TNF-alpha and leptin. Production of the latter relates positively to adipose tissue mass and through its actions on immune function exerts a pro-inflammatory influence.. Recent studies on diseases which involve insulin insensitivity (e.g. obesity, type 2 diabetes and atherosclerosis) also show increased cytokine production and markers of inflammation. Evidence at present favours chronic inflammation as a trigger for chronic insulin insensitivity, rather than the reverse situation.

Topics: Animals; Cytokines; Disease Models, Animal; Glucose; Humans; Inflammation; Insulin; Insulin Resistance; Leptin; Lipid Metabolism; Tumor Necrosis Factor-alpha

Topics: Adiponectin; Animals; Diabetes Mellitus, Lipoatrophic; Disease Models, Animal; Genes, Dominant; Genes, Recessive; GTP-Binding Protein gamma Subunits; Heterotrimeric GTP-Binding Proteins; Humans; Intercellular Signaling Peptides and Proteins; Lamin Type A; Leptin; Mice; Mutation; Prognosis; Proteins; Receptors, Retinoic Acid; Retinoid X Receptors; Transcription Factors

Animal models of hepatic steatosis and steatohepatitis have improved our understanding of the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Three models, genetically obese ob/ob mice, lipoatrophic mice and normal rats fed choline-deficient, methionine-restricted diets, have been particularly informative. All support the multiple 'hit' hypothesis for NAFLD pathogenesis that suggests that fatty livers are unusually vulnerable to oxidants and develop steatohepatitis when secondary insults generate sufficient oxidants to cause liver cell death and inflammation. Steatohepatitis, in turn, increases sensitivity to other insults that induce hepatic fibrosis, promoting the evolution of cirrhosis. Early during NAFLD pathogenesis, inhibitor kappa kinase beta (IKKbeta), an enzyme that induces tumour necrosis factor alpha (TNFalpha) and other proinflammatory cytokines, is activated and this causes insulin resistance. Inhibition of IKKbeta or TNFalpha improves insulin sensitivity, steatosis and steatohepatitis in animals, suggesting novel strategies to prevent and treat early NAFLD in humans.

Topics: Animals; Diet; Disease Models, Animal; Disease Progression; Fatty Acids; Fatty Liver; Insulin Resistance; Leptin; Mice; Mice, Obese; Mice, Transgenic; Oxidation-Reduction; Oxidative Stress; Rats; Rats, Zucker

Genetic advances have made remarkable progress towards our understanding of body weight regulation. Much of our current knowledge has come from the cloning and characterisation of the genes responsible for obesity syndromes in the mouse, and the identification of homologous mutations causing rare forms of obesity in humans. Gene targeting experiments in mice have been instrumental in confirming the importance of many genes in the aetiology of obesity, and the existence of a fundamental physiological pathway that controls energy balance is becoming clear. The genetic determinants that underlie common forms of human obesity are largely polygenic, with most genes producing small effects. Thus, elucidating the many genetic determinants of obesity is a current challenge for modern geneticists. Despite the inherent difficulties, progress has been made through linkage/association studies and a genetic map of quantitative trait loci for human obesity is beginning to emerge. Obesity research is now very much in a transition period. Not so long ago, access to high throughput screening, as well as microarray and proteomic techniques, was prohibitively expensive and available only to the few. In recent years, these technologies have become more accessible to the larger scientific community and, in this paper, we will discuss how such technological advances are likely to drive the next wave of progress in obesity research. For example, large-scale mutagenesis screens in rodents coupled with high throughput screening are likely to emerge as important technologies for identifying genes previously unexpected to be involved in body weight regulation. Furthermore, applications of microarray and proteomic techniques will further refine our understanding of currently known peptides as well as identify novel pathways and molecules which are involved in energy homeostasis.

Topics: Agouti Signaling Protein; Agouti-Related Protein; alpha-MSH; Animals; Body Weight; Cloning, Molecular; Disease Models, Animal; Genomics; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Mice; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Proprotein Convertase 1; Proteins; Proteomics; Receptors, Cell Surface; Receptors, Leptin; Receptors, Melanocortin

Obesity has become the most prevalent nutritional disorder in post-industrialised societies and it is associated with the development of severe and costly complications such as type 2 diabetes mellitus and coronary heart disease or cancer. A large proportion of the risk of obesity is determined by the genetic susceptibility of an individual, but environmental factors conducive for the disorder play an important role in its phenotypic expression. Several candidate genes emerged from studies in animal models of obesity, but human pathophysiology is likely to be more complex. Thus, most cases of human obesity probably result from subtle interactions of susceptibility genes with environmental factors favouring deposition of excess calories as fat. The recent surge of obesity may relate to past evolutionary pressure which favoured selection of mechanisms defending body-weight against caloric restriction rather than against caloric excess. Rapidly developing new techniques in quantitative genetics and growing information from functional genomics will help to understand the interaction of environmental factors with signalling networks that regulate energy metabolism. The role of previously unknown pathways in the aetiology of obesity will be uncovered. The typing of numerous genetic variants will become possible and allow individual risk assessment for obesity and/or its associated disorders. Thus, rational and individually tailored therapies may be developed to combat obesity and its associated disorders.

Topics: Adult; Animals; Body Mass Index; Child; Diabetes Mellitus, Type 2; Disease Models, Animal; Energy Metabolism; Environment; Female; Genetic Predisposition to Disease; Humans; Hyperphagia; Leptin; Male; Mice; Mice, Knockout; Mutation; Obesity; Phenotype; Polymorphism, Genetic; Prevalence; Pro-Opiomelanocortin; Receptors, Cell Surface; Receptors, Leptin; Risk Assessment; Risk Factors; Thermogenesis

The anorexia of aging is a syndrome characterized by unexplained losses in food intake and body weight that occur near the end of life. Proposed etiologies cover a wide range of biological and psychological conditions. The observation of this phenomenon in older laboratory animals suggests that physiological changes play a significant causal role. Research on the neurochemical control of energy balance has received much attention in recent years, and age-related alterations in the neuropeptidergic effectors of food intake have been implicated in the anorexia of aging. This review provides an update on putative mechanisms underlying this dysregulation of feeding during advanced age.

Topics: Aged; Aging; Animals; Anorexia; Appetite Regulation; Disease Models, Animal; Eating; Energy Metabolism; Homeostasis; Humans; Leptin; Neurotransmitter Agents

The objective of this review article is to present the genetic abnormalities in obese animal models up to present times and to suggest the mechanism of ingestive disorder. Leptin is an anorectic ob gene product and activates the anorexigenic POMC and CART neurons in the ARC and suppresses orexigenic NPY and AGRP neurons. TUB gene product also activates the anorexigenic POMC neurons. These anorexigenic neurons project to the second-order hypothalamic neuron, CRH, TRH and so on in the PVN and suppression of orexigenic neurons project to the orexin in the LHA.

Topics: Animals; Disease Models, Animal; Feeding and Eating Disorders; Leptin; Mice; Mice, Obese; Obesity; Rats; Rats, Zucker

Leptin deficiency, found in transgenic lipodystrophic mice and in obese (ob/ob) mice, was shown to cause increased lipogenesis in liver, through action of the sterol regulatory element-binding protein-1c, and increased liver gluconeogenesis, through a decline in the insulin receptor substrate-2. The resulting stimulation of insulin secretion by the pancreas owing to high blood glucose initiates a vicious cycle of insulin resistance.

Topics: Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Insulin; Insulin Resistance; Insulin Secretion; Leptin; Mice; Mice, Obese; Models, Biological

Severely obese children are even more likely to have mutations in obesity genes than are severely obese adults. Thus, investigators searching for obesity genes commonly focus on children, with the result that many human obesity genes were first identified in studies of children. Although the development of obesity depends on living in an obesity-promoting environment, it also is influenced strongly by individual genetic composition. Thus, the discovery of new obesity genes provides new opportunities to identify causes of severe obesity. Finally, identification of individual causes of obesity may, in the future, provide for a safe, effective, and individualized treatment recommendation for each obese person.

Topics: Animals; Disease Models, Animal; Genetic Predisposition to Disease; Humans; Leptin; Mice; Models, Genetic; Obesity; Oligonucleotide Array Sequence Analysis; Pro-Opiomelanocortin; Receptors, Corticotropin; Receptors, Melanocortin

Deficiency of leptin or its receptor produces hyperinsulinemia with marked obesity. Paradoxically, severe insulin resistance also accompanies lipodystrophy. Animal models of these contrasting conditions have enabled us to observe the profound and complicated aspects of the underlying pathologies. In addition, conventional polygenic rodents with known genetic backgrounds, such as the spontaneously hypertensive rat and the Goto-Kakisaki rat, have also been used to investigate these abnormalities.

Topics: Animals; Carrier Proteins; Disease Models, Animal; Humans; Hyperinsulinism; Insulin Resistance; Leptin; Lipid Metabolism; Lipids; Mice; Multifactorial Inheritance; Mutation; Rats; Receptors, Cell Surface; Receptors, Leptin

Sympathetic stimulation has long been recognized to mobilise fatty acids from white adipose tissue. However, it is now apparent that adipose tissue is not only concerned with energy storage as fat, but is a major endocrine and secretory organ. This change has resulted from the identification of leptin as a hormone of energy balance secreted by white adipose tissue. The sympathetic system is a key regulator of leptin production in white fat. Sympathomimetic amines, cold exposure or fasting (which lead to sympathetic stimulation of white fat), decrease ob gene expression in the tissue and leptin production. On the other hand, sympathetic blockade often increases circulating leptin and ob gene expression, and it is postulated that the sympathetic system has a tonic inhibitory action on leptin synthesis. In rodents this action is through stimulation of, beta3-adrenoceptors. The adrenal medulla (as opposed to the direct sympathetic innervation) has been thought to play only a minor role in the catecholaminergic regulation of white adipose tissue. However, in rodents responses of the leptin system to adrenergic blockade vary with the method used. Changes in leptin and ob gene expression are considerably less using methods of blockade that only effect the terminal adrenergic innervation, rather than medullary secretions as well. Stimulation of the leptin system increases sympathetic activity and hence metabolic activity in many tissues. As well as leptin, other (but not all) secretions from white adipose tissue are subject to sympathetic regulation. In obesity the sympathetic sensitivity of adipose tissue is reduced and this factor may underlie the dysregulation of leptin production and other adipose tissue secretions.

Topics: Adipose Tissue; Animals; Disease Models, Animal; Energy Metabolism; Humans; Leptin; Obesity; Rodentia; Sympathetic Nervous System

Progress in mechanism-based cancer prevention research may be facilitated by the use of animal models displaying specific genetic susceptibilities for cancer such as mice deficient in the p53 tumor suppressor gene, the most frequently altered gene in human cancer. We observed in p53-knockout (p53-/-) mice that calorie restriction (CR; 60% of the control group's intake of carbohydrate energy) increased the latency of spontaneous tumor development (mostly lymphomas) approximately 75%, decreased serum insulin-like growth factor (IGF)-1 and leptin levels, significantly slowed thymocyte cell cycle traverse and induced apoptosis in immature thymocytes. In heterozygous p53-deficient (p53+/-) mice, CR and 1 d/wk of food deprivation each significantly delayed spontaneous tumor development (a mix of lymphomas, sarcomas and epithelial tumors) and decreased serum IGF-1 and leptin levels even when begun late in life. We have also developed a rapid and relevant p53+/- mouse mammary tumor model by crossing p53-deficient mice with MMTV-Wnt-1 transgenic mice, and found that CR and 1 d/wk food deprivation significantly increased mammary tumor latency (greater than twofold) and reduced the mean serum IGF-1 and leptin levels to <50% of that of control mice (P < 0.0001). In addition, fluasterone, fenretinide and soy each delayed tumor development but had little effect on IGF-1 or leptin levels. We have capitalized on the susceptibility of p53+/- mice to chronic, low dose, aromatic amine-induced bladder carcinogenesis to develop a useful model for evaluating bladder cancer prevention approaches such as cyclooxygenase-2 inhibition. As demonstrated by these examples, mice with specific (and human-like) genetic susceptibilities for cancer provide powerful new tools for testing and characterizing interventions that may inhibit the process of carcinogenesis in humans.

Topics: Animals; Crosses, Genetic; Diet; Diet, Reducing; Disease Models, Animal; Humans; Insulin-Like Growth Factor I; Leptin; Mammary Neoplasms, Experimental; Mice; Mice, Knockout; Mice, Transgenic; Neoplasms; Neoplasms, Experimental; Tumor Suppressor Protein p53; Urinary Bladder Neoplasms

Topics: Adipocytes; Adipose Tissue; Adipose Tissue, Brown; Animals; Carrier Proteins; Disease Models, Animal; Energy Metabolism; Humans; Ion Channels; Leptin; Membrane Proteins; Mice; Mice, Transgenic; Mitochondrial Proteins; Obesity; Phenotype; Rats; Receptors, Adrenergic; Thermogenesis; Uncoupling Protein 1

Poor periodontal health is known to be associated with Type 2 diabetes mellitus (DM). This relationship and underlying mechanisms are discussed elsewhere in this issue. Less is known concerning the link between the metabolic precursors to DM, including insulin resistance (IR), and its possible association with periodontitis. Indeed, there has been relatively little research to date in human populations concerning periodontal disease, IR, and the subsequent risk of chronic diseases, including DM. This paper will present an epidemiologist's view of how IR may link periodontal disease with DM and suggest several avenues of investigation to help clarify some of the outstanding issues.

Topics: Adipocytes; Animals; Chronic Disease; Diabetes Mellitus, Type 2; Disease Models, Animal; Epidemiologic Methods; Forecasting; Glucose Clamp Technique; Glucose Tolerance Test; Homeostasis; Humans; Insulin; Insulin Resistance; Leptin; Models, Biological; Periodontal Diseases; Periodontitis; Research Design; Risk Factors; Tumor Necrosis Factor-alpha

Energy homeostasis is accomplished through a highly integrated and redundant neurohumoral system. Recently, novel molecular mediators and regulatory pathways for feeding and body weight regulation have been identified in the brain and the periphery. Because of the multitude and complexity of disturbances in energy intake, expenditure, and partitioning that are associated with obesity, it has been difficult to determine which abnormalities are causative versus less important phenomena that are consequences of the altered neuroendocrine and metabolic milieu. Transgenic technology has provided new opportunities to modify the complex body weight-regulating system and to assess the relative importance of the individual components. Observations of mutant mice have shed new light on the understanding of energy homeostasis equation. Once created, transgenic animal models may be useful in assessing the efficacy or determining the mode of action of potential new therapeutic agents. However, the interpretation of targeted mutation is sometimes not straightforward in unraveling the physiology because of the redundancy and compensation of the regulatory machinery, as well as the inherent problems of manipulation of the gene. Modifying the synthesis of a particular gene at all sites and developmental stages may be a relatively crude way of investigating its functions. Advanced gene-targeting strategies aimed at specific alterations (on and off) of a gene product at desired tissues and times could lead to a better understanding of the system.

Topics: Animals; Animals, Genetically Modified; Body Weight; Disease Models, Animal; Humans; Hypothalamus; Leptin; Mice; Mice, Transgenic; Obesity

Obesity is the most common cause of human essential hypertension in most industrialized countries. Although the precise mechanisms of obesity hypertension are not fully understood, considerable evidence suggests that excess renal sodium reabsorption and a hypertensive shift of pressure natriuresis play a major role. Sympathetic activation appears to mediate at least part of the obesity-induced sodium retention and hypertension since adrenergic blockade or renal denervation markedly attenuates these changes. Recent observations suggest that leptin and its multiple interactions with neuropeptides in the hypothalamus may link excess weight gain with increased sympathetic activity. Leptin is produced mainly in adipocytes and is believed to regulate energy balance by acting on the hypothalamus to reduce food intake and to increase energy expenditure via sympathetic activation. Short-term administration of leptin into the cerebral ventricles increases renal sympathetic activity, and long-term leptin infusion at rates that mimic plasma concentrations found in obesity raises arterial pressure and heart rate via adrenergic activation in non-obese rodents. Transgenic mice overexpressing leptin also develop hypertension. Acute studies suggest that the renal sympathetic effects of leptin may depend on interactions with other neurochemical pathways in the hypothalamus, including the melanocortin-4 receptor (MC4-R). However, the role of this pathway in mediating the long-term effects of leptin on blood pressure is unclear. Also, it is uncertain whether there is resistance to the chronic renal sympathetic and blood pressure effects of leptin in obese subjects. In addition, leptin also has other cardiovascular and renal actions, such as stimulation of nitric oxide formation and improvement of insulin sensitivity, which may tend to reduce blood pressure in some conditions. Although the role of these mechanisms in human obesity has not been elucidated, this remains a fruitful area for further investigation, especially in view of the current "epidemic" of obesity in most industrialized countries.

Topics: Animals; Blood Pressure; Body Mass Index; Coronary Circulation; Disease Models, Animal; Dogs; Fatty Acids; Humans; Hypertension; Kidney; Leptin; Natriuresis; Neuropeptides; Obesity; Sodium; Sympathetic Nervous System

Obesity is a common but highly complex disease, which evolved from interactions of multiple genes and the environment. In the past decade, there have been major advances in our understanding of the molecular genetics and pathogenesis of obesity, especially with regards to the genetics and functions of chemical mediators and their receptors, such as leptin, the leptin receptor, neuropeptide Y, the melanocortin-4 receptor, agouti-related protein and the peroxisome-proliferator-activated receptor gamma 2.. Recent studies and reports on the obesity genes and chemical mediators were reviewed.. Despite exciting discoveries of single gene mutations with haploinsufficiency in human subjects, and single-gene disorders resulting in obesity, most cases of obesity are likely the result of subtle interactions of several related genes with environmental factors, which favour the net deposition of calories as fat, culminating in the obese phenotype. Obesity is unlikely to be caused by a single gene defect unless it is extreme (body mass index > 60), or present in an isolated population group. However, research has established that genes at multiple loci may interact centrally to determine satiety, and peripherally to influence the metabolic rate of obese individuals.. The mechanisms of action of these genes in the development of obesity are now being examined, with the aim of eventually discovering a therapeutic intervention for obesity.

Topics: Animals; Body Mass Index; Disease Models, Animal; Energy Metabolism; Genetic Linkage; Homeostasis; Humans; Leptin; Obesity; Phenotype; Receptor, Melanocortin, Type 4; Receptors, Peptide; Satiation; Transcription Factors

The A-ZIP/F-1 mouse is lacking virtually all white adipose tissue. Like humans with extensive deficiencies of adipose tissue, the A-ZIP/F-1 mice develop a severe form of insulin resistant diabetes. We have studied the physiology of the A-ZIP/F-1 mice. Their adaptation to fasting is notable for its rapidity and the use of torpor, a hibernation-like state, to minimize energy needs. Transplantation of adipose tissue reversed the metabolic manifestations in the mice, demonstrating that the lack of adipose tissue is the cause of the insulin resistance. Leptin replacement is not very effective in reversing the diabetes of the A-ZIP/F-1 mice, which contrasts with its efficacy in the aP2-SREBP-lc mouse.

Topics: Adipose Tissue; Animals; Body Composition; Diabetes Mellitus, Lipoatrophic; Disease Models, Animal; Fasting; Humans; Insulin Resistance; Leptin; Mice; Mice, Transgenic; Phenotype; Transcription Factors

The cloning of five rodent obesity genes has constituted a major advance in our understanding of body weight homeostasis. Breakthroughs in human molecular genetics have identified mutations disrupting either rodent homologue/analogue genes or genes involved in the same pathways in obese patients. Three rare cases of human morbid obesity of early onset associated with hypogodatropic hypogodanism are due to mutations in the leptin and the leptin receptor genes. These studies have confirmed that leptin plays not only a crucial role in the control of body weight in the human but also in several endocrine functions. Other Human obesity syndromes are linked to mutations in the genes encoding brain-expressed targets of leptin, particularly some key components of the melanocortin system. Patients compound heterozygous for mutations in the POMC gene display severe obesity of early onset, congenital adrenal insufficiency and red hair. Another genetic cause of obesity is due to mutation in the Proconvertase gene (PC1), the enzyme required for the cleavage of POMC into ACTH and alpha MSH, and also of Proinsulin to insulin. The subject compound heterozygous for the PC1 mutation displays besides obesity, a partial ACTH deficiency, elevated POMC and late post absorptive hypoglycemia due to the accumulation of high pro-insulinemia. Contrasting largely with these rare syndromic forms of obesity, several mutations located in the melanocortin 4 receptor gene have been showed to cause an early onset dominant form of obesity with no other associated abnormalities indifferent populations. These mutations in MC4-R could represent a "frequent" cause of common monogenic forms of obesity in human. More generally, these researches into human obesity have opened new exciting understandings in some of the pathways regulating body fat mass.

Topics: Adrenocorticotropic Hormone; alpha-MSH; Animals; Body Weight; Carrier Proteins; Disease Models, Animal; Genes, Regulator; Heterozygote; Humans; Leptin; Mice; Mice, Obese; Obesity; Pedigree; Pro-Opiomelanocortin; Receptors, Cell Surface; Receptors, Leptin

Topics: Animals; Anti-Obesity Agents; Disease Models, Animal; Humans; Hypothalamus; Leptin; Mice; Obesity; Rodentia; Signal Transduction

Anorexia during infection is thought to be mediated by immunoregulatory cytokines such as interleukins 1 and 6 and tumor necrosis factor. This article reviews the potential mechanisms of action by which these cytokines are thought to suppress food intake during infection and examines the proposition that blocking of cytokine activity might be one approach to improving food intake of the infected host.

Topics: Acute-Phase Reaction; Animals; Anorexia; Cholecystokinin; Cytokines; Dinoprostone; Disease Models, Animal; Eating; Fever; Gastroparesis; Humans; Infections; Inflammation Mediators; Leptin; Vagus Nerve

The discovery of the Ob gene and its product, leptin, is a good example of the contribution made by molecular biology to the understanding of mechanisms initially hypothesized from classic physiological studies. Leptin is produced in adipose tissue and acts on the central nervous system to regulate multiple neuroendocrine secretions. In three rare cases of human morbid obesity, the discovery of mutations in the leptin and leptin receptor genes shows that leptin plays a crucial role in the control of weight and several endocrine functions (particularly reproduction). These studies also illustrate the limits of genetics in the investigation of monogenic forms of animal obesity, and the difficulties of linking molecular findings to the pathophysiology of complex diseases, such as human common obesity. Previous searches for mutations in the leptin and leptin receptor genes indicated that these are probably not major genes for common forms of human obesity. This review focuses on the recent molecular findings that have indicated a putative role for the leptin axis in human obesity.

Topics: Animals; Disease Models, Animal; Humans; Leptin; Molecular Biology; Obesity; Prevalence; Proteins; Risk Assessment; Rodentia; Sensitivity and Specificity

Maintenance of appropriate stores of metabolic fuels depends on carefully matching caloric intake to caloric expenditure. Achieving such 'energy balance' is a product of complex interactions of peripheral hormones with effector systems in the central nervous system (CNS) that regulate food intake and energy expenditure. Leptin is a hormone that is made in the adipocytes, circulates in the blood and interacts with receptors in the CNS. These receptors can be found in two different types of systems. One effector system is termed 'anabolic' and is activated by low levels of leptin during negative energy balance. This system (exemplified by the hypothalamic neuropeptide Y system) increases food intake and decreases energy expenditure to facilitate the regaining of lost energy stores. The other effector system is termed 'catabolic' and is activated by high levels of leptin during positive energy balance. This system (exemplified by the hypothalamic melanocortin and corticotrophin-releasing hormone systems) decreases food intake and increases energy expenditure to facilitate the loss of excess energy stores. Further understanding of these systems is necessary to develop adequate treatments for disorders of energy balance, such as obesity and wasting.

Topics: Animals; Disease Models, Animal; Eating; Energy Metabolism; Humans; Leptin; Neurosecretory Systems; Obesity; Prognosis; Proteins

Pathological deviations in bodyweight is a major increasing health problem in industrialized societies. It is currently unclear what genetic mechanisms are involved in the long-term control of human body-weight and to what extent these genes are involved in pathological deviations of bodyweight control such as anorexia and obesity. Major support for the concept of genetic control of bodyweight has recently emerged from different animal models. A number of new genes have been found during recent years that, when mutated, have a negative effect on bodyweight in animals and sometimes also in man. Although available evidence points toward a multifactorial nature of weight disorders in most human subjects, the single genes isolated in animal models may become powerful tools to elucidate the genetics also in man. In addition, these genes may serve to promote the development of targeted small-drug pharmaceuticals aimed at novel biochemical pathways. Finally, the uncovering of several quantitative trait loci (QTL) influencing body mass, body fat or fat topography in the mouse and rat has now also made it possible to perform studies of polygenically caused obesity in rodents. The role of the Genome Project in developing a complete gene map will greatly facilitate transforming these OTLs to actual molecules involved in the biology of bodyweight.

Topics: Adipose Tissue; Animals; Anorexia; Disease Models, Animal; Humans; Insulin Resistance; Leptin; Mice; Mice, Inbred Strains; Mutation; Obesity; Proteins; Rats

Unexplained weight loss during the latter stages of aging is commonly preceded by a spontaneous diminution in food intake. Multiple etiologies of age-related anorexia in humans, ranging from social isolation to impaired gastrointestinal function, have been proposed. The observation of this phenomenon in older laboratory animals suggests that physiological changes play a significant causal role. A continually expanding body of information on the neurochemical control of food intake supports a contribution of altered neurochemistry to dysregulated feeding behavior. This review provides an update on the relationship between declining food intake during advanced age and physiological (specifically neurochemical) function. The complexity of the control of food intake as well as the variety of investigative methods used in this field of study render the identification of definitive causes difficult. Evidence presented here is evaluated and possible etiologic factors are suggested.

Topics: Aging; Animals; Anorexia; Appetite Stimulants; Disease Models, Animal; Feeding Behavior; Humans; Leptin; Narcotics; Neuropeptide Y; Neurotransmitter Agents; Proteins

Leptin, a peptide hormone (167 aa) mainly expressed in adipocytes, and its hypothalamic receptors are integral components of a complex physiological system evolved to regulate fuel stores and energy expenditure. Thus, leptin discovery has constituted a great breakthrough in the understanding of body weight regulation and in the role of the fat tissue as an endocrine organ. Increasing scientific evidences suggest that, leptin has overall effects on metabolism. Leptin mRNA and/or protein are produced by placenta, fetal tissues, gastric mucosa and hepatic stellate cells and can participate in many physiological functions such as fetal growth, gut-derived satiety, immune or proinflammatory responses, reproduction, nutrient intestinal absorption, angiogenesis and lipolysis. The leptin participation in body weight homeostasis and obesity as well as other peripheral actions are revisited.

Topics: Animals; Body Weight; Carrier Proteins; Disease Models, Animal; Energy Metabolism; Humans; Leptin; Mutation; Obesity; Proteins; Receptors, Cell Surface; Receptors, Leptin; Signal Transduction

The yellow mouse obesity syndrome is due to dominant mutations at the Agouti locus, which is characterized by obesity, hyperinsulinemia, insulin resistance, hyperglycemia, hyperleptinemia, increased linear growth, and yellow coat color. This syndrome is caused by ectopic expression of Agouti in multiple tissues. Mechanisms of Agouti action in obesity seem to involve, at least in part, competitive melanocortin antagonism. Both central and peripheral effects have been implicated in Agouti-induced obesity. An Agouti-Related Protein (AGRP) has been described recently. It has been shown to be expressed in mice hypothalamus and to act similarly to agouti as a potent antagonist to central melanocortin receptor MC4-R, suggesting that AGRP is an endogenous MC4-R ligand. Mice lacking MC4-R become hyperphagic and develop obesity, implying that agouti may lead to obesity by interfering with MC4-R signaling in the brain and consequently regulating food intake. Furthermore, food intake is inhibited by intracerebroventricular injection of a potent melanocortin agonist and was reversed by administration of an MC4-R antagonist. The direct cellular actions of Agouti include stimulation of fatty acid and triglyceride synthesis via a Ca(2+)-dependent mechanism. Agouti and insulin act in an additive manner to increase lipogenesis. This additive effect of agouti and insulin is demonstrated by the necessity of insulin in eliciting weight gain in transgenic mice expressing agouti specifically in adipose tissue. This suggests that agouti expression in adipose tissue combined with hyperinsulinemia may lead to increased adiposity. The roles of melanocortin receptors or agouti-specific receptor(s) in agouti regulation of adipocyte metabolism and other peripheral effects remain to be determined. In conclusion, both central and peripheral actions of agouti contribute to the yellow mouse obesity syndrome and this action is mediated at least in part by antagonism with melanocortin receptors and/or regulation of intracellular calcium.

Topics: Agouti Signaling Protein; Agouti-Related Protein; Animals; Disease Models, Animal; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Melanocyte-Stimulating Hormones; Mice; Mice, Obese; Mutation; Obesity; Proteins; Receptors, Corticotropin; Receptors, Melanocortin; Signal Transduction; Syndrome

Obesity is an extremely challenging medical condition because it is a multifactorial disease that lies at the interface between the biology of body energy regulation and an environment (physical and sensory) that has been increasingly characterized as 'hostile to good health'. The deceptively straightforward anthropomorphic definition of obesity is the excessive accumulation of body fat. However, obesity is a chronic disease that is much more than excessive fat. It involves genetic predisposition and metabolic, hormonal and behavioural aspects and results in significant morbidity, reduced quality of life, discrimination and early mortality. The development and maintenance of obesity can be considered to result from the integration, or the accumulation, of small daily errors in energy balance over several months and years. The biological factors involved increase the predisposition toward the expansion of adipose tissue mass together with the consequences of an environment that promotes increased food intake and decreased physical activity. Multiple aetiologies may result in similar degrees of obesity.

Topics: Animals; Attitude to Health; Body Mass Index; Cultural Characteristics; Disease Models, Animal; Energy Intake; Energy Metabolism; Feeding Behavior; Genetic Predisposition to Disease; Humans; Insulin Resistance; Leptin; Mutation; Obesity; Socioeconomic Factors

Topics: Animals; Body Temperature Regulation; Disease Models, Animal; Glucagon; Insulin; Leptin; Mice; Mice, Obese; Obesity; Proteins

Topics: Animals; Carrier Proteins; Disease Models, Animal; Hyperinsulinism; Insulin Resistance; Leptin; Obesity; Proteins; Rats; Rats, Wistar; Receptors, Cell Surface; Receptors, Leptin

Leptin, a 16-kDa protein secreted from white adipocytes, has been implicated in the regulation of food intake, energy expenditure, and whole-body energy balance in rodents and humans. The gene encoding leptin was identified by positional cloning and is the mutation leading to the profound obese phenotype of the ob/ob mouse. Exogenous administration of leptin to ob/ob mice leads to a significant improvement in reproductive and endocrine status as well as reduced food intake and weight loss. The expression and secretion of leptin is highly correlated with body fat mass and adipocyte size. Cortisol and insulin are potent stimulators of leptin expression, and expression is attenuated by beta-adrenergic agonists, cAMP, and thiazolidinediones. The role of other hormones and growth factors in the regulation of leptin expression and secretion is emerging. Leptin circulates specifically bound to proteins in serum, which may regulate its half-life and biological activity. Isoforms of the leptin receptor, members of the interleukin-6 cytokine family of receptors, are found in multiple tissues, including the brain. Many of leptin's effects on food intake and energy expenditure are thought to be mediated centrally via neurotransmitters such as neuropeptide Y. Multiple peripheral effects of leptin have also been recently described, including the regulation of insulin secretion by pancreatic beta cells and regulation of insulin action and energy metabolism in adipocytes and skeletal muscle. Leptin is thought to be a metabolic signal that regulates nutritional status effects on reproductive function. Leptin also plays a major role in hematopoeisis and in the anorexia accompanying an acute cytokine challenge. The profound effects of leptin on regulating body energy balance make it a prime candidate for drug therapies for humans and animals.

Topics: Animal Husbandry; Animals; Animals, Domestic; Carrier Proteins; Disease Models, Animal; Energy Metabolism; Gene Expression; Humans; Leptin; Mice; Mice, Obese; Obesity; Proteins; Receptors, Cell Surface; Receptors, Leptin; Reproduction

The application of molecular and genetic techniques to the study of body weight regulation have produced exciting new insights into the physiological systems governing energy expenditure, appetite, and metabolic signaling. A number of new peptides have been identified that play important roles in these regulatory systems. These include the hormone leptin, the short and long forms of the leptin receptor, uncoupling proteins, agouti protein, melanocortin receptor isoforms, melanin-concentrating hormone, and the proteins responsible for tub and fat, two monogenic mouse models of obesity. This article reviews some of the new insights gained from studies of these peptides. Although much of this new knowledge has come from studies of obesity, there may be implications for the clinical syndromes associated with weight loss. As more is learned about these systems, potential new targets for therapeutic intervention will likely become evident. These interventions may develop first as obesity treatments, but investigators and clinicians involved in the care of cachectic patients should follow these scientific developments as well.

Topics: Animals; Appetite; Body Weight; Cachexia; Disease Models, Animal; Energy Intake; Humans; Leptin; Melanins; Metabolism; Mice; Obesity; Proteins; Receptors, Peptide; Uncoupling Agents

Serotonin (5-HT) has been implicated in the control of eating behavior and body weight. Stimulants of this monoamine reduce food intake and weight gain and increase energy expenditure, both in animals and in humans. This article reviews evidence that supports a role for hypothalamic serotonergic receptor mechanisms in the mediation of these effects. A variety of studies in rodents indicate that, at low doses, 5-HT or drugs that enhance the release of this neurotransmitter preferentially inhibit the ingestion of carbohydrate, more than fat or protein. This phenomenon is mediated, in part, by 5-HT receptors located in various medial hypothalamic nuclei. A negative feedback loop exists between the consumption of this macronutrient and the turnover of 5-HT in the hypothalamus. That is, carbohydrate ingestion enhances the synthesis and release of hypothalamic 5-HT, which in turn serves to control the size of carbohydrate-rich meals. A model is described that proposes the involvement of circulating hormones and glucose in this feedback process. These hormones, including insulin, corticosterone, and the adipose tissue-derived hormone, leptin, have impact on serotonergic function as well as satiety. This model further suggests that 5-HT exerts its strongest effect on appetite at the start of the natural feeding cycle, when carbohydrate is normally preferred. Clinical studies provide evidence that is consistent with the proposed model and that implicates 5-HT in disturbances of eating and body weight disorders.

Topics: Animals; Appetite Regulation; Body Weight; Choice Behavior; Circadian Rhythm; Dietary Carbohydrates; Dietary Fats; Disease Models, Animal; Eating; Energy Metabolism; Feedback; Feeding and Eating Disorders; Feeding Behavior; Humans; Hypothalamus; Leptin; Models, Neurological; Obesity; Proteins; Receptors, Serotonin; Satiation; Serotonin; Serotonin Agents; Sex Factors

Topics: Animals; Body Weight; Brain; Diabetes Mellitus, Type 2; Disease Models, Animal; Energy Metabolism; Humans; Leptin; Mice; Mice, Obese; Proteins

Topics: Animals; Diabetes Mellitus, Experimental; Disease Models, Animal; Humans; Insulin Resistance; Leptin; Mice; Mice, Obese; Mutation; Obesity; Proteins

The Israeli Sand Rat (Psammomys obesus) is an excellent polygenic model for the study of obesity and diabetes. The metabolic characteristics and the heterogeneous development of these defects, including elevated leptin levels, mimic those found in susceptible human populations. Interestingly, only animals that develop metabolic abnormalities demonstrate hyperleptinemia and, in these animals, leptin administration at the same dose that is effective in ob/ob mice is ineffective in reducing food intake or body weight. Perhaps leptin resistance needs to develop in Israeli Sand Rats to allow the development of obesity and, in fact, leptin resistance may be the "thrifty gene" that predisposes individuals to the development of obesity and subsequent metabolic abnormalities. However, there remain many unanswered questions about the physiological actions of leptin. The widespread tissue location of receptors and the actions of leptin independent of food intake highlight the need for further research aimed at determining the major physiological action of this newly discovered and exciting hormone.

Topics: Animals; Disease Models, Animal; Gerbillinae; Humans; Insulin Resistance; Leptin; Mice; Mutation; Obesity; Proteins; Rats

Topics: Adipocytes; Animals; Brain Chemistry; Disease Models, Animal; Humans; Insulin Resistance; Leptin; Mice; Mice, Obese; Obesity; Proteins; Signal Transduction

The high prevalence of obesity and its well documented association with the cardiovascular risk factors diabetes mellitus, dyslipidemia and hypertension represents a major problem for the general health status of industrialized societies. Although numerous studies have shown that genetic factors have a major influence on the regulation of energy homeostasis and the susceptibility to obesity, the genes and predisposing mutations involved are insufficiently understood. Among several known rodent models of obesity due to single gene mutations, mice homozygous for the obese (ob) gene exhibit massive early-onset obesity, hyperphagia, non-insulin-dependent diabetes mellitus, defective thermoregulation and infertility. Recently the ob gene was identified by positional cloning and shown to be mutated in ob/ob mice. Leptin, the product of the ob gene, is a 167-amino acid secreted protein that is synthesized exclusively in adipose tissue. With the exception of ob/ob mice, circulating plasma leptin is elevated in obesity. Administration of recombinant leptin to ob/ob mice reduces fat mass, food intake, hyperglycemia and hyperinsulinemia. The various effects of the hormone are mediated by leptin receptors expressed at high levels in the hypothalamus, but also in several other non-neuronal tissues. A mutation in the leptin receptor gene is responsible for the obese phenotype of db/db mice. Plasma leptin in humans is positively correlated with body fat mass, suggesting that leptin resistance rather than leptin deficiency is a common feature of human obesity. This review briefly summarizes the current status of the rapidly growing evidence that leptin plays an important role in the regulation of body weight and fat deposition.

Topics: Adipocytes; Animals; Body Mass Index; Body Weight; Carrier Proteins; Disease Models, Animal; Energy Metabolism; Humans; Leptin; Mice; Mice, Mutant Strains; Neuropeptide Y; Obesity; Protein Biosynthesis; Proteins; Receptors, Cell Surface; Receptors, Leptin

Several twin and adoption studies as well as animal models have confirmed that obesity has a strong genetic component. It is apparent that obesity in humans has a complex polygenic background; that is, the phenotype is determined by an unknown number of genes together with environmental factors. However, there may well be single genes playing a major role within certain families, but the gene may vary from family to family. Two interesting gene candidates have been found in mouse experiments, the ob and the db gene, the products of which are probably a satiety hormone and its receptor, respectively, which regulate food intake. The recent cloning of the ob gene and its human homologue constitute a major breakthrough in this field. The 16-kD protein encoded by the ob gene is called leptin, and is well conserved among vertebrate species. The pig could be a valuable large animal model for human obesity. A fatness locus has been mapped to pig chromosome 4 and most probably a similar locus resides on human chromosome 1q. A more precise definition of the pig-human homology as regards this region is currently being investigated.

Topics: Animals; Disease Models, Animal; Eating; Gene Expression Regulation; Humans; Leptin; Mice; Obesity; Phenotype; Proteins; Swine

Physiological investigation has demonstrated that the central nervous system monitors body composition and adjusts energy intake and expenditure to stabilize total adipose tissue mass. Genetic variations in the signalling molecules involved in this regulatory system account for the heritable component of body fat content. The application of molecular techniques to rodent models of Mendelian obesity has resulted in the characterization of five loci at which mutations produce an abnormal accumulation of body fat. The genes at these loci include agouti, which encodes a molecule that antagonizes the binding of alpha melanocyte-stimulating hormone to its receptor; fat, which encodes carboxypeptidase E; tubby, which encodes a putative phosphodiesterase; obese, which encodes a circulating satiety protein; and diabetes, which encodes the receptor for the obese gene product. A more detailed understanding of the functional interrelationships of these genes should lead to important new insights into the causes and potential therapies for human obesity.

Topics: Adaptor Proteins, Signal Transducing; Adipose Tissue; Agouti Signaling Protein; alpha-MSH; Animals; Brain; Carrier Proteins; Chromosome Mapping; Disease Models, Animal; Eating; Energy Metabolism; Gene Expression Regulation; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Obesity; Proteins; Receptors, Cell Surface; Receptors, Leptin; Receptors, Pituitary Hormone; Satiation; Signal Transduction; Weight Loss

Topics: Adipose Tissue; Animals; CCAAT-Enhancer-Binding Proteins; Cell Differentiation; Disease Models, Animal; DNA-Binding Proteins; High Mobility Group Proteins; Humans; Leptin; Mice; Nuclear Proteins; Obesity; Proteins; Receptors, Cytoplasmic and Nuclear; Transcription Factors

Topics: Adaptor Proteins, Signal Transducing; Agouti Signaling Protein; Animals; Carboxypeptidase H; Carboxypeptidases; Chromosome Mapping; Diabetes Mellitus; Disease Models, Animal; Female; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Male; Mice; Mice, Inbred Strains; Mice, Obese; Mutation; Obesity; Proteins; Rats

A highly conserved protein called 'leptin' was recently discovered to play a role in regulation of the energy balance in humans and rodents. This 167-amino-acid-containing protein is only produced and secreted by mature adipocytes. Absence of the protein in mutant ob/ob mice and resistance to its effects in db/db mice lead to extreme obesity and type II diabetes mellitus. No mutation of the ob-gene encoding for leptin has been found in obese humans so far. ob mRNA in adipocytes and serum leptin levels are positively related to adipose tissue mass. Receptors for leptin have been found in the choroid plexus and hypothalamus. A feedback inhibition of leptin on hypothalamic neuropeptide Y (NY) production is postulated, as hypothalamic NY concentrations are increased in ob/ob mice and NY induces food intake, insulin secretion and autonomic nervous system activity. Insulin increases triglyceride stores in fat cells and could thereby stimulate leptin secretion. The ultimate intracellular pathway within the adipocyte that stimulates or shuts off ob mRNA expression and consequent leptin production and secretion remains to be elucidated. Whether leptin will ever come to play a role in the treatment of human obesity remains an unanswered question at the present time.

Topics: Adipocytes; Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Female; Humans; Leptin; Male; Mice; Mice, Obese; Obesity; Proteins

Topics: Animals; Disease Models, Animal; Humans; Leptin; Mice; Mice, Obese; Obesity; Protein Biosynthesis; Proteins; Recombinant Proteins

OB protein (also known as leptin), a previously unknown protein signal, is secreted from adipose tissue, circulates in the blood, probably bound to a family of binding proteins, and acts on central neural networks that regulate ingestive behavior and energy balance. OB protein provides a communication link from fat tissue and the brain. Rapidly accumulating evidence suggests that OB protein appears to play a major role in the control of body fat stores through coordinated regulation of feeding behavior, metabolism, autonomic nervous system and body energy balance in rodents, primates and humans. The field has rapidly moved from cloning of the ob gene to demonstration of complex regulation of ob gene expression in adipose tissue in rats and humans, and then the demonstration of potent biological activity of OB protein in ob/ob, diet-induced, and lean mice as well as obese and lean rats but not in db/db obese mice. A significant milestone was our demonstration that central administration of OB protein lead to reductions in food intake, body weight and alterations in metabolism consistent with activation of the autonomic nervous system. These findings were followed by the identification of a central binding site for labelled OB protein in the choroid plexus in ob/ob, db/db and lean mice as well as lean and obese Zucker rats. The expression cloning of a central receptor, OB-R, from the mouse choroid plexus soon followed. The OB-R receptor was found to be expressed in the choroid plexus, the hypothalamus as well as several peripheral tissues. OB-R exists in multiple forms; the two major forms are a short form (with a truncated intracellular domain) and long form (with the complete intracellular domain). The long form is thought to be the form that signals and mediates the biological effects of OB protein. Initial in situ hybridization studies have demonstrated the mRNA for the long form OB-R receptor to be localized to the hypothalamus as well as peripheral sites. Recently, it was demonstrated that the db gene encodes the OB-R receptor. Evidence has been provided for a specific transport system for OB protein to cross the blood-brain-barrier and enter the brain of mice, rats and humans. The rate of transport can be decreased by high plasma concentrations of OB protein. Thus, reduced entry of OB protein to the brain may be one of the mechanisms of reduced sensitivity of the OB protein pathway in obese individuals. OB protein appears to also play a role in the i

Topics: Adipose Tissue; Amino Acid Sequence; Animals; Carrier Proteins; Disease Models, Animal; Humans; Leptin; Molecular Sequence Data; Neural Pathways; Obesity; Proteins; Receptors, Cell Surface; Receptors, Leptin

Topics: Animals; Carrier Proteins; Disease Models, Animal; Endocrine Glands; Energy Metabolism; Humans; Hypothalamus; Leptin; Mice; Mice, Obese; Mutation; Obesity; Proteins; Receptors, Cell Surface; Receptors, Leptin

Individual susceptibility to obesity is recognized to be influenced significantly by genetic inheritance. Recently, candidate obesity genes have been identified that may contribute to the inheritance of body fat mass and the partitioning of fat between central and peripheral fat depots. In studies of animal models of obesity, the genetic basis for obesity in the obese (Ob/Ob) mouse, the Fat mouse, and the Yellow (Vvy) mouse has been identified. Further research is needed to determine whether abnormalities in these genes contribute to human obesity as well. In studies of humans, sequence variation in at least six genes has been linked to increased body fatness and/or susceptibility to obesity. In addition, five other encoding genes have been linked to a disproportionate storage of fat in the abdominal region. These genes identified in studies of humans are currently thought to be modifying or background genes, each separately conferring a modest increase in susceptibility to fatness. Further research is needed to identify additional candidate genes that confer susceptibility to obesity and to determine the relative importance of each one in a range of human populations with distinct environments.

Topics: Adipose Tissue; Agouti Signaling Protein; Animals; Apolipoproteins; Body Composition; Carrier Proteins; Disease Models, Animal; Humans; Intercellular Signaling Peptides and Proteins; Ion Channels; Leptin; Membrane Proteins; Mitochondrial Proteins; Obesity; Proteins; Uncoupling Protein 1

The present study aimed to assess the prevalence of symptoms of anxiety and depression among health professionals in the three most affected regions in Cameroon.. The study was a descriptive cross-sectional type. Participants were health care professionals working in the three chosen regions of Cameroon. The non_probability convinient sample technique and that of the snowball were valued via a web questionnaire. The non-exhaustive sample size was 292. The diagnosis of anxiety and depression was made by the HAD (Hospital Anxiety and Depression scale).. Les auteurs rapportent que le secteur médical est classé à un plus grand risque de contracter le COVID-19 et de le propager potentiellement à d’autres. Le nombre sans cesse croissant de cas confirmés et suspects, la pression dans les soins, l’épuisement des équipements de protection individuelle et le manque de médicaments spécifiques peuvent contribuer à un vécu anxio-dépressif significatif. La présente étude s’est donnée pour ambition d’évaluer la prévalence des symptômes de l’anxiété et de la dépression chez les professionnels de santé dans les trois Régions les plus concernées au Cameroun.. Le choix des trois Régions du Cameroun se justifie non seulement par le fait qu’elles totalisent 95,8 % des cas de coronavirus au pays depuis le début de la pandémie, mais aussi parce qu’elles disposent de plus de la moitié des personnels de santé (56 %). Il s’agit d’une étude transversale, descriptive et analytique. Les participants sont des professionnels de la santé en service dans les Régions du Centre, Littoral et de l’Ouest du Cameroun. La méthode d’échantillonnage non probabiliste de convenance couplée à celle de boule de neige via un web questionnaire a été adoptée. La collecte des données a duré du 5 au 19 avril 2020, intervalle de temps après lequel on n’avait plus eu de répondants. À la fin de cette période, la taille de l’échantillon non exhaustive était de 292 professionnels. Le diagnostic de l’état anxio-dépressive était posé via l’échelle de HAD (Hospital Anxiety and Depression scale). Dans le HAD, chaque réponse cotée évalue de manière semi-quantitative l’intensité du symptôme au cours de la semaine écoulée. Un score total est obtenu ainsi que des scores aux deux sous-échelles : le score maximal est de 42 pour l’échelle globale et de 21 pour chacune des sous-échelles. Le coefficient alpha de Cronbach est de 0,70 pour la dépression et de 0,74 pour l’anxiété. Certains auteurs après plusieurs travaux ont proposé qu’une note inférieure ou égale à 7 indique une absence d’anxiété ou de dépression ; celle comprise entre 8 et 10 suggère une anxiété ou une dépression faible à bénigne ; entre 11 et 14, pour une anxiété ou une dépression modérée ; enfin, une note comprise entre 15 et 21 est révélatrice d’une anxiété sévère. Le logiciel Excel 2013 et Epi Info version 7.2.2.6 ont été utilisés pour les traitements statistiques. Les liens entre les variables ont été considérées significatifs pour une valeur de. L’amélioration des conditions de travail et notamment la fourniture d’équipement de protection, la mise en place des cellules spéciales d’écoute pour le personnel de santé pourraient être proposées.. Taken together with satisfactory selectivity index (SI) values, the acetone and methanol extracts of. During a mean follow-up period of 25.6 ± 13.9 months, 38 (18.4%) VAs and 78 (37.7%) end-stage events occurred. Big ET-1 was positively correlated with NYHA class (. In primary prevention ICD indication patients, plasma big ET-1 levels can predict VAs and end-stage events and may facilitate ICD-implantation risk stratification.. Beyond age, cognitive impairment was associated with prior MI/stroke, higher hsCRP, statin use, less education, lower eGFR, BMI and LVEF.. These data demonstrate that even a short period of detraining is harmful for elderly women who regularly participate in a program of strength training, since it impairs physical performance, insulin sensitivity and cholesterol metabolism.. Exposure to PM. Respiratory sinus arrhythmia is reduced after PVI in patients with paroxysmal AF. Our findings suggest that this is related to a decrease in cardiac vagal tone. Whether and how this affects the clinical outcome including exercise capacity need to be determined.. BDNF and leptin were not associated with weight. We found that miR-214-5p exerted a protective role in I/R injured cardiac cells by direct targeting FASLG. The results indicated that the MGO injection reduced all CCl. The hepatoprotective effects of MGO might be due to histopathological suppression and inflammation inhibition in the liver.. OVEO showed moderate antifungal activity, whereas its main components carvacrol and thymol have great application potential as natural fungicides or lead compounds for commercial fungicides in preventing and controlling plant diseases caused by. PF trajectories were mainly related to income, pregestational BMI, birth weight, hospitalisation due to respiratory diseases in childhood, participant's BMI, report of wheezing, medical diagnosis and family history of asthma, gestational exposure to tobacco and current smoking status in adolescence and young adult age.. In chronic pain patients on opioids, administration of certain benzodiazepine sedatives induced a mild respiratory depression but paradoxically reduced sleep apnoea risk and severity by increasing the respiratory arousal threshold.. Quantitative measurements of sensory disturbances using the PainVision. The serum level of 20S-proteasome may be a useful marker for disease activity in AAV.. The electrophysiological data and MD simulations collectively suggest a crucial role of the interactions between the HA helix and S4-S5 linker in the apparent Ca. Invited for the cover of this issue are Vanesa Fernández-Moreira, Nils Metzler-Nolte, M. Concepción Gimeno and co-workers at Universidad de Zaragoza and Ruhr-Universität Bochum. The image depicts the reported bimetallic bioconjugates as planes directing the gold fragment towards the target (lysosomes). Read the full text of the article at 10.1002/chem.202002067.. The optimal CRT pacing configuration changes during dobutamine infusion while LV and RV activation timing does not. Further studies investigating the usefulness of automated dynamic changes to CRT pacing configuration according to physiologic condition may be warranted.

Topics: 3' Untranslated Regions; 5'-Nucleotidase; A549 Cells; Accidental Falls; Acetylcholinesterase; Acrylic Resins; Actinobacillus; Acute Disease; Acute Kidney Injury; Adaptor Proteins, Signal Transducing; Adenosine; Adenosine Triphosphate; Administration, Inhalation; Administration, Oral; Adolescent; Adult; Advance Care Planning; Africa, Northern; Age Factors; Aged; Aged, 80 and over; Air Pollutants; Air Pollution; Air Pollution, Indoor; Albendazole; Aluminum Oxide; Anastomosis, Surgical; Ancylostoma; Ancylostomiasis; Androstadienes; Angiogenesis Inhibitors; Angiotensin II; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antibodies, Bispecific; Antibodies, Viral; Anticoagulants; Antihypertensive Agents; Antinematodal Agents; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antiporters; Antiviral Agents; Apoptosis; Aptamers, Nucleotide; Aromatase Inhibitors; Asian People; Astrocytes; Atrial Fibrillation; Auditory Threshold; Aurora Kinase B; Australia; Autophagy; Autophagy-Related Protein 5; Autotrophic Processes; Bacillus cereus; Bacillus thuringiensis; Bacterial Proteins; Beclin-1; Belgium; Benzene; Benzene Derivatives; Benzhydryl Compounds; beta Catenin; beta-Arrestin 2; Biliary Tract Diseases; Biofilms; Biofuels; Biomarkers; Biomarkers, Tumor; Biomass; Biomechanical Phenomena; Bioreactors; Biosensing Techniques; Biosynthetic Pathways; Bismuth; Blood Platelets; Bone and Bones; Bone Regeneration; Bortezomib; Botulinum Toxins, Type A; Brain; Brain Injuries; Brain Ischemia; Brain Neoplasms; Breast Neoplasms; Breath Tests; Bronchodilator Agents; Calcium Phosphates; Cannabis; Carbon Dioxide; Carbon Isotopes; Carcinogenesis; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cardiac Resynchronization Therapy; Cardiac Resynchronization Therapy Devices; Cardiomyopathies; Cardiovascular Diseases; Cariostatic Agents; Case Managers; Case-Control Studies; Catalysis; Cation Transport Proteins; CD8-Positive T-Lymphocytes; Cecropia Plant; Cell Adhesion; Cell Count; Cell Differentiation; Cell Division; Cell Line; Cell Line, Tumor; Cell Membrane; Cell Movement; Cell Proliferation; Cell Self Renewal; Cell Survival; Cells, Cultured; Cellular Reprogramming; Cellulose; Charcoal; Chemical and Drug Induced Liver Injury; Chemical Phenomena; Chemokines; Chemoradiotherapy; Chemoreceptor Cells; Child; Child Abuse; Child, Preschool; China; Chlorogenic Acid; Chloroquine; Chromatography, Gas; Chronic Disease; Clinical Competence; Coated Materials, Biocompatible; Cochlea; Cohort Studies; Color; Comorbidity; Computer Simulation; Computer-Aided Design; Contraception; Contraceptive Agents, Female; Contrast Media; COP-Coated Vesicles; Coronavirus Infections; Cost of Illness; Coturnix; COVID-19; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Culex; Curriculum; Cyclic N-Oxides; Cytokines; Cytoplasm; Cytotoxicity, Immunologic; Cytotoxins; Databases, Factual; Deep Learning; Delivery, Obstetric; Denitrification; Dental Caries; Denture, Complete; Dexamethasone; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dielectric Spectroscopy; Diet, High-Fat; Dietary Fiber; Disease Models, Animal; Disease Progression; DNA; DNA Copy Number Variations; DNA, Mitochondrial; Dog Diseases; Dogs; Dopaminergic Neurons; Double-Blind Method; Down-Regulation; Doxorubicin; Drug Carriers; Drug Design; Drug Interactions; Drug Resistance, Bacterial; Drug Resistance, Neoplasm; Drug-Related Side Effects and Adverse Reactions; Drugs, Chinese Herbal; Dry Powder Inhalers; Dust; E2F1 Transcription Factor; Ecosystem; Education, Nursing; Education, Nursing, Baccalaureate; Electric Impedance; Electricity; Electrocardiography; Electrochemical Techniques; Electrochemistry; Electrodes; Electrophoresis, Polyacrylamide Gel; Endoplasmic Reticulum; Endothelial Cells; Environmental Monitoring; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Estrogen Receptor Modulators; Europe; Evoked Potentials, Auditory, Brain Stem; Exosomes; Feasibility Studies; Female; Ferricyanides; Ferrocyanides; Fibrinogen; Finite Element Analysis; Fistula; Fluorescent Dyes; Fluorides, Topical; Fluorodeoxyglucose F18; Fluticasone; Follow-Up Studies; Food Contamination; Food Microbiology; Foods, Specialized; Forensic Medicine; Frail Elderly; France; Free Radicals; Fresh Water; Fungi; Fungicides, Industrial; Galactosamine; Gastrointestinal Neoplasms; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Frequency; Genetic Predisposition to Disease; Genotype; Gingival Hemorrhage; Glioblastoma; Glioma; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Glucose; Glucose Transport Proteins, Facilitative; Glucosides; Glutamine; Glycolysis; Gold; GPI-Linked Proteins; Gram-Negative Bacteria; Gram-Positive Bacteria; Graphite; Haplotypes; HCT116 Cells; Healthy Volunteers; Hearing Loss; Heart Failure; Hedgehog Proteins; HEK293 Cells; HeLa Cells; Hemodynamics; Hemorrhage; Hepatocytes; Hippo Signaling Pathway; Histone Deacetylases; Homeostasis; Hospital Mortality; Hospitalization; Humans; Hydantoins; Hydrazines; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Hydroxylamines; Hypoglycemic Agents; Immunity, Innate; Immunoglobulin G; Immunohistochemistry; Immunologic Factors; Immunomodulation; Immunophenotyping; Immunotherapy; Incidence; Indazoles; Indonesia; Infant; Infant, Newborn; Infarction, Middle Cerebral Artery; Inflammation; Injections, Intramuscular; Insecticides; Insulin-Like Growth Factor I; Insurance, Health; Intention to Treat Analysis; Interleukin-1 Receptor-Associated Kinases; Interleukin-6; Intrauterine Devices; Intrauterine Devices, Copper; Iron; Ischemia; Jordan; Keratinocytes; Kidney; Kidney Diseases; Kir5.1 Channel; Klebsiella Infections; Klebsiella pneumoniae; Lab-On-A-Chip Devices; Laparoscopy; Lasers; Lasers, Semiconductor; Lenalidomide; Leptin; Lethal Dose 50; Levonorgestrel; Limit of Detection; Lipid Metabolism; Lipid Metabolism Disorders; Lipogenesis; Lipopolysaccharides; Liquid Biopsy; Liver; Liver Abscess, Pyogenic; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Longevity; Lung Neoplasms; Luteolin; Lymph Nodes; Lymphocyte Activation; Macaca fascicularis; Macrophages; Mad2 Proteins; Magnetic Resonance Imaging; Male; Mammary Glands, Human; Manganese; Manganese Compounds; MAP Kinase Signaling System; Materials Testing; Maternal Health Services; MCF-7 Cells; Medicaid; Medicine, Chinese Traditional; Melanoma; Membrane Proteins; Mental Health; Mercury; Metal Nanoparticles; Metals, Heavy; Metformin; Methionine Adenosyltransferase; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Knockout; Mice, Nude; Microalgae; Microbial Sensitivity Tests; Microglia; MicroRNAs; Microscopy, Atomic Force; Microscopy, Electron, Scanning; Middle Aged; Mitochondria; Mitochondrial Proteins; Mitral Valve; Mitral Valve Insufficiency; Models, Anatomic; Molecular Structure; Molybdenum; Monocarboxylic Acid Transporters; Moths; MPTP Poisoning; Multigene Family; Multiparametric Magnetic Resonance Imaging; Multiple Myeloma; Muscle, Skeletal; Mutagens; Mutation; Myeloid Cells; Nanocomposites; Nanofibers; Nanomedicine; Nanoparticles; Nanowires; Neoadjuvant Therapy; Neomycin; Neoplasm Grading; Neoplasm Recurrence, Local; Neoplasms; Neoplastic Stem Cells; Neostriatum; Neovascularization, Pathologic; Netherlands; Neuromuscular Agents; Neurons; NF-E2-Related Factor 2; NF-kappa B; Nickel; Nitrogen Oxides; Non-alcoholic Fatty Liver Disease; Nucleosides; Nucleotidyltransferases; Nutritional Status; Obesity, Morbid; Ofloxacin; Oils, Volatile; Oligopeptides; Oncogene Protein v-akt; Optical Imaging; Organic Cation Transport Proteins; Organophosphonates; Osteoarthritis; Osteoarthritis, Hip; Osteoarthritis, Knee; Osteoblasts; Osteogenesis; Oxidation-Reduction; Oxidative Stress; Oxides; Oxygen Isotopes; Pancreas; Pancreaticoduodenectomy; Pandemics; Particle Size; Particulate Matter; Patient Acceptance of Health Care; Patient Compliance; PC-3 Cells; Peptide Fragments; Peptides; Periodontal Attachment Loss; Periodontal Index; Periodontal Pocket; Periodontitis; Peroxides; Peru; Pest Control, Biological; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Phylogeny; Pilot Projects; Piperidines; Plant Bark; Plant Extracts; Plant Leaves; Plasmids; Platelet Function Tests; Pneumonia, Viral; Podocytes; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Polyethylene Terephthalates; Polymers; Polymorphism, Single Nucleotide; Porosity; Portugal; Positron-Emission Tomography; Postoperative Complications; Postural Balance; Potassium Channels, Inwardly Rectifying; Povidone; Powders; Precancerous Conditions; Precision Medicine; Predictive Value of Tests; Pregnancy; Prenatal Care; Prognosis; Promoter Regions, Genetic; Prospective Studies; Prostatectomy; Prostatic Neoplasms; Proteasome Inhibitors; Protective Agents; Protein Binding; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Protein Transport; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-akt; Psychiatric Nursing; PTEN Phosphohydrolase; Pulmonary Embolism; Pyrimethamine; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Rats, Wistar; Reactive Oxygen Species; Receptor, ErbB-2; Receptor, IGF Type 1; Receptors, Estrogen; Receptors, G-Protein-Coupled; Recombinational DNA Repair; Recovery of Function; Regional Blood Flow; Renal Dialysis; Renin; Renin-Angiotensin System; Reperfusion Injury; Reproducibility of Results; Republic of Korea; Respiratory Distress Syndrome; Retrospective Studies; Rhodamines; Risk Assessment; Risk Factors; RNA, Long Noncoding; RNA, Messenger; Running; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Salinity; Salmeterol Xinafoate; Sarcoma; Seasons; Shoulder Injuries; Signal Transduction; Silicon Dioxide; Silver; Sirtuin 1; Sirtuins; Skull Fractures; Social Determinants of Health; Sodium; Sodium Fluoride; Sodium Potassium Chloride Symporter Inhibitors; Sodium-Glucose Transporter 2 Inhibitors; Soil; Soil Pollutants; Spain; Spectrophotometry; Spectroscopy, Fourier Transform Infrared; Staphylococcal Protein A; Staphylococcus aureus; Stem Cells; Stereoisomerism; Stomach Neoplasms; Streptomyces; Strontium; Structure-Activity Relationship; Students, Nursing; Substance-Related Disorders; Succinic Acid; Sulfur; Surface Properties; Survival Rate; Survivin; Symporters; T-Lymphocytes; Temozolomide; Tensile Strength; Thiazoles; Thiobacillus; Thiohydantoins; Thiourea; Thrombectomy; Time Factors; Titanium; Tobacco Mosaic Virus; Tobacco Use Disorder; Toll-Like Receptor 4; Toluene; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Toxicity Tests, Acute; Toxicity Tests, Subacute; Transcriptional Activation; Treatment Outcome; Troponin I; Tumor Cells, Cultured; Tumor Escape; Tumor Hypoxia; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Tyrosine; Ubiquitin-Protein Ligases; Ubiquitination; Ultrasonic Waves; United Kingdom; United States; United States Department of Veterans Affairs; Up-Regulation; Urea; Uric Acid; Urinary Bladder Neoplasms; Urinary Bladder, Neurogenic; Urine; Urodynamics; User-Computer Interface; Vemurafenib; Verbenaceae; Veterans; Veterans Health; Viral Load; Virtual Reality; Vitiligo; Water Pollutants, Chemical; Wildfires; Wnt Signaling Pathway; Wound Healing; X-Ray Diffraction; Xenograft Model Antitumor Assays; Xylenes; Young Adult; Zinc; Zinc Oxide; Zinc Sulfate; Zoonoses

Non-alcoholic fatty liver disease (NAFLD) is the emerging cause of chronic liver disease globally and lack of approved therapies. Here, we investigated the feasibility of combinatorial effects of low molecular weight fucoidan and high stability fucoxanthin (LMF-HSFx) as a therapeutic approach against NAFLD. We evaluated the inhibitory effects of LMF-HSFx or placebo in 42 NAFLD patients for 24 weeks and related mechanism in high fat diet (HFD) mice model and HepaRG

Topics: Adiponectin; Adult; Aged; Animals; Cell Line; Diet, High-Fat; Disease Models, Animal; Drug Therapy, Combination; Humans; Inflammation; Insulin Resistance; Leptin; Lipid Metabolism; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Mice, Nude; Middle Aged; Non-alcoholic Fatty Liver Disease; Polysaccharides; Xanthophylls; Young Adult

This study was to investigate the effect of proprioceptive neuromuscular facilitation techniques (NFT) on osteoporosis and serum leptin level in cerebral infarction patients or rats.. Forty cerebral infarction rats were randomly grouped into control, sham operation, conventional treatment (CT) group and CT+NFT group. Fifty-two stroke patients with hemiplegia were included in this study.. The bone mineral densities (BMD) of proximal hemiplegia limbs and serum ALP, BALP, BGP, IL-6 and leptin levels were detected using commercial kits.. In cerebral infarction rats, the BMD, BGP, BALP, ALP and leptin concentrations in the CT+NFT group was higher compared with the control and CT group, while serum IL-6 level was more reduced by CT+NFT than control and CT. In cerebral infarction patients, both CT and CT+NFT increased the BMD, ALP, BGP and leptin levels. In addition, compared with CT, the BMD, ALP, BGP and leptin levels were markedly increased by CT+NFT. C Conclusion: NFC elevated the BMD of hemiplegia limbs, serum ALP, BGP, IL-6 and leptin levels and, thus, alleviated osteoporosis in rats and patients with cerebral infarction.

Topics: Aged; Analysis of Variance; Animals; Bone Density; Cerebral Infarction; Disease Models, Animal; Female; Follow-Up Studies; Hemiplegia; Humans; Leptin; Magnetic Resonance Imaging; Male; Middle Aged; Muscle Stretching Exercises; Osteoporosis; Rats; Tomography Scanners, X-Ray Computed

Phosphate is an essential nutrient required for important biological reactions that maintain the normal homoeostatic control of the cell. The adverse effects of phosphate metabolism in obesity have not been studied in detail, chiefly because such an association is thought to be uncommon. However, in some animal models of obesity, serum phosphate levels were noted to be higher than the nonobese controls. For example, leptin-deficient (ob/ob) mice become severely obese and have high serum phosphate levels. In this study, we analyzed the phosphate content in saliva collected from children (n = 77; 10.5 ± 1.8) to evaluate association with body mass index; there is a significant increase of salivary phosphate content in obese compared to normal-weight children (ANOVA p < 0.001). The correlation coefficient (r) between BMI and phosphate was 0.33 (p = 0.0032). Our results suggest that the human salivary phosphate level may be an early biomarker of the genesis of obesity in children. The diagnostic importance lies in the fact that the salivary phosphate level could provide a noninvasive predictive marker in the development of obesity. Further studies will be required to understand the underlying mechanism of increased salivary phosphate accumulation in obese and overweight children. Nevertheless, its occurrence without systemic changes could be of diagnostic value, particularly in monitoring evolvement of obesity.

Topics: Animals; Anthropometry; Biomarkers; Blood Pressure; Body Mass Index; Child; Disease Models, Animal; Disease Progression; Early Diagnosis; Female; Heart Rate; Humans; Leptin; Male; Mice, Obese; Obesity; Overweight; Phosphates; Physical Fitness; Saliva

Key pathological features of Alzheimer's disease (AD) include build-up of amyloid β (Aβ), which promotes synaptic abnormalities and ultimately leads to neuronal cell death. Metabolic dysfunction is known to influence the risk of developing AD. Impairments in the leptin system have been detected in AD patients, which has fuelled interest in targeting this system to treat AD. Increasing evidence supports pro-cognitive and neuroprotective actions of leptin and these beneficial effects of leptin are mirrored by a bioactive leptin fragment (leptin

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Alzheimer Disease; Amyloid beta-Peptides; Animals; Disease Models, Animal; Hippocampus; Humans; Leptin; Neuronal Plasticity; Receptors, AMPA

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

Introduction: Sepsis is a dysregulated host response to infection that can lead to life-threatening organ dysfunction. Clinical and animal studies consistently demonstrate that female subjects are less susceptible to the adverse effects of sepsis, demonstrating the importance of understanding how sex influences sepsis outcomes. The signal transducer and activator of transcription 3 (STAT3) pathway are a major signaling pathway that facilitates inflammation during sepsis. STAT3 is abundantly expressed in white adipose tissue; however, little is known about the contribution of white adipose tissue STAT3 activation during sepsis. We hypothesize that adipocyte STAT3 inhibition during severe sepsis will exaggerate the inflammatory response and impact organ injury, in a sex-dependent manner. Methods: We generated STAT3 flox/flox (wild-type [WT]) and adipocyte STAT3 knock out (A-STAT3 KO) mice using Cre-lox technology. Studies were done in 12- to 16-week-old male and female mice. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP). Control nonseptic mice did not undergo CLP (0 h CLP). Tissues were harvested 18 h after CLP. Body composition was determined by echo magnetic resonance imaging. Energy metabolism was determined by indirect calorimetry. White adipose tissue morphology was determined by hematoxylin and eosin staining, while STAT3 activation in the white adipose tissue was determined by western blot analysis and immunohistochemistry staining of STAT3 activation/phosphorylation at tyrosine 705. Plasma cytokines (TNF-α, IL-6, and leptin) were determined by luminex assay. Neutrophil infiltration of the lung and liver was assessed by myeloperoxidase activity assay. Histological signs of organ injury on lung and liver tissue were assessed by hematoxylin and eosin staining. Liver injury was further assessed by measuring plasma alanine and aspartate aminotransferase. In a separate cohort of mice, sepsis was induced by CLP and mice were monitored every 6-12 h over a 7-day period to assess survival rate. Results: We demonstrate that neither body composition nor energy metabolism is altered with adipocyte STAT3 inhibition in male or female mice, under nonseptic conditions. Sepsis was associated with reduced adipocyte size in female WT and A-STAT3 KO mice, suggesting that this event is STAT3 independent. Sepsis did not alter adipocyte size in male WT and A-STAT3 KO mice, suggesting that this event is also sex dependent. Although STAT3 phosphorylat

Topics: Adipocytes; Animals; Cytokines; Disease Models, Animal; Eosine Yellowish-(YS); Hematoxylin; Inflammation; Interleukin-6; Leptin; Lung Injury; Male; Mice; Mice, Inbred C57BL; Sepsis; STAT3 Transcription Factor; Tumor Necrosis Factor-alpha

Obesity-related asthma is a kind of nonallergic asthma with excessive neutrophil infiltration in the airways. However, the underlying mechanisms have been poorly elucidated. Among the adipokines related to obesity, leptin is related to the inflammatory response. However, little is understood about how leptin acts on the leptin receptor (obR) in neutrophilic airway inflammation in obesity-associated asthma. We explored the inflammatory effects of leptin/obR signaling in an obesity-related neutrophilic airway inflammation mouse model.. We established a neutrophilic airway inflammation mouse model using lipopolysaccharide (LPS)/ovalbumin (OVA) sensitization and OVA challenge (LPS + OVA/OVA) in lean, obese, or db/db (obR deficiency) female mice. Histopathological, bronchoalveolar lavage fluid (BALF) inflammatory cell, and lung inflammatory cytokine analyses were used to analyze airway inflammation severity. Western blotting, flow cytometry, reverse transcription-polymerase chain reaction (RT-PCR), and enzyme-linked immunosorbent assay (ELISA) were used to evaluate the underlying mechanisms. In vitro bone marrow-derived macrophage (BMDM) and bone marrow-derived neutrophil experiments were performed.. We found that the serum leptin level was higher in obese than in lean female mice. Compared to LPS/OVA + OVA-treated lean female mice, LPS/OVA + OVA-treated obese female mice had higher peribronchial inflammation levels, neutrophil counts, Th1/Th17-related inflammatory cytokine levels, M1 macrophage polarization levels, and long isoform obR activation, which could be decreased by the obR blockade (Allo-Aca) or obR deficiency, suggesting a critical role of leptin/obR signaling in the pathogenesis of obesity-related neutrophilic airway inflammation in female mice. In in vitro experiments, leptin synergized with LPS/IFN-γ to promote the phosphorylation of the long isoform obR and JNK/STAT3/AKT signaling pathway members to increase M1 macrophage polarization, which was reversed by Allo-Aca. Moreover, leptin/obR-mediated M1 macrophage activity significantly elevated CXCL2 production and neutrophil recruitment by regulating the JNK/STAT3/AKT pathways. In clinical studies, obese patients with asthma had higher serum leptin levels and M1 macrophage polarization levels in induced sputum than non-obese patients with asthma. Serum leptin levels were positively correlated with M1 macrophage polarization levels in patients with asthma.. Our results demonstrate leptin/obR signaling plays an important role in the pathogenesis of obesity-related neutrophilic airway inflammation in females by promoting M1 macrophage polarization.

Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Female; Inflammation; Leptin; Lipopolysaccharides; Lung; Macrophages; Mice; Mice, Inbred BALB C; Obesity; Ovalbumin; Proto-Oncogene Proteins c-akt; Receptors, Leptin; Signal Transduction

The purpose of this study was to evaluate the effect of curcumin, an active polyphenol, on the leptin induced lowering of miR-122 in Hepatic stellate cells (HSCs) in vivo and an animal model. Gene expression was evaluated by transfection assay, real-time PCR, or Western blot analysis. The liver fibrosis model of leptin deficient mouse was used for in vivo experiment. As a result, curcumin showed inhibitory effect on leptin induced lowering of the miR-122 in HSCs. Curcumin suppressed leptin induced sonic hedgehog (Shh) expression and blocked leptin induced Shh signaling pathway, which was essential for curcumin inhibition of the negative role of leptin in miR-122 expression in HSCs. The influence of curcumin on the negative effect of leptin on miR-122 level was followed by the attenuation of liver fibrosis caused by leptin in leptin-deficient mouse model. In conclusion, curcumin could reduce the decrease of miR-122 level in HSCs induced by leptin and inhibit liver fibrosis induced by leptin. These data may have potential implications to treat with liver fibrosis by elevating the expression of leptin in humans especially obese patients.

Topics: Animals; Curcumin; Disease Models, Animal; Hedgehog Proteins; Hepatic Stellate Cells; Humans; Leptin; Liver Cirrhosis; Mice; MicroRNAs

Obesity is recognized as an independent risk factor for abdominal aortic aneurysm (AAA). While mutations in the melanocortin-4 receptor (MC4R) gene is the most common cause of obesity caused by mutations in a single gene, the link between MC4R function and vascular disease has still remained unclear. Here, by using melanocortin-4 receptor (MC4R) deficient mice, we confirmed MC4R deficiency promotes AAA and atherosclerosis. We demonstrated the contribution of two novel factors towards vascular vulnerability in this model: leptin signaling in vascular smooth muscle cells (VSMCs) and loss of MC4R signaling in macrophages. Leptin was shown to promote vascular vulnerability via PI3K-dependent upregulation of Spp1 expression in VSMC. Additionally, Ang II-induced AAA incidence was significantly reduced when MC4R gene expression was myeloid cell-specifically rescued in MC4R deficient (MC4R

Topics: Angiotensin II; Animals; Aortic Aneurysm, Abdominal; Disease Models, Animal; Leptin; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B; Obesity; Phosphatidylinositol 3-Kinases; Receptor, Melanocortin, Type 4

The murine postnatal leptin surge occurs within the first 4 weeks of life and is critical for neuronal projection development within hypothalamic feeding circuits. Here we describe the influence of nutritional status on the timing and magnitude of the postnatal leptin surge in mice.. Plasma leptin concentrations were measured 1-3 times per week for the first 4 weeks of life in C57BL/6J pups reared in litters adjusted to 3 (small), 7-8 (normal), or 11-12 (large) pups per dam fed breeder chow or raised in litters of 7-8 by dams fed high-fat diet (HFD) ad libitum starting either prior to conception or at parturition.. Mice raised in small litters become fatter than pups raised in either normal or large litters. The leptin surge in small litter pups starts earlier, lasts longer, and is dramatically larger in magnitude compared to normal litter pups, even when leptin concentrations are normalized to fat mass. In mice reared in large litters, weight gain is diminished and the surge is both significantly delayed and lower in magnitude compared to control pups. Pups reared by HFD-fed dams (starting preconception or at parturition) are fatter and have augmented leptin surge magnitude compared to pups suckled by chow-fed dams. Surge timing varies depending upon nutritional status of the pup; the source of the surge is primarily subcutaneous adipose tissue. At peak leptin surge, within each group, fat mass and plasma leptin are uncorrelated; in comparison with adults, pups overproduce leptin relative to fat mass. Plasma leptin elevation persists longer than previously described; at postnatal day 27 mice continue overproducing leptin relative to fat mass.. In mice, small litter size and maternal HFD feeding during the perinatal period augment the plasma leptin surge whereas large litter size is associated with a delayed surge of reduced magnitude.

Topics: Animals; Area Under Curve; Disease Models, Animal; Leptin; Mice; Mice, Inbred C57BL; Nutritional Status; Postpartum Period; ROC Curve; Time Factors

Leptin resistance occurs in obese patients, but its independent contribution to adiposity and the accompanying metabolic diseases, i.e., diabetes, liver steatosis, and steatohepatitis, remains to be established. This study was conducted in an extreme model of leptin resistance to investigate mechanisms initiating diabetes, fat expansion, liver steatosis, and inflammatory disease, focusing on the involvement of glucose intolerance and organ-specific glucose uptake in brown and subcutaneous adipose tissues (BAT, SAT) and in the liver.. We studied preobese and adult Zucker rats (fa/fa, fa/+ ) during fasting or glucose loading to assess glucose tolerance. Relevant pancreatic and intestinal hormonal levels were measured by Milliplex. Imaging of. Preobese fa/fa pups showed impaired glucose tolerance, adipocyte enlargement, hepatic microsteatosis, and lobular inflammation, with elevated hepatic post-glucose load glucose uptake and production. Adult fa/fa rats had more severe glucose intolerance, fasting hyperglycemia, hormonal abnormalities, elevated glucose uptake in SAT and BAT, and more markedly in the liver, together with macrosteatosis, and highly prevalent hepatic inflammation. Organ glucose uptake was proportional to the degree of fat accumulation and tissue inflammation and was able to dissect healthy from NAFLD and NAFLD/NASH livers. Most severe NASH livers showed a decline in glucose uptake and liver enzymes.. In fa/fa Zucker rats, leptin resistance leads to glucose intolerance, mainly due to hepatic glucose overproduction, preceding obesity, and explaining pancreatic and intestinal hormonal changes and fat accumulation in adipocytes and hepatocytes. Our data support the involvement of liver glucose uptake in the pathogenesis of liver inflammatory disease. Its potential as more generalized biomarker or diagnostic approach remains to be established outside of our leptin-receptor-deficient rat model.

Topics: Adipocytes; Animals; Disease Models, Animal; Fatty Liver; Glucose; Leptin; Obesity; Rats; Rats, Zucker

Obesity and type 2 diabetes are two interrelated metabolic disorders characterized by insulin resistance and a mild chronic inflammatory state. We previously observed that leptin (ob/ob) and leptin receptor (db/db) knockout mice display a distinct inflammatory tone in the liver and adipose tissue. The present study aimed at investigating whether alterations in these tissues of the molecules belonging to the endocannabinoidome (eCBome), an extension of the endocannabinoid (eCB) signaling system, whose functions are important in the context of metabolic disorders and inflammation, could reflect their different inflammatory phenotypes.. The basal eCBome lipid and gene expression profiles, measured by targeted lipidomics and qPCR transcriptomics, respectively, in the liver and subcutaneous or visceral adipose tissues, highlighted a differentially altered eCBome tone, which may explain the impaired hepatic function and more pronounced liver inflammation remarked in the ob/ob mice, as well as the more pronounced inflammatory state observed in the subcutaneous adipose tissue of db/db mice. In particular, the levels of linoleic acid-derived endocannabinoid-like molecules, of one of their 12-lipoxygenase metabolites and of Trpv2 expression, were always altered in tissues exhibiting the highest inflammation. Correlation studies suggested the possible interactions with some gut microbiota bacterial taxa, whose respective absolute abundances were significantly different between ob/ob and the db/db mice.. The present findings emphasize the possibility that bioactive lipids and the respective receptors and enzymes belonging to the eCBome may sustain the tissue-dependent inflammatory state that characterizes obesity and diabetes, possibly in relation with gut microbiome alterations.

Topics: Adipose Tissue; Animals; Arachidonate 12-Lipoxygenase; Calcium Channels; Diabetes Mellitus, Type 2; Disease Models, Animal; Endocannabinoids; Gastrointestinal Microbiome; Gene Expression Regulation; Humans; Inflammation; Leptin; Mice; Mice, Inbred NOD; Mice, Obese; Obesity; Receptors, Leptin; Transcriptome; TRPV Cation Channels

Leptin is an adipokine with roles in food intake and energy metabolism through its actions on neurons in the hypothalamus. The role of leptin in obesity and cardiovascular disorders is well documented. However, its influence on liver conditions such as cholestasis is poorly understood. The effects of exogenous leptin and leptin-neutralizing antibody on biliary hyperplasia, hepatic fibrosis, and inflammation in the multidrug resistance protein 2 knockout (Mdr2KO) mouse model of cholestasis were assessed by quantifying markers specific for cholangiocytes, activated hepatic stellate cells (HSCs), and cytokines. Serum and hepatic leptin were increased in Mdr2KO mice compared with FVB/NJ (FVBN) controls, and exogenous leptin enhanced biliary hyperplasia and liver fibrosis in Mdr2KO and FVBN mice. Leptin administration increased hepatic expression of C-C motif chemokine ligand 2 and IL-6 in Mdr2KO mice. In contrast, leptin-neutralizing antibody reduced intrahepatic bile duct mass and decreased HSC activation in Mdr2KO mice compared with FVBN controls. Sex-related differences were noted, with female Mdr2KO mice having more leptin than males. In cholangiocytes and LX2 cells in vitro, leptin increased phosphorylated Akt and stimulated cell proliferation. Leptin receptor siRNA and inhibitors of Akt phosphorylation impaired leptin-induced cell proliferation and proinflammatory cytokines. The current data suggest that leptin is abnormally increased in cholestatic mice, and excess leptin increases ductular reaction, hepatic fibrosis, and inflammation via leptin receptor-mediated phosphorylation of Akt in cholangiocytes and HSCs.

Topics: Animals; Antibodies, Neutralizing; Cholestasis; Cytokines; Disease Models, Animal; Female; Hepatic Stellate Cells; Hyperplasia; Inflammation; Leptin; Liver; Liver Cirrhosis; Male; Mice; Mice, Knockout; Proto-Oncogene Proteins c-akt; Receptors, Leptin

Targeting leptin could represent a rational strategy to treat amyotrophic lateral sclerosis (ALS), as previously clinical studies have shown its levels to be associated with a lower risk of ALS disease. However, very little is known about the potential influence of leptin in altering disease progression in ALS, as it has thus far been correlated with the protection exerted by increased fat mass stores.. We studied the impact of leptin treatment beginning at 42-days of age (asymptomatic stage of disease) in the TDP-43 (TDP43. Our study shows that leptin treatment was associated with altered expression of adipokines and metabolic proteins in TDP43. Collectively, our results support leptin as a potential novel treatment approach for ALS.

Topics: Amyotrophic Lateral Sclerosis; Animals; Disease Models, Animal; Disease Progression; Leptin; Mice; Mice, Transgenic

The opioid buprenorphine alters breathing and the cytokine leptin stimulates breathing. Obesity increases the risk for respiratory disorders and can lead to leptin resistance. This study tested the hypothesis that buprenorphine causes dose-dependent changes in breathing that vary as a function of obesity, leptin status, and sex. Breathing measures were acquired from four congenic mouse lines: female and male wild type C57BL/6J (B6) mice, obese db/db and ob/ob mice with leptin dysfunction, and male B6 mice with diet-induced obesity. Mice were injected intraperitoneally with saline (control) and five doses of buprenorphine (0.1, 0.3, 1.0, 3.0, 10 mg/kg). Buprenorphine caused dose-dependent decreases in respiratory frequency while increasing tidal volume, minute ventilation, and respiratory duty cycle. The effects of buprenorphine varied significantly with leptin status and sex. Buprenorphine decreased minute ventilation variability in all mice. The present findings highlight leptin status as an important modulator of respiration and encourage future studies aiming to elucidate the mechanisms through which leptin status alters breathing.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Pulmonary Ventilation; Respiratory Physiological Phenomena; Respiratory Rate; Sex Characteristics; Tidal Volume

Hyperglycemia exerts various harmful effects on the vasculature. Studies have shown an association between the levels of the adipokines leptin and adiponectin (APN) and vascular complications in diabetes mellitus. The aim of our study was to investigate the molecular mechanisms mediated by APN and leptin that are involved in hyperglycemia-induced vascular remodeling, especially at the level of oxidative stress and actin cytoskeleton dynamics. Rat aorta organ culture was used to investigate the effect of hyperglycemia on APN and leptin protein expression in vascular smooth muscle cells (VSMCs) using Western blot analysis and immunohistochemistry. Hyperglycemia lead to a significant increase in APN synthesis in VSMCs, mainly through caveolae, but this increase failed to provide vascular protection because of the decreased expression of APN receptors, especially AdipoR2, which was assessed by qPCR. In addition, hyperglycemia significantly upregulated leptin expression in VSMCs through caveolae and the RhoA/ROCK pathway. These variations lead to a marked increase in reactive oxygen species (ROS) production, detected by dihydroethidium (DHE) staining, and in NADPH oxidase type 4 (Nox4) expression. Moreover, Nox4 mediated the synthesis of APN in hyperglycemia in VSMCs. Finally, hyperglycemia activated the RhoA/ROCK pathway and subsequently induced the polymerization of globular actin (G-actin) into filamentous actin (F-actin), decreasing the G/F-actin ratio. Taken together, these data show that hyperglycemia increases oxidative stress and changes actin cytoskeleton dynamics in the aorta via caveolae, favoring vascular remodeling.

Topics: Adiponectin; Animals; Caveolae; Disease Models, Animal; Hyperglycemia; Leptin; Male; Muscle, Smooth, Vascular; Rats; Rats, Sprague-Dawley; Vascular Remodeling

Brain reperfusion following an ischemic event is essential for tissue viability, however, it also involves processes that promote neuronal cell death. We have recently shown that local expression of the hormone leptin in cardiovascular organs drives deleterious remodeling. As cerebral ischemia-reperfusion (IR) lesions derive expression of both the leptin hormone and its receptor, we hypothesized that blocking leptin activity in the injured brain area will reduce the deleterious effects of IR injury.. C57BL6 male mice underwent bilateral common carotid artery and external carotid artery ligation. The right hemisphere was reperfused after 12 minutes, followed by intraarterial injection of either a low-dose leptin antagonist or saline solution via the ipsilateral ICA. The left common carotid artery remained ligated. Fifteen IR/leptin antagonist-injected and fourteen IR/saline-injected mice completed the experiment. Five days after surgery brains were collected and samples of the hippocampal CA1 region were analyzed for cell viability (H&E) and apoptosis (TUNEL and caspase3), for neuroinflammation (Iba1), and for signaling pathways of pSTAT3 and pSmad2.. The right hemisphere hippocampal CA1 region subjected to IR and saline injection exhibited increased apoptosis and necrosis of pyramidal cells. Also, increased density of activated microglia/macrophages was evident around the CA1 region. Comparatively, leptin antagonist treatment at reperfusion reduced apoptosis and necrosis of pyramidal cells, as indicated by increased number of viable cells (p < 0.01), and reduced TUNEL (p < 0.001) and caspase3-positive cells (p<0.05). Furthermore, this treatment reduced the density of activated microglia/macrophages (p < 0.001) in the CA1 region. Signaling pathway analysis revealed that while pSTAT3 and pSmad2-positive cells were found surrounding the stratum pyramidal in saline-treated animals, pSTAT3 signal was undetected and pSmad2 was greatly reduced in this territory following leptin antagonist treatment (p < 0.01).. Inhibition of leptin activity in hemispheric IR injury preserved the viability of ipsilateral hippocampal CA1 neurons, likely by preventing apoptosis and local inflammation. These results indicate that intraarterial anti-leptin therapy may have clinical potential in reducing hemispheric brain IR injury.

Topics: Animals; Apoptosis; CA1 Region, Hippocampal; Disease Models, Animal; Infusions, Intra-Arterial; Leptin; Macrophages; Male; Mice; Mice, Inbred C57BL; Microglia; Protective Agents; Reperfusion Injury; Signal Transduction; Smad2 Protein; STAT3 Transcription Factor

Asthma patients with comorbid obesity exhibit increased disease severity, in part, due to airway remodeling, which is also observed in mouse models of asthma and obesity. A mediator of remodeling that is increased in obesity is leptin. We hypothesized that in a mouse model of allergic airways disease, mice receiving exogenous leptin would display increased airway inflammation and fibrosis.. Five-week-old male and female C57BL/6J mice were challenged with intranasal house dust mite (HDM) allergen or saline 5 days per week for 6 weeks (n = 6-9 per sex, per group). Following each HDM exposure, mice received subcutaneous recombinant human leptin or saline. At 48 h after the final HDM challenge, lung mechanics were evaluated and the mice were sacrificed. Bronchoalveolar lavage was performed and differential cell counts were determined. Lung tissue was stained with Masson's trichrome, periodic acid-Schiff, and hematoxylin and eosin stains. Mouse lung fibroblasts were cultured, and whole lung mRNA was isolated.. Leptin did not affect mouse body weight, but HDM+leptin increased baseline blood glucose. In mixed-sex groups, leptin increased mouse lung fibroblast invasiveness and increased lung Col1a1 mRNA expression. Total lung resistance and tissue damping were increased with HDM+leptin treatment, but not leptin or HDM alone. Female mice exhibited enhanced airway responsiveness to methacholine with HDM+leptin treatment, while leptin alone decreased total respiratory system resistance in male mice.. In HDM-induced allergic airways disease, administration of exogenous leptin to mice enhanced lung resistance and increased markers of fibrosis, with differing effects between males and females.

Topics: Allergens; Animals; Asthma; Biomarkers; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Female; Fibrosis; Humans; Hypersensitivity; Leptin; Lung; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Obesity; Pulmonary Disease, Chronic Obstructive; Pulmonary Fibrosis; Pyroglyphidae; RNA, Messenger

Resolvin E1 (RvE1), a specialized pro-resolving mediator (SPM), improves glucose homeostasis in inbred mouse models of obesity. However, an impediment toward translation is that obesity is a highly heterogenous disease in which individuals will respond very differently to interventions such as RvE1. Thus, there is a need to study SPMs in the context of modeling the heterogeneity of obesity that is observed in humans. We investigated how RvE1 controls the concentration of key circulating metabolic biomarkers using diversity outbred (DO) mice, which mimic human heterogeneity. We first demonstrate that weights of DO mice can be classified into distinct distributions of fat mass (i.e., modeling differing classes of obesity) in response to a high-fat diet and in the human population when examining body composition. Next, we show RvE1 administration based on body weight for four consecutive days after giving mice a high-fat diet led to approximately half of the mice responding positively for serum total gastric inhibitory polypeptide (GIP), glucagon, insulin, glucose, leptin, and resistin. Interestingly, RvE1 improved hyperleptinemia most effectively in the lowest class of fat mass despite adjusting the dose of RvE1 with increasing adiposity. Furthermore, leptin levels after RvE1 treatment were the lowest in those mice that were also RvE1 positive responders for insulin and resistin. Collectively, these results suggest a therapeutic fat mass-dependent window for RvE1, which should be considered in future clinical trials. Moreover, the data underscore the importance of studying SPMs with heterogenous mice as a step toward precision SPM administration in humans.

Topics: Animals; Collaborative Cross Mice; Disease Models, Animal; Eicosapentaenoic Acid; Glucose; Humans; Insulins; Leptin; Mice; Obesity; Resistin

Stress resilience, and behavioural and cardiovascular impacts of chronic stress, are theorised to involve integrated neuro-endocrine/inflammatory/transmitter/trophin signalling. We tested for this integration, and whether behaviour/emotionality, together with myocardial ischaemic tolerance, are consistently linked to these pathways across diverse conditions in male C57Bl/6 mice. This included Restraint Stress (RS), 1 h restraint/day for 14 days; Chronic Unpredictable Mild Stress (CUMS), seven stressors randomised over 21 days; Social Stress (SS), 35 days social isolation with brief social encounters in final 13 days; and Control conditions (CTRL; un-stressed mice). Behaviour was assessed via open field (OFT) and sucrose preference (SPT) tests, and neurobiology from frontal cortex (FC) and hippocampal transcripts. Endocrine factors, and function and ischaemic tolerance in isolated hearts, were also measured. Model characteristics ranged from no behavioural or myocardial changes with homotypic RS, to increased emotionality and cardiac ischaemic injury (with apparently distinct endocrine/neurobiological profiles) in CUMS and SS models. Highly integrated expression of HPA axis, neuro-inflammatory, BDNF, monoamine, GABA, cannabinoid and opioid signalling genes was confirmed across conditions, and consistent/potentially causal correlations identified for (i) locomotor activity (noradrenaline, ghrelin; FC Crhr1, Tnfrsf1b, Il33, Nfkb1, Maoa, Gabra1; hippocampal Il33); (ii) thigmotaxis (adrenaline, leptin); (iii) anxiety-like behaviour (adrenaline, leptin; FC Tnfrsf1a; hippocampal Il33); (iv) depressive-like behaviour (ghrelin; FC/hippocampal s100a8); and (v) cardiac stress-resistance (noradrenaline, leptin; FC Il33, Tnfrsf1b, Htr1a, Gabra1, Gabrg2; hippocampal Il33, Tnfrsf1a, Maoa, Drd2). Data support highly integrated pathway responses to stress, and consistent adipokine, sympatho-adrenergic, inflammatory and monoamine involvement in mood and myocardial disturbances across diverse conditions.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Brain-Derived Neurotrophic Factor; Depression; Disease Models, Animal; Epinephrine; Ghrelin; Hypothalamo-Hypophyseal System; Interleukin-33; Leptin; Male; Mice; Mice, Inbred C57BL; Norepinephrine; Pituitary-Adrenal System; Stress, Psychological

Egg-derived peptides play important roles in insulin secretion and sensitivity, oxidative stress, and inflammation, suggesting their possible involvement in obesity management. Hence, the aim of this study is to explore the alleviating effects of IRW (lle-Arg-Trp) and IQW (lle-Gln-Trp) on obesity via the mouse model induced by a high-fat diet. The entire experimental period lasted eight weeks. The results demonstrated that IQW prevented weight gain (6.52%), decreased the glucose, low-density lipoprotein (LDL), malonaldehyde, triglycerides, total cholesterol (TC), and leptin levels, and increased the concentration of adiponectin (p < 0.05, n = 8). Although IRW failed to prevent weight gain, it reduced the concentration of glucose, high-density lipoprotein (HDL), LDL, and leptin, and increased the concentration of adiponectin (p < 0.05, n = 8). Moreover, IRW and IQW increased glucose tolerance and insulin resistance based on the results of the intraperitoneal glucose test and insulin tolerance test (p < 0.05, n = 8). The quantitative polymerase chain reaction results revealed that IRW and IQW downregulated the mRNA expression of DGAT1 (Diacylglycerol O-Acyltransferase 1), DGAT2 (Diacylglycerol O-Acyltransferase 2), TNF-α, IL-6, and IL-1β of liver tissue (p < 0.05, n = 8). The results of the 16S ribosomal RNA amplicon sequencing showed that IQW and IRW tended to reduce the relative abundance of Firmicutes and Parabacteroides, and that IRW enhanced the abundance of Bacteroides (p < 0.05, n = 8). Collectively, IRW and IQW supplementation could alleviate the progression of obesity due to the fact that the supplementation reduced lipid deposition, maintained energy balance, and reprogrammed gut microbiota.

Topics: Adiponectin; Animals; Cholesterol; Diacylglycerol O-Acyltransferase; Diet, High-Fat; Disease Models, Animal; Egg Proteins; Gastrointestinal Microbiome; Glucose; Insulins; Interleukin-6; Leptin; Lipoproteins, HDL; Lipoproteins, LDL; Malondialdehyde; Membrane Proteins; Mice; Mice, Inbred C57BL; Obesity; Peptides; RNA, Messenger; RNA, Ribosomal, 16S; Transferrin; Triglycerides; Tumor Necrosis Factor-alpha; Weight Gain

The close relationship between Alzheimer's disease (AD) and obesity was recognized many years ago. However, complete understanding of the pathological mechanisms underlying the interactions between degeneration of CNS and fat metabolism is still missing. The leptin a key adipokine of white adipose tissue has been suggested as one of the major mediators linking the obesity and AD. Here we investigated the association between peripheral levels of leptin, general metabolic status and stage of the pathogenesis in rat transgenic model of AD. We demonstrate significantly decreased levels of plasma leptin in animals with experimentally induced progressive neurofibrillary pathology, which represents only 62.3% (P = 0.0015) of those observed in normal wild type control animals. More detailed analysis showed a strong and statistically significant inverse correlation between the load of neurofibrillary pathology and peripheral levels of leptin (r = - 0.7248, P = 0.0177). We also observed a loss of body weight during development of neurodegeneration (about 14% less than control animals, P = 0.0004) and decrease in several metabolic parameters such as glucose, insulin, triglycerides and VLDL in plasma of the transgenic animals. Our data suggest that plasma leptin could serve as a convenient peripheral biomarker for tauopathies and Alzheimer's disease. Decrease in gene expression of leptin in fat tissue and its plasma level was found as one of the consequences of experimentally induced neurodegeneration. Our data may help to design rational diagnostic and therapeutic strategies for patients suffering from Alzheimer's disease or other forms of tauopathy.

Topics: Alzheimer Disease; Animals; Disease Models, Animal; Humans; Leptin; Obesity; Rats; tau Proteins; Tauopathies

<b>Background and Objective:</b> Arcuate nucleus (ARC), a component of appetite-regulatory factors, contains populations of both orexigenic and anorexigenic neurons and one of the fundamental components of its system is leptin. Studies have evidenced the critical neurotrophic role in the development of ARC. To determine such effects on neuron development, N1E-115 neuroblastoma cells were used as an ARC model. <b>Materials and Methods:</b> N1E-115 neuroblastoma cells were treated with leptin [10 nM] for 24, 48 and 72 hrs. Dimethyl sulfoxide (DMSO) 1.5% was used as a known drug that promotes neurite expression. Cells percentage (%) that developed neurites was evaluated by bright field microscopy. Patch-clamp electrophysiology was used to analyze membrane ion currents, RT-PCR for quantifying changes in mRNA expression of anorexic peptides, proopiomelanocortin (POMC) and cocaine and amphetamine-related transcript (CART), in addition to principal Na_v, Ca_v ion channel subunits. <b>Results:</b> N1E-115 cells treated with leptin show neurite expression after 24 hrs of treatment, similar effects were obtained with DMSO. Leptin (time-dependent) increases the inward current in comparison with the control value at 72 hrs. Outward currents were not affected by leptin. Leptin and DMSO increased Na⁺ and Ca²⁺ current without changes in the kinetic properties. Lastly, leptin promotes an increase in mRNA level expression of transcripts to POMC, CART, Na_v1.2 and Ca_v1.3. <b>Conclusion:</b> Leptin chronic treatment promotes neurite expression, Up-regulation of Na⁺ and Ca²⁺ ion channels determining neuronal excitability, besides increasing the mRNA level expression of anorexic peptides POMC and CART in neuroblastoma N1E-115.

Topics: Animals; Cell Differentiation; Disease Models, Animal; Gene Expression; Ion Channels; Leptin; Mexico; Mice; Neuroblastoma

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia. While cognitive deficits remain the major manifestation of AD, metabolic and non-cognitive abnormalities, such as alterations in food intake, body weight and energy balance are also present, both in AD patients and animal models. In this sense, the tauroursodeoxycholic acid (TUDCA) has shown beneficial effects both in reducing the central and cognitive markers of AD, as well as in attenuating the metabolic disorders associated with it. We previously demonstrated that TUDCA improves glucose homeostasis and decreases the main AD neuromarkers in the streptozotocin-induced AD mouse model (Stz). Besides that, TUDCA-treated Stz mice showed lower body weight and adiposity. Here, we investigated the actions of TUDCA involved in the regulation of body weight and adiposity in Stz mice, since the effects of TUDCA in hypothalamic appetite control and energy homeostasis have not yet been explored in an AD mice model. The TUDCA-treated mice (Stz + TUDCA) displayed lower food intake, higher energy expenditure (EE) and respiratory quotient. In addition, we observed in the hypothalamus of the Stz + TUDCA mice reduced fluorescence and gene expression of inflammatory markers, as well as normalization of the orexigenic neuropeptides AgRP and NPY expression. Moreover, leptin-induced p-JAK2 and p-STAT3 signaling in the hypothalamus of Stz + TUDCA mice was improved, accompanied by reduced acute food intake after leptin stimulation. Taken together, we demonstrate that TUDCA treatment restores energy metabolism in Stz mice, a phenomenon that is associated with reduced food intake, increased EE and improved hypothalamic leptin signaling. These findings suggest treatment with TUDCA as a promising therapeutic intervention for the control of energy homeostasis in AD individuals.

Topics: Adiposity; Alzheimer Disease; Animals; Biomarkers; Body Weight; Disease Management; Disease Models, Animal; Energy Metabolism; Gene Expression; Homeostasis; Immunohistochemistry; Inflammation Mediators; Leptin; Male; Mice; Organ Specificity; Signal Transduction; Streptozocin; Taurochenodeoxycholic Acid; Thermogenesis

Although innate immunity is linked to metabolic health, the effect of leptin signaling in cells from the innate immune system on glucose homeostasis has not been thoroughly investigated. We generated two mouse models using Cre-lox methodology to determine the effect of myeloid cell-specific leptin receptor (Lepr) reconstitution and Lepr knockdown on in vivo glucose metabolism. Male mice with myeloid cell-specific Lepr reconstitution (Lyz2Cre

Topics: Animals; Biomarkers; Blood Glucose; Disease Models, Animal; Disease Susceptibility; Energy Metabolism; Gene Knockdown Techniques; Glucose; Homeostasis; Leptin; Male; Metabolic Diseases; Mice; Myeloid Cells; Signal Transduction

Biomarkers are essential tools in osteoarthritis (OA) research, clinical trials, and drug development. Detecting and evaluating biomarkers in OA research can open new avenues for researching and developing new therapeutics. In the present report, we have explored the serological detection of various osteoarthritis-related biomarkers in the preclinical model of OA. In this surgical OA model, we disrupted the medial tibial cartilage's integrity via anterior cruciate ligament transection combined with medial meniscectomy (ACLT+MMx) of a single joint of Wistar rats. The progression of OA was verified, as shown by the microscopic deterioration of cartilage and the increasing cartilage degeneration scoring from 4 to 12 weeks postsurgery. The concentration of serological biomarkers was measured at two timepoints, along with the complete blood count and bone electrolytes, with biochemical analysis further conducted. The panel evaluated inflammatory biomarkers, bone/cartilage biomarkers, and lipid metabolic pathway biomarkers. In chronic OA rats, we found a significant reduction of total vitamin D3 and C-telopeptide fragments of type II (CTX-II) levels in the serum as compared to sham-operated rats. In contrast, the serological levels of adiponectin, leptin, and matrix metallopeptidase (MMP3) were significantly enhanced in chronic OA rats. The inflammatory markers, blood cell composition, and biochemical profile remained unchanged after surgery. In conclusion, we found that a preclinical model of single-joint OA with significant deterioration of the cartilage can lead to serological changes to the cartilage and metabolic-related biomarkers without alteration of the systemic blood and biochemical profile. Thus, this biomarker profile provides a new tool for diagnostic/therapeutic assessment in OA scientific research.

Topics: Adiponectin; Animals; Anterior Cruciate Ligament; Anterior Cruciate Ligament Injuries; Biomarkers; Cartilage, Articular; Cholecalciferol; Collagen Type II; Disease Models, Animal; Leptin; Matrix Metalloproteinase 3; Meniscectomy; Menisci, Tibial; Osteoarthritis; Peptide Fragments; Rats; Rats, Wistar; Tibia

The adipokine leptin, which is best-known for its role in the control of metabolic function, is also a master regulator of cardiovascular function. While leptin has been approved for the treatment of metabolic disorders in patients with congenital generalized lipodystrophy (CGL), the effects of chronic leptin deficiency and the treatment on vascular contractility remain unknown. Herein, we investigated the effects of leptin deficiency and treatment (0.3 mg/day/7 days) on aortic contractility in male Berardinelli-Seip 2 gene deficient mice (gBscl2

Topics: Adrenergic Agents; Animals; Aorta, Thoracic; Disease Models, Animal; Endothelium, Vascular; GTP-Binding Protein gamma Subunits; Leptin; Lipodystrophy, Congenital Generalized; Male; Mice; Mice, Knockout; Muscle Contraction; Muscle, Smooth, Vascular; Nitric Oxide Synthase Type I; Receptors, Leptin; Signal Transduction; Treatment Outcome

The study is aimed at investigating the curative effect of acupuncture on simple obesity and its influence on serum levels of prostaglandin E and leptin in Sprague-Dawley (SD) rats.. In the study, there are 50 male SD rats. We took 10 as healthy controls and fed 40 with a diet of high fat for 8 weeks. After the 40 rat model was established successfully, we fed 10 rats in the model group with a normal diet and treated 10 rats in the acupuncture group by acupuncture. During the experiment, the body fat and body length of rats were measured weekly, and Lee's index was calculated. After the treatment, the levels of leptin, prostaglandin E, C-reactive protein (CRP), triacylglycerol (TG), cholesterol (CHO), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) were detected, and the liver fat morphology was observed by electron microscope.. Acupuncture significantly downregulated the serum levels of CRP, TG, CHO, LDL, leptin, and prostaglandin E and upregulated the serum levels of HDL in rats with simple obesity.. On basis of these results, it was found that acupuncture could boost fat metabolism and weight loss by inhibiting the production of leptin and prostaglandin E.

Topics: Acupuncture Therapy; Adipose Tissue; Animals; C-Reactive Protein; Computational Biology; Disease Models, Animal; Leptin; Lipids; Liver; Male; Obesity; Prostaglandins E; Rats; Rats, Sprague-Dawley; Weight Loss

We investigated whether peripheral combination treatment of a sodium-glucose cotransporter 2 (SGLT2) inhibitor and leptin improves glucose metabolism in insulin-dependent diabetes mellitus (IDDM) model mice. Twelve-week-old male C57BL6 mice were intraperitoneally administered a high dose of streptozotocin to produce IDDM. IDDM mice were then divided into five groups: SGLT2 inhibitor treatment alone, leptin treatment alone, leptin and SGLT2 inhibitor co-treatment, untreated IDDM mice, and healthy mice groups. The blood glucose (BG) level at the end of the dark cycle was measured, and a glucose tolerance test (GTT) was performed and compared between the five groups. Leptin was peripherally administered at 20 μg/day using an osmotic pump, and an SGLT2 inhibitor, ipragliflozin, was orally administered at 3 mg/kg/day. Monotherapy with SGLT2 inhibitor or leptin significantly improved glucose metabolism in mice as evaluated by BG and GTT compared with the untreated group, whereas the co-treatment group with SGLT2 inhibitor and leptin further improved glucose metabolism as compared with the monotherapy group. Notably, glucose metabolism in the co-treatment group improved to the same level as that in the healthy mice group. Thus, peripheral combination treatment with leptin and SGLT2 inhibitor improved glucose metabolism in IDDM mice without the use of insulin.

Topics: Administration, Oral; Animals; Diabetes Mellitus, Type 1; Disease Models, Animal; Drug Therapy, Combination; Glucose; Glucosides; Infusions, Intravenous; Leptin; Male; Mice, Inbred C57BL; Sodium-Glucose Transporter 2 Inhibitors; Thiophenes

Changes in functionality and composition of gut microbiota (GM) have been associated and may contribute to the development and maintenance of obesity and related diseases. The aim of our study was to investigate for the first time the impact of

Topics: Adipocytes; Adipose Tissue, White; Animal Feed; Animals; Biodiversity; Blood Glucose; Diet, High-Fat; Dietary Supplements; Disease Models, Animal; DNA, Bacterial; Feces; Gastrointestinal Microbiome; Leptin; Lipid Metabolism; Lipoproteins, LDL; Liver; Male; Obesity; Probiotics; Rats; Rats, Sprague-Dawley; RNA, Ribosomal, 16S; Weight Gain

Type 1 diabetes (T1D) is characterized by hyperphagia, hyperglycemia and activation of the hypothalamic-pituitary-adrenal (HPA) axis. We have reported previously that daily leptin injections help to alleviate these symptoms. Therefore, we hypothesized that leptin gene therapy could help to normalize the neuroendocrine dysfunction seen in T1D. Adult male Sprague Dawley rats were injected i.v. with a lentiviral vector containing the leptin gene or green fluorescent protein. Ten days later, they were injected with the vehicle or streptozotocin (STZ). HPA function was assessed by measuring norepinephrine (NE) levels in the paraventricular nucleus (PVN) and serum corticosterone (CS). Treatment with the leptin lentiviral vector (Lepvv) increased leptin and insulin levels in non-diabetic rats, but not in diabetic animals. There was a significant reduction in blood glucose levels in diabetic rats due to Lepvv treatment. Both NE levels in the PVN and serum CS were reduced in diabetic rats treated with Lepvv. Results from this study provide evidence that leptin gene therapy in STZ-induced diabetic rats was able to partially normalize some of the neuroendocrine abnormalities, but studies with higher doses of the Lepvv are needed to develop this into a viable option for treating T1D.

Topics: Animals; Corticosterone; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Models, Animal; Genetic Therapy; Genetic Vectors; Injections, Intravenous; Lentivirus; Leptin; Male; Norepinephrine; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley

Topics: Adenylate Kinase; Allosteric Regulation; Animals; Area Under Curve; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Disease Models, Animal; Drug Therapy, Combination; Estradiol; Gene Expression Regulation; Glycated Hemoglobin; Insulin; Insulin Resistance; Leptin; Male; Metformin; Phosphorylation; Rats, Wistar; Receptors, LH; Seminiferous Tubules; Spermatogenesis; Steroids; Testosterone

Metabolic dysfunction is now recognized as a pivotal component of Alzheimer's disease (AD), the most common dementia worldwide. However, the precise molecular mechanisms linking metabolic dysfunction to AD remain elusive.. Here, we investigated the direct impact of soluble oligomeric amyloid beta (Aβ) peptides, the main molecular hallmark of AD, on the leptin system, a major component of central energy metabolism regulation.. We developed a new time-resolved fluorescence resonance energy transfer-based Aβ binding assay for the leptin receptor (LepR) and studied the effect of Aβ on LepR function in several in vitro assays. The in vivo effect of Aβ on LepR function was studied in an Aβ-specific AD mouse model and in pro-opiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus.. We revealed specific and high-affinity (Ki = 0.1 nM) binding of Aβ to LepR. Pharmacological characterization of this interaction showed that Aβ binds allosterically to the extracellular domain of LepR and negatively affects receptor function. Negative allosteric modulation of LepR by Aβ was detected at the level of signaling pathways (STAT-3, AKT, and ERK) in vitroand in vivo. Importantly, the leptin-induced response of POMC neurons, key players in the regulation of metabolic function, was completely abolished in the presence of Aβ.. Our data indicate that Aβ is a negative allosteric modulator of LepR, resulting in impaired leptin action, and qualify LepR as a new and direct target of Aβ oligomers. Preventing the interaction of Aβ with LepR might improve both the metabolic and cognitive dysfunctions in AD condition.

Topics: Allosteric Regulation; Alzheimer Disease; Amyloid beta-Peptides; Animals; Arcuate Nucleus of Hypothalamus; Cell Line; Disease Models, Animal; HEK293 Cells; Humans; Leptin; Male; Mice; Pro-Opiomelanocortin; Receptors, Leptin; Signal Transduction

Systemic retinol (vitamin A) homeostasis is controlled by the liver, involving close collaboration between hepatocytes and hepatic stellate cells (HSCs). Genetic variants in retinol metabolism (PNPLA3 and HSD17B13) are associated with non-alcoholic fatty liver disease (NAFLD) and disease progression. Still, little mechanistic details are known about hepatic vitamin A metabolism in NAFLD, which may affect carbohydrate and lipid metabolism, inflammation, oxidative stress and the development of fibrosis and cancer, e.g. all risk factors of NAFLD.. Hepatic retinol and retinol binding protein 4 (RBP4) levels were significantly reduced in both mouse models of NAFLD. In contrast, hepatic retinyl palmitate levels (the vitamin A storage form) were significantly elevated in these mice. Transcriptome analysis revealed a hyperdynamic state of hepatic vitamin A metabolism, with enhanced retinol storage and metabolism (upregulated Lrat, Dgat1, Pnpla3, Raldh's and RAR/RXR-target genes) in fatty livers, in conjunction with induced hepatic inflammation (upregulated Cd68, Tnfα, Nos2, Il1β, Il-6) and fibrosis (upregulated Col1a1, Acta2, Tgfβ, Timp1). Autofluorescence analyses revealed prominent vitamin A accumulation in hepatocytes rather than HSC in HFC-fed mice. Palmitic acid exposure increased Lrat mRNA levels in primary rat hepatocytes and promoted retinyl palmitate accumulation when co-treated with retinol, which was not detected for similarly-treated primary rat HSCs.. NAFLD leads to cell type-specific rearrangements in retinol metabolism leading to vitamin A accumulation in hepatocytes. This may promote disease progression and/or affect therapeutic approaches targeting nuclear receptors.

Topics: 17-Hydroxysteroid Dehydrogenases; Animals; Diet, High-Fat; Disease Models, Animal; Disease Progression; Female; Hepatic Stellate Cells; Hepatocytes; Humans; Leptin; Lipid Metabolism; Liver; Male; Mice; Mice, Transgenic; Non-alcoholic Fatty Liver Disease; Phospholipases A2, Calcium-Independent; Retinol-Binding Proteins, Plasma; Vitamin A

Polycystic ovary syndrome (PCOS) affects over 10% of women. Insulin resistance, elevated free fatty acids (FFAs) and increased adiposity are key factors contributing to metabolic dysfunction in PCOS. We hypothesised that aberrant adipogenesis during adolescence, and downstream metabolic perturbations, contributes to the metabolic phenotype of adult PCOS. We used prenatally androgenised (PA) sheep as a clinically realistic model of PCOS. During adolescence, but not during fetal or early life of PA sheep, adipogenesis was decreased in subcutaneous adipose tissue (SAT) accompanied by decreased leptin, adiponectin, and increased FFAs. In adulthood, PA sheep developed adipocyte hypertrophy in SAT paralleled by increased expression of inflammatory markers, elevated FFAs and increased expression of genes linked to fat accumulation in visceral adipose tissue. This study provides better understanding into the pathophysiology of PCOS from puberty to adulthood and identifies opportunity for early clinical intervention to normalise adipogenesis and ameliorate the metabolic phenotype.

Topics: Adipogenesis; Adiponectin; Aging; Animals; Biomarkers; Disease Models, Animal; Fatty Acids; Female; Leptin; Polycystic Ovary Syndrome; RNA, Messenger; Sexual Maturation; Sheep; Subcutaneous Fat; Transcription, Genetic

In amyotrophic lateral sclerosis (ALS), motor neuron degeneration occurs simultaneously with systemic metabolic dysfunction and neuro-inflammation. The fibroblast growth factor 21 (FGF21) plays an important role in the regulation of both phenomena and is a major hormone of energetic homeostasis. In this study, we aimed to determine the relevance of FGF21 pathway stimulation in a male mouse model of ALS (mutated SOD1-G93A mice) by using a pharmacological agonist of FGF21, R1Mab1. Mice (SOD1-WT and mutant SOD1-G93A) were treated with R1Mab1 or vehicle. Longitudinal data about clinical status (motor function, body weight) and biological parameters (including hormonal, immunological, and metabolomics profiles) were collected from the first symptoms to euthanasia at week 20. Multivariate models were performed to identify the main parameters associated with R1Mab1 treatment and to link them with clinical status, and metabolic pathways involving the discriminant metabolites were also determined. A beneficial clinical effect of R1Mab1 was revealed on slow rotarod (p = 0.032), despite a significant decrease in body weight of ALS mice (p < 0.001). We observed a decrease in serum TNF-α, MCP-1, and insulin levels (p = 0.0059, p = 0.003, and p = 0.01, respectively). At 16 weeks, metabolomics analyses revealed a clear discrimination (CV-ANOVA = 0.0086) according to the treatment and the most discriminant pathways, including sphingolipid metabolism, butanoate metabolism, pantothenate and CoA biosynthesis, and the metabolism of amino acids like tyrosine, arginine, proline, glycine, serine, alanine, aspartate, and glutamate. Mice treated with R1Mab1 had mildly higher performance on slow rotarod despite a decrease on body weight and could be linked with the anti-inflammatory effect of R1Mab1. These results indicate that FGF21 pathway is an interesting target in ALS, with a slight improvement in motor function combined with metabolic and anti-inflammatory effects.

Topics: Amyotrophic Lateral Sclerosis; Animals; Antibodies, Monoclonal; Chemokine CCL2; Disease Models, Animal; Fibroblast Growth Factors; Interleukin-6; Leptin; Male; Metabolomics; Mice; Mice, Inbred C57BL; Mice, Transgenic; Resistin; Rotarod Performance Test; Signal Transduction; Transcriptome; Tumor Necrosis Factor-alpha

Leptin is a pleiotropic adipokine that regulates immunometabolism centrally and peripherally. Obese individuals present increased levels of leptin in the blood and develop hypothalamic resistance to this adipokine. Here we investigated whether leptin effects on the periphery are maintained despite the hypothalamic resistance. We previously reported that leptin injection induces in vivo neutrophil migration and peritoneal macrophage activation in lean mice through TNF-α- and CXCL1-dependent mechanisms. However, leptin effects on leukocyte biology during obesity remain unclear. In this study, we investigated the in vivo responsiveness of leukocytes to i.p. injected leptin in mice with diet-induced obesity (DIO). After 14-16 wk, high-sucrose, high-fat diet (HFD)-fed mice showed hyperglycemia, hyperleptinemia, and dyslipidemia compared to normal-sucrose, normal-fat diet (ND). Exogenous leptin did not reduce food intake in DIO mice in contrast to control mice, indicating that DIO mice were centrally resistant to leptin. Regardless of the diet, we found increased levels of TNF-α and CXCL1 in the animals injected with leptin, alongside a pronounced neutrophil migration to the peritoneal cavity and enhanced biogenesis of lipid droplets in peritoneal macrophages. Supporting our in vivo results, data from ex vivo leptin stimulation experiments confirmed hypothalamic resistance in DIO mice, whereas bone marrow cells responded to leptin stimulation through mTOR signaling despite obesity. Altogether, our results show that leukocytes responded equally to leptin in ND- or HFD-fed mice. These results support a role for leptin in the innate immune response also in obesity, contributing to the inflammatory status that leads to the development of metabolic disease.

Topics: Animals; Biomarkers; Cytokines; Diet, High-Fat; Disease Models, Animal; Immunity, Innate; Leptin; Leukocytes; Mice; Obesity; Signal Transduction

Nonalcoholic steatohepatitis (NASH) is a global public health challenge. Overwhelmed oxidative stress and impaired autophagy play an important role in the progression of NASH. Chemerin is an adipokine that has attracted much attention in inflammation and metabolic diseases. This study aimed to examine the effects of chemerin in NASH and its association with oxidative stress and autophagy. In this study, chemerin was found to significantly ameliorate high-fat diet (HFD) induced NASH, marked by decreased serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α), decreased insulin resistance (IR) and leptin resistance (LR), and improved liver lesions. Besides, chemerin prevented enhanced oxidative stress in NASH mice by regulating the antioxidant defense system (MDA downregulation and upregulation of superoxide dismutase (SOD)). Moreover, chemerin contributed to the alleviation of NASH through autophagy activation (p62 downregulation, and upregulation of beclin-1 and LC3). Furthermore, these effects were related to increased phosphorylation of JAK2-STAT3 stimulated by chemerin, which could be inhibited by the CMKLR1 specific inhibitor α-NETA. In conclusion, excess chemerin highly probably ameliorated NASH by alleviating oxidative stress and promoting autophagy, the mechanism responsible for this process was related, at least in part, to the increased phosphorylation of JAK2-STAT3 stimulated by chemerin/CMKLR1. Rh-chemerin may represent promising therapeutic targets in the treatment of NASH.

Topics: Animals; Autophagy; Chemokines; Diet, High-Fat; Disease Models, Animal; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Janus Kinase 2; Leptin; Liver; Mice; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Signal Transduction; STAT3 Transcription Factor

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease, which causes serious health problems worldwide. Hyperleptinemia and inflammatory stress are crucial in the progression of NAFLD. However, the relationship between leptin and immune cells or hepatocytes is still unclear.. This study aimed to clarify the regulatory mechanism of leptin-mediated disease progression through immune cells and its relationship with hepatocytes.. An NAFLD rat model was established to verify the relationship between hyperleptinemia and CD8+ T lymphocytes and cytokines in liver tissue. CD8+ T lymphocytes isolated from blood mononuclear cells were co-cultured with macrophages or hepatocytes stimulated with leptin or treated with granzyme inhibitors to observe target cell morphology and expression of pivotal protein family members.. CD8+ T lymphocyte infiltration positively correlated with blood leptin, IL-18 and IL-1β levels and was related to macrophage recruitment and differentiation in a rat model of NAFLD. Leptin could induce activated caspase-1 and caspase-3 in hepatocytes and trigger hepatocyte pyroptosis.. Leptin may regulate the pyroptotic-like death of macrophages and hepatocytes through CD8+ T lymphocytes in NAFLD progression. The intervention of related pathways of leptin and immune cells may provide a promising strategy for treating NAFLD.

Topics: Animals; CD8-Positive T-Lymphocytes; Cell Death; Disease Models, Animal; Disease Progression; Hepatocytes; Humans; Leptin; Macrophages; Non-alcoholic Fatty Liver Disease; Rats; Rats, Wistar

Alzheimer's disease (AD) is the most common dementia worldwide and is characterized by the presence of senile plaques by amyloid-beta (Aβ) and neurofibrillary tangles of hyperphosphorylated Tau protein. These changes lead to progressive neuronal degeneration and dysfunction, resulting in severe brain atrophy and cognitive deficits. With the discovery that neurogenesis persists in the adult mammalian brain, including brain regions affected by AD, studies of the use of neural stem cells (NSCs) for the treatment of neurodegenerative diseases to repair or prevent neuronal cell loss have increased. Here we demonstrate that leptin administration increases the neurogenic process in the dentate gyrus of the hippocampus as well as in the subventricular zone of lateral ventricles of adult and aged mice. Chronic treatment with leptin increased NSCs proliferation with significant effects on proliferation and differentiation of newborn cells. The expression of the long form of the leptin receptor, LepRb, was detected in the neurogenic niches by reverse qPCR and immunohistochemistry. Moreover, leptin modulated astrogliosis, microglial cell number and the formation of senile plaques. Additionally, leptin led to attenuation of Aβ-induced neurodegeneration and superoxide anion production as revealed by Fluoro-Jade B and dihydroethidium staining. Our study contributes to the understanding of the effects of leptin in the brain that may lead to the development of new therapies to treat Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Proliferation; Disease Models, Animal; Gliosis; Hippocampus; Humans; Lateral Ventricles; Leptin; Mice; Microglia; Neural Stem Cells; Neurogenesis; Plaque, Amyloid; Receptors, Leptin; Superoxides

The increase in obesity worldwide underlines the need for research concerning its metabolic and genetic determinants. One of the most intriguing mechanisms regarding obesity involves leptin and its signaling cascade. Leptin is a key regulator contributing to the fine-tuned crosstalk between nutrient availability and appetite signaling in the central nervous system. Owing to ethical concerns, many human tissues are not readily available and pigs can serve as a good animal model owing to their comparable anatomy, metabolism and genetics. In the present study, we utilized the pig to investigate the possible impact of increased adiposity on the development of alterations within the leptin signaling pathway. Two divergent groups of pigs (High and Low) were defined based on a high and low amount of mesenteric fat. Cortex, cerebellum, hypothalamus, mesenteric, subcutaneous and retroperitoneal fat tissues were used to study changes in expression levels of 94 mRNA transcripts related to the leptin signaling pathway using the qPCR approach. No significant differences were found at the central nervous system, whereas the expression level of STAT1 was reduced in mesenteric fat and leptin (LEP) and interleukin 6 (IL6) were shown to be consistently increased in all analyzed fat compartments from pigs with a high amount of mesenteric fat. These results could imply the onset of leptin and pro-inflammatory cytokine overexpression at early stages of obesity in the analyzed pigs without affecting any key components in the central nervous system. Thus, these pigs showing a unique leptin deregulation in adipose tissues could be a useful translational resource for studies of obesity and leptin resistance phenotypes.

Topics: Adipose Tissue; Adiposity; Animals; Disease Models, Animal; Interleukin-6; Leptin; Obesity; Signal Transduction; STAT1 Transcription Factor; Swine; Swine, Miniature

This study aimed to evaluate the effects of leptin, ghrelin and neuropeptide-Y on the development of nonconvulsive seizure activity and their role on combating oxidative stress and cytokines produced by the systemic immune response in the WAG/Rij rat model for genetic absence epilepsy. Current study showed that all three peptides aggravated spike wave discharges activity and affected the oxidative stress in WAG/Rij rats without any significant changes in the levels of IL-1β, IL-6 and TNF-α except leptin that only induced an increment in the concentration of IL-1β. Our results support the modulatory role of these endogenous peptides on absence epilepsy.

Topics: Animals; Disease Models, Animal; Epilepsy, Absence; Ghrelin; Leptin; Male; Neuropeptide Y; Oxidative Stress; Rats

The human gut microbiota has emerged as a key factor in the development of obesity. Certain probiotic strains have shown anti-obesity effects. The objective of this study was to investigate whether Bifidobacterium longum APC1472 has anti-obesity effects in high-fat diet (HFD)-induced obese mice and whether B. longum APC1472 supplementation reduces body-mass index (BMI) in healthy overweight/obese individuals as the primary outcome. B. longum APC1472 effects on waist-to-hip ratio (W/H ratio) and on obesity-associated plasma biomarkers were analysed as secondary outcomes.. B. longum APC1472 was administered to HFD-fed C57BL/6 mice in drinking water for 16 weeks. In the human intervention trial, participants received B. longum APC1472 or placebo supplementation for 12 weeks, during which primary and secondary outcomes were measured at the beginning and end of the intervention.. B. longum APC1472 supplementation was associated with decreased bodyweight, fat depots accumulation and increased glucose tolerance in HFD-fed mice. While, in healthy overweight/obese adults, the supplementation of B. longum APC1472 strain did not change primary outcomes of BMI (0.03, 95% CI [-0.4, 0.3]) or W/H ratio (0.003, 95% CI [-0.01, 0.01]), a positive effect on the secondary outcome of fasting blood glucose levels was found (-0.299, 95% CI [-0.44, -0.09]).. This study shows a positive translational effect of B. longum APC1472 on fasting blood glucose from a preclinical mouse model of obesity to a human intervention study in otherwise healthy overweight and obese individuals. This highlights the promising potential of B. longum APC1472 to be developed as a valuable supplement in reducing specific markers of obesity.. This research was funded in part by Science Foundation Ireland in the form of a Research Centre grant (SFI/12/RC/2273) to APC Microbiome Ireland and by a research grant from Cremo S.A.

Topics: Adiposity; Adrenal Cortex Hormones; Animals; Bifidobacterium longum; Biomarkers; Body Weight; Diet, High-Fat; Dietary Supplements; Disease Models, Animal; Disease Resistance; Energy Metabolism; Glucose; Host Microbial Interactions; Leptin; Male; Mice; Neuropeptides; Obesity; Probiotics; Rodentia; Translational Research, Biomedical

The role and significance of liver-derived cytokines in cancer-associated cachexia syndrome remain elusive. Here we report that combinatorial counterbalances of the leptin and Igf1 signaling pathways in hepatocellular carcinoma (HCC) models significantly relieves cachexia. Double transgenic zebrafish models of HCC that stably displayed focal lesions, anorexia, and wasting of adipose and muscle tissues were first generated. Knockout of lepr or mc4r from these zebrafish partially restored appetite and exerted moderate or no effect on tissue wasting. However, genetic replenishment of Igf1 in a lepr-mutant background effectively relieved the cachexia-like phenotype without affecting tumor growth. Similarly, administration of napabucasin, a Stat3/Socs3 inhibitor, on the zebrafish HCC model, mammalian cell lines with exogenous IGF1, and two mouse xenograft models restored insulin sensitivity and rescued the wasting of nontumor tissues. Together, these results describe the synergistic impact of leptin and Igf1 normalization in treating certain HCC-associated cachexia as a practical strategy. SIGNIFICANCE: Disruption of leptin signaling with normalized Igf1 expression significantly rescues anorexia, muscle wasting, and adipose wasting in Ras- and Myc-driven zebrafish models of HCC.

Topics: 3T3-L1 Cells; Adipose Tissue; Animals; Animals, Genetically Modified; Benzofurans; Cachexia; Carcinoma, Hepatocellular; Cells, Cultured; Cytokines; Disease Models, Animal; Drug Synergism; HEK293 Cells; Hep G2 Cells; Humans; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Liver; Liver Neoplasms; Mice; Muscular Atrophy; Naphthoquinones; Receptors, Leptin; Signal Transduction; Wasting Syndrome; Xenograft Model Antitumor Assays; Zebrafish

We aimed to determine whether the sodium/glucose cotransporter family member SGLT3, a proposed glucose sensor, is expressed in the intestine and/or kidney, and if its expression is altered in mouse models of obesity and in humans before and after weight-loss surgery.. We used in-situ hybridization and quantitative PCR to determine whether the Sglt3 isoforms 3a and 3b were expressed in the intestine and kidney of C57, leptin-deficient ob/ob, and diabetic BTBR ob/ob mice. Western blotting and immunohistochemistry were also used to assess SGLT3 protein levels in jejunal biopsies from obese patients before and after weight-loss Roux-en-Y gastric bypass surgery (RYGB), and in lean healthy controls.. Sglt3a/3b mRNA was detected in the small intestine (duodenum, jejunum and ileum), but not in the large intestine or kidneys of mice. Both isoforms were detected in epithelial cells (confirmed using intestinal organoids). Expression of Sglt3a/3b mRNA in duodenum and jejunum was significantly lower in ob/ob and BTBR ob/ob mice than in normal-weight littermates. Jejunal SGLT3 protein levels in aged obese patients before RYGB were lower than in lean individuals, but substantially upregulated 6 months post-RYGB.. Our study shows that Sglt3a/3b is expressed primarily in epithelial cells of the small intestine in mice. Furthermore, we observed an association between intestinal mRNA Sglt3a/3b expression and obesity in mice, and between jejunal SGLT3 protein levels and obesity in humans. Further studies are required to determine the possible role of SGLT3 in obesity.

Topics: Adult; Animals; Disease Models, Animal; Down-Regulation; Female; Gastric Bypass; Gene Expression; Humans; Insulin; Insulin Resistance; Intestinal Mucosa; Intestine, Small; Jejunum; Leptin; Male; Mice; Mice, Inbred C57BL; Middle Aged; Obesity; Protein Isoforms; RNA, Messenger; Sodium-Glucose Transport Proteins; Transcriptome; Weight Loss

Previous studies indicate that oxytocin (OT) administration reduces body weight in high-fat diet (HFD)-induced obese (DIO) rodents through both reductions in food intake and increases in energy expenditure. We recently demonstrated that chronic hindbrain [fourth ventricular (4V)] infusions of OT evoke weight loss in DIO rats. Based on these findings, we hypothesized that chronic 4V OT would elicit weight loss in DIO mice. We assessed the effects of 4V infusions of OT (16 nmol/day) or vehicle over 28 days on body weight, food intake, and body composition. OT reduced body weight by approximately 4.5% ± 1.4% in DIO mice relative to OT pretreatment body weight (

Topics: Adipocytes, Brown; Adipocytes, White; Adiposity; Animals; Anti-Obesity Agents; Diet, High-Fat; Disease Models, Animal; Eating; Energy Intake; Infusions, Intraventricular; Leptin; Male; Mice, Inbred C57BL; Obesity; Oxytocin; Rhombencephalon; Thermogenesis; Uncoupling Protein 1; Weight Loss

Topics: Adiponectin; Animals; Breast Neoplasms; Caloric Restriction; Disease Models, Animal; Female; Leptin; Mice; Mice, Inbred C57BL; MicroRNAs; Signal Transduction

Literature reports that insults, such as hormonal disturbances, during critical periods of development may modulate organism physiology and metabolism favoring cardiovascular diseases (CVDs) later in life. Studies show that leptin administration during lactation leads to cardiovascular dysfunction in young and adult male Wistar rats. However, there are sex differences regarding CVD. Thus, the present work aimed to investigate neonatal leptin administration's consequences on different outcomes in female rats at prepubertal and adult age. Newborn Wistar female rats were divided into two groups, Leptin and Control, receiving daily subcutaneous injections of this adipokine (8 μg/100 g) or saline for the first 10 of 21 d of lactation. Nutritional, biometric, hemodynamic, and echocardiographic parameters, as well as maximal effort ergometer performance, were determined at postnatal days (PND) 30 and 150. Leptin group presented lower food intake (p = 0.0003) and higher feed efficiency (p = 0.0058) between PND 21 and 30. Differences concerning echocardiographic parameters revealed higher left ventricle internal diameter (LVID) in systole (p = 0.0051), as well as lower left ventricle ejection fraction (LVEF) (p = 0.0111) and fractional shortening (FS) (p = 0.0405) for this group at PND 30. Older rats treated with leptin during lactation presented only higher LVID in systole (p = 0.0270). Systolic blood pressure and maximum effort ergometer test performance was similar between groups at both ages. These data suggest that nutritional, biometric, and cardiac outcomes due to neonatal leptin administration in female rats are age-dependent.

Topics: Animals; Cardiovascular Diseases; Disease Models, Animal; Female; Lactation; Leptin; Rats; Rats, Wistar; Sex Characteristics; Stroke Volume

Since alterations of the gut microbiota have been shown to play a major role in obesity, probiotics have attracted attention. Our aim was to identify probiotic candidates for the management of obesity using a combination of in vitro and in vivo approaches. We evaluated in vitro the ability of 23 strains to limit lipid accumulation in adipocytes and to enhance the secretion of satiety-promoting gut peptide in enteroendocrine cells. Following the in vitro screening, selected strains were further investigated in vivo, single, or as mixtures, using a murine model of diet-induced obesity. Strain

Topics: Adipocytes; Animals; Bile Acids and Salts; Diet; Disease Models, Animal; Enteroendocrine Cells; Gastrointestinal Hormones; Gastrointestinal Microbiome; Hypothalamus; Leptin; Mice; Obesity; Obesity Management; Probiotics; Receptors, Leptin; Weight Gain

Topics: Adipocytes; Animals; Disease Models, Animal; Fats; Fruit and Vegetable Juices; Ghrelin; Leptin; Molecular Structure; Obesity; Plant Extracts; RNA, Messenger; Vitis; Zebrafish

Hypothalamic inflammation and endoplasmic reticulum (ER) stress are extensively linked to leptin resistance and overnutrition-related diseases. Surgical intervention remains the most efficient long-term weight-loss strategy for morbid obesity, but mechanisms underlying sustained feeding suppression remain largely elusive. This study investigated whether Roux-en-Y gastric bypass (RYGB) interacts with obesity-associated hypothalamic inflammation to restore central leptin signaling as a mechanistic account for post-operative appetite suppression.. RYGB or sham surgery was performed in high-fat diet-induced obese Wistar rats. Sham-operated rats were fed ad libitum or by weight matching to RYGB via calorie restriction (CR) before hypothalamic leptin signaling, microglia reactivity, and the inflammatory pathways were examined to be under the control of gut microbiota-derived circulating signaling.. RYGB, other than CR-induced adiposity reduction, ameliorates hypothalamic gliosis, inflammatory signaling, and ER stress, which are linked to enhanced hypothalamic leptin signaling and responsiveness. Mechanistically, we demonstrate that RYGB interferes with hypothalamic ER stress and toll-like receptor 4 (TLR4) signaling to restore the anorexigenic action of leptin, which most likely results from modulation of a circulating factor derived from the altered gut microbial environment upon RYGB surgery.. Our data demonstrate that RYGB interferes with hypothalamic TLR4 signaling to restore the anorexigenic action of leptin, which most likely results from modulation of a circulating factor derived from the post-surgical altered gut microbial environment.

Topics: Animals; Caloric Restriction; Diet, High-Fat; Disease Models, Animal; Gastric Bypass; Gastrointestinal Microbiome; Hypothalamus; Inflammation; Leptin; Male; Microglia; Neurons; Obesity, Morbid; Rats; Rats, Wistar; Signal Transduction; Treatment Outcome; Weight Loss

Topics: Administration, Intranasal; Analgesics, Opioid; Animals; Disease Models, Animal; Leptin; Mice; Opiate Overdose

Iron overload is tightly connected with metabolic disorders. Excess iron in the adipose and its roles in dyslipidemia are of interest to be identified. In acute iron overload mice receiving intraperitoneal injection of 100 mg/kg/day dextran-iron for 5 days, the epididymis adipose showed a remarkable increase in iron. Serum triglyceride and low-density lipoprotein cholesterol (LDL-C) levels were increased and high-density lipoprotein cholesterol (HDL-C) level was decreased, while serum alkaline phosphatase, aspartate aminotransferase, glucose, and insulin were not affected. The serum-cytokine-microarray showed that adipocytokines, including adiponectin, leptin, and resistin were significantly decreased. Other serum cytokines, including pro-insulin cytokines, inflammatory cytokines, chemokines, and growth factors were not changed, except that ghrelin and chemokine RANTES were increased. Iron overload decreased expressions of adiponectin and leptin both in vivo and in vitro. Intraperitoneal injection of recombinant leptin at 1 μg/g in acute iron overload mice had no significant effects on serum levels of TC, TG, HDL-C, and LDL-C, while intraperitoneal injection of recombinant adiponectin at 3 μg/g partially restored serum TG level through improving activities of lipoprotein lipase and hepatic lipase, but abnormal serum LDL-C and HDL-C were not redressed, suggesting other mechanisms also existed. In conclusion, the adipose responds to iron overload at an early stage to interfere with lipid metabolism by secreting adipocytokines, which may further affect glucose metabolism, inflammation, and other iron overload-induced effects on the body.

Topics: 3T3-L1 Cells; Adipocytes; Adiponectin; Animals; Disease Models, Animal; Dyslipidemias; Iron; Iron Overload; Iron-Dextran Complex; Leptin; Liver; Mice; Mice, Inbred C57BL; Triglycerides

Aging is associated with a reduced ability to identify and discriminate scents, and olfactory dysfunction has been linked to preclinical stages of neurodegenerative diseases in humans. Moreover, emerging evidence suggests that smell-driven behaviors are regulated by hormones like insulin or leptin, and by metabolic parameters like glucose, which in turn may influence monoaminergic neurotransmission in brain areas related to cognition. Several studies have suggested that dietary interventions like caloric restriction (CR) can mitigate the age-induced decline in memory by modifying metabolic parameters and brain monoaminergic levels. The present study explored the effects of CR on age-dependent olfactory memory deficits, as well as their relationship with peripheral leptin, insulin and glucose levels, and brain monoamines. To this end, aged rats (24-months-old) fed on a CR diet or with ad libitum access to food, and adult rats (3-4 months), were trained in an odor discrimination task (ODT). The peripheral plasma levels of insulin, leptin, and glucose, and of monoamines and metabolites/precursors in brain areas related to olfactory learning and memory processes, such as the striatum and frontal cortex (FC), were determined. The data obtained indicated that CR attenuated the age-dependent decline in olfactory sensitivity in old animals fed ad libitum, which was correlated with the performance in ODT retention trial, as well as with leptin plasma levels. CR enhanced dopamine levels in the striatum, while it attenuated the age-related decline in serotonin levels in the striatum and FC. Such findings support a positive effect of CR on age-dependent olfactory sensitivity decline and dysfunctions in brain monoamine levels.

Topics: Aging; Animals; Behavior, Animal; Caloric Restriction; Corpus Striatum; Disease Models, Animal; Dopamine; Leptin; Male; Memory Disorders; Olfactory Perception; Prefrontal Cortex; Rats; Rats, Wistar; Serotonin

Multiple sclerosis (MS) is the most common non-traumatic neurological cause of disability in young adults. Physical activity, particularly exercise training, is an evidence-based approach to managing symptoms, restoring function, and improving overall wellness in people with MS. As well, the use of probiotics can be effective in reducing the damage from inflammation in MS patients.. The study aimed to address changes in leptin, serotonin, and cortisol following eight weeks of aerobic exercise along with probiotic intake in a cuprizone-induced demyelination mouse model of MS.. Mice were exposed to cuprizone for 12 weeks. After 5 weeks, beam and performance tests were performed on them. The mice (n = 5 per group) were randomly divided into five groups: control (C), MS, MS with exercise (MS + Exe), MS with probiotic (MS + Prob), and MS with probiotic and exercise (MS + Prob + Exe). Exercise groups performed aerobic exercises 5 days a week, 10 min in the first week, 20 min in the second week, and 30 min daily in the third week until the eighth week. In the probiotic groups, the mice received probiotic by gavage. They were sacrificed after 3 months. Biochemical and molecular biology analyses were performed.. The results showed that leptin gene expression values in the MS + Prob + Exe, MS + Prob, and MS + Exe groups showed a decrease compared to the MS group, but the reduction was not significant (p > 0.05). Also, the leptin Elisa test in these intervention groups showed a significant decrease (P < 0.05). The serotonin gene expression values in the MS + Prob + Exe, MS + Prob, and MS + Exe groups were increased compared to the MS group, but the increase was not significant (p > 0.05). Furthermore, the serotonin Elisa test in these intervention groups showed a significant increase (P < 0.05). The cortisol Elisa test values in the MS + Exe and MS + Prob groups exhibited a decrease compared to the MS group, but the reduction was not significant (p > 0.05).. Overall, these results suggest that lifestyle interventions can be effective in improving pathological factors in patients with MS.

Topics: Animals; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Female; Hydrocortisone; Inflammation; Leptin; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Physical Conditioning, Animal; Probiotics; Serotonin

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

Obesity-associated asthma is a phenotype of severe asthma. Late-onset, non-eosinophilic and female-dominant phenotype is highly symptomatic and difficult to treat. Leptin, an adipokine, exerts an immunomodulatory effect. IL-33 associated with innate immunity induces type 2 inflammation and is present in adipose tissue. The purpose of this study was to elucidate the pathogenesis of obesity-associated asthma by focusing on the interaction between leptin and IL-33.. In leptin-deficient obese (ob/ob) and wild-type mice, IL-33 was instilled intranasally on three consecutive days. In part of the mice, leptin was injected intraperitoneally prior to IL-33 treatment. The mice were challenged with methacholine, and airway hyperresponsiveness (AHR) was assessed by resistance (Rrs) and elastance (Ers) of the respiratory system using the forced oscillation technique. Cell differentiation, IL-5, IL-13, eotaxin, keratinocyte-derived chemokine (KC) in bronchoalveolar lavage fluid (BALF) and histology of the lung were analyzed. For the in vitro study, NCI-H292 cells were stimulated with IL-33 in the presence or absence of leptin. Mucin-5AC (MUC5AC) levels were measured using an enzyme-linked immunosorbent assay.. Ob/ob mice showed greater Rrs and Ers than wild-type mice. IL-33 with leptin, but not IL-33 alone, enhanced Ers rather than Rrs challenged with methacholine in ob/ob mice, whereas it enhanced Rrs alone in wild-type mice. IL-33-induced eosinophil numbers, cytokine levels in BALF, eosinophilic infiltration around the bronchi, and goblet cell metaplasia were less in ob/ob mice than in wild-type mice. However, leptin pretreatment attenuated these changes in ob/ob mice. MUC5AC levels were increased by co-stimulation with IL-33 and leptin in vitro.. Ob/ob mice show innate AHR. IL-33 with leptin, but not IL-33 alone, induces airway inflammation and goblet cell metaplasia and enhances AHR involving peripheral airway closure. This is presumably accelerated by mucus in ob/ob mice. These results may explain some aspects of the pathogenesis of obesity-associated asthma.

Topics: Animals; Asthma; Bronchi; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Female; Goblet Cells; Inflammation; Interleukin-33; Leptin; Metaplasia; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity

To investigate the response of the infrapatellar fat pad (IFP) to running at different intensities and further explore the underlying mechanisms of these responses under different running-induced loadings.. Animals were randomly assigned into the sedentary (SED), low-intensity running (LIR), medium-intensity running (MIR), and high-intensity running (HIR) groups. The rats in the LIR, MIR, and HIR groups were subjected to an 8-week treadmill running protocol. In each group, the IFP was examined at the baseline and at the 8th week to perform histomorphology, immunohistochemistry, and mRNA expression analyses.. Compared with LIR and MIR, HIR for 8 weeks led to a substantial increase in the surface cellularity (1.67 ± 1.15), fibrosis (1.29 ± 0.36), and vascularity (33.31 ± 8.43) of the IFP but did not increase IFP inflammation or M1 macrophage polarization. Low-to-medium-intensity running resulted in unchanged or decreased fibrosis, vascularity, and surface cellularity in the IFP compared to those of the SED group. Furthermore, serum leptin and visfatin levels were significantly lower in the LIR and MIR groups than in the SED group or the HIR group (P < 0.05).. The effect of running on IFP remodeling was intensity dependent. In contrast to LIR and MIR, HIR increased the fibrosis and vascularity of the IFP. HIR-induced IFP fibrosis was probably due to mechanical stress, rather than pathological proinflammatory M1/M2 polarization.

Topics: Adipose Tissue; Animals; Biomechanical Phenomena; Cartilage, Articular; Disease Models, Animal; Exercise Test; Fibrosis; Inflammation; Knee Joint; Leptin; Male; Nicotinamide Phosphoribosyltransferase; Osteoarthritis, Knee; Patella; Rats, Sprague-Dawley; Running; Stress, Mechanical

This study evaluated the effect of green banana flour (GBF) consumption on obesity-related conditions in mice fed high-fat diets. GBF was prepared using stage 1 green banana pulp, which was dehydrated and milled. Mice were fed a control diet (

Topics: Adiposity; Animals; Diet, High-Fat; Disease Models, Animal; Food, Fortified; Gastrointestinal Microbiome; Inflammation; Interleukin-6; Leptin; Male; Mice, Inbred C57BL; Mice, Obese; Musa; Obesity; Tumor Necrosis Factor-alpha; Weight Gain

Energy restriction is a first therapy in the treatment of obesity, but the underlying biological mechanisms have not been completely clarified. We analyzed the effects of restriction of high-fat diet (HFD) on weight loss, circulating gut hormone levels and expression of hypothalamic neuropeptides. Ten-week-old male Wistar rats (

Topics: Adiposity; Agouti-Related Protein; Animals; Caloric Restriction; Diet, Fat-Restricted; Diet, High-Fat; Dietary Fats; Disease Models, Animal; Eating; Ghrelin; Hypothalamus; Leptin; Male; Metabolic Diseases; Neuropeptide Y; Neuropeptides; Obesity; Pro-Opiomelanocortin; Rats; Rats, Wistar; Weight Loss

Background Hypothalamic leptin-mediated signaling contributes to the exaggerated sympatho-excitation and increased blood pressure in obesity-associated hypertension. The aim of the study was to investigate the roles of energy-sensing enzyme sirtuin1 (Sirt1) and forkhead box protein O1 (FoxO1) on the hypothalamic leptin-mediated high sympathetic nerve activity and inflammation in obesity. Methods and Results Sprague Dawley rats were fed with high-fat diet (HFD) for 12 weeks. In vivo, the potential of Srit1 and FoxO1 in the sympathetic effects of leptin was investigated via siRNA injection to knockdown Sirt1 or FoxO1 gene in the arcuate nucleus (ARCN) of hypothalamus in rats. In vitro, the effects of Sirt1 or FoxO1 on leptin-mediated inflammation were observed in proopiomelanocortin (POMC) and microglial cells. Knockdown Sirt1 by siRNA significantly reduced the renal sympathetic nerve activity (RSNA) and blood pressure responses to leptin injection in the ARCN in the HFD rats. Conversely, knockdown FoxO1 significantly enhanced the RSNA and blood pressure responses to leptin injection in the HFD rats. Knockdown Sirt1 reduced the levels of pro-inflammatory cytokines interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), C1q/TNF-related protein-1 (CTRP1), and immune cell infiltration in the ARCN in the HFD rats. Knockdown FoxO1 significantly increased the level of IL-6 in the ARCN of HFD rats. In cultured hypothalamic POMC and microglial cells, knockdown Sirt1 significantly reduced leptin-induced IL-6 expression, affected the levels of AMP-activated protein kinase (AMPK) and serine/threonine-specific protein kinase (Akt). Knockdown FoxO1 significantly increased leptin-induced IL-6 in both POMC cells and microglial cells. Conclusions These data suggest that both Sirt1 and FoxO1 are the key modulators of leptin signaling in the hypothalamus contributed to the over sympathetic activation and inflammation in obesity.

Topics: Animals; Blotting, Western; Cells, Cultured; Diet, High-Fat; Disease Models, Animal; Energy Metabolism; Gene Expression Regulation; Gene Knockdown Techniques; Hypothalamus; Inflammation; Leptin; Male; Mice; Mice, Knockout; Obesity; Rats; Rats, Sprague-Dawley; RNA; Sirtuin 1

Topics: Animals; Cryptochromes; Disease Models, Animal; Epigenesis, Genetic; Histones; Leptin; Male; Mice; Mice, Obese; Obesity; Signal Transduction

Obesity increases the risk of metabolic disorders, partly through increased oxidative stress. Here, we examined the effects of a dietary micronutrient supplement (consisting of folate, vitamin B6, choline, betaine, and zinc) with antioxidant and methyl donor activities. Male Sprague Dawley rats (3 weeks old, 17/group) were weaned onto control (C) or high-fat diet (HFD) or same diets with added micronutrient supplement (CS; HS). At 14.5 weeks of age, body composition was measured by magnetic resonance imaging. At 21 weeks of age, respiratory quotient and energy expenditure was measured using Comprehensive Lab Animal Monitoring System. At 22 weeks of age, an oral glucose tolerance test (OGTT) was performed, and using fasting glucose and insulin values, Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) was calculated as a surrogate measure of insulin resistance. At 30.5 weeks of age, blood and liver tissues were harvested. Liver antioxidant capacity, lipids and expression of genes involved in lipid metabolism (

Topics: Animals; Antioxidants; Diet, High-Fat; Dietary Supplements; Disease Models, Animal; Gene Expression Regulation; Glucose; Leptin; Lipid Metabolism; Lipids; Liver; Micronutrients; Obesity; Rats, Sprague-Dawley; Thiobarbituric Acid Reactive Substances

Because the world's population is deficient in dietary calcium, it is important to search for new sources of this essential mineral for the bones and the entire body. One of the innovative foods that could act as such a source is pumpkin enriched with calcium lactate by means of osmotic dehydration. Providing the body with easily absorbable calcium may have beneficial effects on the reconstruction of bone tissue. Postmenopausal osteoporosis is associated with body weight and fat mass gain, and the aim of the present study was to evaluate the effect of consuming enriched pumpkin on the levels of adipokines and cytokines produced by the adipose tissue. This study was conducted on 12-month-old female Wistar rats that received nutritional intervention for 12 weeks. After termination of the rats, the levels of leptin, adiponectin, interleukin 31 and interleukin 33 in serum and adipose tissue were determined, and the femurs were examined histopathologically. It was demonstrated that calcium-enriched pumpkin reduced bone marrow femoral adipocytes and also markedly decreased serum leptin levels in groups of rats after ovariectomy, which was associated with a decrease of fat content. Additionally, it seems that calcium-enriched pumpkin may reduce body weight gain often observed after menopause.

Topics: Adiponectin; Adipose Tissue; Animals; Calcium, Dietary; Cucurbita; Disease Models, Animal; Female; Food, Fortified; Humans; Interleukins; Leptin; Osteoporosis, Postmenopausal; Ovariectomy; Rats; Rats, Wistar

Lipodystrophy syndromes (LD) are a heterogeneous group of very rare congenital or acquired disorders characterized by a generalized or partial lack of adipose tissue. They are strongly associated with severe metabolic dysfunction due to ectopic fat accumulation in the liver and other organs and the dysregulation of several key adipokines, including leptin. Treatment with leptin or its analogues is therefore sufficient to reverse some of the metabolic symptoms of LD in patients and in mouse models through distinct mechanisms. Brown adipose tissue (BAT) thermogenesis has emerged as an important regulator of systemic metabolism in rodents and in humans, but it is poorly understood how leptin impacts BAT in LD. Here, we show in transgenic C57Bl/6 mice overexpressing sterol regulatory element-binding protein 1c in adipose tissue (Tg (aP2-nSREBP1c)), an established model of congenital LD, that daily subcutaneous administration of 3 mg/kg leptin for 6 to 8 weeks increases body temperature without affecting food intake or body weight. This is associated with increased protein expression of the thermogenic molecule uncoupling protein 1 (UCP1) and the sympathetic nerve marker tyrosine hydroxylase (TH) in BAT. These findings suggest that leptin treatment in LD stimulates BAT thermogenesis through sympathetic nerves, which might contribute to some of its metabolic benefits by providing a healthy reservoir for excess circulating nutrients.

Topics: Adipose Tissue, Brown; Animals; Disease Models, Animal; Leptin; Lipodystrophy; Male; Mice, Inbred C57BL; Mice, Transgenic; Receptors, LDL; Sterol Regulatory Element Binding Protein 1; Sympathetic Nervous System; Thermogenesis; Tyrosine 3-Monooxygenase; Uncoupling Protein 1

Although bariatric surgery is approved for a woman of child-bearing age with an interest in subsequent pregnancy, reports of in utero growth issues during pregnancy have garnered a closer look at the impact of maternal surgical weight loss on the pre- and postpartum periods. Offspring of dams having received vertical sleeve gastrectomy (VSG) are born small-for-gestational age and have increased risk for metabolic syndrome later in life. Here, we aimed to determine whether the postnatal catch-up growth trajectory of bariatric offspring may be affected by milk composition. Milk samples were collected at postnatal day 15/16 from dams having received VSG surgery and fed a high-fat diet (HFD) (H-VSG), Sham surgery and fed chow (C-Sham), or Sham surgery and fed HFD (H-Sham). Milk obtained from H-VSG dams had elevated glucose (P < 0.05) and significantly reduced triglyceride content (P < 0.01). Milk from H-Sham dams had the lowest amount of milk protein (P < 0.05). Fatty acid composition measured by fractionation was largely not affected by surgery but rather maternal diet. No difference was observed in milk leptin levels; however, insulin, adiponectin, and growth hormone levels were significantly increased in milk from H-VSG animals. H-Sham had the lowest level of immunoglobulin (Ig)A, whereas IgG was significantly reduced in H-VSG. Taken together, the quality of milk from H-VSG dams suggests that milk composition could be a factor in reducing the rate of growth during the lactation period.

Topics: Adiponectin; Animals; Animals, Suckling; Bariatric Surgery; Diet, High-Fat; Disease Models, Animal; Female; Gastrectomy; Glucose; Growth Disorders; Growth Hormone; Humans; Insulin; Lactation; Leptin; Male; Milk; Nutrients; Obesity; Postoperative Period; Rats; Rats, Long-Evans; Weight Loss

The most common injury of preterm infants is periventricular leukomalacia (PVL) and to date there is still no safe and effective treatment. In our previous studies, leptin has been found to have neuroprotective effects on the preterm ischemia-hypoxia brain damage model rats in animal behavior. To gain insight into the neuroprotective mechanisms of leptin on preterm brain damage model rats, we constructed a comparative peptidomic profiling of hippocampal tissue between leptin-treated after model and preterm ischemia-hypoxia brain damage model rats using a stable isobaric labeling strategy involving tandem mass tag reagents, followed by nano liquid chromatography tandem mass spectrometry. We identified and quantified 4164 peptides, 238 of which were differential expressed in hippocampal tissue in the two groups. A total of 150 peptides were up regulated and 88 peptides were down regulated. These peptides were imported into the Ingenuity Pathway Analysis (IPA) and identified putative roles in nervous system development, function and diseases. We concluded that the preterm ischemia-hypoxia brain damage model with leptin treatment induced peptides changes in hippocampus, and these peptides, especially for the peptides associated "microtubule-associated protein 1b (MAP1b), Elastin (Eln), Piccolo presynaptic cytomatrix protein (Pclo), Zinc finger homeobox 3(Zfhx3), Alpha-kinase 3(Alpk3) and Myosin XVA(Myo15a) ", could be candidate bio-active peptides and participate in neuroprotection of leptin. These may advance our current understanding of the mechanism of leptin's neuroprotective effect on preterm brain damage and may be involved in the etiology of preterm brain damage. Meanwhile, we found that repression of ILK signaling pathway plays a significant role in neuroprotection of leptin. A better understanding of the role of ILK signaling pathway in neuroprotective mechanisms will help scientists and researchers to develop selective, safe and efficacious drug for therapy against human nervous system disorders.

Topics: Animals; Animals, Newborn; Brain; Carotid Artery, Common; Cytoskeletal Proteins; Disease Models, Animal; Elastin; Hippocampus; Homeodomain Proteins; Hypoxia-Ischemia, Brain; Leptin; Leukomalacia, Periventricular; Ligation; Microtubule-Associated Proteins; Myosins; Neuropeptides; Neuroprotective Agents; Peptides; Protein Serine-Threonine Kinases; Rats; Signal Transduction

Obesity is a worldwide health problem. Semaphorins are involved in axonal guidance; however, the role of secretory semaphorin 3G (SEMA3G) in regulating adipocyte differentiation remains unclear. Microarray analysis showed that the SEMA3G gene was upregulated in an in vitro model of adipogenesis. In this study, SEMA3G was highly expressed in the white adipose tissue and liver. Analysis of 3T3-L1 cell and primary mouse preadipocyte differentiation showed that SEMA3G mRNA and protein levels were increased during the middle stage of cell development. In vitro experiments also showed that adipocyte differentiation was promoted by SEMA3G; however, SEMA3G inhibition using a recombinant lentiviral vector expressing a specific shRNA showed the opposite results. Mice were fed a chow or high-fat diet (HFD); knockdown of SEMA3G was found to inhibit weight gain, reduce fat mass in the tissues, prevent lipogenesis in the liver tissue, reduce insulin resistance and ameliorate glucose tolerance in HFD mice. Additionally, the effect of SEMA3G on HFD-induced obesity was activated through PI3K/Akt/GSK3β signaling in the adipose tissue and the AMPK/SREBP-1c pathway in the liver. Moreover, the plasma concentrations of SEMA3G and leptin were measured in 20 obese and 20 non-obese human subjects. Both proteins were increased in obese subjects, who also exhibited a lower level of adiponectin and presented with insulin resistance. In summary, we demonstrated that SEMA3G is an adipokine essential for adipogenesis, lipogenesis, and insulin resistance and is associated with obesity. SEMA3G inhibition may, therefore, be useful for treating diet-induced obesity and its complications.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Adult; Animals; Cell Differentiation; Diet, High-Fat; Disease Models, Animal; Female; Gene Knockdown Techniques; Humans; Insulin Resistance; Leptin; Lipogenesis; Male; Mice; Obesity; Semaphorins; Weight Gain

The possibility to use leptin therapeutically for lowering glucose levels in patients with type 1 diabetes has attracted interest. However, earlier animal models of type 1 diabetes are severely catabolic with very low endogenous leptin levels, unlike most patients with diabetes. Here, we aim to test glucose-lowering effects of leptin in novel, more human-like murine models. We examined the glucose-lowering potential of leptin in diabetic models of two types: streptozotocin-treated mice and mice treated with the insulin receptor antagonist S961. To prevent hypoleptinemia, we used combinations of thermoneutral temperature and high-fat feeding. Leptin fully normalized hyperglycemia in standard chow-fed streptozotocin-treated diabetic mice. However, more humanized physiological conditions (high-fat diets or thermoneutral temperatures) that increased adiposity - and thus also leptin levels - in the diabetic mice abrogated the effects of leptin, i.e., the mice developed leptin resistance also in this respect. The glucose-lowering effect of leptin was not dependent on the presence of the uncoupling protein-1 and was not associated with alterations in plasma insulin, insulin-like growth factor 1, food intake or corticosterone but fully correlated with decreased plasma glucagon levels and gluconeogenesis. An important implication of these observations is that the therapeutic potential of leptin as an additional treatment in patients with type 1 diabetes is probably limited. This is because such patients are treated with insulin and do not display low leptin levels. Thus, the potential for a glucose-lowering effect of leptin would already have been attained with standard insulin therapy, and further effects on blood glucose level through additional leptin cannot be anticipated.

Topics: Adipose Tissue, Brown; Adipose Tissue, White; Animals; Blood Glucose; Corticosterone; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Models, Animal; Eating; Glucagon; Gluconeogenesis; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Mice; Mice, Knockout; Oxygen Consumption; Peptides; Pyruvic Acid; Receptor, Insulin; Transcriptome; Uncoupling Protein 1

Both NLRP3 inflammasome and Th17 cells play important roles in the pathogenesis of systemic lupus erythematosus (SLE). Here we tried to investigate whether leptin promotes the differentiation of Th17 cells from lupus mice by activating the NLRP3 inflammasome. Th17 cells induced from MRL/Mp-Fas lpr mice splenocytes under Th17 polarizing condition were treated with leptin at scalar doses during the last 18 h of culture. The mRNA levels of IL-17A, IL-17F, RORγt, IL-1β, IL-18, NLRP3, ASC, and IL-1R1 were detected by quantitative PCR. IL-17A, IL-17F, IL-1β, and IL-18 were tested by ELISA, while the activity of caspase-1 and number of Th17 cells were counted by flow cytometry before/after inhibition of the NLRP3 inflammasome. We found that leptin pushed up the expression of IL-17A, IL-17F, NLRP3, and IL-1β and increased the number of Th17 cells in lupus mice, while the expression of IL-17A, RORγt, and IL-1β and the number of Th17 cells were decreased after inhibition of the NLRP3 inflammasome. Leptin promoted the differentiation of Th17 cells from lupus mice by activating the NLRP3 inflammasome.

Topics: Animals; Cell Differentiation; Cells, Cultured; Cytokines; Disease Models, Animal; Humans; Inflammasomes; Inflammation Mediators; Leptin; Lupus Erythematosus, Systemic; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mice, Inbred MRL lpr; NLR Family, Pyrin Domain-Containing 3 Protein; Th17 Cells

Mulberry leaves are the dry leaves of Morus nigra L. trees, which are widely cultivated in central and southern China. Mulberry has a long history of medicinal use, such as anti-stress, lowering blood glucose and anti-obesity.. Explore the effects of mulberry leaves on fat deposition as well as the underlying mechanisms.. Total of 48 fattening pigs weighing about 70 kg were randomly allotted to normal diet or die supplemented with 5% (w/w) mulberry leave powder. Changes of fat mass, indicated by backfat thickness was measured with Piggyback tester, blood triglyceride and cholesterol were tested using commercial biochemical kits, serum hormones were estimated by ELISA, and leptin-related signaling activity were assessed using western-blot.. Supplementation with Mulberry leaf feed (MF) significantly reduced serum triglyceride and free cholesterol concentrations and increased the ratio of high-density lipoprotein cholesterol (HDL-c) to low-density lipoprotein cholesterol (LDL-c), while serum glucose and free fatty acids remained unchanged. Dietary MF resulted in a significant reduction in the size of adipocytes and backfat thickness (P < 0.05). Accordingly, hormone-sensitive lipase (HSL) in backfat was significantly up-regulated and fatty acid synthase (FAS) was down-regulated by MF supplementation (both P < 0.05). Furthermore, MF supplementation significantly elevated circulating leptin and adiponectin without influencing serum insulin and glucocorticoid. Moreover, significantly higher leptin receptor (Leptin-R) and phosphorylated signal transducer and activator of transcription 3 (p-STAT3) were detected in MF-supplemented pigs, suggesting an enhanced leptin signaling induced by MF in the subcutaneous fat.. Mulberry leaves have obvious anti-obesity effects, providing a theoretical basis for the development of mulberry leaves as a drug against obesity.

Topics: Animals; Diet, High-Fat; Dietary Supplements; Disease Models, Animal; Humans; Leptin; Lipolysis; Morus; Obesity; Plant Leaves; Plant Preparations; Sus scrofa

Benign prostatic hyperplasia (BPH) is a common disease in older men, and there is evidence that obesity is a causal factor. It is currently unclear whether the hormone leptin, which is positively correlated to obesity, is involved in BPH. The aim of this study was to determine the effect of leptin on testosterone-induced BPH in mice and to explore possible underlying mechanisms. Testosterone (3 mg/kg) was injected into wild-type and leptin-deficient ob/ob male mice for 14 consecutive days, and prostate tissues were subjected to various analyses. Additionally, BPH epithelial-1 (BPH-1) cells were treated with leptin to further investigate the underlying mechanisms. Leptin deficiency attenuated testosterone-induced morphological and pathological changes of BPH in mice. Furthermore, leptin deficiency alleviated the process of epithelial-mesenchymal transition (EMT) and suppressed the downregulation of bone morphogenic protein and activin membrane-bound inhibitor (BAMBI) in testosterone-treated mice. The in vitro data revealed that leptin significantly increased the expression of the EMT-associated marker vimentin but decreased the expression of E-cadherin, and that upregulation of BAMBI mitigated the intensity of leptin-induced EMT responses. Our results suggest that leptin can promote EMT in BPH through downregulating BAMBI. Suppressing leptin might be a potential therapeutic approach in preventing BPH development and progression.

Topics: Animals; Cadherins; Cell Line; Disease Models, Animal; Down-Regulation; Epithelial-Mesenchymal Transition; Humans; Leptin; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Prostate; Prostatic Hyperplasia; Signal Transduction; Testosterone; Up-Regulation; Vimentin

Leptin resistance in endothelial cells leads to vascular endothelial dysfunction, which is the beginning and crucial link of atherosclerosis. However, the mechanism of leptin resistance remains obscure. Acid sphingomyelinase (ASM) catalyzes the hydrolysis of sphingomyelin to produce ceramide, which plays an important role in the progression of metabolic and cardiovascular diseases. In this study, we investigated whether ASM could regulate leptin resistance in vascular endothelial cells. We induced endothelial leptin resistance in rat aortic endothelial cells through treatment with palmitic acid (0.3 mM) or knockdown of leptin receptor (Ob-Rb), which resulted in the increase of suppressor of cytokine signaling 3 expression, the decrease of Ob-Rb expression, and signal transducer and activator of transcription 3 (STAT3) phosphorylation at Tyr705. We found that these indicators of leptin resistance were reversed by knockdown of ASM or by the selective ASM inhibitors amitriptyline (AMI) and imipramine (IMI). Supplementation of ceramide inhibited Ob-Rb expression and STAT3 phosphorylation by inhibiting extracellular signal-regulated kinase 1/2 activation. Furthermore, we found that knockdown of ASM enhanced endothelial nitric oxide (NO) synthase activity and NO production, as well as the Akt phosphorylation at ser473, which was regulated by STAT3. High-fat diet (HFD) feeding-induced leptin resistance in rats in vivo; administration of AMI and IMI (10 mg· kg

Topics: Amitriptyline; Animals; Biocatalysis; Cells, Cultured; Disease Models, Animal; Down-Regulation; Endothelial Cells; Enzyme Inhibitors; Imipramine; Leptin; Male; Palmitic Acid; Rats; Rats, Sprague-Dawley; Receptors, Leptin; Sphingomyelin Phosphodiesterase

The ciliopathies Bardet-Biedl syndrome and Alström syndrome are genetically inherited pleiotropic disorders with hyperphagia and obesity as primary clinical features. Methionine aminopeptidase 2 inhibitors (MetAP2i) have been shown in preclinical and clinical studies to reduce food intake, body weight, and adiposity. Here, we investigated the effects of MetAP2i administration in a mouse model of ciliopathy produced by conditional deletion of the Thm1 gene in adulthood. Thm1 conditional knockout (cko) mice showed decreased hypothalamic proopiomelanocortin expression as well as hyperphagia, obesity, metabolic disease, and hepatic steatosis. In obese Thm1-cko mice, 2-week administration of MetAP2i reduced daily food intake and reduced body weight 17.1% from baseline (vs. 5% reduction for vehicle). This was accompanied by decreased levels of blood glucose, insulin, and leptin. Further, MetAP2i reduced gonadal adipose depots and adipocyte size and improved liver morphology. This is the first report to our knowledge of MetAP2i reducing hyperphagia and body weight and ameliorating metabolic indices in a mouse model of ciliopathy. These results support further investigation of MetAP2 inhibition as a potential therapeutic strategy for ciliary-mediated forms of obesity.

Topics: Adaptor Proteins, Signal Transducing; Animals; Blood Glucose; Body Weight; Ciliopathies; Disease Models, Animal; Eating; Enzyme Inhibitors; Fatty Liver; Leptin; Liver; Male; Methionyl Aminopeptidases; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Obesity; Transcriptome

Resveratrol (RES) has a protective effect on osteoarthritis (OA), nevertheless, the underlying mechanisms of RES towards obesity-related OA are still unclear. This study is aimed to determine whether leptin resistant mechanism presents in articular cartilage of obesity-related OA and whether the protective effect of RES is involved in the regulation of leptin signal by affecting suppressor of cytokine signaling 3 (SOCS3). Male C57BL/6 J mice were fed with standard chow diet, high fat diet (HFD) or high fat diet with RES (45 mg/kg.bw) for 22 weeks. Knee joints of mice were evaluated by histological and immunohistochemistry analysis. Serum level of leptin was measured by ELISA. The leptin, leptin receptor (OB-Rb), SOCS3 mRNA expression and JAK2, STAT3, OB-Rb and SOCS3 protein expression in cartilage were determined by real-time RT-PCR and western blot. In addition, SW1353 cells were pretreated with or without AG490, and stimulated with leptin in the presence or absence of RES to detect JAK2, STAT3, matrix metalloproteinase-13 (MMP-13) and SOCS3 expression. We found that HFD could induce obesity-related OA and RES prevented its progression. Serum leptin and mRNA expression in cartilage was up-regulated by HFD, while RES ameliorated the elevation. Besides, RES significantly inhibited the JAK2/STAT3 signaling pathway in cartilage, as well as SOCS3. In in vitro study, RES exhibited the same effect in SW1353 cells which stimulated with leptin. In conclusion, no significant leptin resistance existed in cartilage of obesity-related OA and the inhibitory effect of RES on obesity-related OA via alleviating JAK2/STAT3 signaling pathway is independent of SOCS3.

Topics: Animals; Cell Line, Tumor; Diet, High-Fat; Disease Models, Animal; Disease Progression; Humans; Janus Kinase 2; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Osteoarthritis; Resveratrol; Signal Transduction; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein

Leptin resistance and co-existing insulin resistance is considered as hallmark of diet-induced obesity. Here, we investigated therapeutic potential of hesperidin to improve leptin and insulin resistance using high fat diet (HFD)-induced obese experimental animal model. We also performed in silico studies to validate therapeutic effectiveness of hesperidin by performing protein-ligand docking and molecular dynamics simulation studies. Group 1 was identified as control group receiving vehicle only. Group 2 was marked as non-treated group receiving 60% HFD. While, other groups were treated daily with orlistat (120 mg/kg/d), hesperidin (55 mg/kg/d), combination of hesperidin (55 mg/kg/d) + orlistat (120 mg/kg/d). Hesperidin alone (P<0.001) and particularly in combination with orlistat (P<0.001), resulted in controlling the levels of HFD-altered biomarkers including random and fasting state of glycemia, leptin and insulin resistance. Similarly, hesperidin also improved the serum and tissue levels of leptin, interleukin-6 and tumor necrosis factor-alpha more significantly (P<0.05) when compared with that of orlistat. These results were found to be in accordance with the results of histopathological examination of pancreas, liver and adipose tissues. In-silico studies also proved that hesperidin binds to leptin receptor with higher affinity as compared to that of orlistat and induces the favorable variations in geometrical conformation of leptin receptor to promote its association with leptin which may lead to the cascades of reactions culminating the lipolysis of fats that may ultimately lead to cure obesity. The results of this study may be a significant expectation among the forthcoming treatment strategies for leptin and insulin resistance.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Obesity Agents; Diet, High-Fat; Disease Models, Animal; Drug Therapy, Combination; Hesperidin; Hyperlipidemias; Inflammation; Insulin Resistance; Leptin; Molecular Docking Simulation; Molecular Dynamics Simulation; Obesity; Orlistat; Rats, Wistar

Levels of weight gain have hit an epidemic level with rates of overweight and obesity diagnoses topping all-time highs. Elevated body weight has been linked to increased rates of cardiac problems, blood pressure issues, and risk of developing type 2 diabetes. Leptin, a hormone produced by the body that is involved in energy balance by inhibiting hunger has been implicated as an underlying mechanism that differentially contributes to food-seeking motivation. Using a scientifically validated animal model of obesity, the fatty Zucker rat, which has mutated leptin receptor genes, leptin's role in behavioral motivation can be assessed. Animals were on a 2 -h food access restriction with one-hour access to rewards in session and one hour of free-feeding access. Pre-session and post-session food access differences were evaluated in looking at motivation for food rewards during satiation while responding on differing levels of fixed-ratio schedules. The results showed robust differential behavior from satiation, demonstrating a basis for a biological mechanism involving leptin sensitivity that could underlie obesity. Although further experimentation is needed, understanding leptin could help bridge the gap in our understanding of satiation and non-satiation.

Topics: Animals; Behavior, Animal; Disease Models, Animal; Feeding Behavior; Leptin; Motivation; Obesity; Rats; Rats, Zucker; Receptors, Leptin; Satiation; Satiety Response

Consumption of poor nutrients diets is associated with fat tissue expansion and with a central and peripheral low-grade inflammation. In this sense, the microglial cells in the central nervous system are activated and release pro-inflammatory cytokines that up-regulate the inducible nitric oxide synthase (iNOS), promoting Nitric Oxide (NO) production. The excess of NO has been proposed to facilitate anxious states in humans and rodents. We evaluated whether consumption of a high-refined carbohydrate-containing diet (HC) in mice induced anxiety-like behavior in the Novelty Suppressed Feeding Test (NFST) trough facilitation of NO, in the prefrontal cortex (PFC) and hippocampus (HIP). We also verified if HC diet induces activation of microglial cells, alterations in cytokine and leptin levels in such regions. Male BALB/c mice received a standard diet or a HC diet for 3 days or 12 weeks. The chronic consumption of HC diet, but not acute, induced an anxiogenic-like effect in the NSF test and an increase in the nitrite levels in the PFC and HIP. The preferential iNOS inhibitor, aminoguanidine (50 mg/kg, i.p.), attenuated such effects. Moreover, microglial cells in the HIP and PFC were activated after chronic consumption of HC diet. Finally, the expression of iNOS in the PFC and TNF, IL6 and leptin levels in HIP were higher in chronically HC fed mice. Taken together, our data reinforce the notion that diets containing high-refined carbohydrate facilitate anxiety-like behavior, mainly after a long period of consumption. The mechanisms involve, at least in part, the augmentation of neuroinflammatory processes in brain areas responsible for anxiety control.

Topics: Adipose Tissue; Animals; Anxiety; Behavior, Animal; Dietary Carbohydrates; Disease Models, Animal; Guanidines; Hippocampus; Inflammation; Leptin; Male; Mice; Mice, Inbred BALB C; Nitric Oxide Synthase Type II; Nitrites; Prefrontal Cortex

Topics: Adipose Tissue, Brown; Adipose Tissue, White; Animals; Congenital Hypothyroidism; Disease Models, Animal; Female; Insulin; Leptin; PPAR gamma; Sheep; Signal Transduction; Thermogenesis; Transcriptome; Uncoupling Protein 1

Many animal models that are currently used in appetite and obesity research share at least some main features of human obesity and its comorbidities. Hence, even though no animal model replicates all aspects of "common" human obesity, animal models are imperative in studying the control of energy balance and reasons for its imbalance that may eventually lead to overt obesity. The most frequently used animal models are small rodents that may be based on mutations or manipulations of individual or several genes and on the exposure to obesogenic diets or other manipulations that predispose the animals to gaining or maintaining excessive weight. Characteristics include hyperphagia or changes in energy metabolism and at least in some models the frequent comorbidities of obesity, like hyperglycemia, insulin resistance, or diabetes-like syndromes. Some of the most frequently used animal models of obesity research involve animals with monogenic mutations of the leptin pathway which in fact are useful to study specific mechanistic aspects of eating controls, but typically do not recapitulate "common" obesity in the human population. Hence, this review will mention advantages and disadvantages of respective animal models in order to build a basis for the most appropriate use in biomedical research.

Topics: Animals; Animals, Genetically Modified; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet; Disease Models, Animal; Leptin; Mice; Mice, Mutant Strains; Obesity; Rats; Rats, Mutant Strains

Aberration in leptin expression is one of the most frequent features in the onset and progression of obesity, but the underlying mechanisms are still unclear and need to be clarified. This study investigated the effects of the absence of gut microbiota on body weight and the expression and promoter methylation of the leptin. Male C57 BL/6 J germ-free (GF) and conventional (CV) mice (aged 4-5 weeks) were fed either a normal-fat diet (NFD) or a high-fat diet (HFD) for 16 weeks. Six to eight mice from each group, at 15 weeks, were administered exogenous leptin for 7 d. Leptin expression and body weight gain in GF mice were increased by NFD with more CpG sites hypermethylated at the leptin promoter, whereas there was no change with HFD, compared with CV mice. Adipose or hepatic expression of genes associated with fat synthesis (Acc1, Fas and Srebp-1c), hydrolysis and oxidation (Atgl, Cpt1a, Cpt1c, Ppar-α and Pgc-1α) was lower, and hypothalamus expression of Pomc and Socs3 was higher in GF mice than levels in CV mice, particularly with NFD feeding. Exogenous leptin reduced body weight in both types of mice, with a greater effect on CV mice with NFD. Adipose Lep-R expression was up-regulated, and hepatic Fas and hypothalamic Socs3 were down-regulated in both types of mice. Expression of fat hydrolysis and oxidative genes (Atgl, Hsl, Cpt1a, Cpt1c, Ppar-α and Pgc-1α) was up-regulated in CV mice. Therefore, the effects of gut microbiota on the leptin expression and body weight were affected by dietary fat intake.

Topics: Adipose Tissue; Adiposity; Animals; Body Weight; Diet, High-Fat; Disease Models, Animal; Gastrointestinal Microbiome; Hypothalamus; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Obesity; Pro-Opiomelanocortin; Receptors, Leptin

Leptin stimulates the sympathetic nervous system (SNS), energy expenditure, and weight loss; however, the underlying molecular mechanism remains elusive. Here, we uncover Sh2b1 in leptin receptor (LepR) neurons as a critical component of a SNS/brown adipose tissue (BAT)/thermogenesis axis. LepR neuron-specific deletion of Sh2b1 abrogates leptin-stimulated sympathetic nerve activation and impairs BAT thermogenic programs, leading to reduced core body temperature and cold intolerance. The adipose SNS degenerates progressively in mutant mice after 8 weeks of age. Adult-onset ablation of Sh2b1 in the mediobasal hypothalamus also impairs the SNS/BAT/thermogenesis axis; conversely, hypothalamic overexpression of human SH2B1 has the opposite effects. Mice with either LepR neuron-specific or adult-onset, hypothalamus-specific ablation of Sh2b1 develop obesity, insulin resistance, and liver steatosis. In contrast, hypothalamic overexpression of SH2B1 protects against high fat diet-induced obesity and metabolic syndromes. Our results unravel an unrecognized LepR neuron Sh2b1/SNS/BAT/thermogenesis axis that combats obesity and metabolic disease.

Topics: Adaptor Proteins, Signal Transducing; Adipose Tissue, Brown; Animals; Diet, High-Fat; Disease Models, Animal; Fatty Liver; Female; Gene Knock-In Techniques; Gene Knockout Techniques; Humans; Hypothalamus; Insulin Resistance; Leptin; Liver; Male; Mice; Mice, Transgenic; Neurons; Obesity; Receptors, Leptin; Sympathetic Nervous System; Thermogenesis

Long-term caloric restriction (CR) has been shown to be beneficial to various tissues and organs. In contrast, CR exerts differential effects on bone, which could be due in part to the nature of the protein regime utilized. Male Sprague Dawley rats (8-month-old) were subjected for 12 months to 40% CR in macronutrients and compared with rats fed ad libitum for the same period. Casein- and soy-fed groups were compared. There was a significant decrease in bone quality in both CR groups, which was independent of the source of protein in the diet. In contrast, the group fed soy protein ad libitum showed better bone quality and higher levels of bone formation compared with casein-fed animals. Notably, bone marrow adipocytes were not mobilized upon CR as demonstrated by an absence of change in adipocyte number and tissue expression of leptin. This study demonstrates that the negative effect of CR on bone quality could not be prevented by the most common protein regimes.

Topics: Adipocytes; Adipose Tissue; Aging; Animals; Bone Marrow; Caloric Restriction; Caseins; Dietary Proteins; Disease Models, Animal; Leptin; Male; Osteogenesis; Osteoporosis; Rats; Rats, Sprague-Dawley; Soybean Proteins

Obesity is associated with the activation of cellular responses, such as endoplasmic reticulum (ER) stress. Here, we show that leptin-deficient ob/ob mice display elevated hypothalamic ER stress as early as postnatal day 10, i.e., prior to the development of obesity in this mouse model. Neonatal treatment of ob/ob mice with the ER stress-relieving drug tauroursodeoxycholic acid (TUDCA) causes long-term amelioration of body weight, food intake, glucose homeostasis, and pro-opiomelanocortin (POMC) projections. Cells exposed to ER stress often activate autophagy. Accordingly, we report that in vitro induction of ER stress and neonatal leptin deficiency in vivo activate hypothalamic autophagy-related genes. Furthermore, genetic deletion of autophagy in pro-opiomelanocortin neurons of ob/ob mice worsens their glucose homeostasis, adiposity, hyperphagia, and POMC neuronal projections, all of which are ameliorated with neonatal TUDCA treatment. Together, our data highlight the importance of early life ER stress-autophagy pathway in influencing hypothalamic circuits and metabolic regulation.

Topics: Adiposity; Animals; Antiviral Agents; Autophagy; Autophagy-Related Protein 7; Body Weight; Cholagogues and Choleretics; Disease Models, Animal; Eating; Endoplasmic Reticulum Stress; Energy Metabolism; Feeding Behavior; Homeostasis; Hyperphagia; Hypothalamus; Leptin; Male; Metabolic Diseases; Mice; Mice, Inbred Strains; Mice, Knockout; Neuroendocrinology; Neurogenesis; Obesity; Pro-Opiomelanocortin; Taurochenodeoxycholic Acid

Obesity is associated with infertility, decreased ovarian performance and lipotoxicity. However, little is known about the aetiology of these reproductive impairments. Here, we hypothesise that the majority of changes in ovarian physiology in diet-induced obesity (DIO) are a consequence of transcriptional changes downstream of altered leptin signalling. Therefore, we investigated the extent to which leptin signalling is altered in the ovary upon obesity with particular emphasis on effects on cumulus cells (CCs), the intimate functional companions of the oocyte. Furthermore, we used the pharmacological hyperleptinemic (LEPT) mouse model to compare transcriptional profiles to DIO.. Mice were subjected to DIO for 4 and 16 weeks (wk) and leptin treatment for 16 days, to study effects in the ovary in components of leptin signalling at the transcript and protein levels, using Western blot, Real-time PCR and immunostaining. Furthermore, we used low-cell RNA sequencing to characterise changes in the transcriptome of CCs in these models.. In the DIO model, obesity led to establishment of ovarian leptin resistance after 16 wk high fat diet (HFD), as evidenced by increases in the feedback regulator suppressor of cytokine signalling 3 (SOCS3) and decreases in the positive effectors phosphorylation of tyrosine 985 of leptin receptor (ObRb-pTyr985) and Janus kinase 2 (pJAK2). Transcriptome analysis of the CCs revealed a complex response to DIO, with large numbers and distinct sets of genes deregulated at early and late stages of obesity; in addition, there was a striking correlation between body weight and global transcriptome profile of CCs. Further analysis indicated that the transcriptome profile in 4 wk HFD CCs resembled that of LEPT CCs, in the upregulation of cellular trafficking and impairment in cytoskeleton organisation. Conversely, after 16 wk HFD CCs showed expression changes indicative of augmented inflammatory responses, cell morphogenesis, and decreased metabolism and transport, mainly as a consequence of the physiological changes of obesity.. Obesity leads to ovarian leptin resistance and major time-dependent changes in gene expression in CCs, which in early obesity may be caused by increased leptin signalling in the ovary, whereas in late obesity are likely to be a consequence of metabolic changes taking place in the obese mother.

Topics: Animals; Cumulus Cells; Disease Models, Animal; Female; Gene Expression Regulation; Inflammation; Janus Kinase 2; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Oocytes; Ovary; Phosphorylation; Receptors, Leptin; RNA-Seq; Signal Transduction; Suppressor of Cytokine Signaling 3 Protein

Type 2 diabetes and obesity are associated with back pain in juveniles and adults and are implicated in intervertebral disc (IVD) degeneration. Hypercaloric Western diets are associated with both obesity and type 2 diabetes. The objective of this study was to determine if obesity and type 2 diabetes result in spinal pathology in a sex-specific manner using in vivo diabetic and dietary mouse models. Leptin is an appetite-regulating hormone, and its deficiency leads to polyphagia, resulting in obesity and diabetes. Leptin is also associated with IVD degeneration, and increased expression of its receptor was identified in degenerated IVDs. We used young, leptin receptor deficient (Db/Db) mice to mimic the effect of diet and diabetes on adolescents. Db/Db and Control mice were fed either Western or Control diets, and were sacrificed at 3 months of age. Db/Db mice were obese, while only female mice developed diabetes. Female Db/Db mice displayed altered IVD morphology, with increased intradiscal notochordal band area, suggesting delayed IVD cell proliferation and differentiation, rather than IVD degeneration. Motion segments from Db/Db mice exhibited increased failure risk with decreased torsional failure strength. Db/Db mice also had inferior bone quality, which was most prominent in females. We conclude that obesity and diabetes due to impaired leptin signaling contribute to pathological changes in vertebrae, as well as an immature IVD phenotype, particularly of females, suggesting a sex-dependent role of leptin in the spine.

Topics: Animals; Diabetes Mellitus, Type 2; Diet, Western; Disease Models, Animal; Female; Humans; Intervertebral Disc; Intervertebral Disc Degeneration; Leptin; Male; Mice; Mice, Inbred NOD; Obesity; Receptors, Leptin; Sex Characteristics; Signal Transduction; Spine

Background Marfan syndrome (MFS) is a genetically transmitted connective tissue disorder characterized by aortic root dilatation, dissection, and rupture. Molecularly, MFS pathological features have been shown to be driven by increased angiotensin II in the aortic wall. Using an angiotensin II-driven aneurysm mouse model, we have recently demonstrated that local inhibition of leptin activity restricts aneurysm formation in the ascending and abdominal aorta. As we observed de novo leptin synthesis in the ascending aortic aneurysm wall of patients with MFS, we hypothesized that local counteracting of leptin activity in MFS may also prevent aortic cardiovascular complications in this context. Methods and Results

Topics: Animals; Aorta; Aortic Aneurysm; Dilatation, Pathologic; Disease Models, Animal; Fibrillin-1; Hormone Antagonists; Leptin; Male; Marfan Syndrome; Mice, Mutant Strains; Signal Transduction; Systole; Vascular Remodeling; Ventricular Dysfunction, Left; Ventricular Function, Left

Topics: Acer; Adipokines; Adiponectin; Administration, Ophthalmic; Alzheimer Disease; Amyloid Precursor Protein Secretases; Amyloidosis; Animals; Brain; Diet, High-Fat; Disease Models, Animal; Leptin; Obesity; Phytotherapy; Plant Extracts; Presenilin-1; Quercetin

There is an increased risk for obese patients with chronic low-grade inflammation to develop depression. Stress induces microglial activation and neuroinflammation that play crucial roles in the pathogenesis of depression. Peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear transcription factor, regulates microglial polarization and neuroinflammation. Our study aimed to investigate the role of PPARγ in the development of depressive symptoms and neuroinflammation induced by chronic unpredictable mild stress (CUMS) in wild-type/C57BL/6J (wt) and leptin-deficient (ob/ob) mice.. CUMS was used to build a depression model with wt and ob/ob mice. Depressive-like behaviors were evaluated by sucrose preference test, open field test, tail suspension test, and Morris water maze test. Cytokines, the activated microglial state, and nuclear factor-κB (NF-κB) and PPARγ expression in the prefrontal cortex (PFC) and hippocampus (HIP) were examined by enzyme-linked immunosorbent assay (ELISA), immunofluorescence, and western blotting. Additionally, pioglitazone, an agonist of PPARγ, was used as a treatment intervention.. After CUMS, ob/ob mice exhibited severe behavioral disorders and spatial memory impairment, and higher levels of pro-inflammatory cytokines, M1/M2 ratios, and NF-κB activation, as well as lower levels of anti-inflammatory cytokines and PPARγ expression in the PFC and HIP compared to wt mice. Administration of pioglitazone relieved these alterations in wt and ob/ob mice.. CUMS was able to induce severe depressive-like behaviors, neuroinflammation, and reduced expression of PPARγ in ob/ob mice as compared to wt mice. This suggests that PPARγ mediates the microglial activation phenotype, which might be related to the susceptibility of stressed ob/ob mice to develop depressive disorder.

Topics: Animals; Behavior, Animal; Cognitive Dysfunction; Cytokines; Depression; Disease Models, Animal; Hippocampus; Hypoglycemic Agents; Inflammation; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Microglia; Obesity; Phenotype; Pioglitazone; PPAR gamma; Prefrontal Cortex; Stress, Psychological

Estrogen is involved in lipid metabolism. Menopausal women with low estrogen secretion usually gain weight and develop steatosis associated with abnormal lipid metabolism. A previous study showed that blackcurrant (

Topics: Adipocytes; Adiponectin; Alanine Transaminase; Animals; Aspartate Aminotransferases; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Diet, High-Fat; Dietary Supplements; Disease Models, Animal; Dyslipidemias; Fatty Liver; Female; gamma-Glutamyltransferase; Intra-Abdominal Fat; Leptin; Lipid Metabolism; Liver; Menopause; Non-alcoholic Fatty Liver Disease; Ovariectomy; Phytoestrogens; Plant Extracts; Rats; Rats, Sprague-Dawley; Ribes; Triglycerides

This study investigated the effects of leptin on intestinal flora and inflammation in mice with high-fat diet (HFD)-induced obesity.. Mice were fed an HFD for 8 weeks; some were concurrently administered oral leptin for 4 weeks. Pathological changes in adipose tissue were detected using hematoxylin-eosin staining; endotoxin content in adipose tissue was measured by enzyme-linked immunosorbent assay. Intestinal flora were characterized by 16S bacterial rDNA sequencing. Levels of Toll-like receptor 4 (TLR4), nuclear factor-κB inhibitor α (IκB-α), and phosphorylated c-Jun N-terminal kinase (p-JNK) were detected by western blotting.. Mice in the HFD group exhibited weight gain, elevated endotoxin content, and adipocyte hypertrophy, compared with the non-obese control group. Moreover, abundance of bacteria in the. Leptin administration improved intestinal flora dysfunction and inflammation in mice with HFD-induced obesity.

Topics: Adipose Tissue; Administration, Oral; Animals; Diet, High-Fat; Disease Models, Animal; Endotoxins; Gastrointestinal Microbiome; Humans; Inflammation; Leptin; Male; Mice; Obesity

High altitude hypobaric hypoxia environment impairs male's reproductive function. Leptin is an adipose tissue-derived hormone which regulates body weight homeostasis. Its receptor (LepR) has been found in all levels of male reproductive axis, indicating that it can affect male reproductive system in a direct or (and) indirect way. However, the role of leptin signaling in hypobaric hypoxia induced male reproductive dysfunction remains to be elucidated. In this study, we investigated the changes of leptin levels in male SD rats in stimulated altitude of 5500 m hypobaric hypoxia environment and their effects on the hypothalamus-pituitary-gonad axis (HPG axis). A hypoxia animal model was established using a hypobaric hypoxia chamber. Rats were divided randomly into 1, 7, 14, 28-day hypoxia group, recovery group (14 days hypoxia+14 days normoxia) and their control groups. Hypoxia groups displayed obvious changes of testicular and epididymis index compared to control groups. The total number of sperm and sperm motility rate decreased dramatically, while sperm deformity rate increased in hypoxia groups. The flow cytometry analysis showed that the percentage of haploid in 1-day, 7-day and 28-day hypoxia groups increased while the proportion of diploid decreased in 14-day and 28-day hypoxia group. TUNEL staining showed that the testis cells apoptosis index (AI) of hypoxia groups increased significantly, and the apoptosis of cells mainly focus on spermatogonia and spermatocytes. The expression of GnRH in hypothalamus decreased dramatically under hypoxia condition, accompanied with the reduction of serum testosterone (T) level in 1-day and 28-day hypoxia groups and free-testosterone level (FT) in 1-day and 14-day hypoxia groups. Importantly, ELISA analysis showed that serum leptin level decreased in 7-day hypoxia groups and acylated-ghrelin, gastrin also changed, accompanying with reduction of LepR in hypothalamus in hypoxia groups. Immunohistochemical staining exhibited increased leptin and LepR in testis under hypobaric hypoxia conditions. Our results suggested that simulated high altitude hypobaric hypoxia environment decreased male reproductive function, depressed HPG axis activity and altered the serum concentration of hormones related to food intake in adult male rats. Additionally, hypobaric hypoxia induced the leptin-LepR expression in adult male rats' testis, suggesting leptin-LepR signaling may mediate hypoxia-induced impairment in male rats' reproductive

Topics: Altitude; Altitude Sickness; Animals; Apoptosis; Disease Models, Animal; Humans; Hypothalamo-Hypophyseal System; Hypoxia; Leptin; Male; Rats; Rats, Sprague-Dawley; Receptors, Leptin; Reproduction; Sperm Count; Sperm Motility; Spermatogenesis; Testis

Obesity caused by overeating plays a pivotal role in the development of type 2 diabetes. However, it remains poorly understood how individual meal size differences are determined before the development of obesity. Here, we investigated the underlying mechanisms in determining spontaneous food intake in newly established Oikawa-Nagao Diabetes-Prone (ON-DP) and Diabetes-Resistant (ON-DR) mice.. Food intake and metabolic phenotypes of ON-DP and ON-DR mice under high-fat-diet feeding were compared from 5 weeks to 10 weeks of age. Differences in leptin status at 5 weeks of age were assessed between the two mouse lines. Adipose tissue explant culture was also performed to evaluate leptin production capacity in vitro.. ON-DP mice showed spontaneous overfeeding compared with ON-DR mice. Excessive body weight gain and fat accumulation in ON-DP mice were completely suppressed to the levels seen in ON-DR mice by pair-feeding with ON-DR mice. Deterioration of glucose tolerance in ON-DP mice was also ameliorated under the pair-feeding conditions. While no differences were seen in body weight and adipose tissue mass when comparing the two mouse lines at 5 weeks of age, the ON-DP mice had lower plasma leptin concentrations and adipose tissue leptin gene expression levels. In accordance with peripheral leptin status, ON-DP mice displayed lower anorexigenic leptin signalling in the hypothalamic arcuate nucleus when compared with ON-DR mice without apparent leptin resistance. Explant culture studies revealed that ON-DP mice had lower leptin production capacity in adipose tissue. ON-DP mice also displayed higher DNA methylation levels in the leptin gene promoter region of adipocytes when compared with ON-DR mice.. The results suggest that heritable lower leptin production capacity plays a critical role in overfeeding-induced obesity and subsequent deterioration of glucose tolerance in ON-DP mice. Leptin production capacity in adipocytes, especially before the development of obesity, may have diagnostic potential for predicting individual risk of obesity caused by overeating and future onset of type 2 diabetes. Graphical abstract.

Topics: Adipocytes; Adiponectin; Animals; CCAAT-Enhancer-Binding Proteins; Circadian Rhythm; Diabetes Mellitus, Type 2; Disease Models, Animal; Disease Susceptibility; Eating; Fatty Acid-Binding Proteins; Feeding Behavior; Glucose Tolerance Test; Hyperphagia; Leptin; Locomotion; Mice; Obesity; PPAR gamma

Respiratory depression is the main cause of morbidity and mortality associated with opioids. Obesity increases opioid-related mortality, which is mostly related to comorbid obstructive sleep apnea. Naloxone, a μ-opioid receptor blocker, is an effective antidote, but it reverses analgesia. Like humans with obesity, mice with diet-induced obesity hypoventilate during sleep and develop obstructive sleep apnea, which can be treated with intranasal leptin. We hypothesized that intranasal leptin reverses opioid-induced sleep-disordered breathing in obese mice without decreasing analgesia. To test this hypothesis, mice with diet-induced obesity were treated with morphine at 10 mg/kg subcutaneously and with leptin or placebo intranasally. Sleep and breathing were recorded by barometric plethysmography, and pain sensitivity was measured by the tail-flick test. Excitatory postsynaptic currents were recorded

Topics: Administration, Intranasal; Analgesia; Analgesics, Opioid; Animals; Disease Models, Animal; Enkephalins; Excitatory Postsynaptic Potentials; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Morphine; Motor Neurons; Receptors, Opioid, mu; Respiration; Sleep; Sleep Apnea Syndromes; Synaptic Transmission

Alström syndrome is a rare recessive genetic disease caused by mutations in ALMS1, which encodes a protein that is related to cilia function and intracellular endosome trafficking. The syndrome has been linked to impaired glucose metabolism and CKD. Polymorphisms in Alms1 have likewise been linked to CKD, but little is known about the modification of the phenotype by environmental factors.. To gain further insights, the fat aussie (foz) mouse strain, a genetic murine model of Alström syndrome, was exposed to a normal chow (NC) or to a Western diet (WD, 20% fat, 34% sucrose by weight, and 0.2% cholesterol) and renal outcomes were measured.. Body weight and albuminuria were higher in foz than in wild-type (WT) mice on both diets but WD significantly increased the difference. Measurement of plasma creatinine and cystatin C indicated that glomerular filtration rate was preserved in foz versus WT independent of diet. Renal markers of injury, inflammation, and fibrosis were similar in both genotypes on NC but significantly greater in foz than in WT mice on WD. A glucose tolerance test performed in foz and WT mice on WD revealed similar basal blood glucose levels and subsequent blood glucose profiles.. WD sensitizes a murine model of Alström syndrome to kidney injury, inflammation, and fibrosis, an effect that may not be solely due to effects on glucose metabolism. Polymorphisms in Alms1 may induce CKD in part by modulating the deleterious effects of high dietary fat and sucrose on kidney outcome.

Topics: Alstrom Syndrome; Animals; Blood Glucose; Cell Cycle Proteins; Cilia; Diet, Western; Disease Models, Animal; Fibrosis; Glomerular Filtration Rate; Glycosuria; Kidney; Kidney Tubules; Leptin; Male; Mice; Nephritis; Obesity; Organ Size; Renin

Topics: Acyclic Monoterpenes; Administration, Inhalation; Animals; Anti-Obesity Agents; Blood Preservation; Blood Pressure; Body Weight; Disease Models, Animal; Eating; Leptin; Lipoproteins, HDL; Lipoproteins, LDL; Male; Obesity; Oils, Volatile; Phytotherapy; Pogostemon; Rats, Sprague-Dawley

Topics: Animals; Biological Factors; Breast Neoplasms; Diet Therapy; Diet, Healthy; Disease Models, Animal; Disease Progression; Drug Resistance, Neoplasm; Early Growth Response Protein 1; Fasting; Female; Fulvestrant; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; MCF-7 Cells; Mice, Inbred NOD; Mice, SCID; Piperazines; PTEN Phosphohydrolase; Pyridines; Receptors, Estrogen; Receptors, Progesterone; Tamoxifen; Xenograft Model Antitumor Assays

The purpose of this study was to explore the potential contracting effect of leptin on isolated guinea pig tracheal smooth muscle (TSM), the possible mechanism, and the impact of epithelium denudation or allergen sensitization, respectively. An in vitro experiment investigated the effect of leptin at a concentration of 250-1000 nmol/L on isolated guinea pig TSM with an intact or denuded epithelium. Ovalbumin and IgE were used to test the impact of active and passive sensitization. The isolated TSM strips were incubated in Krebs solution and aerated with carbogen (95% O

Topics: Animals; Asthma; Disease Models, Animal; Guinea Pigs; Humans; Leptin; Male; Muscle Contraction; Muscle, Smooth; Ovalbumin; Receptors, Leptin; Trachea

Elafin is an antimicrobial and anti-inflammatory protein. We hypothesize that elafin expression correlates with diabetes. Among non-diabetic and prediabetic groups, men have significantly higher serum elafin levels than women. Men with type 2 diabetes mellitus (T2DM) have significantly lower serum elafin levels than men without T2DM. Serum elafin levels are inversely correlated with fasting blood glucose and hemoglobin A1c levels in men with T2DM, but not women with T2DM. Lentiviral elafin overexpression inhibited obesity, hyperglycemia, and liver steatosis in high-fat diet (HFD)-treated male mice. Elafin-overexpressing HFD-treated male mice had increased serum leptin levels, and serum exosomal miR181b-5p and miR219-5p expression. Transplantation of splenocytes and serum exosomes from elafin-overexpressing HFD-treated donor mice reduced food consumption and fat mass, and increased adipose tissue leptin mRNA expression in HFD-treated recipient mice. Elafin improved leptin sensitivity via reduced interferon-gamma expression and induced adipose leptin expression via increased miR181b-5p and miR219-5p expression. Subcutaneous and oral administration of modified elafin inhibited obesity, hyperglycemia, and liver steatosis in the HFD-treated mice. Circulating elafin levels are associated with hyperglycemia in men with T2DM. Elafin, via immune-derived miRNAs and cytokine, activates leptin sensitivity and expression that subsequently inhibit food consumption, obesity, hyperglycemia, and liver steatosis in HFD-treated male mice.

Topics: Adipose Tissue; Animals; Cytokines; Diet, High-Fat; Disease Models, Animal; Eating; Elafin; Fatty Liver; Female; Gene Expression; Humans; Hyperglycemia; Interferon-gamma; Leptin; Male; Mice, Inbred C57BL; Obesity; Sex Characteristics

Extracellular beta-amyloid (Aβ), intra-neuronal hyper-phosphorylated tau protein, and chronic inflammation are neuropathological hallmarks of Alzheimer's Disease (AD). A link between AD, insulin dysfunction, and tumor necrosis factor-alpha (TNF-α) in promoting both tau and Aβ pathologies in vivo has been proposed.. MA-[D-Leu-4]-OB3 was given, with or without insulin, to streptozotocin (STZ)-treated male Swiss Webster mice, and to male diet-induced obese (DIO) mice. Brains were excised, and coronal sections were imaged with fluoro jade-C (FJC), thioflavin-S, or hematoxylin and eosin (H&E). Serum TNF-α and IGF-1 were measured by ELISA. Histopathological changes in the cerebral cortex (CC) and hippocampus (HC) were correlated with changes in glycemic regulation, episodic memory, and serum levels of TNF-α and IGF-1.. In STZ-treated mice, blood glucose and serum TNF-α and IGF-1 were reduced by insulin alone, and normalized when MA-[D-Leu-4]-OB3 was given in combination with insulin. Improvement in episodic memory was inversely correlated with the number of FJC-positive cells in the CC and HC and serum TNF-α and IGF-1. FJC, thioflavin-S and H&E staining indicated no Aβ deposition. Similar results were observed in DIO mice treated with MA-[D-Leu-4]-OB3.. The mechanism by which MA-[D-Leu-4]-OB3 improves episodic memory in mouse models of TIDM and T2DM appears to be related to improved insulin sensitivity and reduced TNF-α-induced neurodegeneration.. MA-[D-Leu-4]-OB3 may have application to human pre-clinical and clinical AD and AD-like dementia by interrupting the cascade of insulin resistance, neuro-inflammation, and neurodegeneration, that characterizes these diseases.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Disease Models, Animal; Humans; Insulin Resistance; Leptin; Male; Memory, Episodic; Mice; Neuroprotective Agents; Peptides; Tumor Necrosis Factor-alpha

Parental high-fat diet (HFD) programs for obesity and hypertension in female offspring in rats, but it is unknown how the pregnancies of these offspring are impacted. Therefore, the hypothesis was tested that parental HFD exaggerates obesity and hypertension during pregnancy of the offspring. Wistar Hannover rat dams (the parental, P generation) were maintained on normal-fat diet (NFD) or HFD from weaning and were kept on respective diets through pregnancy and lactation. Their offspring (the first filial, F1 generation) were weaned onto the same diet as the P generation, or they were changed to the other diet to determine if combined HFD in the P and F1 generations exaggerates body weight and blood pressure levels during pregnancy in these offspring. This diet paradigm resulted in the following groups of pregnant F1 offspring: P-NFD/F1-NFD, P-HFD/F1-NFD, P-NFD/F1-HFD, and P-HFD/F1-HFD. Maternal body and adipose tissue weights were greatest in the P-HFD/F1-HFD group compared to the other 3 groups by the end of pregnancy. Plasma leptin and conscious mean arterial blood pressure were not significantly different between any group, although there was a main effect for increased blood pressure in the F1-HFD groups. Circulating levels of the antihypertensive pregnancy factor, placental growth factor (PlGF), were assessed. Although average PlGF levels were similar among all groups, correlative studies revealed that lower levels of PlGF were associated with higher blood pressure only in the P-HFD/F1-HFD group. In summary, HFD feeding from the P generation exaggerated HFD-induced body and adipose tissue weights in the pregnant offspring.

Topics: Adiposity; Animals; Blood Pressure; Body Weight; Diet, High-Fat; Disease Models, Animal; Female; Humans; Hypertension; Leptin; Male; Maternal Inheritance; Obesity; Placenta Growth Factor; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Weaning

Early life stress (ELS) is an independent risk factor for increased BMI and cardiometabolic disease risk later in life. We have previously shown that a mouse model of ELS, maternal separation and early weaning (MSEW), exacerbates high-fat diet (HF)-induced obesity only in adult female mice. Therefore, the aim of this study was to investigate

Topics: Adipose Tissue; Animals; Diet, High-Fat; Disease Models, Animal; Female; Leptin; Maternal Deprivation; Mice; Obesity; Stress, Psychological; Up-Regulation

An imbalance between hepatic fatty acid uptake and removal results in ectopic fat accumulation, which leads to non-alcoholic fatty liver disease (NAFLD). The amount and type of accumulated triglycerides seem to play roles in NAFLD progression; however, a complete understanding of how triglycerides contribute to NAFLD evolution is lacking. Our aim was to evaluate triglyceride accumulation in NAFLD in a murine model and its associations with molecular mechanisms involved in liver damage and adipose tissue-liver cross talk by employing lipidomic and molecular imaging techniques. C57BL/6J mice fed a high-fat diet (HFD) for 12 weeks were used as a NAFLD model. Standard-diet (STD)-fed animals were used as controls. Standard liver pathology was assessed using conventional techniques. The liver lipidome was analyzed by liquid chromatography-mass spectrometry (LC-MS) and laser desorption/ionization-mass spectrometry (LDI-MS) tissue imaging. Liver triglycerides were identified by MS/MS. The transcriptome of genes involved in intracellular lipid metabolism and inflammation was assessed by RT-PCR. Plasma leptin, resistin, adiponectin, and FABP4 levels were determined using commercial kits. HFD-fed mice displayed increased liver lipid content. LC-MS analyses identified 14 triglyceride types that were upregulated in livers from HFD-fed animals. Among these 14 types, 10 were identified in liver cross sections by LDI-MS tissue imaging. The accumulation of these triglycerides was associated with the upregulation of lipogenesis and inflammatory genes and the downregulation of β-oxidation genes. Interestingly, the levels of plasma FABP4, but not of other adipokines, were positively associated with 8 of these triglycerides in HFD-fed mice but not in STD-fed mice. Our findings suggest a putative role of FABP4 in the liver-adipose tissue cross talk in NAFLD.

Topics: Adipokines; Adiponectin; Adipose Tissue; Animals; Chromatography, Liquid; Diet, High-Fat; Disease Models, Animal; Fatty Acid-Binding Proteins; Fatty Acids; Inflammation; Leptin; Lipid Metabolism; Lipidomics; Liver; Male; Mice, Inbred C57BL; Molecular Imaging; Non-alcoholic Fatty Liver Disease; Resistin; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tandem Mass Spectrometry; Triglycerides

The present study was designed to determine the effects of pineal gland‑derived melatonin on obesity by employing a rat pinealectomy (Pnx) model. After 10 weeks of a high‑fat diet, rats received sham or Pnx surgery followed by a normal chow diet for 10 weeks. Reverse transcription‑quantitative PCR, western blotting analysis, immunohistochemistry and ELISA were used to determine the effects of Pnx. Pnx decreased the expression of melatonin receptor (MTNR)1A and MTNR1B, in brown adipose tissues (BAT) and white adipose tissues (WAT). Pnx rats showed increased insulin sensitivity compared with those that received sham surgery. Leptin levels were significantly decreased in the serum of the Pnx group. In addition, Pnx stimulated thermogenic genes in BAT and attenuated lipogenic genes in both WAT and the liver. Histological analyses revealed a marked decrease in the size of lipid droplets and increased expression of uncoupling protein 1 in BAT. In the liver of the Pnx group, the size and number of lipid droplets had also decreased. In conclusion, the results presented in the current study suggested that Pnx increases thermogenesis in BAT and decreases lipogenesis in WAT and the liver.

Topics: Adipose Tissue, Brown; Adipose Tissue, White; Animals; Disease Models, Animal; Down-Regulation; Gene Expression Regulation; Insulin Resistance; Leptin; Lipogenesis; Liver; Male; Obesity; Pinealectomy; Rats; Receptor, Melatonin, MT1; Thermogenesis

The aim of this study was to investigate the effect of high fat diet and excessive compressive mechanical force on temporomandibular joint. In vivo, a mouse model of temporomandibular joint compressive loading device was used. A high fat diet mouse model and a combined mouse model intraperitoneally treated with or without simvastatin were used in the study. The pathological changes of mandibular condylar cartilage were assessed by Safranin-O staining. The IL-1β, MMP-3, leptin expression changes in the cartilage were detected by immunohistochemistry. In vitro, the mandibular condylar chondrocytes were treated with or without L-1β and simvastatin. The mRNA expression level of matrix MMPs and leptin were assessed. Both excessive compressive mechanical force and high fat diet induced obesity caused TMJ osteoarthritis-like changes and increased expression of IL-1β, MMP-3, and leptin. These pathological changes were much more serious when the two interventions were exerted together, while simvastatin could obviously alleviate these changes. The mRNA expression of MMP-3, MMP-13, and leptin increased in the IL-1β treated chondrocytes treated with IL-1β, and decreased with simvastatin treatment. The development of temporomandibular joint pathological changes could be caused by the excessive compressive mechanical force and high fat diet induced obesity.

Topics: Animals; Chondrocytes; Diet, High-Fat; Disease Models, Animal; Interleukin-1beta; Leptin; Male; Mandible; Matrix Metalloproteinase 3; Mice; Mice, Inbred C57BL; Obesity; Phenazines; Risk Factors; Simvastatin; Stress, Mechanical; Temporomandibular Joint

The impact of early life protein source (whey vs. casein) on short- and long-term glucose homeostasis and adiposity is unknown and was investigated in this study. At the end of the suckling period, non-IUGR (intrauterine growth restriction) and IUGR pups were separated from dams and were randomized into four groups. From age 21-49 days, non-IUGR and IUGR pups were fed ad-libitum chow or a semi-synthetic diet (20% from protein; casein or whey) and from age 50-199 days, all groups were fed ad-libitum chow. Food intake, body composition, glucose, and insulin homeostasis were assessed. Among the chow groups, IUGR had slower growth and higher fasting glucose at age 42 days, as well as higher fasting and AUC glucose at age 192 days relative to non-IUGR. The whey IUGR group had a slower growth rate and higher fasting glycemia in early life (age 21-49 days) and higher HOMA-IR later in life (age 120-122 and 190-192 days) relative to casein IUGR. This study shows the potential advantage of casein relative to whey during weaning on short term energy intake, growth, and glucose homeostasis in an IUGR model and reveals, for the first time, its long term impact on insulin sensitivity, which may have implications for later metabolic health, particularly in small-for-gestational-age populations at risk of type 2 diabetes.

Topics: Adiposity; Animals; Area Under Curve; Birth Weight; Blood Glucose; Body Composition; Caseins; Disease Models, Animal; Energy Intake; Fasting; Female; Fetal Development; Fetal Growth Retardation; Glucose; Homeostasis; Insulin; Insulin Resistance; Leptin; Lipids; Organ Size; Rats, Sprague-Dawley; Time Factors; Weaning; Whey

Obesity is a widely spread disease and a crucial risk factor for malign disorders, including breast cancer of women in the postmenopause. Studies demonstrated that in case of obesity crucial natural killer (NK) cell functions like combating tumor cells are affected. This study aims to analyze NK cells and NK cell receptor expression of obese mice in a model for postmenopausal breast cancer. Therefore, female BALB/c mice were fed either a high fat or a standard diet. Thereafter, ovaries were ectomized and a syngeneic and orthotopical injection of 4T1-luc2 mouse mammary tumor cells into the mammary adipose tissue pad was performed. Obese mice showed increased body weights and visceral fat mass as well as increased levels of leptin and IL-6 in plasma. Moreover, compared to the lean littermates, tumor growth was increased and the NKp46-expression on circulating NK cells was decreased. Furthermore, the activating NK cell receptor NKG2D ligand (MULT1) expression was enhanced in adipose tissue of obese tumor bearing mice. The present study gives novel insights into gene expression of NK cell receptors in obesity and aims to promote possible links of the obesity-impaired NK cell physiology and the elevated breast cancer risk in obese women.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Disease Models, Animal; Female; Histocompatibility Antigens Class I; Interleukin-6; Killer Cells, Natural; Leptin; Mammary Neoplasms, Animal; Membrane Proteins; Mice; Mice, Inbred BALB C; Mice, Obese; Obesity; Postmenopause

Recent studies on insulin, leptin, osteocalcin (OCN), and bone remodeling have evoked interest in the interdependence of bone formation and energy household. Accordingly, this study attempts to investigate trauma specific hormone changes in a murine trauma model and its influence on fracture healing. Thereunto 120 female wild type (WT) and leptin-deficient mice underwent either long bone fracture (Fx), traumatic brain injury (TBI), combined trauma (Combined), or neither of it and therefore served as controls (C). Blood samples were taken weekly after trauma and analyzed for insulin and OCN concentrations. Here, WT-mice with Fx and, moreover, with combined trauma showed a greater change in posttraumatic insulin and OCN levels than mice with TBI alone. In the case of leptin-deficiency, insulin changes were still increased after bony lesion, but the posttraumatic OCN was no longer trauma specific. Four weeks after trauma, hormone levels recovered to normal/basal line level in both mouse strains. Thus, WT- and leptin-deficient mice show a trauma specific hyperinsulinaemic stress reaction leading to a reduction in OCN synthesis and release. In WT-mice, this causes a disinhibition and acceleration of fracture healing after combined trauma. In leptin-deficiency, posttraumatic OCN changes are no longer specific and fracture healing is impaired regardless of the preceding trauma.

Topics: Animals; Biomarkers; Brain Injuries, Traumatic; Disease Models, Animal; Female; Fracture Healing; Fractures, Bone; Hormones; Insulin; Leptin; Mice; Mice, Knockout; Models, Biological; Osteocalcin; Osteogenesis

Although genetic predisposition influences the onset and progression of insulin resistance and diabetes, dietary nutrients are critical. In general, protein is beneficial relative to carbohydrate and fat but dependent on protein source. Our recent study demonstrated that 70% replacement of dietary casein protein with the equivalent quantity of protein derived from herring milt protein hydrolysate (HMPH; herring milt with proteins being enzymatically hydrolyzed) significantly improved insulin resistance and glucose homeostasis in high-fat diet-induced obese mice. As production of protein hydrolysate increases the cost of the product, it is important to determine whether a simply dried and ground herring milt product possesses similar benefits. Therefore, the current study was conducted to investigate the effect of herring milt dry powder (HMDP) on glucose control and the associated metabolic phenotypes and further to compare its efficacy with HMPH. Male C57BL/6J mice on a high-fat diet for 7 weeks were randomized based on body weight and blood glucose into three groups. One group continued on the high-fat diet and was used as the insulin-resistant/diabetic control and the other two groups were given the high-fat diet modified to have 70% of casein protein being replaced with the same amount of protein from HMDP or HMPH. A group of mice on a low-fat diet all the time was used as the normal control. The results demonstrated that mice on the high-fat diet increased weight gain and showed higher blood concentrations of glucose, insulin, and leptin, as well as impaired glucose tolerance and pancreatic β-cell function relative to those on the normal control diet. In comparison with the high-fat diet, the replacement of 70% dietary casein protein with the same amount of HMDP or HMPH protein decreased weight gain and significantly improved the aforementioned biomarkers, insulin sensitivity or resistance, and β-cell function. The HMDP and HMPH showed similar effects on every parameter except blood lipids where HMDP decreased total cholesterol and non-HDL-cholesterol levels while the effect of HMPH was not significant. The results demonstrate that substituting 70% of dietary casein protein with the equivalent amount of HMDP or HMPH protein protects against obesity and diabetes, and HMDP is also beneficial to cholesterol homeostasis.

Topics: Animal Feed; Animals; Biomarkers; Blood Glucose; Diet, High-Fat; Disease Models, Animal; Energy Intake; Fatty Acids, Nonesterified; Fish Proteins, Dietary; Glycemic Control; Insulin; Insulin Resistance; Insulin-Secreting Cells; Leptin; Male; Mice, Inbred C57BL; Obesity; Protein Hydrolysates; Weight Loss

(1) Background: We characterized a novel animal model with obesity-induced constipation because constipation is rarely known in genetically engineered mice (GEM); (2) Methods: The changes in the constipation parameters and mechanisms were analyzed in CRISPR-Cas9-mediated leptin (Lep) knockout (KO) mice from eight to 24 weeks; (3) Results: Significant constipation phenotypes were observed in the Lep KO mice since 16 weeks old. These mice showed a significant decrease in the gastrointestinal motility, mucosal layer thickness and ability for mucin secretion as well as the abnormal ultrastructure of Lieberkühn crypts in the transverse colon. The density or function of the enteric neurons, intestinal Cajal cells (ICC), smooth muscle cells, and the concentration of gastrointestinal (GI) hormones for the GI motility were remarkably changed in Lep KO mice. The downstream signaling pathway of muscarinic acetylcholine receptors (mAChRs) were activated in Lep KO mice, while the expression of adipogenesis-regulating genes were alternatively reduced in the transverse colon of the same mice; (4) Conclusions: These results provide the first strong evidence that Lep KO mice can represent constipation successfully through dysregulation of the GI motility mediated by myenteric neurons, ICC, and smooth muscle cells in the transverse colon during an abnormal function of the lipid metabolism.

Topics: Adipogenesis; Animals; Aquaporin 3; Aquaporins; Colon; Constipation; CRISPR-Cas Systems; Disease Models, Animal; Female; Gastrointestinal Hormones; Gastrointestinal Motility; Interstitial Cells of Cajal; Leptin; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Electron, Transmission; Mucins; Myocytes, Smooth Muscle; Neurons; Obesity; Receptors, Muscarinic; Signal Transduction

Leptin is a peptide hormone produced primarily in adipose tissues. Leptin is considered a biomarker associated with obesity and obesity-mediated diseases. Biosensor detection of leptin in the blood may play a critical role as an indicator of dynamic pathological changes. In this paper, we introduce an electrochemical biosensor that adopts o-Phenylenediamine (oPD) on screen-printed gold electrodes (SPGEs) for detecting the leptin from a mouse model of diet-induced obesity (DIO). A linear calibration curve for the leptin concentration was obtained in the ranges from 0.1 to 20 ng/mL with a lower detection limit of 0.033 ng/mL. The leptin concentration was quantified with HRP (horseradish peroxidase)-catalyzed oxidation of oPD by two voltammetry methods: cyclic voltammetry (CV) and square-wave voltammetry (SWV). The proposed sandwich enzyme-linked immunosorbent assay (ELISA)-based electrochemical biosensor for the leptin in mouse blood serum showed high stability, sensitivity, selectivity, and effectivity compared to the commercial Leptin ELISA measurement. Thus, we believe that this leptin biosensor can be a sensitive analytical tool to detect low-levels of biomarkers in clinics and point-of-care testing (POCT).

Topics: Animals; Biomarkers; Biosensing Techniques; Diet; Disease Models, Animal; Electrochemical Techniques; Electrodes; Enzyme-Linked Immunosorbent Assay; Gold; Humans; Leptin; Mice; Obesity

Alzheimer's disease (AD) has challenged single-target therapeutic strategies, raising the possibility that combined therapies may offer a more effective treatment strategy.. There is substantial evidence for the efficacy of leptin (L) (neuroprotective hormone) and pioglitazone (P) (anti-inflammatory agent) as monotherapies in AD. We have previously shown that combination treatment of L+P in APP/PS1 mice at the onset of pathology significantly improved memory and reduced brain Aβ levels relative to control mice. In this new study, we sought to replicate our previous findings in a new cohort of APP/PS1 mice to further confirm whether the combined treatment of L+P is superior to each treatment individually.. We have re-evaluated the effects of L+P co-treatment in APP/PS1 mice using thioflavin-S staining, MOAβ immunolabeling, and enzyme-linked immunosorbent assay (ELISA) to examine effects on Aβ levels and pathology, relative to animals that received L or P individually.. We demonstrated that a combination of L and P significantly enhances the anti-Aβ effect of L or P in the hippocampus of APP/PS1 mice.. Our findings suggest that combining L and P significantly enhances the anti-Aβ effect of L or P in the hippocampus of APP/PS1 mice and maybe a potential new effective strategy for AD therapy.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Disease Models, Animal; Hippocampus; Humans; Hypoglycemic Agents; Leptin; Male; Memory; Mice; Mice, Transgenic; Pioglitazone

To determine whether (-)-epicatechin (Epi) could decrease visceral adipose tissue and improve the metabolic profile of male offspring rats, after maternal obesity was induced by a high-fat diet (HFD).. Maternal obesity in albino Wistar rats was induced with a HFD, whereas male offspring were fed with chow diet throughout the study. Eight male offspring per group, from different litters, were randomly assigned to the experimental or to the control groups. In the experimental group, Epi was administered at a dose of 1 mg/kg of body weight to the male offspring twice daily for two weeks, beginning at postnatal day (PND).. Weight of visceral adipose tissue, adipocyte size, and several metabolic parameters.. Epi administration in the male offspring induced a significant decrease in the amount of visceral fat (11.61 g less, P < 0.05) and in the size of adipose cells (28% smaller, P < 0.01). Besides, Epi was able to decrease insulin, leptin, and Homeostasis Model Assessment -Insulin Resistance (HOMA-IR) (P < 0.05), as well as triglycerides, when the experimental group was compared to the untreated male offspring of obese rats (P < 0.01).. Epi administration can reverse the negative effects that maternal obesity has on the male offspring. This could be because Epi reduces the amount of visceral fat and improves metabolic profile.

Topics: Adiposity; Animals; Body Weight; Catechin; Diet, High-Fat; Disease Models, Animal; Female; Humans; Insulin Resistance; Leptin; Male; Obesity, Maternal; Pregnancy; Prenatal Exposure Delayed Effects; Rats

Since foods with high hedonic value are often consumed in excess of energetic needs, this study was designed to identify the mechanisms that may counter anorexigenic signalling in the presence of hedonic foods in lean animals.. Mice, in different states of satiety (fed/fasted, or fed/fasted and treated with ghrelin or leptin, respectively), were allowed to choose between high-fat/high-sucrose and standard foods. Intake of each food type and the activity of hypothalamic neuropetidergic neurons that regulate appetite were monitored. In some cases, food choice was monitored in leptin-injected fasted mice that received microinjections of galanin receptor agonists into the lateral hypothalamus.. Appetite-stimulating orexin neurons in the lateral hypothalamus are rapidly activated when lean, satiated mice consume a highly palatable food (PF); such activation (upregulated c-Fos expression) occurred even after administration of the anorexigenic hormone leptin and despite intact leptin signalling in the hypothalamus. The ability of leptin to restrain PF eating is restored when a galanin receptor 2 (Gal2R) agonist is injected into the lateral hypothalamus.. Hedonically-loaded foods interrupt the inhibitory actions of leptin on orexin neurons and interfere with the homeostatic control of feeding. Overeating of palatable foods can be curtailed in lean animals by activating Gal2R in the lateral hypothalamus.

Topics: Animals; Disease Models, Animal; Eating; Galanin; Ghrelin; Hyperphagia; Hypothalamic Area, Lateral; Leptin; Male; Mice; Mice, Inbred C57BL; Neurons; Orexins; Receptor, Galanin, Type 2

Body weight has been shown to be a predictor of clinical progression in Huntington's disease (HD). Alongside widespread neuronal pathology, both HD patients and the R6/2 mouse model of HD exhibit weight loss and increased energy expenditure, providing a rationale for targeting whole-body energy metabolism in HD. Leptin-deficient mice display low energy expenditure and increased body weight. We therefore hypothesized that normalizing energy metabolism in R6/2 mice, utilizing leptin- deficiency, would lead to a slower disease progression in the R6/2 mouse. In this study, we show that R6/2 mice on a leptin-deficient genetic background display increased body weight and increased fat mass compared to R6/2 mice, as well as wild type littermates. The increased body weight was accompanied by low energy expenditure, illustrated by a reduction in respiratory exchange rate. Leptin-deficient R6/2 mice had large white adipocytes with white adipocyte gene expression characteristics, in contrast to white adipose tissue in R6/2 mice, where white adipose tissue showed signs of browning. Leptin-deficient R6/2 mice did not exhibit improved neuropathological measures. Our results indicate that lowering energy metabolism in HD, by increasing fat mass and reducing respiratory exchange rate, is not sufficient to affect neuropathology. Further studies targeting energy metabolism in HD are warranted.

Topics: Animals; Disease Models, Animal; Energy Metabolism; Female; Huntington Disease; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Obese; Mice, Transgenic; Weight Loss

What is the central question of this study? What is the impact and drawbacks of subcutaneous lipectomy on body metabolism? What is the main finding and its importance? Subcutaneous lipectomy resulted in deterioration of hepatic functions, atherosclerotic lipid profile and disturbed redox state. While the results support lipectomy as an effective treatment for obesity, lipectomy induces unfavourable changes in health.. The number of obese older adults is on the rise, but data about proper treatment of obesity in the elderly is controversial. The present study was designed to investigate the effectiveness and consequences of partial subcutaneous lipectomy, as a rapid medical intervention against increased accumulation of body fat, in adult obese rats. The study was conducted on adult (9-12 months) female rats, in which obesity was induced by bilateral surgical ovariectomy. They were randomized into two main groups: short term (5 weeks) and long term (10 weeks). Both groups were subdivided into control, ovariectomized (OVX) and ovariectomized lipectomized groups. Body weight (BW) was measured and body mass index (BMI) calculated. Fasting blood glucose, lipid profile and plasma levels of total proteins, albumin, liver enzymes, malondialdehyde (MDA), leptin and adiponectin were determined. The content of both blood and hepatic tissue of reduced glutathione was estimated. In addition, histological study of the liver, aorta and peri-renal fat was performed. Compared to controls, OVX rats showed significant increase in BW, BMI and plasma levels of liver enzymes, MDA and leptin. Histological study revealed vacuolated ballooned hepatocytes and enlarged irregular visceral adipocytes with atherosclerotic changes in the wall of aorta. Following subcutaneous lipectomy, rats exhibited significant fasting hyperglycaemia, dyslipidaemia, lowered plasma albumin and disturbed redox state with aggravation of the histological changes. The findings indicate that although subcutaneous lipectomy appears to be effective in combating obesity in older females, it has unfavourable effects on both metabolic and hepatic functions.

Topics: Adiponectin; Adipose Tissue; Animals; Blood Glucose; Body Mass Index; Body Weight; Disease Models, Animal; Fasting; Female; Insulin; Insulin Resistance; Leptin; Lipectomy; Liver; Malondialdehyde; Obesity; Rats

Excess of fat intake leads to obesity and causes a variety of metabolic diseases and cancer. We previously demonstrated that high-lard diet induces intestinal metaplasia, a precancerous lesion of the stomach mediated by leptin signaling. This study aims to investigate which kinds of dietary fat cause the intestinal metaplasia onset. We fed eight kinds of high-fat diets (HFDs) of animal or plant origin to mice evaluated their effect on gastric pathogenesis. Five types of dietary fat were divided according to their observed effects: Obese with high metaplasia (group I; beef tallow, lard, and hydrogenated coconut oil), non-obese with high metaplasia (group II; linseed oil), obese without metaplasia (group III; corn oil and olive oil), non-obese without metaplasia (group IV, soybean oil) and lean without metaplasia (group V; cocoa butter). The group I and II diets induced leptin, phosphorylated leptin receptor (ObR), signal transducer and activator 3 (STAT3), and increased intracellular β-catenin accumulation in the stomach. Moreover, mice fed these HFDs with 1-methyl-3-nitro-1-nitrosoguanidine (MNNG), a gastric carcinogen, and further accelerated dysplasia in the stomach.

Topics: Animals; beta Catenin; Carcinogenesis; Diet, High-Fat; Dietary Fats; Disease Models, Animal; Gastric Mucosa; Leptin; Metaplasia; Mice; Obesity; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor; Stomach

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and ovulatory dysfunction. Women with PCOS have an elevated prevalence of cardiometabolic risk factors that worsen after menopause. Liraglutide (Lira), a glucagon-like peptide-1 receptor agonist, has shown beneficial metabolic effects in small clinic trials in reproductive-age women with PCOS. We have shown that chronic hyperandrogenemia in an experimental model of postmenopausal PCOS is associated with an adverse cardiometabolic profile and upregulation of the intrarenal renin-angiotensin system (RAS). We analyzed the effect of Lira in the cardiometabolic profile, intrarenal RAS, and blood pressure (BP) in postmenopausal PCOS. Four-week-old female Sprague Dawley rats were treated with DHT or placebo for 17 months. Lira administration during the last 3 weeks caused a bigger reduction in food intake, body weight, fat mass, and homeostasis model assessment of insulin resistance index in PCOS than in control rats. Moreover, Lira improved dyslipidemia and elevated leptin levels in PCOS. In contrast, Lira decreased intrarenal expression of RAS components only in the control group. Lira transiently increased heart rate and decreased BP in control rats. However, Lira did not modify BP but increased heart rate in PCOS. The angiotensin-converting-enzyme inhibitor enalapril abolished the BP differences between PCOS and control rats. However, Lira coadministration with enalapril further reduced BP only in control rats. In summary, Lira has beneficial effects for several cardiometabolic risk factors in postmenopausal PCOS. However, hyperandrogenemia blunted the BP-lowering effect of Lira in postmenopausal PCOS. Androgen-induced activation of intrarenal RAS may play a major role mediating increases in BP in postmenopausal PCOS.

Topics: Animals; Blood Pressure; Body Composition; Body Weight; Disease Models, Animal; Drug Evaluation, Preclinical; Eating; Female; Glucagon-Like Peptide-1 Receptor; Heart Rate; Hyperandrogenism; Insulin Resistance; Leptin; Lipids; Liraglutide; Metabolic Syndrome; Polycystic Ovary Syndrome; Postmenopause; Random Allocation; Rats, Sprague-Dawley; Renin-Angiotensin System

Type 2 diabetes mellitus is a major health concern worldwide; however, the molecular mechanism underlying its development is poorly understood. The hormone amylin is postulated to be involved, as human amylin forms amyloid in the pancreases of diabetic patients, and oligomers have been shown to be cytotoxic to β-cells. As rodent amylin is non-amyloidogenic, mice expressing human amylin have been developed to investigate this hypothesis. However, it is not possible to differentiate the effects of amylin overexpression from β-cell loss in these models. We have developed transgenic mice that overexpress [

Topics: Animals; Blood Glucose; Body Weight; Brain; Diabetes Mellitus, Type 2; Disease Models, Animal; Gene Expression Profiling; Gene Expression Regulation; Humans; Insulin; Islet Amyloid Polypeptide; Leptin; Male; Mice; Mice, Transgenic; Nerve Tissue Proteins; Neuropeptide Y; Obesity; Phenotype; Phosphorylation; Pro-Opiomelanocortin; Proto-Oncogene Proteins c-fos; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein

This study was to investigate the degree of susceptibility to intermittent hypoxia (IH), a hallmark of obstructive sleep apnea (OSA), between the two mice inbred lines C57BL/6N (6N) and C57BL/6J (6J).. Four-week old male mice of 6N and 6J substrains (n = 8) were randomized to standard diet (SD) group or high fat (HF) diet group. At the age of 13-week, all two groups of mice were subjected to either air or IH (IH30; thirty hypoxic events per hour) for one week.. All mice fed with HF diet exhibited obesity with more body weight and fat mass (percentage to body weight) gain. IH reduced serum LDL, HDL and total cholesterol levels in lean 6J mice. In obese mice, IH lowered obesity-induced serum total cholesterol level in 6J substrain but raised further in 6N substrain. Furthermore, IH caused elevation of serum FFA and MDA levels, and pro-inflammatory cytokines MCP-1 and IL-6 levels in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) of lean 6J but not lean 6N mice. There was reduced number of adipocytes and elevation of macrophages in SAT and VAT of HF-induced obese mice of both substrains. IH led to increased number of adipocytes and macrophages in SAT of lean 6J mice.. The genetic difference between 6N and 6J mice may have direct impact on metabolic and inflammatory responses after IH. Therefore, attention must be given for the selection of C57BL mice substrains in the experimental IH-exposed mouse model.

Topics: Adiponectin; Animals; Biomarkers; Blood Glucose; Diet, High-Fat; Disease Models, Animal; Hypoxia; Inflammation; Inflammation Mediators; Insulin Resistance; Intra-Abdominal Fat; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Thinness; Weight Gain

The Wnt/β‑catenin pathway confers a chain of molecular events in livers affected by non‑alcoholic steatohepatitis (NASH). Namodenoson, a selective agonist of the A3 adenosine receptor (A3AR), which is highly expressed in pathological liver cells, induces a robust anti‑inflammatory effect in the liver, mediated via the de‑regulation of the Wnt/β‑catenin pathway. Namodenoson also acts as a liver protective agent by inhibiting ischemia/reperfusion injury. Based on these unique characteristics, we investigated the anti‑NASH effect of Namodenoson in murine models of steatohepatitis and in the LX2 human hepatic stellate cell line (HSC). In the STAM model, Namodenoson significantly decreased the non‑alcoholic fatty liver disease (NAFLD) activity score, NAS, demonstrating anti‑inflammatory and anti‑steatotic effects. In the carbon tetrachloride (CCl4) model, Namodenoson reversed alanine aminotransferase (ALT) to normal values and significantly improved liver inflammation and fibrosis, as well as the adiponectin and leptin levels. Namodenoson de‑regulated the Wnt/β‑catenin pathway in the liver extracts of the CCl4 model mice and in the LX2 HSCs, manifested by a decrease in the expression of phosphoinositide 3‑kinase (PI3K), nuclear factor κ‑light‑chain‑enhancer of activated B cells (NF‑κB), β‑catenin, lymphoid enhancer‑binding factor 1 (Lef‑1) and cyclin D1, and an increase in the expression level of glycogen synthase kinase 3β (GSK‑3β). The fibrosis marker, α‑smooth muscle actin (α‑SMA) was also de‑regulated, supporting the anti‑fibrotic effect of Namodenoson. On the whole, the findings of this study demonstrate that Namodenoson exerts an anti‑NASH effect mediated via the de‑regulation of the PI3K/NF‑κB/Wnt/β‑catenin signaling pathway. Thus, targeting A3AR may prove to be a novel direction in the pharmacotherapy of NAFLD/NASH.

Topics: Actins; Adenosine A3 Receptor Agonists; Adiponectin; Animals; Carbon Tetrachloride; Disease Models, Animal; Gene Expression Regulation; Humans; Leptin; Liver; Mice; NF-kappa B; Non-alcoholic Fatty Liver Disease; Phosphatidylinositol 3-Kinases; Receptor, Adenosine A3; Wnt Signaling Pathway

Leptin is the current treatment for metabolic disorders associated with acquired and congenital generalized lipodystrophy (CGL). Although excess leptin levels have been associated with vascular inflammation and cardiovascular disease in the context of obesity, the effects of chronic leptin treatment on vascular function remain unknown in CGL. Here, we hypothesized that leptin treatment will improve endothelial function via direct vascular mechanisms. We investigated the cardiovascular consequences of leptin deficiency and supplementation in male gBscl2

Topics: Analysis of Variance; Animals; Disease Models, Animal; Endothelium, Vascular; Leptin; Lipodystrophy, Congenital Generalized; Male; Mice; Mice, Inbred C57BL; NADPH Oxidase 1; PPAR gamma; Random Allocation; Reactive Oxygen Species; Reference Values; Treatment Outcome

Leptin, a critical mediator of feeding, metabolism and diabetes, is expressed on an incidental basis according to satiety. The genetic regulation of leptin should similarly be episodic.. Data from three mouse cohorts hosted by the Jackson Laboratory- 402 (174F, 228M) F2 Dilute Brown non-Agouti (DBA/2)×DU6i intercrosses, 142 Non Obese Diabetic (NOD/ShiLtJ×(NOD/ShiLtJ×129S1/SvImJ.H2g7) N2 backcross females, and 204 male Nonobese Nondiabetic (NON)×New Zealand Obese (NZO/HlLtJ) reciprocal backcrosses-were used to test for loci associated with absolute residuals in plasma leptin and arcsin-transformed percent fat ('phenotypic dispersion'; PDpLep and PDAFP). Individual data from 1,780 mice from 43 inbred strains was also used to estimate genetic variances and covariances for dispersion in each trait.. Several loci for PDpLep were detected, including possibly syntenic Chr 17 loci, but there was only a single position on Chr 6 for PDAFP. Coding SNP in genes linked to the consensus Chr 17 PDpLep locus occurred in immunological and cancer genes, genes linked to diabetes and energy regulation, post-transcriptional processors and vomeronasal variants. There was evidence of intersexual differences in the genetic architecture of PDpLep. PDpLep had moderate heritability [Formula: see text] and PDAFP low heritability [Formula: see text]; dispersion in these traits was highly genetically correlated r = 0.8).. Greater genetic variance for dispersion in plasma leptin, a physiological trait, may reflect its more ephemeral nature compared to body fat, an accrued progressive character. Genetic effects on incidental phenotypes such as leptin might be effectively characterized with randomization-detection methodologies in addition to classical approaches, helping identify incipient or borderline cases or providing new therapeutic targets.

Topics: Adipose Tissue; Animals; Chromosome Mapping; Crosses, Genetic; Diabetes Mellitus; Disease Models, Animal; Genotype; Humans; Leptin; Mice; Microsatellite Repeats; New Zealand; Obesity; Phenotype; Quantitative Trait, Heritable

Catecholamine excess reflecting an adrenergic overdrive of the sympathetic nervous system (SNS) has been proposed to link to hyperleptinemia in obesity and may contribute to the development of metabolic disorders. However, relationship between the catecholamine level and plasma leptin in obesity has not yet been investigated. Moreover, whether pharmacological blockade of the adrenergic overdrive in obesity by the third-generation beta-blocker agents such as carvedilol could help to prevent metabolic disorders is controversial and remains to be determined. Using the high fat diet (HFD)-induced obese mouse model, we found that basal plasma norepinephrine, the principal catecholamine as an index of SNS activity, was persistently elevated and highly correlated with plasma leptin concentration during obesity development. Targeting the adrenergic overdrive from this chronic norepinephrine excess in HFD-induced obesity with carvedilol, a third-generation beta-blocker with vasodilating action, blunted the HFD-induced hepatic glucose over-production by suppressing the induction of gluconeogenic enzymes, and enhanced the muscular insulin signaling pathway. Furthermore, carvedilol treatment in HFD-induced obese mice decreased the enlargement of white adipose tissue and improved the glucose tolerance and insulin sensitivity without affecting body weight and blood glucose levels. Our results suggested that catecholamine excess in obesity might directly link to the hyperleptinemic condition and the therapeutic targeting of chronic adrenergic overdrive in obesity with carvedilol might be helpful to attenuate obesity-related metabolic disorders.

Topics: Adipose Tissue, White; Administration, Oral; Adrenergic Agents; Adrenergic beta-Antagonists; Animals; Carvedilol; Diet, High-Fat; Disease Models, Animal; Glucose; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Leptin; Liver; Male; Mice; Norepinephrine; Obesity; Signal Transduction

Excessive food intake and metabolic disorder promote obesity and diabetes. In China, peanut skin is used as a herbal medicine to treat hemophilia, thrombocytopenic purpura, and hepatic hemorrhage. In the present study, we demonstrated that peanut skin extract (PSE) safely reduced appetite, body weight, fat tissue, plasma TG and TC, and blood glucose level in mice with diet-induced obesity (DIO). Moreover, the leptin/leptin receptor/neuropeptide Y (NPY) and adiponectin signaling pathways involved in the antiobesity effects of PSE are confirmed through leptin and adiponectin overexpression and leptin receptor silencing in mice. PSE consisted of oligosaccharide and polyphenol in a mass ratio of 45 : 55, and both parts were important for the antiobesity function of PSE. Our results suggested that PSE can be developed as functional medical food to treat metabolic disorders and obesity.

Topics: Adiponectin; Adipose Tissue; Animals; Anti-Obesity Agents; Arachis; Body Weight; China; Diet, High-Fat; Disease Models, Animal; Humans; Leptin; Mice; Mice, Inbred ICR; Neuropeptide Y; Obesity; Plant Extracts; Receptors, Leptin; Signal Transduction

Topics: Adipose Tissue; Animals; Brain; Diet; Disease Models, Animal; Eating; Endoplasmic Reticulum Stress; Inflammation; Leptin; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Obese; NF-kappa B; Obesity; Phaeophyceae; Phloroglucinol; Pyrogallol; RAW 264.7 Cells; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Toll-Like Receptor 4; Weight Gain

BACKGROUND Intestinal dysbiosis, or dysbacteriosis, is an abnormal interaction between the intestinal microbiota and the host cells due to altered microbial diversity. This study aimed to investigate the metabolic effects and changes in the intestinal microbiota in newborn rats following exposure to increased levels of maternal androgens in a rat model of maternal polycystic ovary syndrome (PCOS). MATERIAL AND METHODS The administration of androgen developed the rat maternal PCOS model during pregnancy. Maternal rat ovarian follicles were counting and assessed by histology. The metabolic phenotype of newborn rats was evaluated and included an insulin tolerance test, a glucose tolerance test, and measurement of serum levels of triglyceride, insulin, cholesterol, adiponectin, and leptin. Expression of pro-inflammatory cytokines was detected using quantitative reverse transcription-polymerase chain reaction (qRT-PCR), serum levels were measured by enzyme-linked immunosorbent assay (ELISA), and proteins associated with adipose tissue remodeling and adipocyte differentiation were measured by Western blot. RESULTS Markers of systemic inflammation were significantly increased in the female offspring but not in the male offspring born to rat in the PCOS model. Following birth, newborn rats that received antibiotics showed an improved metabolic phenotype, with reduced serum lipid levels, insulin resistance, body weight, inflammation of adipose tissue, and serum levels of inflammatory cytokines compared with controls. Probiotics had no significant effects on these parameters in newborn rats. CONCLUSIONS In a rat model of maternal PCOS, exposure to androgens in utero resulted in dysbiosis of the intestinal microbiota and metabolic disorders of the newborn female rats.

Topics: Adipose Tissue; Androgens; Animals; Animals, Newborn; Body Weight; China; Disease Models, Animal; Dysbiosis; Female; Gastrointestinal Microbiome; Glucose; Glucose Tolerance Test; Insulin; Insulin Resistance; Leptin; Male; Metabolic Diseases; Obesity; Ovarian Follicle; Polycystic Ovary Syndrome; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley

Energy imbalance due to excess of calories is considered to be a major player in the current worldwide obesity pandemic and could be accompanied by systemic and central inflammation and mitochondrial dysfunctions. This hypothesis was tested by comparing the wild-derived diet-induced obesity- (DIO-) resistant mouse strain WSB/EiJ to the obesity-prone C57BL/6J strain. We analysed circulating and hypothalamic markers of inflammatory status and hypothalamic mitochondrial activity in both strains exposed to high-fat diet (HFD). We further analysed the regulations of hypothalamic genes involved in inflammation and mitochondrial pathways by high throughput microfluidic qPCR on RNA extracted from laser micro-dissected arcuate (ARC) and paraventricular (PVN) hypothalamic nuclei. HFD induced increased body weight gain, circulating levels of leptin, cholesterol, HDL and LDL in C57BL/6J whereas WSB/EiJ mice displayed a lower inflammatory status, both peripherally (lower levels of circulating cytokines) and centrally (less activated microglia in the hypothalamus) as well as more reactive mitochondria in the hypothalamus. The gene expression data analysis allowed identifying strain-specific hypothalamic metabolic pathways involved in the respective responses to HFD. Our results point to the involvement of hypothalamic inflammatory and mitochondrial pathways as key factors in the control of energy homeostasis and the resistance to DIO.

Topics: Animals; Cytokines; Diet, High-Fat; Disease Models, Animal; Energy Metabolism; Hypothalamus; Inflammation; Inflammation Mediators; Leptin; Lipid Metabolism; Male; Metabolic Networks and Pathways; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondrial Dynamics; Obesity; Paraventricular Hypothalamic Nucleus; Species Specificity; Transcriptome

Variation in blood flow mediated by the posterior communicating collateral arteries (PComs) contributes to variation in the severity of tissue injury in obstructive disease. Evidence in animals and humans indicates that differences in the extent of PComs, i.e., their anatomic lumen diameter and whether they are present bilaterally, unilaterally, or absent, are a major factor. These differences arise during development since they are present at birth. However, the causal mechanisms are unknown. We used angiography after maximal dilation to examine involvement of genetic, environmental, and stochastic factors. The extent of PComs varied widely among seven genetically diverse strains of mice. Like pial collaterals in the microcirculation, aging and hypertension reduced PCom diameter, while in contrast, obesity, hyperlipidemia, metabolic syndrome, and diabetes mellitus had no effect. Naturally occurring intrauterine growth restriction had no effect on extent of PCom or pial collaterals in the adult. The number and diameter of PComs evidenced much larger apparent stochastic-dependent variation than pial collaterals. In addition, both PComs underwent flow-mediated outward remodeling after unilateral permanent MCA occlusion that varied with genetic background and was greater on the ipsilesional side. These findings indicate that variation in the number and diameter of PCom collateral arteries arises from stochastic factors and naturally occurring genetic variants that differ from those that cause variation in pial collateral arterioles. Environmental factors also contribute: aging and hypertension reduce PCom diameter. Our results suggest possible sources of variation of PComs in humans and provide information relevant when studying mouse models of occlusive cerebrovascular disease.

Topics: Aging; Animals; Apolipoproteins E; Cerebrovascular Circulation; Circle of Willis; Collateral Circulation; Disease Models, Animal; Glucose Metabolism Disorders; Hypertension; Leptin; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Renin

Obesity is associated with periodontitis, but the mechanisms underlying this association have yet to be unraveled. The present investigation was to evaluate a common rat model, in which obesity is induced by high-fat, high-sucrose diet (HFSD), for its applicability in periodontal research.. Ten male Wistar rats were fed a 3-month HFSD along with a matching control group. Afterwards, the body weight, adipocyte morphology, leptin and adiponectin levels in adipose tissue, gingiva, and serum as well as the serum levels of triglyceride, cholesterol, and glucose were analyzed. For statistical analyses, parametric and non-parametric tests were applied (p < 0.05).. Body weight was significantly higher in the HFSD group after dieting as compared to control. HFSD caused a significant increase in serum triglyceride, low-density lipoprotein cholesterol, and leptin levels and a significant decrease in high-density lipoprotein cholesterol. Furthermore, adipose tissue from HFSD rats exhibited significantly larger adipocytes, displayed a significant upregulation of leptin and, surprisingly, elevated adiponectin levels, which is in contrast to chronic obesity in humans. Although leptin and adiponectin were also observed in gingival biopsies, no obvious differences between the groups were found.. Although this rat diet-induced obesity model is characterized by changes typical of obesity, it also has limitations, which have to be considered when data, especially with regard to adipokines, are extrapolated to humans.. The rodent diet-induced obesity model may be useful for unraveling pathomechanisms underlying the association between obesity and periodontal destruction but conclusions have to be drawn with caution.

Topics: Adiponectin; Animals; Biomarkers; Diet, High-Fat; Dietary Sucrose; Disease Models, Animal; Leptin; Lipids; Male; Obesity; Periodontitis; Rats; Rats, Wistar

Metabolic inflammation is a distinct feature of obesity. Increased inflammation in the adipose tissue and the liver has been so far implicated to affect metabolic homeostasis, mainly insulin resistance. In addition to the peripherals, the inflammation in the hypothalamus which governs systemic metabolism by linking neuronal and endocrine signals has been suggested to be linked to the metabolic disease. However, the underlying molecular mechanisms are poorly understood. We hypothesized that a high-fat diet (HFD) led to central metabolic inflammation via transcriptional changes in the hypothalamus. To address the hypothesis, we characterized obesity-related hypothalamic, transcriptional alterations, and their effects on functional networks. Male C57BL/6J mice were fed with either a control diet (CD) or an HFD for 20 weeks. Microarray and gene ontology analyses of the hypothalamus demonstrated that immune-related pathways, including inflammatory and cytokine signaling, were overrepresented in the hypothalamus of HFD-fed mice compared to that of CD mice. In addition, through secondary analysis of leptin-deficient obese (ob/ob) mouse hypothalamus, we found that enriched gene sets for tumor necrosis factor-α signaling pathways and cancer pathways were common in both the obese mouse models. The results suggest that inflammatory pathway is transcriptionally enriched in the hypothalamus in obesity models and is related with hyperadiposity rather than the primary causes of obesity including the dietary fat and the genetic mutation.

Topics: Adipose Tissue; Adiposity; Animals; Diet, High-Fat; Dietary Fats; Disease Models, Animal; Hypothalamus; Inflammation; Insulin Resistance; Leptin; Liver; Male; Metabolic Diseases; Mice, Inbred C57BL; Mice, Obese; Neoplasms; Obesity; Transcription, Genetic; Tumor Necrosis Factor-alpha

Individuals carrying loss-of-function gene mutations for the adipocyte hormone leptin are morbidly obese, but respond favorably to replacement therapy. Recombinant leptin is however largely ineffective for the vast majority of obese individuals due to leptin resistance. One theory underlying leptin resistance is impaired leptin transport across the blood-brain-barrier (BBB). Here, we aim to gain new insights into the mechanisms of leptin BBB transport, and its role in leptin resistance.. We developed a novel tool for visualizing leptin transport using infrared fluorescently labeled leptin, combined with tissue clearing and light-sheet fluorescence microscopy. We corroborated these data using western blotting.. Using 3D whole brain imaging, we display comparable leptin accumulation in circumventricular organs of lean and obese mice, predominantly in the choroid plexus (CP). Protein quantification revealed comparable leptin levels in microdissected mediobasal hypothalami (MBH) of lean and obese mice (p = 0.99). We further found increased leptin receptor expression in the CP (p = 0.025, p = 0.0002) and a trend toward elevated leptin protein levels in the MBH (p = 0.17, p = 0.078) of obese mice undergoing weight loss interventions by calorie restriction or exendin-4 treatment.. Overall, our findings suggest a crucial role for the CP in controlling the transport of leptin into the cerebrospinal fluid and from there to target areas such as the MBH, potentially mediated via the leptin receptor. Similar leptin levels in circumventricular organs and the MBH of lean and obese mice further suggest intact leptin BBB transport in leptin resistant mice.

Topics: Animals; Biological Transport; Blood-Brain Barrier; Blotting, Western; Brain; Disease Models, Animal; Fluorescence; HEK293 Cells; Humans; Imaging, Three-Dimensional; Leptin; Mice; Mice, Obese; Molecular Imaging; Obesity, Morbid

Previously, apoE-derived ABCA1 agonist peptides have been shown to possess anti-atherosclerotic and possibly antidiabetic properties. Here we assessed the in vitro and in vivo actions of a second generation of ABCA1 peptide agonists, CS6253 and T6991-2, on glucose homeostasis. The results show that these two peptides improve glucose tolerance in a prediabetic diet-induced obesity mouse model by enhancing insulin secretion. It was further demonstrated that T6991-2 also improved glucose tolerance in leptin-deficient (ob/ob) mice. CS6253 increased insulin secretion both under basal conditions and in response to high glucose stimulation in pancreatic INS-1 β-cells rendered leptin receptor deficient with specific siRNA. Additional in vitro cell studies suggest that the CS6253 agonist attenuates hepatic gluconeogenesis and glucose transport. It also potentiates insulin-stimulated glucose uptake and utilization. These observed anti-diabetic actions suggest additional benefits of the CS6253 and T6991-2 ABCA1 peptide agonists for cardiovascular disease beyond their direct anti-atherosclerosis properties previously described.

Topics: Animals; Atherosclerosis; ATP Binding Cassette Transporter 1; Cell Line; Cell Line, Tumor; Diet, High-Fat; Disease Models, Animal; Exenatide; Gluconeogenesis; Glucose; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Resistance; Insulin Secretion; Leptin; Liver; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Obesity; Peptides; Rats; Triglycerides

The aim of this study was to identify the effects of leptin upon the intervertebral disc (IVD) and to determine whether these responses are potentiated within an environment of existing degeneration. Obesity is a significant risk factor for low back pain (LBP) and IVD degeneration. Adipokines, such as leptin, are novel cytokines produced primarily by adipose tissue and have been implicated in degradative and inflammatory processes. Obese individuals are known to have higher concentrations of serum leptin, and IVD cells express leptin receptors. We hypothesise that adipokines, such as leptin, mediate a biochemical link between obesity, IVD degeneration and LBP.. The bovine intervertebral disc was used as a model system to investigate the biochemical effects of obesity, mediated by leptin, upon the intervertebral disc. Freshly isolated cells, embedded in 3D alginate beads, were subsequently cultured under varying concentrations of leptin, alone or together with the pro-inflammatory cytokines TNF-α, IL-1β or IL-6. Responses in relation to production of nitric oxide, lactate, glycosaminoglycans and expression of anabolic and catabolic genes were analysed.. Leptin influenced the cellular metabolism leading particularly to greater production of proteases and NO. Addition of leptin to an inflammatory environment demonstrated a marked deleterious synergistic effect with greater production of NO, MMPs and potentiation of pro-inflammatory cytokine production.. Leptin can initiate processes involved in IVD degeneration. This effect is potentiated in an environment of existing degeneration and inflammation. Hence, a biochemical mechanism may underlie the link between obesity, intervertebral disc degeneration and low back pain. These slides can be retrieved under Electronic Supplementary Material.

Topics: Animals; Cattle; Cells, Cultured; Cytokines; Disease Models, Animal; Inflammation Mediators; Interleukin-1beta; Intervertebral Disc; Intervertebral Disc Degeneration; Leptin; Low Back Pain; Obesity

Obesity has reached global epidemic proportions and is associated with serious medical comorbidities and economic consequences. In this preclinical study, we characterized how the palatable diet changed food intake pattern, caloric intake, metabolic profile and hormone levels. We also evaluated the expression of dopamine D2 receptors in the rat striatum.. Male Wistar rats were fed with either high-fat or high-sucrose diet for 5 weeks according to different feeding regimes: ad libitum access or scheduled for a 2-h period each day without caloric restriction during the remainder of the day.. Both diets resulted in an enhancement in caloric intake and total body weight. Post-meal data showed that high-fat diet increased cholesterol, triglycerides and glucose concentrations. Animals fed on high sucrose diet were only hyperglycemic. High-fat diet schedules resulted in the enhancement of leptin concentrations, while increases in blood levels of ghrelin were noted after intermitted high-fat or continuous high-sucrose diet. Finally, we report that only ad libitum high-sucrose evoked a significant enhancement of the dopamine D2 receptor protein level and a reduction in the D2 mRNA and receptor affinity in the rat striatum. Independently of the diet type, a similar reduction in dopamine D2 receptor affinity (decrease in KD value) was found in the striatum of rats with intermittent food access.. The findings provide a better understanding of eating disorders and indicate that diet composition leading to obesity induces distinct changes in dopamine D2 receptor signaling in the striatum.

Topics: Animal Nutritional Physiological Phenomena; Animals; Biomarkers; Blood Glucose; Cholesterol; Corpus Striatum; Diet, High-Fat; Dietary Sucrose; Disease Models, Animal; Energy Intake; Energy Metabolism; Feeding Behavior; Ghrelin; Hormones; Leptin; Male; Nutritional Status; Obesity; Rats, Wistar; Receptors, Dopamine D2; Signal Transduction; Time Factors; Triglycerides; Weight Gain

The dopamine system-essential for mood and movement-can be activated in two ways: by excitatory inputs that cause burst firing and stamp-in learning or by slow excitatory or inhibitory inputs-like leptin, insulin, ghrelin, or corticosterone-that decrease or increase single-spike (pacemaker) firing rate and that modulate motivation. In the present study we monitored blood samples taken prior to and during intravenous cocaine or saline self-administration in rats. During cocaine-taking, growth hormone and acetylated ghrelin increased 10-fold; glucagon-like peptide-1 (GLP-1) doubled; non-acetylated ghrelin, insulin-like growth factor-1 (IGF-1), and corticosterone increased by 50% and adiponectin increased by 17%. In the same blood samples, leptin, insulin, gastric inhibitory polypeptide (GIP), and prolactin decreased by 40-70%. On the first day of testing under extinction conditions-where the animals earned unexpected saline instead of cocaine-5-fold increases were seen for growth hormone and acetylated ghrelin and equal changes-in amplitude and latency-were seen in each of the other cases except for IGF-1 (which increased at a slower rate). Single-spike firing affects the tonic activation level of the dopamine system, involving very different controls than those that drive burst firing; thus, the present data suggest interesting new targets for medications that might be used in the early stages of drug abstinence.

Topics: Adiponectin; Animals; Cocaine; Cocaine-Related Disorders; Corticosterone; Disease Models, Animal; Drug Substitution; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Growth Hormone; Injections, Intravenous; Insulin; Leptin; Prolactin; Rats; Reward; Saline Solution; Self Administration; Signal Transduction

In metabolic disorders, adiponectin and adiponectin receptors (AdipoR1/R2) signaling has a key role in improving nonalcoholic fatty liver disease (NAFLD) in obesity-associated diabetes.. To the best of our knowledge, here, we reported for the first time the underlying mechanistic therapeutic efficacy of the novel osmotin, a homolog of mammalian adiponectin, against NAFLD in leptin-deficient ob/ob and db/db mice.. The ob/ob and db/db mice were treated with osmotin at a dose of 5 μg/g three times a week for two weeks. To co-relate the in vivo results we used the human liver carcinoma HepG2 cells, subjected to knockdown with small siRNAs of AdipoR1/R2 and PPARα genes and treated with osmotin and palmitic acid (P.A.). MTT assay, Western blotting, immunohistofluorescence assays, and plasma biochemical analyses were applied.. Osmotin stimulated AdipoR1/R2 and its downstream APPL1/PPAR-α/AMPK/SIRT1 pathways in ob/ob and db/db mice, and HepG2 cells exposed to P.A. Mechanistically, we confirmed that knockdown of AdipoR1/R2 and PPARα by their respective siRNAs abolished the osmotin activity in HepG2 cells exposed to P.A. Overall, the in vivo and in vitro results suggested that osmotin protected against NAFLD through activation of AdipoR1/R2 and its downstream APPL1/PPAR-α/AMPK/SIRT1 pathways as shown by the reduced body weight, blood glucose level and glycated hemoglobin, improved glucose tolerance, attenuated insulin resistance and hepatic glucogenesis, regulated serum lipid parameters, and increased fatty acid oxidation and mitochondrial functions.. Our findings strongly suggest that novel osmotin might be a potential novel therapeutic tool against obesity/diabetes-induced NAFLD and other metabolic disorders.

Topics: Adiponectin; Animals; Anti-Obesity Agents; Cytoprotection; Diabetes Mellitus, Experimental; Disease Models, Animal; Hep G2 Cells; Humans; Hypoglycemic Agents; Leptin; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Mice, Transgenic; Non-alcoholic Fatty Liver Disease; Obesity; Plant Proteins; PPAR alpha; Receptors, Adiponectin; Receptors, Leptin; Signal Transduction; Up-Regulation

Plasticizer di-2-ethylhexyl phthalate (DEHP) can induce lipid metabolic disorder. There was a chronic low level inflammatory response in adipose tissue of patients with lipid metabolic disorder. But the effect of inflammation on lipid metabolic disorder induced by DEHP is unclear. The present study was undertaken to explore the effect of di-2-ethylhexyl phthalate on inflammation and lipid metabolic disorder in rats.. Eighty healthy 21-day-old Wistar rats were randomly divided into 4 groups and administered DEHP by gavage at 0, 5, 50, and 500 mg/kg/ d for 8 weeks. Morphological changes of adipose tissue, the levels of IL-1β, TNF-α, LEP, and ADP in rat serum and adipose tissue, the serum TC, TG, HDL-C and LDL-C, the mRNA and protein expression levels of lipid metabolism-related gene CEBP/β and inflammation-related gene CD68 were measured.. After exposure to DEHP, the weight of rats in the high dose group was significantly higher than that in the control group (p < 0.05). And the number of adipose tissue cells in the medium-dose and high-dose DEHP groups increased, with much more macrophage infiltrated. The levels of LDL-C, HDL-C, TC in serum and LEP in adipose tissue of rats exposed to 500 mg/kg DEHP were significantly higher than those in the control group (p < 0.05); while the level of ADP in adipose tissue in rats exposed to DEHP was significantly lower (p < 0.05). The levels of IL-1β and TNF-α in surum and adipose tissue of rats exposed to DEHP were significantly higher than those in the control group (p < 0.05). The mRNA and protein expression levels of CEBP/β and CD68 in adipose tissue of rats exposed to DEHP were significantly higher than those in the control group. The TC, LEP and ADP Levels of rats were significantly different among different subgroup of IL-1β and TNF-α, and in high level subgroup, the TC, LEP and ADP Levels were increased. The levels of TC and LEP was increased in high level subgroup of CD68.. DEHP induced more macrophage infiltrated in adipose tissue of rats, promoted the secretion of IL-1β, TNF-α and the formation of inflammation, and disturbed the normal lipid metabolism and lead to lipid metabolic disorders. What is more, the levels of inflammation were associated with the lipid levels.

Topics: Adipocytes; Adiponectin; Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Body Weight; CCAAT-Enhancer-Binding Protein-beta; Cholesterol; Diethylhexyl Phthalate; Disease Models, Animal; Female; Inflammation; Interleukin-1beta; Leptin; Lipid Metabolism; Male; Metabolic Diseases; Rats; Rats, Wistar; Triglycerides; Tumor Necrosis Factor-alpha

Six-week-old male KK-A

Topics: Administration, Oral; Animals; Blood Glucose; Body Weight; Cholesterol; Diabetes Mellitus, Experimental; Disease Models, Animal; Drinking Water; Drug Combinations; Eating; Glycerylphosphorylcholine; Hyperglycemia; Hyperinsulinism; Hyperlipidemias; Hypoglycemic Agents; Leptin; Male; Mice; Mice, Transgenic; Obesity; S-Adenosylmethionine; Triglycerides

Here, we investigated inflammatory signs of peripheral nerves in leptin-deficient obese ob/ob mice and the modulating effects of the exogenous iron load.. Ob/ob and ob/+ control mice were fed with high, standard, or low iron diet for four months.. We found intraepidermal nerve fiber degeneration in foot skin and low-grade neuropathic abnormalities including mildly slowed motor and compound sensory nerve conduction velocities and low-grade macrophage and T-cell infiltration without overt neuropathology in sciatic nerves of all ob/ob mice. Low dietary iron load caused more pronounced abnormalities than high iron load in ob/ob mice.. Our data suggest that dietary non-heme iron deficiency may be a modulating factor in the pathogenesis of peripheral neuropathy in obese ob/ob mice with metabolic syndrome. Once the mechanisms can be further elucidated, how low dietary iron augments peripheral nerve degeneration and dysfunction via pro-inflammatory pathways and new therapeutic strategies could be developed.. CMAP: compound muscle action potential; cSNCV: compound sensory nerve conduction velocity; IENFD: intraepidermal nerve fiber density; LDL: low-density lipoprotein; MetS: metabolic syndrome; MNCV: motor conduction velocity; NCV: nerve conduction velocity; PN: peripheral neuropathy; PNS: peripheral nervous system; STZ: streptozotocin; T2D: type 2 diabetes mellitus; TNF alpha: tumor necrosis factor alpha; WHO: World Health Organization.

Topics: Animals; Calcium-Binding Proteins; Cytokines; Diabetic Neuropathies; Disease Models, Animal; Iron, Dietary; Leptin; Male; Mice; Mice, Mutant Strains; Microfilament Proteins; Microscopy, Electron, Transmission; Nerve Fibers; Nerve Tissue Proteins; Neural Conduction; Neurogenic Inflammation; Sciatic Nerve; Skin

Ectopic fat deposition is associated with increased tissue production of ceramides. Recent genetic mouse studies suggest that specific sphingolipid C16:0 ceramide produced by ceramide synthase 6 (CerS6) plays an important role in the development of insulin resistance. However, the therapeutic potential of CerS6 inhibition not been demonstrated. Therefore, we pharmacologically investigated the selective ablation of CerS6 using antisense oligonucleotides (ASO) in obese insulin resistance animal models.. We utilized ASO as therapeutic modality, CerS6 ASO molecules designed and synthesized were initially screened for in-vitro knock-down (KD) potency and cytotoxicity. ASOs with >85% inhibition of CerS6 mRNA were selected for further investigations. Most promising ASOs verified for in-vivo KD efficacy in healthy mice. CerS6 ASO (AAGATGAGCCGCACC) was found most active with hepatic reduction of CerS6 mRNA expression. Prior to longitudinal metabolic studies, we performed a dose titration target engagement analysis with CerS6 ASO in healthy mice to select the optimal dose. Next, we utilized leptin deficiency ob/ob and high fat diet (HFD) induced obese mouse models for pharmacological efficacy study.. CerS6 expression were significantly elevated in the liver and brown adipose, this was correlated with significantly elevated C16:0 ceramide concentrations in plasma and liver. Treatment with CerS6 ASO selectively reduced CerS6 expression by ∼90% predominantly in the liver and this CerS6 KD resulted in a significant reduction of C16:0 ceramide by about 50% in both liver and plasma. CerS6 KD resulted in lower body weight gain and accompanied by a significant reduction in whole body fat and fed/fasted blood glucose levels (1% reduction in HbA1c). Moreover, ASO-mediated CerS6 KD significantly improved oral glucose tolerance (during oGTT) and mice displayed improved insulin sensitivity. Thus, CerS6 appear to play an important role in the development of obesity and insulin resistance.. Our investigations identified specific and selective therapeutic valid ASO for CerS6 ablation in in-vivo. CerS6 should specifically be targeted for the reduction of C16:0 ceramides, that results in amelioration of insulin resistance, hyperglycemia and obesity. CerS6 mediated C16:0 ceramide reduction could be a potentially attractive target for the treatment of insulin resistance, obesity and type 2 diabetes.

Topics: Adipose Tissue, Brown; Animals; Blood Glucose; Ceramides; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Gene Knockdown Techniques; Hep G2 Cells; Humans; Insulin Resistance; Leptin; Liver; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Oligonucleotides, Antisense; Sphingosine N-Acyltransferase; Thionucleotides; Weight Gain

Stabilin-1 (STAB1) is a scavenger receptor expressed on alternatively activated macrophages and sinusoidal endothelial cells. Its ligands include oxidized low-density lipoprotein (LDL) and the extracellular matrix glycoprotein SPARC and it is present in both human and murine atherosclerotic lesions. We aimed to investigate the effect of specific deletion of STAB1 in bone marrow-derived cells, including macrophages on atherosclerotic lesion formation in mice.. Lethally irradiated hypercholesterolemic LDL receptor knockout mice received either wildtype (WT) or STAB1 knockout (STAB1 KO) bone marrow. Bone marrow transplanted mice were fed a Western-type diet for 9 weeks to induce atherosclerotic lesion formation.. Interestingly, LDL receptor knockout mice reconstituted with STAB1 KO bone marrow showed increased body weight gain (two-way ANOVA: p < 0.001) and larger white adipocyte cell sizes (43% increase in cell area; p < 0.05) as compared to WT bone marrow transplanted mice, which correlated positively (r = 0.82; p < 0.001). This was paralleled by a significant increase in white adipose tissue relative mRNA expression levels of the adipokine leptin (+94% p < 0.05). Despite these changes, no differences in serum lipid levels, the extent of in vivo macrophage foam cell formation or circulating leukocyte concentrations were observed. Moreover, the size and composition of atherosclerotic lesions was not different between the two experimental groups.. Bone marrow-specific Stabilin-1 deletion does not affect the susceptibility for atherosclerosis in mice. However, the increased body weight gain and adipocyte cell size highlight a potential role for leukocyte STAB1 in the development of metabolic disorders.

Topics: Adipocytes, White; Adipose Tissue, White; Animals; Aortic Diseases; Atherosclerosis; Cell Adhesion Molecules, Neuronal; Diet, Western; Disease Models, Animal; Foam Cells; Hypercholesterolemia; Leptin; Male; Mice, Inbred C57BL; Mice, Knockout; Plaque, Atherosclerotic; Receptors, LDL; Weight Gain

Hypothalamic melanocortin neurons play a pivotal role in weight regulation. Here, we examined the contribution of Semaphorin 3 (SEMA3) signaling to the development of these circuits. In genetic studies, we found 40 rare variants in SEMA3A-G and their receptors (PLXNA1-4; NRP1-2) in 573 severely obese individuals; variants disrupted secretion and/or signaling through multiple molecular mechanisms. Rare variants in this set of genes were significantly enriched in 982 severely obese cases compared to 4,449 controls. In a zebrafish mutagenesis screen, deletion of 7 genes in this pathway led to increased somatic growth and/or adiposity demonstrating that disruption of Semaphorin 3 signaling perturbs energy homeostasis. In mice, deletion of the Neuropilin-2 receptor in Pro-opiomelanocortin neurons disrupted their projections from the arcuate to the paraventricular nucleus, reduced energy expenditure, and caused weight gain. Cumulatively, these studies demonstrate that SEMA3-mediated signaling drives the development of hypothalamic melanocortin circuits involved in energy homeostasis.

Topics: Adolescent; Adult; Animals; Body Weight; Cell Line; Child; Child, Preschool; Disease Models, Animal; Eating; Energy Metabolism; Female; Genetic Variation; Homeostasis; Humans; Hypothalamus; Leptin; Male; Melanocortins; Mice; Mice, Inbred C57BL; Middle Aged; Nerve Tissue Proteins; Neurons; Obesity; Receptors, Cell Surface; Semaphorins; Young Adult; Zebrafish

Antidepressants are among the most-prescribed class of drugs in the world and though weight gain is a common outcome of antidepressant treatment, that effect is not well understood. We employed an animal model comprised of 2 weeks of chronic restraint stress with antidepressant treatment, followed by diet-induced obesity. We showed that short-term antidepressant treatment had long-lasting effects, not only leading to weight gain, but also enhancing trabecular and cortical bone features in rats; therefore, weight gain in this model was different from that of the classic diet-induced obesity. Late in the post-restraint recovery period, antidepressant-treated animals were significantly heavier and had better bone features than saline-treated controls, when assessed in the distal femoral metaphysis. The propensity to gain weight might have influenced the rate of catch-up growth and bone allometry, as heavier animals treated with fluoxetine also had enhanced bone features when compared to non-stressed animals. Therefore, short-term antidepressant treatment ameliorated the long-term effects of stress on body growth and bone. Growth and bone structural features were associated with leptin levels, and the interaction between leptin levels and antidepressant was significant for bone mineral content, suggesting that short-term antidepressants in the context of long-term diet-induced obesity modified the role of leptin in bone formation. To our knowledge this is the first study reporting that short-term antidepressant treatment has long-lasting effects in restoring the effects of chronic stress in body weight and bone formation. Our findings may be relevant to the understanding and treatment of osteoporosis, a condition of increasing prevalence due to the aging population.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Bone Density; Disease Models, Animal; Fluoxetine; Leptin; Male; Obesity; Rats; Rats, Sprague-Dawley; Stress, Psychological; Weight Gain

Obesity is a highly prevalent and modifiable breast cancer risk factor. While the role of obesity in fueling breast cancer progression is well established, the mechanisms linking obesity to breast cancer initiation are poorly understood. A hallmark of breast cancer initiation is the disruption of apical polarity in mammary glands. Here we show that mice with diet-induced obesity display mislocalization of Par3, a regulator of cellular junctional complexes defining mammary epithelial polarity. We found that epithelial polarity loss also occurs in a 3D coculture system that combines acini with human mammary adipose tissue, and establish that a paracrine effect of the tissue adipokine leptin causes loss of polarity by overactivation of the PI3K/Akt pathway. Leptin sensitizes non-neoplastic cells to proliferative stimuli, causes mitotic spindle misalignment, and expands the pool of cells with stem/progenitor characteristics, which are early steps for cancer initiation. We also found that normal breast tissue samples with high leptin/adiponectin transcript ratio characteristic of obesity have an altered distribution of apical polarity markers. This effect is associated with increased epithelial cell layers. Our results provide a molecular basis for early alterations in epithelial architecture during obesity-mediated cancer initiation.

Topics: Adaptor Proteins, Signal Transducing; Adipokines; Adipose Tissue; Animals; Body Mass Index; Breast Neoplasms; Cell Adhesion Molecules; Cell Cycle Proteins; Disease Models, Animal; Epithelial Cells; Female; Humans; Leptin; Mammary Glands, Animal; Mammary Glands, Human; Mice, Inbred BALB C; Obesity; Precancerous Conditions; Spindle Apparatus

The Fragile X Mental Retardation Protein (FMRP) is a widely expressed RNA-binding protein involved in translation regulation. Since the absence of FMRP leads to Fragile X Syndrome (FXS) and autism, FMRP has been extensively studied in brain. The functions of FMRP in peripheral organs and on metabolic homeostasis remain elusive; therefore, we sought to investigate the systemic consequences of its absence.. Using metabolomics, in vivo metabolic phenotyping of the Fmr1-KO FXS mouse model and in vitro approaches, we show that the absence of FMRP induced a metabolic shift towards enhanced glucose tolerance and insulin sensitivity, reduced adiposity, and increased β-adrenergic-driven lipolysis and lipid utilization.. Combining proteomics and cellular assays, we highlight that FMRP loss increased hepatic protein synthesis and impacted pathways notably linked to lipid metabolism. Mapping metabolomic and proteomic phenotypes onto a signaling and metabolic network, we predicted that the coordinated metabolic response to FMRP loss was mediated by dysregulation in the abundances of specific hepatic proteins. We experimentally validated these predictions, demonstrating that the translational regulator FMRP associates with a subset of mRNAs involved in lipid metabolism. Finally, we highlight that FXS patients mirror metabolic variations observed in Fmr1-KO mice with reduced circulating glucose and insulin and increased free fatty acids.. Loss of FMRP results in a widespread coordinated systemic response that notably involves upregulation of protein translation in the liver, increased utilization of lipids, and significant changes in metabolic homeostasis. Our study unravels metabolic phenotypes in FXS and further supports the importance of translational regulation in the homeostatic control of systemic metabolism.

Topics: Adipocytes; Animals; Disease Models, Animal; Fatty Acids, Nonesterified; Female; Fragile X Mental Retardation Protein; Fragile X Syndrome; Gene Knockout Techniques; Glucose; Homeostasis; Humans; Insulin; Leptin; Lipolysis; Liver; Male; Metabolomics; Mice; Mice, Knockout; Protein Biosynthesis; Proteomics; RNA, Messenger

Cancer cachexia affects up to 80% of patients with advanced solid cancer and leads to excessive muscle wasting. Here, using an inducible zebrafish hepatocellular carcinoma (HCC) model driven by oncogenic

Topics: Animals; Carcinogenesis; Carcinoma, Hepatocellular; Disease Models, Animal; Fatty Liver; Feeding Behavior; Gene Knockout Techniques; Humans; Leptin; Liver Neoplasms; Male; Muscular Atrophy; Mutation; Proto-Oncogene Proteins p21(ras); Receptors, Leptin; Signal Transduction; Up-Regulation; Zebrafish; Zebrafish Proteins

Topics: Animals; Cell Line; Disease Models, Animal; Female; Gene Expression Regulation; Hepatocytes; Leptin; Liver Cirrhosis; Male; Mice, Knockout; Nitric Oxide Synthase Type II; Phenotype; Proteolysis; Tenascin

Obesity, and associated metabolic syndrome, have been identified as primary risk factors for the development of knee osteoarthritis (OA), representing nearly 60% of the OA patient population. In this study, we sought to determine the effects of prebiotic fibre supplementation, aerobic exercise, and the combination of the two interventions, on the development of metabolic knee osteoarthritis in a high-fat/high-sucrose (HFS) diet-induced rat model of obesity. Twelve-week-old male Sprague-Dawley rats were randomized into five groups: a non-exercising control group fed a standard chow diet, a non-exercising group fed a HFS diet, a non-exercising group fed a HFS diet combined with prebiotic fibre supplement, an exercise group fed a HFS diet, and an exercise group fed a HFS diet combined with prebiotic fibre supplement. Outcome measures included knee joint damage, percent body fat, insulin sensitivity, serum lipid profile, serum endotoxin, serum and synovial fluid cytokines and adipokines, and cecal microbiota. Prebiotic fibre supplementation, aerobic exercise, and the combination of the two interventions completely prevented knee joint damage that is otherwise observed in this rat model of obesity. Prevention of knee damage was associated with a normalization of insulin resistance, leptin levels, dyslipidemia, gut microbiota, and endotoxemia in the HFS-fed rats.

Topics: Adipose Tissue; Animals; Cytokines; Diet, High-Fat; Disease Models, Animal; Insulin; Knee Joint; Leptin; Male; Obesity; Physical Conditioning, Animal; Prebiotics; Rats; Rats, Sprague-Dawley; Synovial Fluid

Gouty arthritis is an inflammatory disease that is triggered by abnormal uric acid metabolism, which is usually attributed to obesity, a risk factor of hyperuricemia and gout attack. A high level of leptin in plasma is a marker of individuals with obesity. Population studies show that leptin promotes obesity-related arthritis, such as osteoarthritis, but it is unknown whether leptin contributes to gouty arthritis, another form of obesity-related arthritis. Our present study showed that the levels of leptin and leptin receptor in patients with active gouty arthritis were elevated. Leptin facilitates the stimulation of human synoviocytes, mouse peritoneal macrophages, and HL-60 cells induced by monosodium urate, leading to higher levels of acute gout-related proinflammatory factors. Leptin obviously exacerbates the inflammation of monosodium urate-induced acute gouty arthritis in wild-type mice, whereas that in leptin-deficient C57BL6/J

Topics: Animals; Arthritis, Gouty; Disease Models, Animal; Female; HL-60 Cells; Humans; Inflammation; Leptin; Macrophages, Peritoneal; Male; Mechanistic Target of Rapamycin Complex 1; Mice; Signal Transduction; Synoviocytes; Uric Acid

Accumulating evidence demonstrates the beneficial effects of physical exercise on pain conditions; however, the underlying mechanisms are not understood thoroughly. The purpose of the present study was to investigate the effects of regular swimming exercise on neuroma pain and the possible roles of adipokines (leptin and adiponectin) in the pain behaviors modulated by exercise. The results showed that 5 weeks of regular swimming exercise relieved pain behaviors in a rat model of neuroma pain and normalized the dysregulation of circulating leptin and adiponectin in plasma induced by nerve injury. Moreover, regular swimming exercise reversed the altered expressions of leptin receptor and adiponectin receptor 1 in neuroma. In addition, the administration of exogenous leptin to the neuroma site dampened the effects of regular swimming exercise on neuroma pain and adiponectin administration alleviated the neuroma pain in the non-exercised neuroma rats. These findings indicate that leptin and adiponectin might be involved in mediating the beneficial effects of exercise on neuroma pain. PERSPECTIVE: Perspective: Identifying which endogenous processes are activated by specific exercise regimes would likely reveal novel therapeutic targets for the treatment of neuropathic pain. The current study suggests that adipokines might be involved in pain behaviors modulated by exercise and thus presents them as potential targets for pain management.

Topics: Adiponectin; Animals; Disease Models, Animal; Exercise Therapy; Leptin; Male; Neuralgia; Neuroma; Pain Management; Physical Conditioning, Animal; Rats; Rats, Sprague-Dawley; Swimming

Gestational diabetes mellitus (GDM) is a common disorder characterized by abnormal glucose metabolism during pregnancy, affecting 2% to 5% of pregnant women. Currently, clinical treatment for GDM is very limited. The present study was designed to investigate the effect and underlying molecular mechanism of tertiary butylhydroquinone (TBHQ) in a pregnant C57BL/KsJ-Lep db/+ (referred to as db+) GDM mouse model. The results showed that nonpregnant db/+ mice did not show a diabetic phenotype, and TBHQ had no effect on glucose and insulin tolerance in these mice. Moreover, in db/+ pregnant mice exhibiting typical diabetes symptoms, such as hyperglycemia and hypoinsulinemia, TBHQ could remarkably decrease the blood glucose level, increase insulin level, and improve glucose and insulin intolerance. The results also revealed that TBHQ could inhibit oxidative stress in pregnant db/+ mice. Furthermore, TBHQ greatly improved offspring survival rate, glucose metabolism, and insulin tolerance. In addition, TBHQ inhibited oxidative stress by reducing malondialdehyde (MDA) and reactive oxygen species (ROS) levels and increased superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities. Moreover, we found that TBHQ activated the nuclear factor erythroid 2-related factor 2 (Nrf2), thereby increasing the levels of Nrf2, and ultimately upregulating the expression of heme oxygenase 1 (NO-1) and superoxide dismutase 2 (SOD2). In conclusion, our findings demonstrated that TBHQ alleviated GDM via Nrf2 activation.

Topics: Animals; Antioxidants; Blood Glucose; Diabetes, Gestational; Disease Models, Animal; Female; Hydroquinones; Leptin; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Oxidative Stress; Pregnancy; Reactive Oxygen Species; Up-Regulation

Chronic inflammation with aging contributes to sarcopenia. Previous studies have suggested that the accumulation of adipose tissue in skeletal muscle, referred to as intermuscular adipose tissue (IMAT), increases with age and is associated with inflammation. However, the mechanism governing ectopic inflammation in skeletal muscle due to aging is not fully understood. Leptin, an adipocytokine derived from adipose tissue, is an important mediator of inflammatory processes. We examined changes in leptin levels with age and whether leptin contributes to ectopic inflammation.. To evaluate ectopic inflammation in skeletal muscle, we measured alterations to the expression of inflammatory cytokine genes (Il1b, Il6, and Tnfa) and muscle break down-related gene (MuRF1 and Atrogin1) in the quadricep muscles of young (10 weeks) and aged (48 weeks) female rats using quantitative reverse-transcription polymerase chain reaction (Q-RT-PCR). Histological examination was performed to identify the extent of IMAT. Leptin mRNA and leptin protein expression were examined using Q-RT-PCR and enzyme-linked immunosorbent assay, respectively. The effect of leptin on the mRNA expression of Il1b, Il6, and Tnfa in quadricep muscle-derived cells was also examined by stimulating the cells with 0 (control), 1, or 10 μg/mL rat recombinant leptin using Q-RT-PCR.. Aged rats had significantly higher Il6, MuRF1, and Atrogin1 but not Il1b and Tnfa, expression and greater levels of IMAT in their quadricep muscles than young rats. Aged rats also had significantly higher leptin expression and leptin protein concentration in their quadricep muscles than young rats. The addition of exogenous leptin to quadricep muscle-derived cells significantly increased the gene expression of Il1b and Il6 but not Tnfa.. Our results suggest that elevated leptin levels due to aging cause ectopic inflammation through IL-6 in the skeletal muscle of aged rats.

Topics: Adipose Tissue; Aging; Animals; Disease Models, Animal; Female; Interleukin-6; Leptin; Models, Animal; Muscle, Skeletal; Rats; Rats, Sprague-Dawley; Sarcopenia

Breast cancer is the second leading cause of cancer deaths in the USA. Triple-negative breast cancer (TNBC) is a clinically aggressive subtype of breast cancer with high rates of metastasis, tumor recurrence, and resistance to therapeutics. Obesity, defined by a high body mass index (BMI), is an established risk factor for breast cancer. Women with a high BMI have increased incidence and mortality of breast cancer; however, the mechanisms(s) by which obesity promotes tumor progression are not well understood.. In this study, obesity-altered adipose stem cells (obASCs) were used to evaluate obesity-mediated effects of TNBC. Both in vitro and in vivo analyses of TNBC cell lines were co-cultured with six pooled donors of obASCs (BMI > 30) or ASCs isolated from lean women (lnASCs) (BMI < 25).. We found that obASCs promote a pro-metastatic phenotype by upregulating genes associated with epithelial-to-mesenchymal transition and promoting migration in vitro. We confirmed our findings using a TNBC patient-derived xenograft (PDX) model. PDX tumors grown in the presence of obASCS in SCID/beige mice had increased circulating HLA1. Leptin signaling is a potential mechanism through which obASCs promote metastasis of TNBC in both in vitro and in vivo analyses.

Topics: Adipose Tissue; Animals; Biopsy; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Coculture Techniques; Disease Models, Animal; Female; Gene Expression Profiling; Gene Knockout Techniques; Humans; Leptin; Mice; Obesity; Stem Cells; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

Hepatic steatosis develops when lipid influx and production exceed the liver's ability to utilize/export triglycerides. Obesity promotes steatosis and is characterized by leptin resistance. A role of leptin in hepatic lipid handling is highlighted by the observation that recombinant leptin reverses steatosis of hypoleptinemic patients with lipodystrophy by an unknown mechanism. Since leptin mainly functions via CNS signaling, we here examine in rats whether leptin regulates hepatic lipid flux via the brain in a series of stereotaxic infusion experiments. We demonstrate that brain leptin protects from steatosis by promoting hepatic triglyceride export and decreasing de novo lipogenesis independently of caloric intake. Leptin's anti-steatotic effects are generated in the dorsal vagal complex, require hepatic vagal innervation, and are preserved in high-fat-diet-fed rats when the blood brain barrier is bypassed. Thus, CNS leptin protects from ectopic lipid accumulation via a brain-vagus-liver axis and may be a therapeutic strategy to ameliorate obesity-related steatosis.

Topics: Animals; Blood-Brain Barrier; Diet, High-Fat; Disease Models, Animal; Humans; Infusions, Intraventricular; Injections, Intraventricular; Leptin; Lipogenesis; Lipoproteins, VLDL; Liver; Male; Medulla Oblongata; Non-alcoholic Fatty Liver Disease; Polyethylene Glycols; Rats; Rats, Sprague-Dawley; Stereotaxic Techniques; Sympathectomy; Triglycerides; Vagus Nerve

Berardinelli-Seip congenital generalized lipodystrophy is associated with increased bone mass suggesting that fat tissue regulates the skeleton. Because there is little mechanistic information regarding this issue, we generated "fat-free" (FF) mice completely lacking visible visceral, subcutaneous and brown fat. Due to robust osteoblastic activity, trabecular and cortical bone volume is markedly enhanced in these animals. FF mice, like Berardinelli-Seip patients, are diabetic but normalization of glucose tolerance and significant reduction in circulating insulin fails to alter their skeletal phenotype. Importantly, the skeletal phenotype of FF mice is completely rescued by transplantation of adipocyte precursors or white or brown fat depots, indicating that adipocyte derived products regulate bone mass. Confirming such is the case, transplantation of fat derived from adiponectin and leptin double knockout mice, unlike that obtained from their WT counterparts, fails to normalize FF bone. These observations suggest a paucity of leptin and adiponectin may contribute to the increased bone mass of Berardinelli-Seip patients.

Topics: Adipocytes; Adiponectin; Adipose Tissue, Brown; Animals; Bone Density; Disease Models, Animal; Female; Glucose; Humans; Insulin; Intra-Abdominal Fat; Leptin; Lipodystrophy, Congenital Generalized; Mice; Mice, Knockout; Osteosclerosis; Skeleton; Subcutaneous Fat

Kindlin-2 regulates integrin-mediated cell adhesion to and migration on the extracellular matrix. Our recent studies demonstrate important roles of kindlin-2 in regulation of mesenchymal stem cell differentiation and skeletal development. In this study, we generated adipose tissue-specific conditional knockout of kindlin-2 in mice by using Adipoq-Cre BAC-transgenic mice. The results showed that deleting kindlin-2 expression in adipocytes in mice caused a severe lipodystrophy with drastically reduced adipose tissue mass. Kindlin-2 ablation elevated the blood levels of nonesterified fatty acids and triglycerides, resulting in massive fatty livers in the mutant mice fed with high-fat diet (HFD). Furthermore, HFD-fed mutant mice displayed type II diabetes-like phenotypes, including elevated levels of fasting blood glucose, glucose intolerance, and peripheral insulin resistance. Kindlin-2 loss dramatically reduced the expression levels of multiple key factors, including PPARγ, mTOR, AKT, and β-catenin proteins, and suppressed adipocyte gene expression and differentiation. Finally, kindlin-2 loss drastically reduced leptin production and caused a high bone mass phenotype. Collectively, these studies establish a critical role of kindlin-2 in control of adipogenesis and lipid metabolism as well as bone homeostasis.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Adipose Tissue; Adiposity; Animals; Blood Glucose; Cytoskeletal Proteins; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Fatty Acids, Nonesterified; Fatty Liver; Female; Humans; Insulin; Insulin Resistance; Leptin; Lipid Metabolism; Lipodystrophy; Liver; Male; Mice; Mice, Knockout; Muscle Proteins; Severity of Illness Index; Triglycerides

In the context of diabetes, the health benefit of antioxidant treatment has been widely debated. In this study, we investigated the effect of antioxidant treatment during the development of insulin resistance and hyperphagia in obesity and partial lipodystrophy.. We studied the role of antioxidants in the regulation of insulin resistance using the tamoxifen-inducible fat-specific insulin receptor knockout (iFIRKO) mouse model, which allowed us to analyse the antioxidant's effect in a time-resolved manner. In addition, leptin-deficient ob/ob mice were used as a hyperphagic, chronically obese and diabetic mouse model to validate the beneficial effect of antioxidants on metabolism.. Acute induction of insulin receptor knockout in adipocytes changed the substrate preference to fat before induction of a diabetic phenotype including hyperinsulinaemia and hyperglycaemia. In healthy chow-fed animals as well as in morbidly obese mice, this diabetic phase could be reversed within a few weeks. Furthermore, after the induction of insulin receptor knockout in mature adipocytes, iFIRKO mice were protected from subsequent obesity development through high-fat diet feeding. By genetic tracing we show that the persistent fat mass loss in mice after insulin receptor knockout in adipocytes is not caused by the depletion of adipocytes. Treatment of iFIRKO mice with antioxidants postponed and reduced hyperglycaemia by increasing insulin sensitivity. In ob/ob mice, antioxidants rescued both hyperglycaemia and hyperphagia.. We conclude that fat mass reduction through insulin resistance in adipocytes is not reversible. Furthermore, it seems unlikely that adipocytes undergo apoptosis during the process of extreme lipolysis, as a consequence of insulin resistance. Antioxidants have a beneficial health effect not only during the acute phase of diabetes development, but also in a temporary fashion once chronic obesity and diabetes have been established.

Topics: Adipocytes; Adipose Tissue, Brown; Animals; Antioxidants; Blood Glucose; Calorimetry; Diabetes Mellitus; Disease Models, Animal; Glucose; Homeostasis; Hyperinsulinism; Hyperphagia; Insulin; Insulin Resistance; Leptin; Lipodystrophy; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity, Morbid; Receptor, Insulin

Compelling clinical evidence indicates that obesity and its associated metabolic abnormalities supersede the protective effects of female sex-hormones and predisposes premenopausal women to cardiovascular disease. The underlying mechanisms remain poorly defined; however, recent studies have implicated overactivation of the aldosterone-MR (mineralocorticoid receptor) axis as a cause of sex-specific cardiovascular risk in obese females. Experimental evidence indicates that the MR on endothelial cells contributes to obesity-associated, leptin-induced endothelial dysfunction in female experimental models, however, the vascular-specific mechanisms via which females are predisposed to heightened endothelial MR activation remain unknown. Therefore, we hypothesized that endogenous expression of endothelial MR is higher in females than males, which predisposes them to obesity-associated, leptin-mediated endothelial dysfunction. We found that endothelial MR expression is higher in blood vessels from female mice and humans compared with those of males, and further, that PrR (progesterone receptor) activation in endothelial cells is the driving mechanism for sex-dependent increases in endothelial MR expression in females. In addition, we show that genetic deletion of either the endothelial MR or PrR in female mice prevents leptin-induced endothelial dysfunction, providing direct evidence that interaction between the PrR and MR mediates obesity-associated endothelial impairment in females. Collectively, these novel findings suggest that progesterone drives sex-differences in endothelial MR expression and predisposes female mice to leptin-induced endothelial dysfunction, which indicates that MR antagonists may be a promising sex-specific therapy to reduce the risk of cardiovascular diseases in obese premenopausal women.

Topics: Animals; Disease Models, Animal; Endothelium, Vascular; Female; Gene Expression Regulation; Leptin; Male; Mice; Mice, Inbred BALB C; Obesity; Progesterone; Random Allocation; Receptors, Mineralocorticoid; Risk Assessment; Sensitivity and Specificity; Sex Factors; Up-Regulation

Selenium, an essential trace element known mainly for its antioxidant properties, is critical for proper brain function and regulation of energy metabolism. Whole-body knockout of the selenium recycling enzyme, selenocysteine lyase (Scly), increases susceptibility to metabolic syndrome and diet-induced obesity in mice. Scly knockout mice also have decreased selenoprotein expression levels in the hypothalamus, a key regulator of energy homeostasis. This study investigated the role of selenium in whole-body metabolism regulation using a mouse model with hypothalamic knockout of Scly. Agouti-related peptide (Agrp) promoter-driven Scly knockout resulted in reduced weight gain and adiposity while on a high-fat diet (HFD). Scly-Agrp knockout mice had reduced Agrp expression in the hypothalamus, as measured by Western blot and immunohistochemistry (IHC). IHC also revealed that while control mice developed HFD-induced leptin resistance in the arcuate nucleus, Scly-Agrp knockout mice maintained leptin sensitivity. Brown adipose tissue from Scly-Agrp knockout mice had reduced lipid deposition and increased expression of the thermogenic marker uncoupled protein-1. This study sheds light on the important role of selenium utilization in energy homeostasis, provides new information on the interplay between the central nervous system and whole-body metabolism, and may help identify key targets of interest for therapeutic treatment of metabolic disorders.

Topics: Adipose Tissue, Brown; Adiposity; Agouti-Related Protein; Animals; Diet, High-Fat; Disease Models, Animal; Female; Gene Knockout Techniques; Hypothalamus; Leptin; Lyases; Male; Mice, Inbred C57BL; Mice, Knockout; Neurons; Obesity; Signal Transduction; Uncoupling Protein 1; Weight Gain

Functional oligosaccharides, particularly konjac mannan oligosaccharides (KMOS), can regulate glucose metabolism. However, the molecular mechanisms involved in the hypoglycemic effect of KMOS remain largely unknown. Here, the effect of KMOS supplementation on glucose homeostasis was evaluated in both high-fat diet (HFD)-fed C57BL/6J mice and high-glucosamine-induced HepG2 cells. KMOS supplementation remarkably ameliorated the fasting blood glucose, glucose tolerance, and insulin tolerance of HFD-fed mice. Abnormalities of triglyceride and glycogen metabolism in the liver induced by the HFD were reversed by KMOS supplementation. The insulin signaling pathway was activated by KMOS, with stimulation of GLUT2 membrane translocation and glucose uptake in HepG2 cells via the AMPK pathway. Moreover, KMOS suppressed p-mTOR expression and stimulated the GSK-3β/CREB pathway via the AMPK pathway. KMOS significantly upregulated leptin receptor expression and downregulated PTP1B and SOCS3 levels in the liver and brain, with a decreased serum leptin concentration. Phosphorylation of JAK2 and STAT3 in the liver was activated by KMOS supplementation, while the expressions of Sirt1, Tfam, and Pgc1-α in the brain were elevated. Conclusively, KMOS attenuated HFD-induced glucose metabolism dysfunction through the regulation of insulin resistance and leptin resistance. This finding indicates that KMOS have potential value as an anti-hyperglycemic dietary supplement.

Topics: Animals; Biomarkers; Blood Glucose; Diet, High-Fat; Dietary Supplements; Disease Models, Animal; Glucose Metabolism Disorders; Hep G2 Cells; Hepatocytes; Homeostasis; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Liver; Male; Mannans; Mice, Inbred C57BL; Signal Transduction

Leptin, an adipocyte-derived cytokine associated with bone metabolism, is believed to play a critical role in the pathogenesis of heterotopic ossification (HO). The effect and underlying action mechanism of leptin were investigated on osteogenic differentiation of tendon-derived stem cells (TDSCs) in vitro and the HO formation in rat tendons. Isolated rat TDSCs were treated with various concentrations of leptin in the presence or absence of mTORC1 signaling specific inhibitor rapamycin in vitro. A rat model with Achilles tenotomy was employed to evaluate the effect of leptin on HO formation together with or without rapamycin treatment. In vitro studies with TDSCs showed that leptin increased the expression of osteogenic biomarkers (alkaline phosphatase, runt-related transcription factor 2, osterix, osteocalcin) and enhanced mineralization of TDSCs via activating the mTORC1 signal pathway (as indicated by phosphorylation of p70 ribosomal S6 kinase 1 and p70 ribosomal S6). However, mTORC1 signaling blockade with rapamycin treatment suppressed leptin-induced osteogenic differentiation and mineralization. In vivo studies showed that leptin promoted HO formation in the Achilles tendon after tenotomy, and rapamycin treatment blocked leptin-induced HO formation. In conclusion, leptin can promote TDSC osteogenic differentiation and heterotopic bone formation via mTORC1 signaling in both vitro and vivo model, which provides a new potential therapeutic target for HO prevention.

Topics: Animals; Cell Differentiation; Cells, Cultured; Core Binding Factor Alpha 1 Subunit; Disease Models, Animal; Dose-Response Relationship, Drug; Leptin; Male; Mechanistic Target of Rapamycin Complex 1; Ossification, Heterotopic; Osteoblasts; Osteogenesis; Phenotype; Rats, Sprague-Dawley; Receptors, Leptin; Signal Transduction; Stem Cells; Tendons; Transcription Factors

Overpressure blast-wave induced brain injury (OBI) and its long-term neurological outcome pose significant concerns for military personnel. Our aim is to investigate the mechanism of injury due to OBI.. Rats were divided into 3 groups: (1) Control, (2) OBI (exposed 30psi peak pressure, 2-2.5ms), (3) Repeated OBI (r-OBI) (three exposures over one-week period). Lung and brain (cortex and cerebellum) tissues were collected at 24h post injury.. The neurological examination score was worse in OBI and r-OBI (4.2±0.6 and 3.7±0.5, respectively) versus controls (0.7±0.2). A significant positive correlation between lung and brain edema was found. Malondialdehyde (index for lipid peroxidation), significantly increased in OBI and r-OBI groups in cortex (p<0.05) and cerebellum (p<0.01-0.001). The glutathione (endogenous antioxidant) level decreased in cortex (p<0.01) and cerebellum (p<0.05) of r-OBI group when compared with the controls. Myeloperoxidase activity indicating neutrophil infiltration, was significantly (p<0.01-0.05) elevated in r-OBI. Additionally, tissue thromboplastin activity, a coagulation marker, was elevated, indicating a tendency to bleed. NGF and NF-κB proteins along with Iba-1 and GFAP immunoreactivity significantly augmented in the frontal cortex demonstrating microglial activation. Serum biomarkers of injury, NSE, TNF-alpha and leptin, were also elevated.. OBI triggers both inflammation and oxidative injury in the brain. This data in conjunction with our previous observations suggests that OBI triggers a cascade of events beginning with impaired cerebral vascular function leading to ischemia and chronic neurological consequences.

Topics: Animals; Blast Injuries; Blood-Brain Barrier; Brain Edema; Cerebellum; Disease Models, Animal; Frontal Lobe; Gliosis; Glutathione; Inflammation; Leptin; Lung; Male; Malondialdehyde; Microglia; Oxidative Stress; Peroxidase; Rats, Sprague-Dawley; Thromboplastin

Exercise during pregnancy has beneficial effects on maternal and offspring's health in humans and mice. The underlying mechanisms remain unclear. This comparative study aimed to determine the long-term effects of an exercise program on metabolism, weight gain, body composition and changes in hormones [insulin, leptin, brain-derived neurotrophic factor (BDNF)]. Pregnant women (n=34) and mouse dams (n=44) were subjected to an exercise program compared with matched controls (period I). Follow-up in the offspring was performed over 6 months in humans, corresponding to postnatal day (P) 21 in mice (period II). Half of the mouse offspring was challenged with a high-fat diet (HFD) for 6 weeks between P70 and P112 (period III). In period I, exercise during pregnancy led to 6% lower fat content, 40% lower leptin levels and an increase of 50% BDNF levels in humans compared with controls, which was not observed in mice. After period II in humans and mice, offspring body weight did not differ from that of the controls. Further differences were observed in period III. Offspring of exercising mouse dams had significantly lower fat mass and leptin levels compared with controls. In addition, at P112, BDNF levels in offspring were significantly higher from exercising mothers while this effect was completely blunted by HFD feeding. In this study, we found comparable effects on maternal and offspring's weight gain in humans and mice but different effects in insulin, leptin and BDNF. The long-term potential protective effects of exercise on biomarkers should be examined in human studies.

Topics: Adiposity; Adult; Animals; Biomarkers; Brain-Derived Neurotrophic Factor; Diet, High-Fat; Disease Models, Animal; Female; Follow-Up Studies; Humans; Infant; Infant, Newborn; Insulin; Leptin; Mice; Mice, Inbred C57BL; Mothers; Obesity; Physical Conditioning, Animal; Physical Conditioning, Human; Physical Fitness; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Weight Gain

The objective of this study is to characterize the relationship between forkhead box C2 protein (Foxc2) and leptin under adipose inflammatory response.. Lipopolysaccharide (LPS)-induced inflammatory model was conducted. Data from wild-type and ob/ob mice were used to compare the alternative role of leptin on Foxc2-mediated inflammation and browning. Transcriptional regulation and protein-protein interaction were analyzed by bioinformatics and proved by chromatin immunoprecipitation and co-immunoprecipitation experiment.. Foxc2 and leptin correlated with inflammation and browning of white adipose tissue (WAT) in LPS-treated mice. Moreover, Foxc2-mediated inhibition of inflammation involved downstream activation of leptin signal and promoted WAT browning. We then determined CREB, the potential transcriptional factor of leptin, was required for Foxc2-mediated inflammation in the regulation of WAT browning. Foxc2 alleviated adipocyte inflammation by reducing leptin-mediated Janus-activated kinase 2/signal transducer and activator of transcription 3 (STAT3) pathway. Importantly, STAT3 physically interacted with PRDM16 and formed a complex to promote WAT browning. Exogenous Foxc2 overexpression also ameliorated inflammation and promoted adipose browning in high fat diet (HFD)-induced obese mice.. Our results indicated that Foxc2 inhibited inflammation and promoted browning of WAT through positive regulation of leptin signal and the STAT3-PRDM16 complex. These findings identify a new potential means to prevent and treat obese caused metabolic syndrome of mammals.

Topics: Adipose Tissue, Brown; Adipose Tissue, White; Adiposity; Animals; Disease Models, Animal; DNA-Binding Proteins; Forkhead Transcription Factors; Inflammation; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Signal Transduction; STAT3 Transcription Factor; Transcription Factors

Consumption of fat and sugar induces hyperphagia and increases the prevalence of obesity and diabetes type 2. Low-grade inflammation in the hypothalamus, a key brain area involved in the regulation of energy homeostasis is shown to blunt signals of satiety after long term high fat diet. The fact that this mechanism can be activated after a few days of hyperphagia before apparent obesity is present led to our hypothesis that hypothalamic inflammation is induced with fat and sugar consumption. Here, we used a free-choice high-fat high-sugar (fcHFHS) diet-induced obesity model and tested the effects of differential overnight nutrient intake during the final experimental night on markers of hypothalamic inflammation. Male Wistar rats were fed a control diet or fcHFHS diet for one week, and assigned to three different feeding conditions during the final experimental night: 1) fcHFHS-fed, 2) fed a controlled amount of chow diet, or 3) fasted. RT-qPCR and Western blot were utilized to measure hypothalamic gene and protein expression, of cytokines and intermediates of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. Lastly, we investigated the effects of acute fat intake on markers of hypothalamic inflammation in fat-naïve rats. fcHFHS-fed rats consumed more calories, increased adipose tissue, and showed elevated expression of hypothalamic inflammation markers (increased phosphorylation of NF-κB protein, Nfkbia and Il6 gene expression) compared to chow-fed rats. These effects were evident in rats consuming relative high amounts of fat. Removal of the fat and sugar, or fasting, during the final experimental night ameliorated hypothalamic inflammation. Finally, a positive correlation was observed between overnight acute fat consumption and hypothalamic NF-κB phosphorylation in fat-naïve rats. Our data indicate that one week of fcHFHS diet, and especially the fat component, promotes hypothalamic inflammation, and removal of the fat and sugar component reverses these detrimental effects.

Topics: Adiposity; Animals; Cytokines; Diet, High-Fat; Dietary Fats; Dietary Sugars; Disease Models, Animal; Eating; Food Deprivation; Hyperphagia; Hypothalamus; Inflammation; Leptin; Male; NF-kappa B; Obesity; Phosphorylation; Rats; Rats, Wistar

Binge eating is a specific form of overeating characterized by intermittent, excessive eating. To date, several studies have addressed the effects that bingeing on fat has on the rewarding effects of drugs of abuse, but they have found contradictory and highly variable results. Housing conditions could modulate these results, as most studies employ isolated animals to measure the exact amount of food that is ingested. The aim of this study was to evaluate the effects of housing conditions on the response of mice to cocaine, modulated by bingeing on a high-fat diet during adolescence. After 40days of binge-eating for 2h, three days a week (PND 29-69), the reinforcing effects of a non-effective dose of cocaine (1mg/kg) was evaluated using the conditioned place preference (CPP) paradigm. The anxiolytic profile using the Elevated Plus Maze and circulating leptin and corticosterone levels were also assessed. Our results show a significant escalation in the consumption of a high-fat diet between the first and the last week in both types of housed mice. Among the grouped mice, only those exposed to high-fat binge (HFB) developed CPP. Conversely, isolated mice fed with standard diet were more sensitive to the rewarding effects of a subthreshold dose of cocaine than those fed with HFB. Plasma leptin levels were elevated in both groups that developed CPP. Although isolated animals presented higher corticosterone levels with respect to the grouped ones, anxiety levels did not differ. Therefore, our results highlight the importance of housing conditions on the effects that a high-fat diet exerts on cocaine reward.

Topics: Animals; Animals, Outbred Strains; Anxiety; Bulimia; Cocaine; Cocaine-Related Disorders; Conditioning, Psychological; Corticosterone; Diet, High-Fat; Disease Models, Animal; Dopamine Uptake Inhibitors; Housing, Animal; Leptin; Male; Mice; Random Allocation; Reward; Social Isolation; Spatial Behavior

We explored the effects of RNA interference-mediated silencing of TLR4 gene on expressions of adipocytokines in obstructive sleep apnea hyponea syndrome (OSAS) with hypertension in a rat model. Systolic blood pressure of caudal artery and physiological changes were observed when establishing rat models of OSAS with hypertension. Mature rat adipocytes were induced from separated and cultured primary rat adipocytes. To transfect rat mature adipocytes, TLR4 siRNA group and negative control (NC) siRNA group were established. Expressions of TLR4 mRNA of adipocytes were examined after silenced by siRNA by quantitative real-time polymerase chain reaction (qRT-PCR). By enzyme-linked immunosorbent assay (ELISA), expressions of inflammatory cytokines, and adipocytokines of adipocytes were detected. Blood pressure in rat caudal artery was higher in the intermittent hypoxia group than that of the blank control group by 29.87 mmHg, and cardiocytes in the former group showed physiological changes, which indicated successful establishment of rat models of OSAS with hypertension. Red particles could be seen in mature rat adipocytes when stained with Oil Red O. Transfection of TLR4 mRNA was significantly suppressed in the TLR4 siRNA group, which didn't happen in the untransfected control group. Rats in the TLR4 siRNA group had significantly reduced expressions of such inflammatory cytokines as interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α) and such adipocytokines as visfatin, adiponectin (ADN), and leptin than those in the untransfected control group. RNA interference-mediated silencing of TLR4 gene could regulate occurrence and development of OSAS with hypertension in rats by downregulating expressions of adipocytokines.

Topics: Adipocytes; Adipokines; Adiponectin; Animals; Cytokines; Disease Models, Animal; Gene Expression Regulation; Humans; Hypertension; Interleukin-6; Interleukin-8; Leptin; Male; Nicotinamide Phosphoribosyltransferase; Rats; RNA, Small Interfering; Sleep Apnea, Obstructive; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Leptin is a peptide hormone produced by adipose tissue whose basic function is regulating energy balance and sympathetic outflow. Previous studies have shown that increased nerve activity of the left stellate ganglion (LSG) promotes ventricular arrhythmia (VA).. The purpose of this study was to investigate whether leptin could facilitate VA through activation of the LSG.. Sixteen pentobarbital-anesthetized dogs were divided into a control group (saline; n = 8) and a leptin group (leptin; n = 8). Microinjections of either 0.1 mL saline or leptin (18 μg) were injected into the LSG. Action potential duration (APD) of the myocyte and the function and neural activity of the LSG were measured at different time points. VA induced by occlusion of the left anterior descending branch was continuously measured for 1 hour. At the end of the experiment, the LSG tissues were collected for molecular detections.. Compared with the control group, leptin microinjection resulted in (1) significant enhancement in the incidence of VA; (2) significant decrease in APD and increase in APD dispersion; and (3) significant increase in the function and neural activity of the LSG. Mechanistically, the leptin receptor was found in the LSG, and its signaling was significantly activated in the leptin-injected group. Additionally, leptin microinjection markedly increased the expression of proinflammatory cytokines.. LSG activation induced by leptin microinjection promotes ischemia-induced VAs. Activated leptin receptor signaling and up-regulation of proinflammatory cytokines in the LSG may be responsible for these effects.

Topics: Action Potentials; Animals; Disease Models, Animal; Dogs; Electrocardiography; Injections; Leptin; Male; Myocardial Ischemia; Stellate Ganglion; Sympathetic Nervous System; Tachycardia, Ventricular

We have previously shown that following oral delivery in dodecyl maltoside (DDM), [D-Leu-4]-OB3 and its myristic acid conjugate, MA-[D-Leu-4]-OB3, improved energy balance and glucose homeostasis in genetically obese/diabetic mouse models. More recently, we have provided immunohistochemical evidence indicating that these synthetic peptide leptin mimetics cross the blood-brain barrier and concentrate in the area of the arcuate nucleus of the hypothalamus in normal C57BL/6J and Swiss Webster mice, in genetically obese ob/ob mice, and in diet-induced obese (DIO) mice. In the present study, we describe the effects of oral delivery of [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3 on glycemic control in diet-induced (DIO) mice, a non-genetic rodent model of obesity and its associated insulin resistance, which more closely recapitulates common obesity and diabetes in humans. Male C57BL/6J and DIO mice, 17, 20, and 28 weeks of age, were maintained on a low-fat or high-fat diet and given vehicle (DDM) alone or [D-Leu-4]-OB3 or MA-[D-Leu-4]-OB3 in DDM by oral gavage for 12 or 14 days. Body weight gain, food and water intake, fasting blood glucose, oral glucose tolerance, and serum insulin levels were measured. Our data indicate that (1) [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3 restore glucose tolerance in male DIO mice maintained on a high-fat diet to levels comparable to those of non-obese C57BL/6J wild-type mice of the same age and sex maintained on a low-fat diet; and (2) the influence of [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3 on glycemic control appears to be independent of their effects on energy balance. These results suggest that [D-Leu-4]-OB3 and/or MA-[D-Leu-4]-OB3 may have application to the management of the majority of cases of common obesity in humans, a state characterized at least in part, by leptin resistance resulting from a defect in leptin transport across the blood-brain barrier. They further suggest that these small molecule synthetic peptide leptin mimetics, through their influence on glycemic control, may prevent the pre-diabetic state associated with most cases of common obesity from escalating into overt type 2 diabetes mellitus.

Topics: Animals; Biomimetic Materials; Dietary Fats; Disease Models, Animal; Glucose Tolerance Test; Insulin; Leptin; Male; Mice; Mice, Obese; Obesity; Peptides

The mechanism of linking neonatal seizures with long-term brain damage is unclear, and there is no effective drug to block this long-term pathological process. Recently, the fat-derived hormone leptin has been appreciated for its neuroprotective function in neurodegenerative processes, although less is known about the effects of leptin on neonatal seizure-induced brain damage. Here, we developed a "twist" seizure model by coupling pilocarpine-induced neonatal status epilepticus (SE) with later exposure to penicillin to test whether leptin treatment immediately after neonatal SE would exert neuroprotective effects on cognition, seizure threshold and hippocampal mossy fiber sprouting, as well if leptin had any influence on the expression of zinc transporter 3 (ZnT3) and calcium homeostasis-related CB-D28k in the hippocampus. Fifty Sprague-Dawley rats (postnatal day 6, P6) were randomly assigned to four groups: control (n = 10), control with intraperitoneal (i.p.) injection of leptin (Leptin, n = 10), pilocarpine-induced neonatal SE (RS), and RS i.p. leptin injection (RS+Leptin). At P6, all the rats in the RS group and RS+Leptin group were injected with lithium chloride i.p. (5 mEq/kg). Pilocarpine (320 mg/kg, i.p.) was administered 30 min after scopolamine methyl chloride (1 mg/kg) injection at P7 to block the peripheral effect of pilocarpine. From P8 to P14, the animals in the Leptin group and RS+Leptin group were given leptin (4 mg/kg, i.p.). The Morris water maze test was performed during P28-P33. Following routine seizure threshold detection and Timm staining procedures, Western blot analysis was performed for each group. Pilocarpine-induced neonatal SE severely impaired learning and memory abilities, reduced seizure threshold, and induced aberrant hippocampal CA3 mossy fiber sprouting. In parallel, there was a significantly down-regulated protein level of CB-D28k and an up-regulated protein level of ZnT3 in the hippocampus of the RS group. Furthermore, leptin treatment soon after neonatal SE for seven consecutive days counteracted these hyperexcitability-related alterations. These novel findings established that leptin has a neuroprotective role in the model of cholinergic neonatal SE and highlights ZnT3/CB-D28k associated-Zn (2+)/Ca (2+) signaling as a promising therapeutic target.

Topics: Animals; Animals, Newborn; Calbindin 1; Cation Transport Proteins; Disease Models, Animal; Hippocampus; Leptin; Maze Learning; Neuroprotective Agents; Random Allocation; Rats, Sprague-Dawley; Seizures

A trypsin inhibitor isolated from tamarind seed (TTI) has satietogenic effects in animals, increasing the cholecystokinin (CCK) in eutrophy and reducing leptin in obesity. We purified TTI (pTTI), characterised, and observed its effect upon CCK and leptin in obese Wistar rats. By HPLC, and after amplification of resolution, two protein fractions were observed: Fr1 and Fr2, with average mass of [M + 14H]

Topics: Animals; Anti-Obesity Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Leptin; Male; Obesity; Peptides; Plant Proteins; Rats; Rats, Wistar; Seeds; Structure-Activity Relationship; Tamarindus; Trypsin

Excessive fatty acid release from the white adipose tissue (WAT) contributes to the development of alcoholic liver disease (ALD). Lipin1 (LPIN1), as a co-regulator of DNA-bound transcription factors and a phosphatidic acid (PA) phosphatase (PAP) enzyme that dephosphorylates PA to form diacylglycerol (DAG), is dramatically reduced by alcohol in the WAT. This study aimed at determining the role of adipose LPIN1 in alcohol-induced lipodystrophy and the development of ALD. Transgenic mice overexpressing LPIN1 in adipose tissue (LPIN1-Tg) and wild type (WT) mice were fed a Lieber-DeCarli alcohol or isocaloric maltose dextrin control liquid diet for 8 weeks. Alcohol feeding to WT mice resulted in significant liver damage, which was significantly alleviated in the LPIN1-Tg mice. Alcohol feeding significantly reduced epididymal WAT (EWAT) mass, inhibited lipogenesis, and increased lipolysis in WT mice, which were attenuated in the LPIN1-Tg mice. LPIN1 overexpression also partially reversed alcohol-reduced plasma leptin levels. In WT mice, alcohol feeding induced hepatic lipid accumulation and down-regulation of beta-oxidation genes, which were dramatically alleviated in the LPIN1-Tg mice. LPIN1 overexpression also significantly attenuated alcohol-induced hepatic ER stress. These results suggest that overexpression of LPIN1 in adipose tissue restores WAT lipid storage function and secretive function to alleviate alcohol-induced liver injury.

Topics: Adipose Tissue, White; Animals; Cell Line; Disease Models, Animal; Endoplasmic Reticulum Stress; Fatty Liver, Alcoholic; Leptin; Lipodystrophy; Lipogenesis; Lipolysis; Male; Mice; Mice, Transgenic; Nuclear Proteins; Phosphatidate Phosphatase; Phosphatidic Acids

Mouse models of obesity (ob/ob) and diabetes (db/db) in which the leptin (Lep) and leptin receptor (Lepr) genes have been mutated, respectively, have contributed to a better understanding of human obesity and type 2 diabetes and to the prevention, diagnosis, and treatment of these metabolic diseases. In this study, we report the first CRISPR-Cas9-induced Lep and Lepr knockout (KO) mouse models by co-microinjection of Cas9 mRNA and sgRNAs that specifically targeted Lep or Lepr in C57BL/6J embryos. Our newly established Lep and Lepr KO mouse models showed phenotypic disorders nearly identical to those found in ob/ob and db/db mice, such as an increase in body weight, hyperglycemia, and hepatic steatosis. Thus, Cas9-generated Lep and Lepr KO mouse lines will be easier for genotyping, to maintain the lines, and to use for future obesity and diabetes research.

Topics: Animals; CRISPR-Cas Systems; Diabetes Mellitus, Type 2; Disease Models, Animal; Leptin; Mice, Inbred C57BL; Mice, Knockout; Microinjections; Mutation; Obesity; Receptors, Leptin; RNA, Messenger

Visceral fat deposition is associated with impairment of glucose and lipid metabolism while leptin levels are frequently related to subcutaneous fat area. At present, there is considerable controversy regarding the role of visceral adipose tissue accumulation in the development of metabolic syndrome (MS). Here we show the effects of omentectomy on the liver and MS in a diet induced obesity rat model. Our results reveal that undergoing omentectomy previously the establishment of the diet-induced-obesity reduced significantly body weight gain and avoid the development of MS, including non-alcoholic fatty liver disease. Intriguingly, the significantly lower body weight gain was due to decreased food intake. Omentum drives obesity progression through leptin resistance mediated by C-reactive protein, Interleucin (IL)-6 and high lipolysis activity. Omentum removal reversed immediately the increased plasma levels of CRP and IL-6 and gradually food intake, weight gain, and features of MS in diet-induced-obesity. Omentectomy caused no changes in normal-weigh-rats. This report displays causal mechanism by which omentum promotes obesity and propose omentectomy as a promising procedure in MS prevention.

Topics: Adipogenesis; Animals; Appetite; Body Weight; C-Reactive Protein; Disease Models, Animal; Interleukin-6; Leptin; Metabolic Syndrome; Obesity; Omentum; Rats; Surgical Procedures, Operative; Treatment Outcome

Obesity enhances the risk of developing myelodysplastic syndromes. However, the effect of obesity on survival is unclear. Obese people present with monocytosis due to inflammatory signals emanating from obese adipose tissue. We hypothesized that obesity-induced myelopoiesis would promote the transition of myelodysplastic syndrome to acute myeloid leukemia and accelerate mortality in obesity. Obese Ob/Ob mice or their lean littermate controls received a bone marrow transplant from NUP98-HOXD13 transgenic mice, a model of myelodysplastic syndrome. The metabolic parameters of the mice were examined throughout the course of the study, as were blood leukocytes. Myeloid cells were analyzed in the bone, spleen, liver and adipose tissue by flow cytometry halfway through the disease progression and at the endpoint. Survival curves were also calculated. Contrary to our hypothesis, transplantation of NUP98-HOXD13 bone marrow into obese recipient mice significantly increased survival time compared with lean recipient controls. While monocyte skewing was exacerbated in obese mice receiving NUP98-HOXD13 bone marrow, transformation to acute myeloid leukemia was not enhanced. Increased survival of obese mice was associated with a preservation of fat mass as well as increased myeloid cell deposition within the adipose tissue, and a concomitant reduction in detrimental myeloid cell accumulation within other organs. The study herein revealed that obesity increases survival in animals with myelodysplastic syndrome. This may be due to the greater fat mass of Ob/Ob mice, which acts as a sink for myeloid cells, preventing their accumulation in other key organs, such as the liver.

Topics: Animals; Bone Marrow; Bone Marrow Transplantation; Disease Models, Animal; Homeodomain Proteins; Leptin; Leukemia, Myeloid, Acute; Mice; Mice, Transgenic; Myelodysplastic Syndromes; Myeloid Cells; Nuclear Pore Complex Proteins; Obesity; Survival Rate; Transcription Factors

Recent findings demonstrate that leptin plays a significant role in chondrocyte and osteoblast differentiation. However, the mechanisms by which leptin acts on cartilage endplate (CEP) cells to give rise to calcification are still unclear. The aim of this study was to evaluate the effects of leptin that induced mineralization of CEP cells in vitro and in vivo. We constructed a rat model of lumbar disc degeneration and determined that leptin was highly expressed in the presence of CEP calcification. Rat CEP cells treated with or without leptin were used for in vitro analysis using RT-PCR and Western blotting to examine the expression of osteocalcin (OCN) and runt-related transcription factor 2 (Runx2). Both OCN and Runx2 expression levels were significantly increased in a dose- and time-dependent manner. Leptin activated ERK1/2 and STAT3 phosphorylation in a time-dependent manner. Inhibition of phosphorylated ERK1/2 using targeted siRNA suppressed leptin-induced OCN and Runx2 expression and blocked the formation of mineralized nodules in CEP cells. We further demonstrated that exogenous leptin induced matrix mineralization of CEP cells in vivo. We suggest that leptin promotes the osteoblastic differentiation of CEP cells via the MAPK/ERK signal transduction pathway and may be used to investigate the mechanisms of disc degeneration.

Topics: Animals; Calcification, Physiologic; Cartilage; Cell Differentiation; Core Binding Factor Alpha 1 Subunit; Disease Models, Animal; Intervertebral Disc Degeneration; Leptin; Lumbar Vertebrae; Male; MAP Kinase Signaling System; Motor Endplate; Osteocalcin; Osteogenesis; Phosphorylation; Rats, Sprague-Dawley; STAT3 Transcription Factor

Opiate-induced respiratory depression is sexually dimorphic and associated with increased risk among the obese. The mechanisms underlying these associations are unknown. The present study evaluated the two-tailed hypothesis that sex, leptin status, and obesity modulate buprenorphine-induced changes in breathing.. Mice (n = 40 male and 40 female) comprising four congenic lines that differ in leptin signaling and body weight were injected with saline and buprenorphine (0.3 mg/kg). Whole-body plethysmography was used to quantify the effects on minute ventilation. The data were evaluated using three-way analysis of variance, regression, and Poincaré analyses.. Relative to B6 mice with normal leptin, buprenorphine decreased minute ventilation in mice with diet-induced obesity (37.2%; P < 0.0001), ob/ob mice that lack leptin (62.6%; P < 0.0001), and db/db mice with dysfunctional leptin receptors (65.9%; P < 0.0001). Poincaré analyses showed that buprenorphine caused a significant (P < 0.0001) collapse in minute ventilation variability that was greatest in mice with leptin dysfunction. There was no significant effect of sex or body weight on minute ventilation.. The results support the interpretation that leptin status but not body weight or sex contributed to the buprenorphine-induced decrease in minute ventilation. Poincaré plots illustrate that the buprenorphine-induced decrease in minute ventilation variability was greatest in mice with impaired leptin signaling. This is relevant because normal respiratory variability is essential for martialing a compensatory response to ventilatory challenges imposed by disease, obesity, and surgical stress.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Disease Models, Animal; Female; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Respiratory Insufficiency; Sex Factors; Signal Transduction

Chemerin is an adipokine with established roles in inflammation, adipogenesis and the regulation of glucose and lipid homeostasis. Extracellular proteolytic processing of chemerin generates a spectrum of isoforms that differ significantly with respect to the ability to activate the cognate receptors chemokine-like receptor 1 (CMKLR1) and G-protein-coupled receptor 1 (GPR1). Increased total serum chemerin has been widely reported in obese humans as well as in preclinical rodent models of adiposity. However, very little information is available regarding the correspondence, if any, of changes in total serum chemerin protein with chemerin bioactivity.. Total serum chemerin and ex vivo CMKLR1 and GPR1 activation was compared using two widely used murine obesity models: high fat diet feeding (HFD) and leptin deficiency (ob/ob).. Total serum chemerin levels and ex vivo CMKLR1 and GPR1 activation were significantly induced in HFD. The bioactivity ratio (bioactive chemerin/total chemerin) was also increased when measured with CMKLR1, but not GPR1. In contrast, while ob/ob mice exhibited increased total serum chemerin protein, ex vivo receptor activation was observed with GPR1, but not CMKLR1. There was no change in bioactivity ratio for either receptor. Of note, GPR1 but not CMKLR1 bioactivity positively correlated with adipose tissue inflammation.. While increased total serum chemerin is a consistent finding among rodent obesity models, this may not accurately reflect changes in chemerin bioactivity which is the major determinant of biological effects.

Topics: Animals; Chemokines; Diet, High-Fat; Disease Models, Animal; Intercellular Signaling Peptides and Proteins; Leptin; Male; Mice, Inbred C57BL; Mice, Obese; Obesity; Receptors, Chemokine; Receptors, G-Protein-Coupled

Hyperandrogenic state in females is accompanied with metabolic syndrome, insulin resistance and vascular pathologies. A total of 67%-85% of hyperandrogenic women suffer also from vitamin D deficiency. We aimed to check a potential interplay between hyperandrogenism and vitamin D deficiency in producing insulin resistance and effects on coronary resistance arteries. Adolescent female rats were divided into four groups, 11-12 animals in each. Transdermal testosterone-treated and vehicle-treated animals were kept either on vitamin D-deficient or on vitamin D-supplemented diet for 8 weeks. Plasma sexual steroid, insulin, leptin and vitamin D plasma levels were measured, and oral glucose tolerance test was performed. In coronary arterioles, insulin receptor and vitamin D receptor expressions were tested by immunohistochemistry, and insulin-induced relaxation was measured in vitro on isolated coronary resistance artery segments. Testosterone impaired glucose tolerance, and it diminished insulin relaxation but did not affect the expression of insulin and vitamin D receptors in vascular tissue. Vitamin D deficiency elevated postprandial insulin levels and homeostatic model assessment insulin resistance. It also diminished insulin-induced coronary arteriole relaxation, while it raised the expression of vitamin D and insulin receptors in the endothelial and medial layers. Our conclusion is that both hyperandrogenism and vitamin D deficiency reduce sensitivity of coronary vascular tissue to insulin, but they do it with different mechanisms.

Topics: Animals; Arterioles; Biomarkers; Blood Glucose; Coronary Artery Disease; Coronary Vessels; Disease Models, Animal; Female; Glucose Tolerance Test; Gonadal Steroid Hormones; Hyperandrogenism; Insulin; Insulin Resistance; Leptin; Polycystic Ovary Syndrome; Rats, Wistar; Time Factors; Vascular Resistance; Vasodilation; Vitamin D; Vitamin D Deficiency

The dysregulation of adipokine secretion owing to adiposopathy can contribute to the pathogenesis of obesity-related disorders. Being that exercise is an advised strategy against obesity-induced adiposopathy, we aimed to analyze the role of physical exercise as a preventive and therapeutic strategy against high-fat diet (HFD)-induced adipokine and ghrelin alterations. Rats were pair-fed the Lieber De Carli standard diet (S, 35 Kcal% fat) or HFD (71 Kcal% fat) over 17 weeks. Animals were assigned into four groups as follows: standard diet sedentary (SS), standard diet voluntary physical activity (SVPA), high-fat diet sedentary (HS), and high-fat diet voluntary physical activity (HVPA). After 9 weeks of dietary treatment, half of the SS and HS animals were submitted to an 8-week endurance training program, standard diet endurance training (SET), and high-fat-diet endurance training (HET) groups, maintaining the respective diets. Although there were no changes in body weight, HFD increased visceral adiposity, percentage of large adipocytes, hypoxia inducible factor (HIF)-1α, and leptin contents in epididymal adipose tissue (eWAT) and decreased plasma content of adiponectin (AdipQ). Both VPA and ET decreased visceral adiposity and percentage of large adipocytes in HFD-fed animals, but ET also increased the percentage of small- to medium-sized adipocytes. VPA increased plasma growth hormone secretagogue receptor (GHS-R) and decreased leptin protein in HVPA group. ET decreased plasma insulin and leptin levels and eWAT HIF-1α and leptin expression in HET group. Moreover, ET improved insulin sensitivity, plasma high molecular weight, and AdipQ and ghrelin levels and increased eWAT and GHS-R expression. Our data suggest that exercise, particularly ET, reverted adiposopathy and related endocrine alterations induced by an isocaloric HFD pair-fed diet.

Topics: Adiponectin; Adipose Tissue; Animals; Body Weight; Diet, High-Fat; Disease Models, Animal; Endocrine System; Ghrelin; Hypoxia-Inducible Factor 1, alpha Subunit; Insulin; Insulin Resistance; Leptin; Male; Obesity; Physical Conditioning, Animal; Rats, Sprague-Dawley; Receptors, Ghrelin; Vascular Endothelial Growth Factor A

Background Melatonin, an important neurohormone released from the pineal gland, is generally accepted to exercise an inhibitor effect on the thyroid gland. Zinc mediates the effects of many hormones and is found in the structure of numerous hormone receptors. Aim The present study aims to examine the effect of melatonin supplementation and pinealectomy on leptin, neuropeptide Y (NPY), melatonin and zinc levels in rats with hypothyroidism and hyperthyroidism. Methods This study was performed on the 70 male rats. Experimental animals in the study were grouped as follows: control (C); hypothyroidism (PTU); hypothyroidism + melatonin (PTU + M); hypothyroidism + pinealectomy (PTU + Pnx); hyperthyroidism (H); hyperthyroidism + melatonin (H + M) and hyperthyroidism + pinealectomy (H + Pnx). Blood samples collected at the end of 4-week procedures were analyzed to determine melatonin, leptin, NPY and zinc levels. Results It was found that thyroid parameters thyroid stimulating hormone (TSH), free triiodthyronine (FT3), free thyroxine (FT4), total T3 (TT3) and total T4 (TT4) decreased in hypothyroidism groups and increased in the groups with hyperthyroidism. The changes in these hormones remained unaffected by melatonin supplementation and pinealectomy. Melatonin levels rose in hyperthyroidism and fell in hypothyroidism. Leptin and NPY levels increased in both hypothyroidism and hyperthyroidism. Zinc levels, on the other hand, decreased in hypothyroidism and pinealectomy, but increased in hyperthyroidism. Conclusion The results of the study demonstrate that hypothyroidism and hyperthyroidism affect leptin, NPY, melatonin and zinc values in different ways in rats. However, melatonin supplementation and pinealectomy do not have any significant influence on the changes occurring in leptin, NPY and zinc levels in thyroid dysfunction.

Topics: Animals; Biomarkers; Dietary Supplements; Disease Models, Animal; Hyperthyroidism; Hypothyroidism; Leptin; Male; Melatonin; Neuropeptide Y; Pineal Gland; Rats; Thyroid Function Tests; Zinc

The combination of traumatic brain injury (TBI) and long-bone fracture leads to increased formation of callus and mineral density in wild-type (WT) mice. However, this effect was not detected radiologically in leptin-deficient mice. Due to the complex interactions between hormonal and bone metabolism and the important role of leptin in this setting, our aim was to investigate morphologic properties and the tissue composition in the fracture callus comparing WT and leptin-deficient mice.. Female C57/Black6N mice (n=36) and leptin deficient ob/ob mice (n=36) each were assigned to two groups (fracture Fx/combined trauma Fx/TBI). Femoral osteotomy was stabilized with external fixator, TBI was induced with controlled cortical impact injury. After sacrifice of the animals, femora were harvested, cryofixated, and 7 µm slices were prepared. Staining was performed adhering to Movat's Pentachrome protocol. Histomorphometric analysis, quantifying percentage of mineralized bone area, and a semi-quantitative evaluation of bone bridging were performed.. Leptin deficient mice showed a higher rate of non-union after osteotomy, less callus formation in the osteotomy gap, and unexpected bone and cartilage formation independent of the osteotomy region.. Leptin plays an important role in fracture healing and bone formation. Without Leptin, the positive effect of TBI on fracture healing ceases. The comprehension of the underlying pathophysiological process could sign important for novel strategies in stimulation of fracture healing.

Topics: Animals; Brain Injuries, Traumatic; Disease Models, Animal; Female; Femoral Fractures; Femur; Fracture Healing; Leptin; Mice; Osteogenesis; Osteotomy

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

Disruption of leptin signalling has been implicated as playing a role in the development of Alzheimer's disease (AD). Leptin has previously been shown to be affected by amyloid-beta (Aβ)-related signalling; however, pathways that link leptin to the disease pathogenesis have not been determined. To characterize the association between increasing age-dependent Aβ levels with leptin signalling and the vulnerable brain regions in AD, we assessed the mRNA and protein expression profile of leptin and leptin receptor (Ob-Rb) at 9 and 18-month-age in APP/PS1 mice. Immunohistochemical labelling demonstrated that leptin and Ob-Rb proteins were localised to neocortical and hippocampal neurons in APP/PS1 and wildtype (WT) mice. Neuronal leptin and Ob-Rb immunolabelling was more prominent in the neocortex of both groups at 9 month of age, while, at 18 months, labelling was reduced in the hippocampus of APP/PS1 mice relative to WT. Immunoblotting analysis demonstrated decreased hippocampal leptin levels, concomitantly with an increased Ob-Rb levels, in APP/PS1 mice compared with WT controls at 18 month of age. While no leptin mRNA was found in either of the groups analysed, Ob-Rb mRNA was significantly decreased in the hippocampus of APP/PS1 mice at both ages analysed. In addition, a significant decreased protein kinase B (Akt) activity concomitantly with an upregulation of suppressor of cytokine signaling-3 (SOCS3) and protein-tyrosine phosphatase 1B (PTP1B) transcripts was present. Thus, these results collectively indicate alterations of leptin signalling in the hippocampus of APP/PS1 mice, providing novel insights about the pathways that could link aberrant leptin signaling to the pathological changes of AD.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Hippocampus; Leptin; Mice; Mice, Transgenic; Neurons; Presenilin-1; Receptors, Leptin; Signal Transduction

Obese patients, often accompanied by hyperleptinemia, are prone to liver fibrogenesis. Leptin is an adipocyte-derived hormone and plays a promotion role in liver fibrosis. Sterol regulatory element binding protein-1c (SREBP1c) exerts a crucial role in inhibiting hepatic stellate cell (HSC) activation, a key step in liver fibrogenesis. Our previous studies indicated that leptin inhibited SREBP1c expression, contributing to leptin-induced HSC activation and liver fibrosis. microRNAs (miR) have emerged as important layers of regulatory control and regulate gene expression, and are implicated in numerous diseases. The present study revealed leptin up-regulation of miR-27a/b-3p levels in HSCs in vitro and in vivo. Three signaling pathways were required for leptin regulation of miR-27a/b-3p levels. miR-27a/b-3p could reduce SREBP1c and liver x receptor α (LXRα) levels, increased α-smooth muscle actin (α-SMA, a marker for HSC activation) and α1(I)collagen levels in cultured HSCs. miR-27a/b-3p regulation of SREBP1c and LXRα were independent of 3'-untranslated region of SREBP1c and LXRα mRNA. In vivo experiments further demonstrated the miR-27a/b-3p involved in leptin-associated decrease in SREBP1 level in HSCs, HSC activation, and liver fibrosis. These data might have potential implications for our understanding of molecular mechanisms underlying leptin roles in liver fibrogenesis of obese patients with hyperleptinaemia.

Topics: 3' Untranslated Regions; Actins; Animals; Collagen Type I; Disease Models, Animal; Hepatic Stellate Cells; Leptin; Liver Cirrhosis; Liver X Receptors; Mice; Mice, Inbred C57BL; Mice, Obese; MicroRNAs; RNA, Messenger; Signal Transduction; Sterol Regulatory Element Binding Protein 1; Up-Regulation

Topics: Animals; Disease Models, Animal; Leptin; Mice; Myelodysplastic Syndromes; Obesity; Overweight; Survival Rate

Evidence suggests that impulse control deficits contribute to excessive food intake in some individuals with obesity. In addition to its known role in regulating appetite and glucose metabolism, the hormone leptin also directly modulates the activity of central dopamine systems. Although dopamine is involved in regulating impulsivity, the influence of leptin per se on this cognitive domain remains unclear. This study explored the performance of male leptin knockout (KO) and wild type (WT) rats in the 5-Choice Serial Reaction Time task (5CSRTT) of motor impulsivity and visuospatial attention. Behavioural performance was assessed under baseline conditions, following 4 weeks high-fat diet (HFD; 60 kcal%) consumption, and after acute pharmacological challenge with the indirect dopamine agonist, amphetamine. Subjects were also tested for glucose tolerance and insulin sensitivity, and dorsal and ventral striatal tissue was assayed ex vivo for markers of dopaminergic transmission. Obese KO rats learned the 5CSRTT at a slower rate compared to WT rats, in a manner suggestive of mild attentional impairment. However, task performance at baseline and after HFD intake was similar to that of WT controls. HFD intake reduced omissions across all subjects, whereas amphetamine challenge revealed a prominent genotype effect on 5CSRTT performance, with potentiated levels of impulsive responding and faster response times in KO rats compared to WT animals. Effects of amphetamine on other variables were similar between genotypes. Notably, the expression of striatal dopaminergic markers was unchanged in KO rats, and neither chronic food restriction nor HFD intake altered the impairments in glucose or insulin metabolism previously reported in these animals. These data suggest that leptin deficiency enhances impulsive action under conditions of dopaminergic challenge, yet this seems independent of overt changes in the expression of post-synaptic markers of dopamine signalling in striatal regions.

Topics: Amphetamine; Animals; Attention; Brain; Central Nervous System Stimulants; Choice Behavior; Cognition; Diet, High-Fat; Disease Models, Animal; Dopamine Agonists; Gene Knockout Techniques; Impulsive Behavior; Leptin; Male; Motor Activity; Obesity; Rats, Sprague-Dawley; Rats, Transgenic

Arq zeera is a distillate product that prepared from four different herbs namely Trachyspermum ammi L., apiaceae, Zingiber officinale Roxb., zingiberaceae, Carum carvi L.,apiaceae and Cuminum cyminum L., apiaceae. The present study aims to determine the antiobesity effect of arq zeera and its main components thymol and cuminaldehyde in high fat diet induced obese rats and to explore its mechanism of action. In current study, orlistat was used as positive controls. Male Wistar rats were fed with HFD for 42 days to induce obesity. HFD-fed rats were administered with arq zeera, thymol, cumic aldehyde, thymol + cuminaldehyde and orlistat for 28 days. During the course of treatment, body weight and food intake frequently observed and after end of treatments, liver weight, visceral fat pad weight, plasma lipid proflie, alanine aminotransferase, aspartate aminotransferase, glucose, insulin, leptin levels and pancreatic lipase activity were studied on all treated obese rats. The histopathology of liver was also studied. After the treatments of arq zeera and its main components, body weight, food intake, liver weight, visceral fat pad weight and the level of lipid profile, alanine aminotransferase, aspartate aminotranferase, glucose, insulin, and leptin were found to be decreased and pancreatic lipase inhibition were increased. Arq zeera showed more potential antiobesity effect than orlistat. According to our present findings, arq zeera and its main components possessed potent antiobesity effect on high fat diet -induced obese rats and excreted anti-obesity effect partly via hypolipidemic, hypoglycemic, hypoinsulinemic, hypoleptinemic and pancreatic lipase inhibition action.

Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Benzaldehydes; Blood Glucose; Cymenes; Diet, High-Fat; Disease Models, Animal; Humans; India; Leptin; Lipase; Lipid Metabolism; Lipids; Liver; Male; Medicine, Unani; Obesity; Orlistat; Plant Extracts; Plants, Medicinal; Rats; Rats, Wistar; Thymol; Treatment Outcome

Obesity during pregnancy causes adverse maternal and fetal health outcomes and programs offspring for adult-onset diseases, including cardiovascular disease. Obesity also disrupts core body temperature (T

Topics: Adiposity; Animals; Body Temperature Regulation; Circadian Rhythm; Diet, High-Fat; Disease Models, Animal; Estrous Cycle; Female; Gestational Age; Leptin; Obesity; Photoperiod; Pregnancy; Rats, Wistar; Time Factors

The co-occurrence of obesity aggravates asthma symptoms. Diet-induced obesity increases helper T cell (TH) 17 cell differentiation in adipose tissue and the spleen. The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor pravastatin can potentially be used to treat asthma in obese patients by inhibiting interleukin 17 (IL-17) expression. This study investigated the combined effects of pravastatin and anti-IL-17 antibody treatment on allergic inflammation in a mouse model of obesity-related asthma.. High-fat diet (HFD)-induced obesity was induced in C57BL/6 mice with or without ovalbumin (OVA) sensitization and challenge. Mice were administered the anti-IL-17 antibody, pravastatin, or both, and pathophysiological and immunological responses were analyzed.. HFD exacerbated allergic airway inflammation in the bronchoalveolar lavage fluid of HFD-OVA mice as compared to OVA mice. Blockading of the IL-17 in the HFD-OVA mice decreased airway hyper-responsiveness (AHR) and airway inflammation compared to the HFD-OVA mice. Moreover, the administration of the anti-IL-17 antibody decreased the leptin/adiponectin ratio in the HFD-OVA but not the OVA mice. Co-administration of pravastatin and anti-IL-17 inhibited airway inflammation and AHR, decreased goblet cell numbers, and increased adipokine levels in obese asthmatic mice.. These results suggest that the IL-17-leptin/adiponectin axis plays a key role in airway inflammation in obesity-related asthma. Our findings suggest a potential new treatment for IL-17 as a target that may benefit obesity-related asthma patients who respond poorly to typical asthma medications.

Topics: Adiponectin; Adipose Tissue; Animals; Anti-Asthmatic Agents; Antibodies; Asthma; Bronchoconstriction; Diet, High-Fat; Disease Models, Animal; Female; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Interleukin-17; Leptin; Lung; Mice, Inbred C57BL; Obesity; Pravastatin; Th17 Cells; Th2 Cells

Increased adiposity, through adipocyte hypertrophy, and/or hyperplasia, characterizes aging and obesity. Both are leptin-resistant states, associated with disturbed lipid metabolism, reduced insulin sensitivity and inflammation. Nevertheless, fat tissue dysfunction appears earlier in obesity than in normal aging. In contrast, lipodystrophy is accompanied by diabetes, and improving the fat cell capacity to expand rescues the diabetic phenotype. Fat tissue dysfunction is extensively studied in the diet-induced obesity, but remains relatively neglected in the aging-associated obesity. In the Wistar rat, as occurs in humans, early or middle aging is accompanied by an increase in adiposity. Using this experimental model, we describe the molecular mechanisms contributing to the white adipose tissue (WAT) hypertrophy. WAT from middle-old age rats is characterized by decreased basal lipogenesis and lipolysis, increased esterification, as demonstrated by the higher TAG and cholesterol content in visceral WAT, and the maintenance of total ceramide levels within normal values. In addition, we describe alterations in the adipose tissue plasma membrane lipid composition, as increased total ether-phosphatidylcholine, sphingomyelin, and free cholesterol levels that favor an enlarged fat cell size with aging. All these metabolic changes may be regarded as a survival advantage that prevents the aged rats from becoming overtly diabetic.

Topics: Adipocytes; Adipose Tissue, White; Adiposity; Aging; Animals; Diabetes Mellitus; Disease Models, Animal; Hypertrophy; Leptin; Lipid Metabolism; Male; Obesity; Rats; Rats, Wistar

In the hypothalamic arcuate nucleus (ARC), orexigenic agouti-related peptide (AgRP) neurons regulate feeding behavior and energy homeostasis. The 3-phosphoinositide-dependent protein kinase-1 (PDK1) in AgRP neurons serves as a major signaling molecule for leptin and insulin, the hormones regulating feeding behavior, energy homeostasis and circulation. However, it is unclear whether PDK1 in AGRP neurons is also involved in regulation of blood pressure. This study explored it by generating and analyzing AgRP neuron-specific PDK1 knockout (Agrp-Pdk1

Topics: Agouti-Related Protein; Animals; Arcuate Nucleus of Hypothalamus; Blood Pressure; Calcium-Binding Proteins; Disease Models, Animal; DNA-Binding Proteins; Energy Intake; Feeding Behavior; Gene Expression Regulation; Hypertension; Insulin; Leptin; Mice; Mice, Knockout; Nerve Tissue Proteins; Neurons; Norepinephrine; Nucleobindins; Paraventricular Hypothalamic Nucleus; Protein Serine-Threonine Kinases; Pyruvate Dehydrogenase Acetyl-Transferring Kinase; RNA, Messenger; Signal Transduction; Sodium Chloride, Dietary

Leptin, produced primarily by the adipose tissue, acts as a pro-inflammatory modulator, thereby contributing to the development of obesity-related disease. Although high levels of leptin in the obese are closely related to gastroesophageal reflux disease, the mechanism by which leptin influences esophageal inflammation remains unknown. Macrophage migration inhibitory factor (MIF) is produced by immune cells, such as T lymphocytes and macrophages, and MIF is known to induce the production of tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β) and interleukin 6 (IL-6). We therefore investigated the mechanism whereby leptin aggravates reflux esophagitis, by focusing on esophageal tissue levels of MIF and CD3+ T lymphocytes, both of which are crucial for the reflux-induced epithelial damage. Esophageal inflammation was surgically induced in male Wistar rats by ligating the forestomach and narrowing the duodenum to facilitate gastroesophageal reflux, followed by administration of leptin or vehicle with an osmotic pump system for 1 week. We demonstrated that the administration of leptin exacerbated the reflux esophagitis with the apparent infiltration of CD3+ T lymphocytes and caused the significant increase in the esophageal tissue levels of MIF. Moreover, the leptin caused increases in the esophageal tissue levels of TNF-α, IL-1β and IL-6, downstream targets of MIF. Importantly, the increases in these pro-inflammatory cytokines were accompanied by increased protein levels of phospho-STAT3 and phospho-AKT, pivotal molecules of leptin signaling pathways. In conclusion, through enhancing the MIF-induced inflammatory signaling, leptin could contribute to the development of gastroesophageal reflux disease.

Topics: Animals; Body Weight; CD3 Complex; Cytokines; Disease Models, Animal; Esophagitis, Peptic; Esophagus; Feeding Behavior; Inflammation Mediators; Leptin; Macrophage Migration-Inhibitory Factors; Male; Proto-Oncogene Proteins c-akt; Rats, Wistar; Signal Transduction; STAT3 Transcription Factor; T-Lymphocytes

Recent studies suggest that T helper 17 (Th17) cell subset, a distinct pro-inflammatory CD4 +  T cell lineage, may play an important role in the pathophysiology of allergic rhinitis (AR). However, the regulation of Th17 response in allergic disease is not well characterized.. Thirty AR and 30 healthy children were enrolled. Serum leptin and OPN levels were measured, and their correlation with IL-17 expression was analyzed using enzyme-linked immunosorbent assay (ELISA). Th17 cell differentiation and cytokine production in peripheral blood mononuclear cell (PBMCs) stimulated by leptin and OPN and related inhibitors were analyzed by ELISA. AR mice models were also established to verify the effect of leptin and OPN on Th17 cell regulation. Immunoprecipitation was performed to explore the interaction between OPN and leptin in Th17 cells.. Our results showed that elevated serum leptin and OPN in AR children were correlated with serum IL-17 level (r = .53, P < .01). The recombinant leptin and OPN enhanced Th17 responses from PBMCs synergistically through nuclear factor κB (NF-κB), mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK) pathway and β3 integrin receptor. The AR mice showed as more severe Th17 responses and symptoms compared with control mice. Immunoprecipitation showed that OPN and leptin may interact with each other directly, and this process may be mediated by β3 integrin.. Our data provide evidence that upregulation of leptin and OPN promotes Th17 responses in AR, and this process may be achieved through NF-κB, MAPK, and JNK pathway and β3 integrin.

Topics: Animals; Cell Differentiation; Child; Child, Preschool; Cytokines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunoprecipitation; Leptin; Leukocytes, Mononuclear; Male; Mice; Mice, Inbred BALB C; Osteopontin; Rhinitis, Allergic; Signal Transduction; Th17 Cells

Angiopoietin-like 6 (ANGPTL6) is a hepatokine that antagonizes obesity and insulin resistance by increasing energy expenditure. Despite its beneficial effects on metabolism, human studies have shown a paradoxical increase in ANGPTL6 level in the serum of patients with metabolic diseases, which has been interpreted as a compensatory upregulation. However, the regulatory mechanism of ANGPTL6 remains unclear. Since upregulation of ANGPTL6 is induced on metabolic stress, we investigated the hepatic expression of ANGPTL6 by leptin, a representative adipokine of obesity. Mice on a high-fat diet showed increased serum leptin levels and hepatic Angptl6 expression, which were attenuated by exercise training. A single leptin injection also induced hepatic ANGPTL6 expression and increased serum ANGPTL6 levels. In an in vitro model using primary hepatocytes, leptin treatment significantly upregulated ANGPTL6 expression at the mRNA and protein levels, as well as the amount of secreted ANGPTL6 protein in conditioned media. Similarly, exercise training on human participants also showed diminished serum levels of leptin and ANGPTL6. Altogether, these results strongly indicated that hepatic ANGPTL6 expression was determined by leptin.

Topics: Angiopoietin-Like Protein 6; Angiopoietin-like Proteins; Animals; Diet, High-Fat; Disease Models, Animal; Hepatocytes; Humans; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Physical Conditioning, Animal; Stress, Physiological; Up-Regulation

Allergic asthma and obesity are major public health problems in the world. Recent Meta-analysis studies implicated a positive relationship between serum leptin, which is elevated in obese individuals, and the risk of asthma. However, it is not well understood how obesity-associated elevation of leptin increases the risk of asthma. In the current study, we have found that leptin induces the unfolded protein response factor XBP1s in an mTOR- and MAPK-dependent manner in pro-allergic TH2 cells; in vivo, mice fed with high fat diet had increased serum leptin as observed in human obese population and exacerbated asthmatic symptoms, associated with increased XBP1s expression in splenic CD4

Topics: Animals; Asthma; Cells, Cultured; Diet, High-Fat; Disease Models, Animal; Inflammation; Leptin; Mice, Inbred C57BL; Th2 Cells; Unfolded Protein Response; X-Box Binding Protein 1

Early life events are associated with the susceptibility to chronic diseases in adult life. Perturbations of endoplasmic reticulum (ER) homeostasis activate the unfolded protein response (UPR), which contributes to the development of metabolic alterations. Our aim was to evaluate liver UPR in an animal model of intrauterine growth restriction (IUGR). A significantly increased expression of X-box binding protein-1 spliced (XBP1s) mRNA (p<0.01), Endoplasmic Reticulum-localized DnaJ homologue (Erdj4) mRNA (p<0.05) and Bip/GRP78-glucose-regulated protein 78 (Bip) mRNA (p<0.05) was observed in the liver of IUGR rats at birth. Furthermore, the expression of gluconeogenesis genes and lipogenesis genes were significantly upregulated (p<0.05) in IUGR pups. At 105 d, IUGR male rats showed significantly reduced glucose tolerance (p<0.01). A significant decreased expression of XBP1s mRNA (p<0.01) and increased expression of double-stranded RNA-dependent protein kinase-like ER kinase (PERK) and Asparagine synthetase (ASNS) (p<0.05) was observed in the liver of IUGR male adult rats. Liver focal steatosis and periportal fibrosis were observed in IUGR rats. These findings show for the first time that fetal exposure to uteroplacental insufficiency is associated with the activation of hepatic UPR and suggest that UPR signaling may play a role in the metabolic risk.

Topics: Animals; Aspartate-Ammonia Ligase; Disease Models, Animal; Endoplasmic Reticulum; Endoplasmic Reticulum Chaperone BiP; Fatty Acids, Nonesterified; Female; Fetal Growth Retardation; Gene Expression Regulation; Glucose Tolerance Test; Heat-Shock Proteins; Leptin; Liver; Male; Metabolome; Pregnancy; Rats; Rats, Sprague-Dawley; RNA, Messenger; Unfolded Protein Response; X-Box Binding Protein 1

The unique effects of gastric resection after vertical sleeve gastrectomy (VSG) on type 2 diabetes mellitus remain unclear. This work aimed to investigate the effects of VSG on gastric leptin expression and intestinal glucose absorption in high-fat diet-induced obesity.. Male C57BL/6J mice were fed a high-fat diet (HFD) to induce obesity. HFD mice were randomized into VSG and sham-operation groups, and the relevant parameters were measured at 8 weeks postoperation.. Higher gastric leptin expression and increased intestinal glucose transport were observed in the HFD mice. Furthermore, VSG reduced gastric leptin expression and the intestinal absorption of alimentary glucose. Both exogenous leptin replenishment during the oral glucose tolerance test (OGTT) and the addition of leptin into the everted isolated jejunum loops in vitro restored the glucose transport capacity in VSG-operated mice, and this effect was abolished when the glucose transporter GLUT2 was blocked with phloretin. Moreover, phloretin almost completely suppressed glucose transport in the HFD mice. Intestinal immunohistochemistry in the obese mice showed increased GLUT2 and diminished sodium glucose co-transporter 1 (SGLT-1) in the apical membrane of enterocytes. Decreased GLUT2 and enhanced SGLT1 were observed following VSG. VSG also reduced the phosphorylation status of protein kinase C isoenzyme β II (PKCβ II) in the jejunum, which was stimulated by the combination of leptin and glucose.. Our data demonstrated that the decreased secretion of gastric leptin in VSG results in a decrease in intestinal glucose absorption via modulation of GLUT2 translocation.

Topics: Animals; Diet, High-Fat; Disease Models, Animal; Gastrectomy; Glucose; Intestinal Absorption; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity

Obesity may lead to male hypogonadism, the underlying mechanism of which remains unclear. In the present study, we established a murine model of male hypogonadism caused by high-fat diet-induced obesity to verify the following hypotheses: 1) an increased leptin level may be related to decreased secretion of GnRH in obese males, and 2) repression of kisspeptin/GPR54 in the hypothalamus, which is associated with increased leptin levels, may account for the decreased secretion of GnRH and be involved in secondary hypogonadism (SH) in obese males.. Male mice were fed high-fat diet for 19 weeks and divided by body weight gain into diet-induced obesity (DIO) and diet-induced obesity resistant (DIO-R) group. The effect of obesity on the reproductive organs in male mice was observed by measuring sperm count and spermatozoid motility, relative to testis and epididymis weight, testosterone levels, and pathologic changes. Leptin, testosterone, estrogen, and LH in serum were detected by ELISA method. Leptin receptor (Ob-R), Kiss1, GPR54, and GnRH mRNA were measured by real-time PCR in the hypothalamus. Expression of kisspeptin and Ob-R protein was determined by Western blotting. Expression of GnRH and GPR54 protein was determined by immunohistochemical analysis.. We found that diet-induced obesity decreased spermatozoid motility, testis and epididymis relative coefficients, and plasma testosterone and luteinizing hormone levels. An increased number and volume of lipid droplets in Leydig cells were observed in the DIO group compared to the control group. Significantly, higher serum leptin levels were found in the DIO and DIO-R groups. The DIO and DIO-R groups showed significant downregulation of the GnRH, Kiss1, GPR54, and Ob-R genes. We also found decreased levels of GnRH, kisspeptin, GPR54, and Ob-R protein in the DIO and DIO-R groups.. These lines of evidence suggest that downregulation of Ob-R and kisspeptin/GPR54 in the murine hypothalamus may contribute to male hypogonadism caused by high-fat diet-induced obesity.

Topics: Animals; Body Weight; Diet, High-Fat; Disease Models, Animal; Down-Regulation; Gonadotropin-Releasing Hormone; Hypogonadism; Hypothalamus; Kisspeptins; Leptin; Male; Mice; Obesity; Receptors, Kisspeptin-1; Receptors, Leptin; Sperm Motility; Testis

This study investigated whether Heshouwu (Polygonum multiflorum Thunb.) root ethanol extract (PME) has anti-obesity activity using 3T3-L1 cells and high-fat diet (HFD)-induced obese mice. Treatment with PME (5 and 10 μg/mL) dose-dependently suppressed 3T3-L1 pre-adipocyte differentiation to adipocytes and cellular triglyceride contents. In addition, PME inhibited mRNA and protein expression of adipogenic transcription factors such as CCAAT/enhancer-binding protein α (C/EBPα) and peroxisome proliferator-activated receptor γ (PPARγ), which led to down-regulation of fatty acid synthase gene expression. After feeding mice PME (0.05%) with HFD for 12 weeks, their visceral fat mass, size and body weight were significantly reduced compared with the HFD group. Furthermore, PME supplementation significantly up-regulated the PPARα, CPT1, CPT2, UCP1 and HSL mRNA levels compared with the HFD group, whereas it down-regulated expression of the PPARγ and DGAT2 genes. Finally, HFD increased serum leptin, insulin, glucose and insulin and glucose levels; however, PME reversed these changes. These results demonstrated that PME might relieve obesity that occurs via inhibition of adipogenesis and lipogenesis as well as through lipolysis and fatty acid oxidation in 3T3-L1 cells and HFD-induced obese mice.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Adiposity; Animals; Anti-Obesity Agents; Blood Glucose; Disease Models, Animal; Dose-Response Relationship, Drug; Ethanol; Fallopia multiflora; Fatty Acids; Gene Expression Regulation; Insulin; Intra-Abdominal Fat; Leptin; Lipogenesis; Lipolysis; Male; Mice; Mice, Inbred C57BL; Obesity; Oxidation-Reduction; Phytotherapy; Plant Extracts; Plants, Medicinal; Solvents; Time Factors; Triglycerides

Hydrogen sulfide (H2S) is an essential neuromodulator, generates by cystathionine β synthase (CBS) or 3-mecaptopyruvate sulfurtransferase (3MST) in the brain. H2S can mediate paraventricular nucleus (PVN) neuron activity, and regulate neuroendocrine hormones secretion. On the other hand, CBS deficiency caused metabolic disorder and body weight reduction. However, whether CBS/H2S of PVN regulates neuroendocrine hormones to mediate energy metabolism is unknown. Here, we first identified the CBS co-localization with thyrotropin-releasing hormone (TRH) and corticotropin releasing hormone (CRH) positive neurons. In HFD induced obese rats, CBS protein of hypothalamus decreased. By contrast, overexpression CBS in PVN via lentivirus, lowered food uptake, body weight and fat mass, and reduced blood glucose, lipid disorders and insulin resistance. Intriguingly, CBS overexpression increased the pre-TRH expression, slightly elevated plasma thyroxine and thyrotropin level, but decreased the plasma ACTH and corticosterone level. Then, we found that mTOR activation contributed to pre-TRH up-regulation by CBS/H2S system. In db/db obese mice, hypothalamus CBS/H2S system also down-regulated association with reduction pre-TRH expression; in contrast, CBS overexpression in PVN slightly elevated plasma leptin. Next, leptin stimulated FOXO3a nuclear translocation, increased FOXO3a binding activity to two binding sites of CBS promoter, and then enhanced CBS protein expression. In conclusion, leptin activates neuron CBS-H2S system by FOXO3a, regulates neuroendocrine hormones to modulate the energy homeostasis, thus highlights a new brain-adipose feedback axis in energy metabolism.

Topics: Animals; Cells, Cultured; Corticotropin-Releasing Hormone; Cystathionine beta-Synthase; Diet, High-Fat; Disease Models, Animal; Energy Metabolism; Forkhead Box Protein O3; Hydrogen Sulfide; Insulin Resistance; Leptin; Mice; Obesity; Paraventricular Hypothalamic Nucleus; Rats; Thyrotropin; Thyrotropin-Releasing Hormone; Thyroxine

Cachexia syndrome consists of adipose and muscle loss, often despite normal food intake. We hypothesized that cachexia-associated adipose wasting is driven in part by tumor humoral factors that induce adipocyte lipolysis. We developed an assay to purify secreted factors from a cachexia-inducing colon cancer line that increases lipolysis in adipocytes and identified leukemia inhibitory factor (LIF) by mass spectrometry. Recombinant LIF induced lipolysis in vitro. Peripheral LIF administered to mice caused >50% loss of adipose tissue and >10% reduction in body weight despite only transient hypophagia due to decreasing leptin. LIF-injected mice lacking leptin (ob/ob) resulted in persistent hypophagia and loss of adipose tissue and body weight. LIF's peripheral role of initiating lipolysis in adipose loss was confirmed in pair-fed ob/ob mouse studies. Our studies demonstrate that (a) LIF is a tumor-secreted factor that promotes cachexia-like adipose loss when administered peripherally, (b) LIF directly induces adipocyte lipolysis, (c) LIF has the ability to sustain adipose and body weight loss through an equal combination of peripheral and central contributions, and (d) LIF's central effect is counterbalanced by decreased leptin signaling, providing insight into cachexia's wasting, despite normophagia.

Topics: Adipocytes; Adipose Tissue; Animals; Body Weight; Cachexia; Cell Line; Cytokine Receptor gp130; Cytokines; Disease Models, Animal; Leptin; Leukemia Inhibitory Factor; Lipase; Lipolysis; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplasms; Recombinant Proteins; STAT Transcription Factors

Metabolic disorders play an important role in the pathogenesis of many neurological diseases. Recent evidence suggests that leptin levels in peripheral blood and brain are lower in patients with epilepsy. Leptin is an energy-regulating hormone that plays a neuroprotective role in neurodegenerative diseases and brain trauma. However, little is known about the effects and molecular mechanisms of leptin treatment on long-term neurobehavioral impairment caused by developmental seizures. The present study evaluated whether chronic leptin treatment protected against neurobehavioral impairments induced by recurrent seizures in newborns treated with flurothyl. We also examined the effect of leptin on the expression of zinc/cPLA2-related autophagy signaling molecules and CaMKII in the cerebral cortex. Twenty Sprague-Dawley rats (6 days after birth, P6) were randomly divided into two groups, a neonatal seizure group and control group. Rats were subdivided on P13 into control, control + leptin (leptin, 2 mg/kg/day, continuous 10 days), seizure (RS), and seizure + leptin group (RS + leptin, 2 mg/kg/day for 10 consecutive days). Neurological behavioral parameters (negative geotaxis reaction reflex, righting reflex, cliff avoidance reflex, forelimb suspension reflex and open field test) were observed from P23 to P30. mRNA and protein levels in the cerebral cortex were detected using real-time RT-PCR and Western blotting, respectively. Flurothyl-induced seizures (RS group) produced long-term abnormal neurobehavior, which was improved with leptin treatment. Chronic leptin treatment restored several expression parameters affected by neonatal seizures, including seizure-induced up-regulated zinc transporter ZnT1/ZIP7, lipid membrane injury-related cPLA2, autophagy marker beclin-1/bcl2, LC3II/LC3I, and its execution molecule cathepsin-E, and down-regulated memory marker CaMK II alpha. Our results suggest that the early use of leptin after neonatal recurrent seizures may exert neuroprotective effects and antagonize the long-term neurobehavioral impairment caused by seizures. Autophagy-mediated Zn/cPLA2 and CaMK II signaling in the cerebral cortex may be involved in the neuroprotective effect of leptin. Our results provide new clues for anti-epileptogenetic treatment.

Topics: Animals; Animals, Newborn; Autophagy; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Carrier Proteins; Cerebral Cortex; Disease Models, Animal; Flurothyl; Group IV Phospholipases A2; Leptin; Male; Motor Activity; Neuroprotection; Neuroprotective Agents; Random Allocation; Rats, Sprague-Dawley; Seizures; Signal Transduction

Topics: Adipose Tissue, Brown; Alzheimer Disease; Animals; Blood Glucose; Diet, High-Fat; Disease Models, Animal; Eating; Homeostasis; Humans; Hyperphagia; Insulin; Insulin Resistance; Leptin; Metabolic Syndrome; Mice; Mice, Transgenic; Obesity

Dietary interventions in rodents can induce an excess of adipose tissue and metabolic disorders that resemble human obesity. Nevertheless, these approaches are not standardized, and the phenotypes may vary distinctly among studies. The aim of this study was to investigate the effects of different dietary interventions on nutritional, metabolic, biochemical, hormonal, and cardiovascular profiles, as well as to add to development and characterization of an experimental model of obesity.. Male Wistar rats were randomized into four groups: control diet (C), high-sugar (HS), high-fat (HF), or high-sugar and high-fat (HFHS). Weekly measurements of body weight, adiposity, area under the curve (AUC) for glucose, blood pressure (BP) and serum triglycerides, total cholesterol level, and leptin were performed.. HF and HFHS models were led to obesity by increases in adipose tissue deposition and the adiposity index. All hypercaloric diets presented systolic BP increases. In addition, the AUC for glucose was greater in HF and HFHS than in C, and only the HF group presented hyperleptinemia.. HF and HFHS diet approaches promote obesity and comorbidities, and thus represent a useful tool for studying human obesity-related disorders. By contrast, the HS model did not prove to be a good model of obesity.

Topics: Adiposity; Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Biomarkers; Blood Glucose; Blood Pressure; Cholesterol; Dietary Fats; Dietary Sugars; Disease Models, Animal; Energy Intake; Health Status; Leptin; Male; Nutritive Value; Obesity; Rats, Wistar; Time Factors; Triglycerides; Weight Gain

Preterm infants face lifelong disabilities, including learning disorders, as well as visual, auditory and behavioral problems. Recent studies have demonstrated that leptin, an adipocytokine encoded by a gene associated with obesity and expressed in adipose tissue, affects neurocognitive and motor function; however, the mechanisms of brain damage in preterm infants are unclear. In the present study, the neuroprotective effects of leptin in a rat model of preterm hypoxic‑ischemic brain damage were investigated. Rats (2‑days‑old) were subjected to brain damage (ligation of the common carotid artery followed by exposure to 6% oxygen for 2 h) and treated with vehicle (control) or leptin. Spatial memory was analyzed in the present study using the Morris water maze test 19 days following ligation. Over the 24‑day post‑surgical observation period, capture‑resistance test, forelimb suspension and open field tests were conducted to evaluate motor function and anxiety‑associated behavior. Treatment with leptin did not affect survival rate or body weight. Treatment with leptin increased the number of platform crossings in rats with premature brain damage in the Morris water maze test, which was used to assess spatial memory. Multivariate analysis revealed that leptin reduced the latency to finding the platform location, independent of gender and weight. In the capture‑resistance, forelimb suspension and open field tests, there were no differences between animals administered leptin and the sham group. Collectively, the results of the present study suggested that leptin may alleviate spatial memory impairment resulting from premature brain damage, independent of gender or weight. These results may improve understanding of the neuroprotective effects exhibited by leptin in infants with preterm brain damage.

Topics: Animals; Body Weight; Brain Injuries; Cognition; Disease Models, Animal; Humans; Infant; Leptin; Linear Models; Maze Learning; Mice; Motor Activity; Multivariate Analysis; Premature Birth; Rats, Sprague-Dawley

Topics: Adenocarcinoma; Adenoviridae; Aging; Animals; Antibodies, Monoclonal; Cell Line, Tumor; CTLA-4 Antigen; Diet; Disease Models, Animal; Female; Humans; Immunity; Immunotherapy; Kidney Neoplasms; Leptin; Mice; Mice, Inbred BALB C; Mice, Mutant Strains; Obesity; Oligodeoxyribonucleotides; Receptors, Fc; Receptors, Leptin; Recombinant Fusion Proteins; TNF-Related Apoptosis-Inducing Ligand

Leptin is a well-known adipokine that plays a critical role in immune responses. To further explore the immunological roles of leptin, we developed a transgenic leptin pig controlled by the pig leptin (pleptin) promoter to overexpress leptin. Symptoms typically associated with systemic lupus erythematosus (SLE) were evident in this transgenic pig strain, including anemia, leukopenia, and thrombocytopenia as well as kidney and liver impairment. Histologically, there were increased immunoglobulin G (IgG) levels, elevated antiplatelet antibody (APA) levels, and deposition of immune complexes in the kidney and liver. In addition, anti-double-stranded DNA antibodies (dsDNAs), antinuclear antibodies (ANAs), and antinucleosome antibodies (ANuAs) were all significantly increased in serum immunological examinations. These findings were also accompanied by repression of the regulatory T cell (Treg) ratio. Significantly, glucocorticoid experimental therapies partially relieved the autoimmune responses and bleeding symptoms observed in these transgenic leptin pigs. Together, these results indicate that leptin plays a critical role in the development of autoimmune disorders and demonstrate that our transgenic leptin pigs can act as a valuable model of SLE.

Topics: Animals; Animals, Genetically Modified; Antibodies, Antinuclear; Antigen-Antibody Complex; Autoimmunity; Disease Models, Animal; Immunoglobulin G; Leptin; Lupus Erythematosus, Systemic; Nucleosomes; Promoter Regions, Genetic; Swine; T-Lymphocytes, Regulatory

The current obesity pandemic represents a major health burden, given that it predisposes to the development of numerous obesity-associated disorders. The obesity-derived adipokines not only impair systemic insulin action but also increase the incidence of hepatocellular carcinoma (HCC), a highly prevalent cancer with poor prognosis. Thus, worldwide incidences of HCC are expected to further increase, and defining the molecular as well as cellular mechanisms will allow for establishing new potential treatment options. The adipose tissue of obese individuals increases circulating leptin and interleukin-6 (IL-6) levels, which both share similar signaling capacities such as Signal Transducer and Activator of Transcription 3 (STAT3) and Phosphoinositide 3-kinase (PI3K)/Akt activation. While mouse models with deficient IL-6 signaling show an ameliorated but not absent Diethylnitrosamine (DEN)-induced HCC development, the morbid obesity in mice with mutant leptin signaling complicates the dissection of hepatic leptin receptor (LEPR) and IL-6 signaling in HCC development. Here we have investigated the function of compensating hepatic LEPR expression in HCC development of IL-6Rα-deficient mice.. We generated and characterized a mouse model of hepatic LEPR deficiency that was intercrossed with IL-6Rα-deficient mice. Cohorts of single and double knockout mice were subjected to the DEN-HCC model to ascertain liver cancer development and characterize metabolic alterations.. Our findings reveal a compensatory role for hepatic LEPR in HCC development of IL-6Rα-deficient mice and suggest hepatocyte-specific leptin signaling as promoter of HCC under obese conditions.

Topics: Animals; Cell Proliferation; Diet, High-Fat; Diethylnitrosamine; Disease Models, Animal; Female; Gene Expression; Hepatocytes; Interleukin-6 Receptor alpha Subunit; Leptin; Lipid Metabolism; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphatidylinositol 3-Kinases; Phosphorylation; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor

Leptin's role in bone formation has been reported, however, its mechanism of affecting bone metabolism is remaining unclear. In this study, we aimed to test whether leptin has a positive effect on fracture healing through the possible mechanism of increasing vascular endothelial growth factor (VEGF) expression in callus tissue.. Standardized femur fractures were created in leptin-deficient ob/ob and wildtype C57BL/6J mice, and recombinant mouse leptin or its vehicle (physiological saline) was administered intraperitoneally during the study. Body weight, radiological, histologic and immunoblotting analyses were performed at different stages of fracture healing.. The results showed that leptin treatment led to lower rate of body weight change in both mice genotypes. Radiological and histological analyses showed that the experimental groups had better fracture healing at 14, 21 and 28 days compared to the control groups. Leptin-treated groups had significantly higher VEGF expression in callus compared with the control groups at 2 and 3 weeks post-fracture except normal mice at 2 weeks, and leptin-deficient mice had higher VEGF levels in calluses than normal mice at the same timepoint.. Low-dose systemically-administered leptin has a positive effect on promoting fracture healing during the latter stages in a clinically-relevant mouse bone fracture model, and increase callus VEGF levels.

Topics: Animals; Bony Callus; Disease Models, Animal; Femoral Fractures; Fracture Healing; Injections, Intraperitoneal; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; RNA, Messenger; Tomography, X-Ray Computed; Vascular Endothelial Growth Factor A

Obesity has been identified as a risk factor for adverse outcomes of various diseases. However, information regarding the difference between the response of obese and normal subjects to pulmonary inflammation is limited. Mice were fed with the control or high-fat diet to establish the lean and diet-induced obese (DIO) mice. Escherichia coli was intranasally instilled to reproduce non-fatal acute pneumonia model. After infection, serum samples and lung tissues were obtained at 0, 12, 24, and 72 h. DIO mice exhibited increased serum triglyceride (TG) and total cholesterol (TC) contents as well as pulmonary resistin, IL-6, and leptin levels compared with lean mice. E. coli infection caused an acute suppurative inflammation in the lung with increased lung index and serum TG and TC contents; elevated pulmonary tumor necrosis factor-α, interleukin (IL)-1β, IL-6, IL-8, and leptin levels; and oxidative stress in mice. Interestingly, almost all the above-mentioned parameters peaked at 12 h after infection in the lean-E. coli group but after 12 h in the DIO-E. coli group. These results indicated that the DIO mice presented a delayed inflammatory response and oxidative stress in non-fatal acute pneumonia induced by E. coli infection.

Topics: Animals; Cholesterol; Cytokines; Diet, High-Fat; Disease Models, Animal; Escherichia coli; Humans; Inflammation; Interleukins; Leptin; Lung Injury; Mice; Obesity; Oxidative Stress; Pneumonia, Bacterial; Triglycerides; Tumor Necrosis Factor-alpha

Acute MI induces leptin expression in the heart, however the role of myocardial leptin in cardiac ischemia and reperfusion (IR) remains unknown. To shed light on the effects of elevated levels of leptin in the myocardium, we overexpressed cardiac leptin and assessed local remodeling and myocardial function in this context.. Cardiac leptin overexpression was stimulated in mice undergoing IR by a single intraperitoneal injection of leptin antagonist (LepA). All mice exhibited a normal pattern of body weight gain. A rapid, long-term upregulation of leptin mRNA was demonstrated in the heart, adipose, and liver tissues in IR/LepA-treated mice. Overexpressed cardiac leptin mRNA extended beyond postoperative day (POD) 30. Plasma leptin peaked 7.5 hours postoperatively, especially in IR/LepA-treated mice, subsiding to normal levels by 24 hours. On POD-30 IR/LepA-treated mice demonstrated cardiomyocyte hypertrophy and perivascular fibrosis compared to IR/saline controls. Echocardiography on POD-30 demonstrated eccentric hypertrophy and systolic dysfunction in IR/LepA. We recorded reductions in Ejection Fraction (p<0.001), Fraction Shortening (p<0.01), and Endocardial Fraction Area Change (p<0.01), and an increase in Endocardial Area Change (p<0.01). Myocardial remodeling in the context of IR and cardiac leptin overexpression was associated with increased cardiac TGFβ ligand expression, activated Smad2, and downregulation of STAT3 activity.. Cardiac IR coinciding with increased myocardial leptin synthesis promotes cardiomyocyte hypertrophy and fibrosis and potentiates myocardial dysfunction. Plasma leptin levels do not reflect cardiac leptin synthesis, and may not predict leptin-related cardiovascular morbidity. Targeting cardiac leptin is a potential treatment for cardiac IR damage.

Topics: Animals; Disease Models, Animal; Echocardiography; Leptin; Male; Mice; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Smad2 Protein; STAT3 Transcription Factor; Ventricular Dysfunction, Left; Ventricular Remodeling

Leptin receptor (LepRb) signaling pathway in the hypothalamus of the forebrain controls food intake and energy expenditure in response to an altered energy state. Defects in the LepRb signaling pathway can result in leptin-resistance and obesity. Leucine zipper transcription factor like 1 (Lztfl1)/BBS17 is a member of the Bardet-Biedl syndrome (BBS) gene family. Human BBS patients have a wide range of pathologies including obesity. The cellular and molecular mechanisms underlying Lztfl1-regulated obesity are unknown. Here, we generated Lztfl1f/f mouse model in which Lztfl1 can be deleted globally and in tissue-specific manner. Global Lztfl1 deficiency resulted in pleiotropic phenotypes including obesity. Lztfl1-/- mice are hyperphagic and showed similar energy expenditure as WT littermates. The obese phenotype of Lztfl1-/- mice is caused by the loss of Lztfl1 in the brain but not in the adipocytes. Lztfl1-/- mice are leptin-resistant. Inactivation of Lztfl1 abolished phosphorylation of Stat3 in the LepRb signaling pathway in the hypothalamus upon leptin stimulation. Deletion of Lztfl1 had no effect on LepRb membrane localization. Furthermore, we observed that Lztfl1-/- mouse embryonic fibroblasts (MEFs) have significantly longer cilia than WT MEFs. We identified several proteins that potentially interact with Lztfl1. As these proteins are known to be involved in regulation of actin/cytoskeleton dynamics, we suggest that Lztfl1 may regulate leptin signaling and ciliary structure via these proteins. Our study identified Lztfl1 as a novel player in the LepRb signaling pathway in the hypothalamus that controls energy homeostasis.

Topics: Animals; Bardet-Biedl Syndrome; Cilia; Cytoskeleton; Disease Models, Animal; Energy Metabolism; Female; Fibroblasts; Hypothalamus; Leptin; Male; Mice, Inbred C57BL; Mice, Mutant Strains; Obesity; Prosencephalon; Receptors, Leptin; Signal Transduction; Transcription Factors

Leptin, a hormone secreted by peripheral adipose tissues, regulates the appetite in animals. Recently, evidence has shown that leptin also plays roles in behavioral response in addition to controlling appetite. In this study, we examined the potential function of leptin on non-appetite behaviors in zebrafish model. By using genome editing tool of Transcription activator-like effector nuclease (TALEN), we successfully knocked out leptin a (

Topics: Aggression; Animals; Anxiety; Appetite; Biomarkers; Brain Chemistry; Circadian Rhythm; Disease Models, Animal; Fear; Female; Gene Editing; Leptin; Male; Obesity; Sequence Deletion; Stress, Psychological; Zebrafish; Zebrafish Proteins

To further understand the role of lipogenesis and lipotoxicity in the development of obesity and diabetes, lipidomes of various organs from ob/ob mice and their wild type controls were analyzed by shotgun lipidomics at 10, 12, and 16 weeks of age. We observed that the amounts of fatty acyl (FA) chains corresponding to those from de novo synthesis (e.g., 16:0, 16:1, and 18:1 FA) were substantially elevated in ob/ob mice, consistent with increased expression of genes and proteins involved in biosynthesis. Polyunsaturated fatty acid species were moderately increased in the examined tissues of ob/ob mice, since they can only be absorbed from diets or elongated from the ingested n-3 or n-6 FA. Different profiles of FA chains between ob/ob mouse liver and skeletal muscle reflect diverging lipogenesis pathways in these organs. Amounts of vaccenic acids (i.e., 18:1(n-7) FA) in 12- and 16-week ob/ob mouse liver were significantly increased compared to their controls, indicating enhanced de novo synthesis of this acid through 16:1(n-7) FA in the liver starting at 12 weeks of age. Coincidentally, synthesis of triacylglycerol from monoacylglycerol in the liver was also increased in ob/ob mice starting at 12 weeks of age, as revealed by simulation of triacylglycerol synthesis. Moreover, levels of lipotoxic lipid classes were significantly higher in ob/ob mice than their age-matched controls, supporting the notion that elevated lipotoxic components are tightly associated with insulin resistance in ob/ob mice. Taken together, the current study revealed that lipogenesis and lipotoxicity in ob/ob mice likely contribute to insulin resistance and provides great insights into the underlying mechanisms of diabetes and obesity.

Topics: Animals; Disease Models, Animal; Fatty Acids; Insulin Resistance; Leptin; Lipogenesis; Liver; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Obesity

We previously showed that xanthohumol-rich hop extract (XRHE, ~18% xanthohumol) exerts anti-obesity effects in rats fed a high-fat diet through regulation of fatty acid metabolism. In this study, we examined the effects of dietary purified xanthohumol from XRHE (PX, ~91.9% xanthohumol) in KK-Ay mice in order to understand the anti-obesity effects of xanthohumol alone because XRHE contains 82% unknown compounds. Dietary consumption of PX significantly inhibited an increase in the visceral fat weight of mice compared to those fed control diet without PX. Plasma leptin level was significantly lower in the PX-fed group than in the control group. Dietary PX lowered hepatic fatty acid synthesis by down-regulation of SREBP1c mRNA expression in the liver. On the other hand, fatty acid β-oxidation in the liver was promoted by dietary PX through the up-regulation of PPARα mRNA expression. Moreover, the fecal levels of fatty acids and carbohydrates increased by dietary PX. PX inhibited lipase or α-amylase activity in vitro. Thus, we found that PX may exert anti-obesity effects through the regulation of lipid metabolism and inhibition of intestinal fat and carbohydrate absorption, and that xanthohumol alone may exert anti-obesity effects.

Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Blood Glucose; Carbohydrate Metabolism; Diabetes Mellitus; Disease Models, Animal; Fasting; Fatty Acids; Flavonoids; Humulus; Intestinal Mucosa; Leptin; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred Strains; Obesity; Plant Extracts; Propiophenones; Sterol Regulatory Element Binding Protein 1

Bone morphogenetic protein 9 (BMP9) possesses multiple functions, but its effects on breast cancer cells in adipose microenvironment are still unclear. This study aimed to investigate whether BMP9 is able to modulate the interaction between pre-adipocytes/adipocytes and breast cancer cells. An in vitro co-culture system was established by using pre-adipocytes/adipocytes and MDA-MB-231 breast cancer cells with BMP9 over-expression. The leptin expression and leptin-induced signaling pathway were evaluated in this co-culture system. MTT assay, EdU assay and flow cytometry were used to assess the proliferation of MDA-MB-231 cells. Wound-healing assay and Transwell migration assay were used to assess the migration of MDA-MB-231 cells. Immunofluorescence staining was used to detect the expression of leptin recepter (ObR) in MDA-MB-231 cells. The expression of key molecules in leptin signaling pathway in co-culture system were detected by Western blotting. MDA-MB-231 cells and pre-adipocytes/adipocytes were inoculated into nude mice, the tumor volume was measured, and the protein expression of key molecules in leptin signaling pathway was detected. Results showed BMP9 inhibited breast tumor growth in vitro and in vivo and reduced the migration of breast cancer cells in vitro. MDA-MB-231 cells with BMP9 over-expression decreased leptin expression in pre-adipocytes/adipocytes and had reduced phosphorylation of STAT3, ERK1/2 and AKT. Taken together, our study indicates that BMP9 can inhibit the growth and metastasis of breast cancer cells, which may be related to interaction between pre-adipocytes/adipocytes and MDA-MB-231 cells via leptin signaling pathway.

Topics: 3T3-L1 Cells; Adipocytes; Animals; Apoptosis; Breast Neoplasms; Cell Communication; Cell Line, Tumor; Cell Movement; Cell Proliferation; Coculture Techniques; Disease Models, Animal; Female; Gene Expression; Growth Differentiation Factor 2; Heterografts; Humans; Leptin; Mice; Neoplasm Metastasis; Signal Transduction

Inflammatory bowel diseases (IBDs) are a heterogeneous group of disorders exhibited by two major phenotypic forms: Crohn's disease and ulcerative colitis. Although the aetiology of IBD is unknown, several factors coming from the adipose tissue and skeletal muscles, such as cytokines, adipokines and myokines, were suggested in the pathogenesis of ulcerative colitis; however, it has not been extensively studied whether voluntary exercise can ameliorate that disorder. We explored the effect of moderate exercise (i.e., voluntary wheel running) on the disease activity index (DAI), colonic blood flow (CBF), plasma irisin and adiponectin levels and real-time PCR expression of proinflammatory markers in mesenteric fat in mice with 2,4,6-trinitrobenzenesulfonic acid (TNBS) colitis fed a high-fat diet (HFD) compared to those on a standard chow diet (SD). Macroscopic and microscopic colitis in sedentary SD mice was accompanied by a significant fall in CBF, some increase in colonic tissue weight and a significant increase in the plasma levels of tumour necrosis factor-alpha (TNF-α), IL-6, monocyte chemotactic protein 1 (MCP-1) and IL-13 (

Topics: Adiponectin; Adiposity; Animals; Biomarkers; Chemokine CCL2; Colitis; Colon; Diet, High-Fat; Disease Models, Animal; Fibronectins; Interleukin-13; Interleukin-1beta; Interleukin-6; Leptin; Male; Mice; Mice, Inbred C57BL; Physical Conditioning, Animal; Tumor Necrosis Factor-alpha

Increasing evidence has demonstrated that patients with depression have a higher risk of developing type 2 diabetes. Insulin resistance has been identified as the key mechanism linking depression and diabetes. The present study established a rat model of depression complicated by insulin resistance using a 12-week exposure to chronic mild stress (CMS) and investigated the therapeutic effects of curcumin. Sucrose intake tests were used to evaluate depressive-like behaviors, and oral glucose tolerance tests (OGTT) and intraperitoneal insulin tolerance tests (IPITT) were performed to evaluate insulin sensitivity. Serum parameters were detected using commercial kits. Real-time quantitative PCR was used to examine mRNA expression. CMS rats exhibited reduced sucrose consumption, increased serum glucose, insulin, triglyceride (TG), low density lipoprotein-cholesterol (LDL-C), non-esterified fatty acid (NEFA), glucagon, leptin, and corticosterone levels, as well as impaired insulin sensitivity. Curcumin upregulated the phosphorylation of insulin receptor substrate (IRS)-1 and protein kinase B (Akt) in the liver, enhanced insulin sensitivity, and reversed the metabolic abnormalities and depressive-like behaviors mentioned above. Moreover, curcumin increased the hepatic glycogen content by inhibiting glycogen synthase kinase (GSK)-3β and prevented gluconeogenesis by inhibiting phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase). These results suggest that curcumin not only exerted antidepressant-like effects, but also reversed the insulin resistance and metabolic abnormalities induced by CMS. These data may provide evidence to support the potential use of curcumin against depression and/or metabolic disorders.

Topics: Animals; Behavior, Animal; Blood Glucose; Corticosterone; Curcumin; Depression; Disease Models, Animal; Glucagon; Glucose Tolerance Test; Insulin; Insulin Resistance; Leptin; Male; Pioglitazone; Rats; Rats, Sprague-Dawley; Stress, Psychological; Thiazolidinediones

Osteoporosis is associated with widespread periodontitis and impaired periodontal healing. However, there is a lack of information about the outcomes of regenerative approaches under the influence of osteoporosis. This study investigates the effect of leptin (LEP) overexpression on the regenerative potential of bone marrow stromal cells (BMSCs) in an osteoporotic rat periodontal fenestration defect model.. Rat BMSCs were transfected with adenoviruses harboring the human (h)LEP gene. Cell proliferation and osteogenic differentiation were evaluated. A β-tricalcium phosphate scaffold seeded with transfected cells was implanted into nude mice to investigate ectopic osteogenesis and into an osteoporotic rat defect to study periodontal regeneration. Regenerated periodontal and bone-like tissues were analyzed by histologic methods.. hLEP overexpression induced osteogenic differentiation of BMSCs as evidenced by the upregulation of osteogenesis-related genes such as Runt-related transcription factor 2, alkaline phosphatase (ALP), and collagen Type I, as well as increased ALP activity and enhanced mineralization. Mice implanted with hLEP-BMSC-containing scaffolds showed more extensive formation of bone-like tissue than those in other groups. Periodontal defects were also filled to a greater degree when treated with hLEP-BMSCs and contained cementum and a well-organized periodontal ligament after 10 and 28 days.. hLEP overexpression in BMSCs can stimulate periodontal regeneration in osteoporotic conditions and might be a promising strategy for periodontal regeneration in patients with osteoporosis.

Topics: Animals; Bone Marrow Cells; Bone Regeneration; Calcium Phosphates; Cell Differentiation; Cell Proliferation; Coculture Techniques; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Leptin; Mesenchymal Stem Cells; Mice, Inbred BALB C; Mice, Nude; Microscopy, Electron, Scanning; Osteoporosis; Periodontal Diseases; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Tissue Scaffolds; Transfection

The coincidences between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are so compelling that it is attractive to speculate that diabetic conditions might aggravate AD pathologies by calcium dysfunction, although the understanding of the molecular mechanisms involved remains elusive. The present work was undertaken to investigate whether calcium dyshomeostasis is associated with the exacerbated Alzheimer-like cognitive dysfunction observed in diabetic conditions in APP/PS1-ob/ob mice, which were generated by crossing ob/ob mice with APP/PS1 mice. We confirmed that the diabetic condition can aggravate not only Aβ deposition but also tau phosphorylation, synaptic loss, neuronal death, and inflammation, exacerbating cognitive impairment in AD mice. More importantly, we found that the diabetic condition dramatically elevated calcium levels in APP/PS1 mice, thereby stimulating the phosphorylation of the calcium-dependent kinases. Our findings suggest that controlling over-elevation of intracellular calcium may provide novel insights for approaching AD in diabetic patients and delaying AD progression.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Calcium Signaling; Cognitive Dysfunction; Diabetes Mellitus, Type 2; Disease Models, Animal; Humans; Inflammation; Leptin; Male; Memory Disorders; Mice; Mice, Transgenic; Phosphorylation; Protein Aggregation, Pathological; Signal Transduction; Synapses; tau Proteins

In common forms of obesity, leptin fails to convey its regulatory effect. This so called "leptin resistance" is not well understood, and solving this puzzle is a key to understanding how obesity develops. In the present study, we investigated the temporal and regional onset of leptin resistance in response to a diet enriched with long-chain saturated fatty acids (high-fat diet; HFD) in mice. Mice were exposed to either a low-fat diet (LFD) or a HFD for 4 hours, 24 hours, 10 days and 28 days. Mice in each group received an i.p. injection of either phosphate-buffered saline or leptin and the number of phosphorylated signal transducer and activator of transcription-3 (pSTAT3) immunoreactive (-IR) cells in the arcuate nucleus (ARC), ventromedial nucleus of the hypothalamus (VMH) and dorsomedial nucleus of the hypothalamus (DMH) was analysed 30 or 120 minutes after treatment. In the ARC, as soon as 24 hours of HFD, the molecular leptin response was reduced by 40% (P≤.01). Compared to at 24 hours, after 10 days, the number of leptin-induced pSTAT3-IR cells was elevated after 120 minutes, suggesting a sustained response and a partial return of leptin sensitivity. After 28 days, leptin failed to induce the number of pSTAT3-IR over control levels, suggesting a markedly reduced sensitivity to leptin. In the VMH after 24 hours, we observed a 50% reduction in leptin-induced pSTAT-3-IR cells, followed by a further decline after 10 days. However, after 28 days, there was a significant increase in pSTAT-3-IR cells (P≤.05), indicating partial recovery of leptin sensitivity. By contrast to these two regions, in the DMH, no loss of leptin sensitivity was observed at any time-point. These findings demonstrate that a loss of sensitivity to leptin occurs rapidly after exposure to HFD in the ARC and VMH but not the DMH. However, there appears to be a biphasic pattern of leptin responsiveness, with a partial return of leptin sensitivity occurring after 10 days in the arcuate nucleus, and after 28 days in the VMH. By 28 days, the response to leptin in the arcuate nucleus was completely lost. These findings suggest that the molecular responses to leptin are altered after high-fat feeding in a time- and region-specific manner.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Diet, High-Fat; Disease Models, Animal; Dorsomedial Hypothalamic Nucleus; Hypothalamus; Leptin; Male; Mice, Inbred C57BL; Obesity; Phosphorylation; STAT3 Transcription Factor; Ventromedial Hypothalamic Nucleus

The expression and localization of leptin (A and B) and its receptor family in control and diet-induced obese (DIO) adult male zebrafish gut, after 5-weeks overfeeding, administering Artemia nauplii, as fat-rich food, were investigated. Recently, the obese adult zebrafish was considered an experimental model with pathophysiological pathways similar to mammalian obesity. Currently, there are no reports about leptin in fish obesity, or in a state of altered energy balance. By qRT-PCR, leptin A and leptin B expression levels were significantly higher in DIO zebrafish gut than in the control group (CTRL), and the lowest levels of leptin receptor mRNA appeared in DIO zebrafish gut. The presence of leptin and its receptor proteins in the intestinal tract was detected by western blot analysis in both control and DIO zebrafish. By single immunohistochemical staining, leptin and leptin receptor immunoreactive endocrine cells were identified in the intestinal tract either in DIO or control zebrafish. Moreover, leptin immunopositive enteric nervous system elements were observed in both groups. By double immunohistochemical staining, leptin and its receptor were colocalized especially in DIO zebrafish. Thus, our study represents a starting point in the investigation of a possible involvement of leptin in control of energy homeostasis in control and DIO zebrafish.

Topics: Animals; Artemia; Blotting, Western; Diet; Disease Models, Animal; Gastrointestinal Tract; Immunohistochemistry; Leptin; Male; Obesity; Real-Time Polymerase Chain Reaction; Receptors, Leptin; Zebrafish

A hallmark of bone marrow changes with aging is the increase in adipocyte composition, but how this impacts development of multiple myeloma (MM) is unknown. Here, we report the role of the adipokine leptin as master regulator of anti-myeloma tumor immunity by modulating the invariant natural killer T (iNKT) cell function. A marked increase in serum leptin levels and leptin receptor (LR) expression on iNKT cells in MM patients and the 5T33 murine MM model was observed. MM cells and leptin synergistically counteracted anti-tumor functionality of both murine and human iNKT cells. In vivo blockade of LR signaling combined with iNKT stimulation resulted in superior anti-tumor protection. This was linked to persistent IFN-γ secretion upon repeated iNKT cell stimulation and a restoration of the dynamic antigen-induced motility arrest as observed by intravital microscopy, thereby showing alleviation of iNKT cell anergy. Overall our data reveal the LR axis as novel therapeutic target for checkpoint inhibition to treat MM.

Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cytokines; Disease Models, Animal; Galactosylceramides; Humans; Leptin; Lymphocyte Activation; Mice; Mice, Knockout; Molecular Targeted Therapy; Multiple Myeloma; Natural Killer T-Cells; Receptors, Leptin; Xenograft Model Antitumor Assays

This study used an integrated approach to investigate the effects of Gymnema sylvestre (GS) extract as a functional dietary supplement with a high-fat diet. This approach examined insulin resistance, the dysfunction of adipose tissue, and liver steatosis. Male C57BL/6J mice were fed a normal chow or high-fat diet (HFD) for the acute and chronic study, in addition to GS in different doses (100, 250 and 500[Formula: see text]mg/kg body weight). Their body composition changes, serum lipid and glucose parameters, adipose and liver tissue histology, and gene expression were measured. It was found that GS significantly suppressed the increase of body weight, serum levels of lipid, insulin and leptin, and adipose tissue, and liver inflammation. GS also demonstrated hypoglycemic effects due to the amylase inhibition activity. Our results support the existence of a relationship between the HFD induced insulin resistance, adipose dysfunction and liver steatosis. In conclusion, GS works as a functional dietary supplement with preventative effects against metabolic disorder.

Topics: Animals; Blood Glucose; Diet, High-Fat; Dietary Supplements; Disease Models, Animal; Gymnema sylvestre; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Lipids; Male; Metabolic Diseases; Mice, Inbred C57BL; Plant Extracts

Schizophrenia appears to be linked to higher incidence of metabolic syndrome even in the absence of antipsychotic treatment. Atypical antipsychotics substantially differ in their propensity to induce metabolic alterations. Aripiprazole is considered to represent an antipsychotic drug with low risk of metabolic syndrome development. The aim of this study was to evaluate metabolic phenotype of neurodevelopmental polyI:C rat model and assess metabolic effects of chronic aripiprazole treatment with regard to complex neuroendocrine regulations of energy homeostasis. Polyinosinic:polycytidylic acid (polyI:C) was administered subcutaneously at a dose of 8 mg/kg in 10 ml on gestational day 15 to female Wistar rats. For this study 20 polyI:C and 20 control adult male offspring were used, randomly divided into 2 groups per 10 animals for chronic aripiprazole treatment and vehicle. Aripiprazole (5 mg/kg, dissolved tablets, ABILIFY

Topics: Administration, Oral; Animals; Antipsychotic Agents; Aripiprazole; Body Weight; Cytokines; Disease Models, Animal; Ghrelin; Glucagon-Like Peptide 1; Leptin; Male; Metabolic Syndrome; Poly I-C; Random Allocation; Rats, Wistar; Schizophrenia

Moderate alcohol consumption is cardioprotective but the mechanism of action remains unclear. Nuclear factor κ-B regulates the expression of genes involved in inflammation, stress, and apoptosis. We used a swine model of diet-induced metabolic syndrome to investigate the effects of red wine and vodka on nuclear factor κ-B signaling and cytokine activity in chronically ischemic myocardium.. Yorkshire swine were given a high-fat diet for 4 weeks; an ameroid constrictor was then placed on the left circumflex artery. The high-fat diet was continued and the swine were divided into 3 groups for 7 weeks: hypercholesterolemic diet alone (control, n = 8), hypercholesterolemic diet with vodka (vodka, n = 8), and hypercholesterolemic diet with wine (wine, n = 8). Ischemic myocardium was analyzed by Western blot and cytokine array.. Administration of alcohol was associated with decreased expression of inhibitor of κ-B kinase complex α, inhibitor of κ-B kinase complex β, and phosphorylated inhibitor of κ-B β in the ischemic myocardium compared with the control group. Alcohol administration demonstrated an increase in nuclear factor κ-B in the ischemic myocardium. Both wine and vodka demonstrated a significant decrease in leptin, interleukin-1α, IL-13, IL-15, and interferon-γ. Vodka demonstrated a significant decrease in phosphorylated BCL-2 and caspase-9.. In ischemic myocardium, alcohol modulates the nuclear factor κ-B pathway, which may contribute to the adaptive response of tissues to the stress of ischemia. Furthermore, both wine and vodka decreased multiple proinflammatory cytokines. This study provides a mechanism by which alcohol may be cardioprotective in ischemic myocardium.

Topics: Animals; Biomarkers; Biopsy, Needle; Blotting, Western; Chemokines; Diet, High-Fat; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Ethanol; Immunohistochemistry; Interleukins; Leptin; Male; Myocardial Ischemia; NF-kappaB-Inducing Kinase; Protein Serine-Threonine Kinases; Random Allocation; Sensitivity and Specificity; Swine; Wine

Topics: Animals; Disease Models, Animal; Humans; Leptin; Mice; Morphine; Obesity

This article compared the effects of spontaneous obesity on the daily profile in the relative amount of the leptin receptor (LepRb), and its output. That is the precursor Pro-opiomelanocortin (POMC) over a 24-hour period and compared with differences in locomotion and food intake in periods of artificial light. Differences between lean and obese mice were examined, as were sex differences. Body weight, food intake and locomotor activity were monitored in freely moving lean and obese mice. Hypothalamic tissue was collected at 5 h, 10 h, 15 h, 19 h and 24 h. Samples were analyzed by western blotting to determine the relative presence of protein for LepRb, STAT3 phosphorylation (by pSTAT3/STAT3 ratio) and POMC. Obese mice were 60% less active in locomotion than lean mice during the night. While both locomotor activity and food intake were noticeably greater during the day in obese mice than in lean mice, the hypothalamus in obese mice showed a lower relative abundance of POMC and reduced pSTAT3/STAT3 ratio and leptin receptors. Behavioral and biochemical differences were more evident in obese females than in obese males. These results indicate that obesity in N. alstoni affects hypothalamic leptin signaling according to sex.

Topics: Adiposity; Animals; Arvicolinae; Body Composition; Circadian Rhythm; Disease Models, Animal; Eating; Female; Hypothalamus; Leptin; Light; Locomotion; Male; Mice; Obesity; Phosphorylation; Photoperiod; Pro-Opiomelanocortin; Receptors, Leptin; Sex Factors; Signal Transduction; STAT3 Transcription Factor; Time Factors

Iron dysregulation is a potential contributor to the pathology of obesity-related metabolic complications. KK/HIJ (KK) mice, a polygenic obese mouse model, have elevated serum iron levels. A subset of KK male mice display a bronzing of epididymal adipose tissue (eAT) associated with >100-fold (p<0.001) higher iron concentration.. To further phenotype and characterize the adipose tissue iron overload, 27 male KK mice were evaluated. 14 had bronzing eAT and 13 had normal appearing eAT. Fasting serum and tissues were collected for iron content, qPCR, histology and western blot.. High iron levels were confirmed in bronzing eAT (High Iron group, HI) versus normal iron level (NI) in normal appearing eAT. Surprisingly, iron levels in subcutaneous and brown adipose depots were not different between the groups (p>0.05). The eAT histology revealed iron retention, macrophage clustering, tissue fibrosis, cell death as well as accumulation of HIF-2α in the high iron eAT. qPCR showed significantly decreased Lep (leptin) and AdipoQ (adiponectin), whereas Tnfα (tumor necrosis factor α), and Slc40a1 (ferroportin) were up-regulated in HI (p<0.05). Elevated HIF-2α, oxidative stress and local insulin signaling loss was also observed.. Our data suggest that deposition of iron in adipose tissue is limited to the epididymal depot in male KK mice. A robust adipose tissue remodeling is concomitant with the high iron concentration, which causes local adipose tissue insulin resistance.

Topics: Adiponectin; Adipose Tissue; Adiposity; Animals; Blood Glucose; Disease Models, Animal; Epididymis; Insulin Resistance; Iron; Iron Overload; Leptin; Male; Mice; Mice, Mutant Strains; Obesity; Tissue Distribution

Material obesity in rodents is associated with neonatal hyperleptinemia and hypertension of sympathetic origin in adult offspring. Previously, we reported that experimentally induced hyperleptinemia in rat pups results in adulthood hypertension. Here, we addressed the hypothesis that experimental neonatal hyperleptinemia, through renal nerve activation, adversely affects adult renal function.. Sprague-Dawley male and female pups were treated with neonatal leptin (3 mg/kg, intraperitoneal) or neonatal saline, twice daily from postnatal day 9-14. Juvenile (1 month) neonatal leptin and neonatal saline rats were subjected to either bilateral renal denervation, unilateral renal denervation or Sham surgery. Arterial pressure was telemetrically monitored.. Juvenile neonatal leptin rats with intact renal nerves demonstrated increased mean arterial pressure (MAP) accompanied by local renin-angiotensin system overactivity and reduced glomerular filtration rate. Bilateral renal denervation in rats protected against neonatal leptin-induced MAP, renal renin-angiotensin system and impaired glomerular filtration rate. A two-fold increase in sympathetically mediated tubulointerstitial damage in young adult (2 months) neonatal leptin females, was suppressed by unilateral renal denervation, independent of MAP. Neonatal leptin rats also demonstrated increases in urinary protein, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1. Raised blood pressure was associated with increased salt sensitivity and with sustained renal dysfunction in adulthood.. We propose that neonatal hyperleptinemia programmes long-term renal structural and functional damage, through renal sympathetic nerve activation.

Topics: Animals; Blood Pressure; Denervation; Disease Models, Animal; Female; Hypertension; Kidney; Kidney Diseases; Leptin; Lipocalin-2; Male; Rats; Rats, Sprague-Dawley; Sympathetic Nervous System

Obesity is associated with elevated circulating leptin levels and hypothalamic leptin resistance. Leptin receptors (LepRs) are expressed on endothelial cells, and leptin promotes neointima formation in a receptor-dependent manner. Our aim was to examine the importance of endothelial LepR (End.LepR) signaling during vascular remodeling and to determine whether the cardiovascular consequences of obesity are because of hyperleptinemia or endothelial leptin resistance.. Mice with loxP-flanked LepR alleles were mated with mice expressing Cre recombinase controlled by the inducible endothelial receptor tyrosine kinase promoter. Obesity was induced with high-fat diet. Neointima formation was examined after chemical carotid artery injury. Morphometric quantification revealed significantly greater intimal hyperplasia, neointimal cellularity, and proliferation in End.LepR knockout mice, and similar findings were obtained in obese, hyperleptinemic End.LepR wild-type animals. Analysis of primary endothelial cells confirmed abrogated signal transducer and activator of transcription-3 phosphorylation in response to leptin in LepR knockout and obese LepR wild-type mice. Quantitative PCR, ELISA, and immunofluorescence analyses revealed increased expression and release of endothelin-1 in End.LepR-deficient and LepR-resistant cells, and ET receptor A/B antagonists abrogated their paracrine effects on murine aortic smooth muscle cell proliferation. Reduced expression of peroxisome proliferator-activated receptor-γ and increased nuclear activator protein-1 staining was observed in End.LepR-deficient and LepR-resistant cells, and peroxisome proliferator-activated receptor-γ antagonization increased endothelial endothelin-1 expression.. Our findings suggest that intact endothelial leptin signaling limits neointima formation and that obesity represents a state of endothelial leptin resistance. These observations and the identification of endothelin-1 as soluble mediator of the cardiovascular risk factor obesity may have relevant therapeutic implications.

Topics: Animals; Carotid Arteries; Carotid Artery Injuries; Cell Movement; Cell Proliferation; Cells, Cultured; Diet, High-Fat; Disease Models, Animal; Endothelial Cells; Endothelin-1; Female; Genotype; Integrases; Leptin; Male; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neointima; Obesity; Paracrine Communication; Phenotype; Phosphorylation; PPAR gamma; Promoter Regions, Genetic; Receptor, TIE-2; Receptors, Endothelin; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor; Vascular Remodeling

Transplantation of adventitial pericytes (APCs) improves recovery from tissue ischemia in preclinical animal models by still unknown mechanisms. This study investigates the role of the adipokine leptin (LEP) in the regulation of human APC biological functions. Transcriptomic analysis of APCs showed components of the LEP signalling pathway are modulated by hypoxia. Kinetic studies indicate cultured APCs release high amounts of immunoreactive LEP following exposure to hypoxia, continuing upon return to normoxia. Secreted LEP activates an autocrine/paracrine loop through binding to the LEP receptor (LEPR) and induction of STAT3 phosphorylation. Titration studies using recombinant LEP and siRNA knockdown of LEP or LEPR demonstrate the adipokine exerts important regulatory roles in APC growth, survival, migration and promotion of endothelial network formation. Heterogeneity in LEP expression and secretion may influence the reparative proficiency of APC therapy. Accordingly, the levels of LEP secretion predict the microvascular outcome of APCs transplantation in a mouse limb ischemia model. Moreover, we found that the expression of the Lepr gene is upregulated on resident vascular cells from murine ischemic muscles, thus providing a permissive milieu to transplanted LEP-expressing APCs. Results highlight a new mechanism responsible for APC adaptation to hypoxia and instrumental to vascular repair.

Topics: Adult; Adventitia; Aged; Animals; Autocrine Communication; Cell Hypoxia; Disease Models, Animal; Female; Femoral Artery; Gene Expression Regulation; Hindlimb; Humans; Ischemia; Leptin; Male; Mice; Mice, Inbred C57BL; Middle Aged; Neovascularization, Physiologic; Paracrine Communication; Pericytes; Phosphorylation; Primary Cell Culture; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor

Despite the dramatic increase in the prevalence of diabetes, techniques for in situ studies of the underlying pancreatic biochemistry are lacking. Such methods would facilitate obtaining mechanistic understanding of diabetes pathophysiology and aid in prognostic and/or diagnostic assessments. In this report we demonstrate how a multivariate imaging approach (orthogonal projections to latent structures - discriminant analysis) can be applied to generate full vibrational microspectroscopic profiles of pancreatic tissues. These profiles enable extraction of known and previously unrecorded biochemical alterations in models of diabetes, and allow for classification of the investigated tissue with regards to tissue type, strain and stage of disease progression. Most significantly, the approach provided evidence for dramatic alterations of the pancreatic biochemistry at the initial onset of immune-infiltration in the Non Obese Diabetic model for type 1 diabetes. Further, it enabled detection of a previously undocumented accumulation of collagen fibrils in the leptin deficient ob/ob mouse islets. By generating high quality spectral profiles through the tissue capsule of hydrated human pancreata and by in vivo Raman imaging of pancreatic islets transplanted to the anterior chamber of the eye, we provide critical feasibility studies for the translation of this technique to diagnostic assessments of pancreatic biochemistry in vivo.

Topics: Animals; Diabetes Mellitus, Type 1; Disease Models, Animal; Disease Progression; Female; Humans; Leptin; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Pancreas; Spectrum Analysis

Chronic kidney disease (CKD) results in decreased bone strength. Serotonin (5-HT) is one of the critical regulators of bone health, fulfilling distinct functions depending on its synthesis site: brain-derived serotonin (BDS) favors osteoblast proliferation, whereas gut-derived serotonin (GDS) inhibits it. We assessed the role of BDS and peripheral leptin in the regulation of bone metabolism and strength in young rats with 5/6 nephrectomy. BDS synthesis was accelerated during CKD progression. Decreased peripheral leptin in CKD rats was inversely related to BDS content in the hypothalamus, brainstem and frontal cortex. Serotonin in these brain regions affected bone strength and metabolism in the studied animals. The direct effect of circulating leptin on bone was not shown in uremia. At the molecular level, there was an inverse association between elevated GDS and the expression of cAMP responsive element-binding protein (Creb) gene in bone of CKD animals. In contrast, increased expression of activating transcription factor 4 (Atf4) was shown, which was associated with GDS-dependent transcription factor 1 (Foxo1), clock gene - Cry-1, cell cycle genes: c-Myc, cyclins, and osteoblast differentiation genes. These results identified a previously unknown molecular pathway, by which elevated GDS can shift in Foxo1 target genes from Creb to Atf4-dependent response, disrupting the leptin-BDS - dependent gene pathway in the bone of uremic rats. Thus, in the condition of CKD the effect of BDS and GDS on bone metabolism and strength can't be distinguished.

Topics: Alkaline Phosphatase; Animals; Biomarkers; Biomechanical Phenomena; Bone and Bones; Bone Remodeling; Brain; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Femur; Gastrointestinal Tract; Leptin; Male; Rats, Wistar; Renal Insufficiency, Chronic; Serotonin; Signal Transduction; Vanilmandelic Acid; X-Ray Microtomography

Metabolic changes induced by high fat diet (HFD) that contribute to osteoarthritis (OA) are poorly understood. We investigated longitudinal changes to metabolites and their contribution to OA pathogenesis in response to HFD. HFD-fed mice exhibited acceleration of spontaneous age-related and surgically-induced OA compared to lean diet (LD)-fed mice. Using metabolomics, we identified that HFD-fed mice exhibited a distinct and sustained plasma metabolite signature rich in phosphatidylcholines (PC) and lysophosphatidylcholines (lysoPCs), even after resumption of normal chow diet. Using receiver operator curve analysis and prediction modelling, we showed that the concentration of these identified metabolites could efficiently predict the type of diet and OA risk with an accuracy of 93%. Further, longitudinal evaluation of knee joints of HFD- compared to LD- fed mice showed a greater percentage of leptin-positive chondrocytes. Mechanistic data showed that leptin-treated human OA chondrocytes exhibited enhanced production of lysoPCs and expression of autotaxin and catabolic MMP-13. Leptin-induced increased MMP13 expression was reversed by autotaxin inhibition. Together, this study is the first to describe a distinct and sustained HFD-induced metabolite signature. This study suggests that in addition to increased weight, identified metabolites and local leptin-signaling may also contribute in part, towards the accelerated OA-phenotype observed in HFD mice.

Topics: Animals; Biomarkers; Biopsy; Blood Glucose; Body Weight; Cartilage, Articular; Diet, High-Fat; Disease Models, Animal; Immunohistochemistry; Insulin; Leptin; Metabolome; Mice; Osteoarthritis; ROC Curve

We recently reported the in vitro and in vivo antiobesity effects of Tenebrio molitor larvae, a traditional food in many countries, but it remains unknown how the larvae affect appetite regulation in mice with diet-induced obesity. We hypothesized that the extract of T molitor larvae mediates appetite by regulating neuropeptide expression. We investigated T molitor larvae extract's (TME's) effects on anorexigenesis and endoplasmic reticulum (ER) stress-induced orexigenic neuropeptide expression in the hypothalami of obese mice. Intracerebroventricular TME administration suppressed feeding by down-regulating the expression of the orexigenic neuropeptides neuropeptide Y and agouti-related protein. T molitor larvae extract significantly reduced the expression of ER stress response genes. These results suggest that TME and its bioactive components are potential therapeutics for obesity and ER stress-driven disease states.

Topics: Agouti-Related Protein; Animals; Biological Products; Body Weight; Cell Line; Diet; Diet, High-Fat; Disease Models, Animal; Endoplasmic Reticulum Stress; Gene Expression Regulation; Ghrelin; Hypothalamus; Larva; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Mitogen-Activated Protein Kinases; Neuropeptide Y; Obesity; Tenebrio; TOR Serine-Threonine Kinases

Obesity is a multifactorial disease characterized by the abnormal or excessive fat accumulation, which is caused by an energy imbalance between consumed and expended calories. Obesity leads to an inflammatory response that may result in peripheral and central metabolic changes, including insulin and leptin resistance. Insulin and leptin resistance have been associated with metabolic and cognitive dysfunctions. Obesity and some neurodegenerative diseases that lead to dementia affect mainly women. However, the effects of diet-induced obesity on memory consolidation in female rats are poorly understood. Therefore, the aim of this study was to evaluate the effect of a hypercaloric diet on the object recognition memory of female rats and on possible related metabolic changes. The animals submitted to the hypercaloric diet presented a higher food intake in grams and in calories, resulting in increased weight gain and liposomatic index in comparison with the animals exposed to the control diet. These animals presented a memory deficit in the object recognition test and increased serum levels of glucose and leptin. However, no significant differences were found in the serum levels of insulin, TNF-α and IL-1β, in the index of insulin resistance (HOMA), in the hippocampal levels of insulin, TNF-α and IL-1β, as well as on Akt expression or activation in the hippocampus. Our findings indicate that adult female rats submitted to a hypercaloric diet present memory consolidation impairment, which could be associated with diet-induced weight gain and leptin resistance, even without the development of insulin resistance.

Topics: Animals; Blood Glucose; Body Weight; Diet; Disease Models, Animal; Eating; Energy Intake; Exploratory Behavior; Female; Insulin; Leptin; Liposomes; Memory Consolidation; Memory Disorders; Obesity; Rats; Rats, Wistar; Recognition, Psychology; Tumor Necrosis Factor-alpha

Acute pancreatitis (AP) is a common non‑bacterial disease compromising pancreatic tissues. Adipocyte‑derived leptin is closely associated with the severity and clinical outcome of pancreatitis. The potential protective effects of exogenous leptin administration on a rat model of severe AP (SAP) remain to be elucidated, and were examined in the present study. Male Wistar rats were divided into a sham operation group (SO), SAP model group (SAP) and leptin group (LEP). Each group was divided into three sub‑groups by observation time (24, 48 and 72 h). The SAP models were prepared by retrograde injection of 6% sodium taurocholate into the pancreatic‑bile duct. Following model establishment, exogenous leptin was intraperitoneally injected into mice at 50 mg/kg in the LEP group. Subsequently, serum amylase, lipase and glucose levels at particular time‑points were analyzed using a fully‑automatic biochemical analyzer, and serum levels of tumor necrosis factor (TNF)‑α and interleukin (IL)‑10 were detected using an enzyme‑linked immunosorbent assay. The pathological changes in pancreatic tissues were observed using hematoxylin and eosin staining, and the pancreatic expression of the long form of the leptin receptor (OB‑Rb) was detected and evaluated using Nest‑polymerase chain reaction analysis. The mortality rates of the model rats were compared between the groups. Following the administration of exogenous leptin, the serum level of amylase in the LEP group was significantly decreased at 48 h, compared with that in the SAP group, with serum lipase levels decreased at 48 and 72 h, and blood glucose levels decreased at 72 h. Regarding the serum inflammatory factors, the level of TNF‑α in the LEP group was significantly lower, compared with that in the SAP group at 24 h; whereas no significant difference was observed in the serum level of IL‑10 between the two groups. Regarding the pathological changes in the pancreas, the tissues in the LEP group showed significantly alleviated pancreatic inflammation. In addition, the pancreatic expression of OB‑Rb in the LEP group was significantly higher, compared with that in the SAP group at 24 and 48 h. No significant difference in 3‑day mortality rates were observed between the SAP group and the LEP group. Taken together, exogenous leptin administration regulated inflammatory factors and the expression of OB‑Rb at the early stage of AP, which exerted protective effects by through the immunological and endocrinal pathways.

Topics: Acute Disease; Amylases; Animals; Blood Glucose; Disease Models, Animal; Inflammation; Interleukin-10; Leptin; Lipase; Male; Pancreas; Pancreatitis; Protective Agents; Rats; Rats, Wistar; Receptors, Leptin; Severity of Illness Index; Taurocholic Acid; Tumor Necrosis Factor-alpha

In Prader-Willi syndrome (PWS), obesity is caused by the disruption of appetite-controlling pathways in the brain. Two PWS candidate genes encode MAGEL2 and necdin, related melanoma antigen proteins that assemble into ubiquitination complexes. Mice lacking Magel2 are obese and lack leptin sensitivity in hypothalamic pro-opiomelanocortin neurons, suggesting dysregulation of leptin receptor (LepR) activity. Hypothalamus from Magel2-null mice had less LepR and altered levels of ubiquitin pathway proteins that regulate LepR processing (Rnf41, Usp8, and Stam1). MAGEL2 increased the cell surface abundance of LepR and decreased their degradation. LepR interacts with necdin, which interacts with MAGEL2, which complexes with RNF41 and USP8. Mutations in the MAGE homology domain of MAGEL2 suppress RNF41 stabilization and prevent the MAGEL2-mediated increase of cell surface LepR. Thus, MAGEL2 and necdin together control LepR sorting and degradation through a dynamic ubiquitin-dependent pathway. Loss of MAGEL2 and necdin may uncouple LepR from ubiquitination pathways, providing a cellular mechanism for obesity in PWS.

Topics: Animals; Antigens, Neoplasm; Cell Line, Tumor; Disease Models, Animal; Endopeptidases; Endosomal Sorting Complexes Required for Transport; HEK293 Cells; Humans; Hypothalamus; Insulin Receptor Substrate Proteins; Leptin; Mice; Mice, Knockout; Nerve Tissue Proteins; Neurons; Nuclear Proteins; Obesity; Prader-Willi Syndrome; Protein Transport; Proteins; Receptors, Leptin; Ubiquitin Thiolesterase; Ubiquitination

Lafora disease (LD) represents a fatal form of neurodegenerative disorder characterized by the presence of abnormally large number of polyglucosan bodies-called the Lafora bodies-in neurons and other tissues of the affected patients. The disease is caused by defects in the EPM2A gene coding for a protein phosphatase (laforin) or the NHLRC1 gene coding for an ubiquitin ligase (malin). Studies have shown that inhibition of glycogen synthesis in the brain could prevent the formation of Lafora bodies in the neurons and reduce seizure susceptibility in laforin-deficient mouse, an established animal model for LD. Since increased glucose uptake is thought to underlie increased glycogen in LD, and since the adipocyte hormone leptin is known to positively regulate the glucose uptake in neurons, we reasoned that blocking leptin signaling might reduce the neuronal glucose uptake and ameliorate the LD pathology. We demonstrate here that mice that were deficient for both laforin and leptin receptor showed a reduction in the glycogen level, Lafora bodies and gliosis in the brain, and displayed reduced susceptibility to induced seizures as compared to animals that were deficient only for laforin. Thus, blocking leptin signaling could be a one of the effective therapeutic strategies in LD.

Topics: Animals; Disease Models, Animal; Dual-Specificity Phosphatases; Genetic Predisposition to Disease; Glucans; Glycogen; Inclusion Bodies; Lafora Disease; Leptin; Mice; Neurons; Protein Tyrosine Phosphatases, Non-Receptor; Receptors, Leptin; Signal Transduction; Ubiquitin-Protein Ligases

Metabolic syndrome (MetS) is characterized by a cluster of key features, which include abdominal obesity, insulin resistance, hypertension, and dyslipidemia. The aim of this study was to assess the impact of elevated glucocorticoid levels on the development of MetS in middle-aged female rhesus monkeys (Macaca Mulatta) after ovariectomy. Six female ovariectomized rhesus monkeys (9-13years) were randomly assigned to either a control group (normal diet, n=3) or a group in which MetS was facilitated (n=3). The MetS group fed with HFD (15% fat) and received oral prednisone acetate treatment (50mg/day). After 24months, the GCs treatment was withdrawn with continuation of high-fat feeding for a further 12months. After 24months, the MetS group displayed a significant increase in body weight and abdominal circumference. Additionally, the MetS animals displayed abnormal serum lipids, insulin resistance and impaired glucose tolerance. Histology of liver biopsies indicated marked accumulation of lipid droplets in hepatocytes of MetS animals. Withdrawal of GCs treatment led to recovery from above-mentioned metabolic disorders. Whereas GCs treatment increased leptin expression, it lowered expression of adiponectin and other factors in adipose tissue. Expression of Hydroxy-steroid dehydrogenase-1 and glucose transporter type-4 in the livers of MetS animals were reduced. We conclude that in the context of high fat diet, high levels of exogenous GCs contribute to the development of MetS in non-human primates.

Topics: Adipose Tissue; Animals; Body Weight; Diet, High-Fat; Disease Models, Animal; Glucocorticoids; Humans; Insulin; Leptin; Liver; Macaca mulatta; Metabolic Syndrome; Ovariectomy

The safety of testosterone supplements in men remains unclear. In the present study, we tested the hypothesis that in young and old male spontaneously hypertensive rats (SHR), long-term testosterone supplements increase blood pressure and that the mechanism is mediated in part by activation of the renin-angiotensin system.. In untreated males, serum testosterone exhibited a sustained decrease after 5 months of age, reaching a nadir by 18 to 22 months of age. The reductions in serum testosterone were accompanied by an increase in body weight until very old age (18 months). Testosterone supplements were given for 6 weeks to young (12 weeks-YMSHR) and old (21-22 months-OMSHR) male SHR that increased serum testosterone by 2-fold in young males and by 4-fold in old males. Testosterone supplements decreased body weight, fat mass, lean mass, and plasma leptin, and increased plasma estradiol in YMSHR but had no effect in OMSHR. Mean arterial pressure (MAP) was significantly higher in OMSHR than in YMSHR and testosterone supplements decreased MAP in OMSHR, but significantly increased MAP in YMSHR. Enalapril, the angiotensin-converting enzyme inhibitor, reduced MAP in both control and testosterone-supplemented YMSHR, but had a greater effect on MAP in testosterone-treated rats, suggesting the mechanism responsible for the increase in MAP in YMSHR is mediated at least in part by activation of the renin-angiotensin system.. Taken together with previous studies, these data suggest that testosterone supplements may have differential effects on men depending on age, cardiovascular and metabolic status, and dose and whether given long-term or short-term.

Topics: Adiposity; Age Factors; Aging; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Arterial Pressure; Disease Models, Animal; Enalapril; Estradiol; Hormone Replacement Therapy; Hypertension; Leptin; Male; Rats, Inbred SHR; Renin-Angiotensin System; Risk Factors; Testosterone; Weight Gain

Breast tumor recurrence and metastasis represent the main causes of cancer-related death in women, and treatments are still lacking. Here, we define the lipogenic enzyme acetyl-CoA carboxylase (ACC) 1 as a key player in breast cancer metastasis. ACC1 phosphorylation was increased in invading cells both in murine and human breast cancer, serving as a point of convergence for leptin and transforming growth factor (TGF) β signaling. ACC1 phosphorylation was mediated by TGFβ-activated kinase (TAK) 1, and ACC1 inhibition was indispensable for the elevation of cellular acetyl-CoA, the subsequent increase in Smad2 transcription factor acetylation and activation, and ultimately epithelial-mesenchymal transition and metastasis induction. ACC1 deficiency worsened tumor recurrence upon primary tumor resection in mice, and ACC1 phosphorylation levels correlated with metastatic potential in breast and lung cancer patients. Given the demonstrated effectiveness of anti-leptin receptor antibody treatment in halting ACC1-dependent tumor invasiveness, our work defines a "metabolocentric" approach in metastatic breast cancer therapy.

Topics: Acetyl-CoA Carboxylase; Acetylation; Animals; Breast Neoplasms; Disease Models, Animal; Female; HEK293 Cells; Humans; Leptin; Lung Neoplasms; MCF-7 Cells; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasm Recurrence, Local; Tissue Array Analysis

Metabolic syndrome (MS) increases cardiovascular risk and is associated with cardiac dysfunction and arrhythmias, although the precise mechanisms are still under study. Chronic inflammation in MS has emerged as a possible cause of adverse cardiac events. Male Wistar rats fed with 30% sucrose in drinking water and standard chow for 25-27 weeks were compared to a control group. The MS group showed increased weight, visceral fat, blood pressure, and serum triglycerides. The most important increases in serum cytokines included IL-1

Topics: Adrenergic beta-Agonists; Animals; Arrhythmias, Cardiac; Cells, Cultured; Cytokines; Disease Models, Animal; Echocardiography; Heart; Interleukin-1beta; Isoproterenol; Leptin; Male; Metabolic Syndrome; Myocardial Contraction; Myocardium; Myocytes, Cardiac; Rats; Rats, Wistar; Serum; Tomography, X-Ray Computed; Tumor Necrosis Factor-alpha; Ventricular Fibrillation; Whole Body Imaging

The role of PI3K in leptin physiology has been difficult to determine due to its actions downstream of several metabolic cues, including insulin. Here, we used a series of mouse models to dissociate the roles of specific PI3K catalytic subunits and of insulin receptor (InsR) downstream of leptin signaling. We show that disruption of p110α and p110β subunits in leptin receptor cells (LRΔα+β) produces a lean phenotype associated with increased energy expenditure, locomotor activity, and thermogenesis. LRΔα+β mice have deficient growth and delayed puberty. Single subunit deletion (i.e., p110α in LRΔα) resulted in similarly increased energy expenditure, deficient growth, and pubertal development, but LRΔα mice have normal locomotor activity and thermogenesis. Blunted PI3K in leptin receptor (LR) cells enhanced leptin sensitivity in metabolic regulation due to increased basal hypothalamic pAKT, leptin-induced pSTAT3, and decreased PTEN levels. However, these mice are unresponsive to leptin's effects on growth and puberty. We further assessed if these phenotypes were associated with disruption of insulin signaling. LRΔInsR mice have no metabolic or growth deficit and show only mild delay in pubertal completion. Our findings demonstrate that PI3K in LR cells plays an essential role in energy expenditure, growth, and reproduction. These actions are independent from insulin signaling.

Topics: Animals; Disease Models, Animal; Eating; Energy Metabolism; Estrus; Female; Fertility; Gene Deletion; Gene Silencing; Growth; Leptin; Male; Mice, Inbred C57BL; Mice, Knockout; Phosphatidylinositol 3-Kinases; Puberty; Receptor, Insulin; Receptors, Leptin; Sexual Maturation; Signal Transduction

Obesity is associated with increased fever and sickness behavior in response to infection. The hypothalamic-pituitary-adrenal (HPA) axis plays a key role in the reaction to immune stimuli. Bacterial infection, or bacterial lipopolysaccharide (LPS), induces the expression of peripheral cytokines that stimulate the hypothalamus and the hippocampus and activate the HPA axis. In this study, we explored whether the hypothalamic and hippocampal responses to infection are altered during the development of diet-induced obesity. Male mice were exposed to a high-fat diet (HFD) or a low-fat diet (LFD) for 15 days. They were then administered a single intraperitoneal injection of bacterial LPS or vehicle and sacrificed 24 h later. LPS increased circulating levels of insulin and leptin, but only in LFD animals. LPS induced a significant decrease in hypothalamic corticotrophin-releasing hormone and glucocorticoid receptor mRNA levels in LFD animals but exerted the opposite effect in HFD-fed mice. LPS increased the hypothalamic expression of molecules involved in the leptin signaling pathway (SOCS3 and STAT3), nuclear factor-κB pathway members, inflammatory mediators (tumor necrosis factor-α and interleukin-6) and glial proliferation markers (Emr1 and CD68) in LFD animals. These effects were dampened in HFD-fed mice. In contrast, the hippocampal responses to LPS were largely insensitive to HFD. These results suggest that HFD feeding reduced the inflammatory response induced by LPS in the hypothalamus but not in the hippocampus.

Topics: Adiponectin; Analysis of Variance; Animals; Body Weight; Corticotropin-Releasing Hormone; Cytokines; Diet, High-Fat; Dietary Fats; Disease Models, Animal; Eating; Gene Expression Regulation; Hippocampus; Hypothalamus; Inflammation; Insulin; Leptin; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Obesity; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor

Polycystic ovary syndrome (PCOS) is a prevalent endocrinological disorder in reproductive-age women and is often associated with a metabolic syndrome. To investigate whether exercise intervention promotes PCOS prevention, a rat model was used. Polycystic ovary syndrome was induced by letrozole administration, and animals presented with obesity, sex hormone disorder, no ovulation, large cystic follicles, and increasing fasting insulin (FINS) and leptin levels. The intervention was set at 3 different intensities of swimming exercise: low (0.5 h/d), moderate (1 h/d), and high (2 h/d), and compared with a PCOS model group (letrozole administration without exercise intervention) and a control group. The exercise intervention in the low-intensity group did not produce changes in obesity, testosterone, progesterone (P), and follicle-stimulating hormone (FSH) levels. Moderate-intensity exercise reduced body weight, retained ovulation, and P levels were increased but remained lower than those in the control group. The FSH levels were significantly higher, and FINS and leptin levels were lower than in the model group ( P < 0.05) but not in the control group. The high-intensity group demonstrated the greatest effect of PCOS prevention. Testosterone, luteinizing hormone, FINS, and leptin levels were significantly lower in the high-intensity group, and FSH and P levels were higher compared with the model group. These results suggest that high-intensity exercise intervention can effectively prevent PCOS development.

Topics: Animals; Aromatase Inhibitors; Body Weight; Disease Models, Animal; Female; Follicle Stimulating Hormone; Insulin; Leptin; Letrozole; Nitriles; Obesity; Physical Conditioning, Animal; Polycystic Ovary Syndrome; Progesterone; Rats; Testosterone; Triazoles

Anaemia is associated with fatigue and diminished muscular oxygenation, which may affect skeletal muscle (SM). No studies are available about the SM modifications during anaemia recovery; therefore, the aim of this study is to study SM homeostasis during anaemia recovery with fermented milks.. Forty male Wistar rats were placed on a pre-experimental period of 40 days, divided in two groups (control group receiving normal-Fe diet and Fe-deficient group receiving low-Fe diet). Lately, rats were fed with fermented goat or cow milk-based diets, with normal-Fe content during 30 days. After feeding the fermented milks, leptin, adiponectin, non-esterified fatty acids (NEFA) and protein expression (UCP1, PepT1 and irisin) within the SM were assessed.. Adiponectin decreased in both groups of animals fed fermented goat milk, while leptin and NEFA increased. UCP1 protein expression increased in control and anaemic animals fed fermented goat milk. UCP1 also increased in both group of anaemic animals fed either fermented cow or goat milk in comparison with their controls. Irisin increased in both group of animals fed fermented goat milk. Finally, PepT1 also showed an increased expression in control and anaemic rats fed fermented goat milk and the anaemia also induced an over-expression of this transporter in animals fed either fermented cow or goat milk.. Fermented goat milk consumption during anaemia recovery diminishes adiposity depots and enhances lipolysis, increasing UCP1, PepT1 and irisin protein expression, featuring an ergogenic effect in the SM which is an important endocrine regulator of body metabolism.

Topics: Adiponectin; Anemia, Iron-Deficiency; Animals; Body Composition; Cattle; Cultured Milk Products; Diet; Disease Models, Animal; Fatty Acids, Nonesterified; Fermentation; Ferritins; Fibronectins; Gene Expression Regulation; Goats; Hepcidins; Homeostasis; Iron; Iron-Binding Proteins; Leptin; Male; Muscle, Skeletal; Peptide Transporter 1; Performance-Enhancing Substances; Rats; Rats, Wistar; Transferrin; Uncoupling Protein 1

The objective of this study is to examine the effects of the endogenous ligands leptin, ghrelin, and neuropeptide Y (NPY) on seizure generation, the oxidant/antioxidant balance, and cytokine levels, which are a result of immune response in a convulsive seizure model. With this goal, Wistar rats were divided into 5 groups-Group 1: Saline, Group 2: Saline+PTZ (65mg/kg), Group 3: leptin (4mg/kg)+PTZ, Group 4: ghrelin (80μg/kg)+PTZ, and Group 5: NPY (60μg/kg)+PTZ. All injections were delivered intraperitoneally, and simultaneous electroencephalography (EEG) records were obtained. Seizure activity was scored by observing seizure behavior, and the onset time, latency, and seizure duration were determined according to the EEG records. At the end of the experiments, blood samples were obtained in all groups to assess the serum TNF-α, IL-1β, IL-6, FGF-2, galanin, nitric oxide (NOֹ), malondialdehyde (MDA), and glutathione (GSH) levels. The electrophysiological and biochemical findings (p<0.05) of this study show that all three peptides have anticonvulsant effects in the pentylenetetrazol (PTZ)-induced generalized tonic-clonic convulsive seizure model. The reduction of the levels of the pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 caused by leptin, ghrelin, and NPY shows that these peptides may have anti-inflammatory effects in epileptic seizures. Also, leptin significantly increases the serum levels of the endogenous anticonvulsive agent galanin. The fact that each one of these endogenous peptides reduces the levels of MDA and increases the serum levels of GSH leads to the belief that they may have protective effects against oxidative damage that is thought to play a role in the pathogenesis of epilepsy. Our study contributes to the clarification of the role of these peptides in the brain in seizure-induced oxidative stress and immune system physiology and also presents new approaches to the etiology and treatment of tendency to epileptic seizures.

Topics: Animals; Cytokines; Disease Models, Animal; Fibroblast Growth Factor 2; Galanin; Ghrelin; Interleukin-1beta; Interleukin-6; Leptin; Malondialdehyde; Neuropeptide Y; Oxidative Stress; Pentylenetetrazole; Rats; Rats, Wistar; Seizures; Tumor Necrosis Factor-alpha

Cardiotrophin-1 (CT-1) belongs to the IL-6 family of cytokines. Previous studies of our group revealed that CT-1 is a key regulator of glucose and lipid metabolism. The aim of the present study was to analyze the in vitro and in vivo effects of CT-1 on the production of several adipokines involved in body weight regulation, nutrient metabolism, and inflammation. For this purpose, 3T3-L1 adipocytes were incubated with recombinant protein CT-1 (rCT-1) (1-40 ng/ml) for 1 and 18 h. Moreover, the acute effects of rCT-1 administration (0.2 mg/kg, i.v.) for 30 min and 3 h on adipokines levels were also evaluated in high-fat fed obese mice. In 3T3-L1 adipocytes, rCT-1 treatment downregulated the expression and secretion of leptin, resistin, and visfatin. However, rCT-1 significantly stimulated apelin mRNA and secretion. rCT-1 (18 h) also promoted the activation by phosphorylation of AKT, ERK 1/2, and STAT3. Interestingly, pre-treatment with the PI3K inhibitor LY294002 reversed the stimulatory effects of rCT-1 on apelin expression, suggesting that this pathway could be mediating the effects of rCT-1 on apelin production. In contrast, acute administration of rCT-1 (30 min and 3 h) to diet-induced obese mice downregulated leptin and resistin, without significantly modifying apelin or visfatin mRNA in adipose tissue. Furthermore, CT-1 null mice exhibited altered expression of adipokines in adipose tissue. The present study demonstrates that rCT-1 modulates the production of adipokines in vitro and in vivo, suggesting that the regulation of the secretory function of adipocytes could be involved in the metabolic actions of this cytokine. J. Cell. Physiol. 232: 2469-2477, 2017. © 2016 Wiley Periodicals, Inc.

Topics: 3T3-L1 Cells; Adipocytes; Adipokines; Adipose Tissue; Animals; Apelin; Cytokines; Diet, High-Fat; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nicotinamide Phosphoribosyltransferase; Obesity; Phosphatidylinositol 3-Kinase; Phosphorylation; Proto-Oncogene Proteins c-akt; Resistin; Signal Transduction; STAT3 Transcription Factor

Dietary obesity is usually linked with hypothalamic leptin resistance, in which the primary impact is an interference in the homeostatic control of body weight and appetite. Notably, proanthocyanidins (PACs), which are the most abundant phenolic compounds present in human diet, modulate adiposity and food intake. The aim of this study was to assess whether PACs could re-establish appropriate leptin signalling in both the hypothalamus and peripheral tissues.. Male Wistar rats were fed either a standard chow diet (STD group, n=7) or a cafeteria diet (CD) for 13 weeks. The CD-fed rats were treated with either grape-seed PAC extract (GSPE) at 25 mg  per kg of body weight per day (CD+GSPE group, n=7) or with the vehicle (CD group, n=7) for the last 21 days of the study period. Specific markers for intracellular leptin signalling, inflammation and endoplasmic reticulum stress in the hypothalamus, liver, mesenteric white adipose tissue and skeletal muscle were analysed using immunoblotting and quantitative PCR.. GSPE treatment significantly reduced the food intake but did not reverse the hyperleptinemia and body wt gain assessed. However, the animals treated with GSPE exhibited greater hypothalamic activation of signal transducer and activator of transcription-3, which was associated with a rise in the Pomc mRNA levels compared with the CD group. In addition, this restoration of leptin responsiveness was accompanied by lower local inflammation and increased Sirt1 gene expression. The effects of the GSPE treatment in the peripheral tissues were not as evident as those in the hypothalamus, although the GSPE treatment significantly restored the mRNA levels of Socs3 and Ptp1b in the skeletal muscle.. The use of GSPE reduces hyperphagia and improves the central and peripheral leptin resistance associated with diet-induced obesity. Our results suggest that GSPE could exert these effects partially by increasing Sirt1 expression and preventing hypothalamic inflammation.

Topics: Animals; Body Weight; Diet, High-Fat; Disease Models, Animal; Gene Expression Regulation; Grape Seed Extract; Hypothalamus; Leptin; Lipid Metabolism; Male; Obesity; Pro-Opiomelanocortin; Proanthocyanidins; Rats; Rats, Wistar; Signal Transduction; STAT3 Transcription Factor

Combatting overweight or obesity can lead to large fluctuations in an individual's body weight, often referred to as weight cycling or 'yo-yo' dieting. Current evidence regarding the potentially damaging effects of these changes is conflicting.. Here, we assess the metabolic effects of weight cycling in a murine model, comprising three dietary switches to normal or high-fat diets at 6 week intervals; male C57BL/6 mice were fed either a control (C) or high-fat (F) diet for 6 weeks (n=140/group). C and F groups were then either maintained on their initial diet (CC and FF, respectively) or switched to a high-fat (CF) or control (FC) diet (n=35/group). For the final 6 week interval, CC and CF groups were returned to the control diet (CCC and CFC groups), while FC and FF groups were placed on a high-fat diet (FCF and FFF) (n=28/group).. For the majority of metabolic outcomes changes aligned with dietary switches; however, assessment of neuropeptides and receptors involved in appetite regulation and reward signalling pathways reveal variable patterns of expression. Furthermore, we demonstrate that multiple cycling events leads to a significant increase in internal fat deposition, even when compared with animals maintained on a high-fat diet (internal fat: FCF: 7.4±0.2 g vs FFF: 5.6±0.2 g; P<0.01).. Increased internal adipose tissue is strongly linked to the development of metabolic syndrome associated conditions such as type 2 diabetes, cardiovascular disease and hypertension. Although further work will be required to elucidate the mechanisms underlying the neuronal control of energy homoeostasis, these studies provide a causative link between weight cycling and adverse health.

Topics: Adipose Tissue; Animals; Diet, Fat-Restricted; Diet, High-Fat; Disease Models, Animal; Energy Intake; Energy Metabolism; Gastric Inhibitory Polypeptide; Insulin; Interleukin-6; Leptin; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Obesity; Weight Gain; Weight Loss

Hypothalamic lesions or deficient melanocortin (MC) signaling via MC4 receptor (MC4r) mutations often lead to hyperphagia and severe treatment-resistant obesity. We tested the methionine aminopeptidase 2-inhibitor beloranib (ZGN-440) in 2 male rat models of obesity, one modeling hypothalamic obesity with a combined medial hypothalamic lesion (CMHL) and the other modeling a monogenic form of obesity with MC4r mutations (MC4r knockout [MC4rKO]). In CMHL rats (age 3 months), postsurgery excess weight gain was significantly inhibited (ZGN-440, 0.2 ± 0.7 g/d; vehicle, 3.8 ± 0.6 g/d; P < 0.001) during 12 days of ZGN-440 treatment (0.1 mg/kg daily subcutaneously) together with a 30% reduction of daily food intake vs vehicle injection. In addition, ZGN-440 treatment improved glucose tolerance and reduced plasma insulin, and circulating levels of α-melanocyte stimulating hormone were increased. Serum lipid levels did not differ significantly in ZGN-440-treated vs vehicle-treated rats. Similar results were found in MC4rKO rats: ZGN-440 treatment (14-21 d) was associated with significant reductions of body weight gain (MC4rKO, -1.7 ± 0.6 vs 2.8 ± 0.4 g/d; lean wild-type controls, -0.7 ± 0.2 vs 1.7 ± 0.7 g/d; ZGN-440 vs vehicle, respectively), reduction of food intake (MC4rKO, -28%; lean controls, -7.5%), and insulin resistance, whereas circulating levels of interleukin-1β did not change. In both obesity models, body temperature and locomotor activity were not affected by ZGN-440 treatment. In conclusion, the robust reduction of body weight in response to ZGN-440 observed in rats with severe obesity is related to a strong reduction of food intake that is likely related to changes in the central regulation of feeding.

Topics: Aminopeptidases; Animals; Body Temperature; Body Weight; Cinnamates; Cyclohexanes; Disease Models, Animal; Drug Evaluation, Preclinical; Eating; Epoxy Compounds; Gene Expression; Glucose Tolerance Test; Hyperphagia; Hypothalamus, Middle; Insulin Resistance; Leptin; Lipid Metabolism; Liver; Male; Metalloendopeptidases; Obesity; Rats, Sprague-Dawley; Rats, Transgenic; Receptor, Melanocortin, Type 4; Sesquiterpenes

The exchange protein directly activated by cAMP (Epac), which is primarily involved in cAMP signaling, has been known to be essential for controlling body energy metabolism. Epac has two isoforms: Epac1 and Epac2. The function of Epac1 on obesity was unveiled using Epac1 knockout (KO) mice. However, the role of Epac2 in obesity remains unclear.. To evaluate the role of Epac2 in obesity, we used Epac2a KO mice, which is dominantly expressed in neurons and endocrine tissues. Physiological factors related to obesity were analyzed: body weight, fat mass, food intake, plasma leptin and adiponectin levels, energy expenditure, glucose tolerance, and insulin and leptin resistance. To determine the mechanism of Epac2a, mice received exogenous leptin and then hypothalamic leptin signaling was analyzed.. Epac2a KO mice appeared to have normal glucose tolerance and insulin sensitivity until 12 weeks of age, but an early onset increase of plasma leptin levels and decrease of plasma adiponectin levels compared with wild-type mice. Acute leptin injection revealed impaired hypothalamic leptin signaling in KO mice. Consistently, KO mice fed a high-fat diet (HFD) were significantly obese, presenting greater food intake and lower energy expenditure. HFD-fed KO mice were also characterized by greater impairment of hypothalamic leptin signaling and by weaker leptin-induced decrease in food consumption compared with HFD-fed wild-type mice. In wild-type mice, acute exogenous leptin injection or chronic HFD feeding tended to induce hypothalamic Epac2a expression.. Considering that HFD is an inducer of hypothalamic leptin resistance and that Epac2a functions in pancreatic beta cells during demands of greater work load, hypothalamic Epac2a may have a role in facilitating leptin signaling, at least in response to higher metabolic demands. Thus, our data indicate that Epac2a is critical for preventing obesity and thus Epac2a activators may be used to manage obesity and obesity-mediated metabolic disorders.

Topics: Animals; Cyclic AMP; Diet, High-Fat; Disease Models, Animal; Energy Intake; Energy Metabolism; Guanine Nucleotide Exchange Factors; Hypothalamus; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Receptors, Leptin; Signal Transduction

Sjögren's syndrome (SjS) is a systemic autoimmune disease resulting in a severe dry mouth and dry eyes. Currently, care for patients with SjS is palliative, as no established therapeutics target the disease directly, and its pathogenetic mechanisms are uncertain. Leptin activates B cells to induce the secretion of proinflammatory and anti-inflammatory cytokines and is elevated in several autoimmune diseases. In this study, we found the expression of leptin and its receptor OB-R in mouse models of SjS are elevated both locally and systemically during SjS progression. Recombinant serotype 2 adeno-associated viral (rAAV2) vectors expressing either OB-R shRNA (rAAV2-shOB-R) or none (rAAV2-null) were injected into 4 or 16 week-old BALB/c NOD/LtJ (NOD) mice and resulted in a modest reduction in glandular inflammation in the SjS model. In conclusion, Leptin/OB-R signaling may be pathogenically involved in SjS and may serve as a new marker and a potential therapeutic target.

Topics: Animals; Disease Models, Animal; Female; Humans; Inflammation; Leptin; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Receptors, Leptin; Signal Transduction; Sjogren's Syndrome; Up-Regulation

Although the short-term effects of fasting or energy deficit on hypothalamic neuropeptide circuitries are now better understood, the effects of long-term energy deficit and refeeding remain to be elucidated. We showed that after a long-term energy deficit, mice exhibited persistent hypoleptinemia following the refeeding period despite restoration of fat mass, ovarian activity, and feeding behavior. We aimed to examine the hypothalamic adaptations after 10 weeks of energy deficit and after 10 further weeks of nutritional recovery. To do so, we assessed the mRNA levels of the leptin receptor and the main orexigenic and anorexigenic peptides, and their receptors regulated by leptin. Markers of hypothalamic inflammation were assessed as leptin can also participate in this phenomenon. Long-term time-restricted feeding and separation induced significant increase in mRNA levels of hypothalamic orexigenic peptides, while both Y1 and Y5 receptor mRNAs were downregulated. No changes occurred in the mRNA levels of orexin (OX), melanin-concentrating hormone, pro-opiomelanocortin, 26RFa (26-amino acid RF-amide peptide), and their receptors despite an increase in the expression of melanocortin receptors (MC3-R and MC4-R) and OXR1 (OX receptor 1). The refeeding period induced an overexpression of leptin receptor mRNA in the hypothalamus. The other assessed mRNA levels were normalized except for Y2, Y5, MC3-R, and MC4-R, which remained upregulated. No convincing changes were observed in neuroinflammatory markers, even if interleukin-1β mRNA levels were increased in parallel with those of Iba1 (ionized calcium-binding adaptor molecule 1), a marker of microglial activation. Normalization of leptin-regulated functions and hypothalamic gene expressions in refed mice with low plasma leptin levels could be sustained by recalibration of hypothalamic sensitivity to leptin.

Topics: Agouti-Related Protein; Animals; Body Weight; Cytokines; Disease Models, Animal; Eating; Female; Hypolipoproteinemias; Hypothalamic Hormones; Hypothalamus; Leptin; Melanins; Mice; Mice, Inbred C57BL; Neuropeptide Y; Neuropeptides; Orexins; Pituitary Hormones; Receptors, Leptin; Receptors, Neuropeptide; RNA, Messenger

Calorie-restriction during gestation in rats has been seen to produce lasting detrimental effects in the offspring, affecting energy balance control and other related metabolic functions. Our aim was to assess whether leptin supplementation throughout lactation may prevent the dysmetabolic phenotype in adulthood associated with gestational calorie restriction.. Three groups of male Wistar rats were followed: the offspring of ad libitum fed dams (controls); the offspring of 20% calorie-restricted dams during gestation (CR); and CR rats supplemented with physiological doses of leptin throughout lactation (CR-Leptin). Pups were weaned with a standard diet (SD) until 4 months of age, and then half of the animals of each group were moved to a Western diet (WD) until 6 months of age. Body weight and food intake were recorded. Energy expenditure, locomotive activity, blood parameters, liver triglycerides (TG), and gene expression and specific proteins in liver and white adipose tissue (WAT) were measured in adulthood.. Adult CR rats, but not CR-Leptin rats, displayed greater adiposity index and feed efficiency (both under SD) than controls, along with lower locomotive activity and energy expenditure, higher HOMA-IR index and greater circulating TG and leptin levels. CR animals also exhibited increased values of the respiratory exchange ratio and more severe signs of hepatic steatosis under WD than CR-Leptin animals. Gene expression analysis revealed that CR, but not CR-Leptin, animals displayed indicators of lower capacity for WAT expansion, along with decreased lipogenesis and lipolytic capacity under SD, and impaired lipogenic response of the liver to WD feeding, in accordance with diminished insulin sensitivity and WAT leptin signaling.. Oral leptin supplementation in physiological doses throughout lactation in rats prevents most of the detrimental effects on energy homeostasis and metabolic alterations in adulthood caused by inadequate fetal nutrition.

Topics: Adipose Tissue, White; Administration, Oral; Animals; Animals, Suckling; Caloric Restriction; Disease Models, Animal; Female; Fetal Nutrition Disorders; Lactation; Leptin; Male; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar

The major goal of animal production is to obtain abundant and healthy meat for consumers. Maternal food restriction (MFR) is often applied in farms to reduce production costs. However, the suitability of MFR in livestock animals is questionable, as this management may compromise maternal fitness due to a severe negative energetic balance and can induce Intrauterine Growth Restriction (IUGR) and prenatal programming in the offspring. Here, we sought to determine, using pregnant rabbits, the consequences of MFR on maternal endocrine and metabolic status and conceptus development. Pregnant dams were distributed into three groups: CONTROL (ad libitum feeding throughout the entire pregnancy; mean pregnancy length being around 31 days), UNDERFED (50% MFR during the entire pregnancy) and EARLY-UNDERFED (50% MFR only during the preimplantation period, Days 0-7). Maternal leptin concentrations and glycemic and lipid profiles were determined throughout pregnancy, whilst conceptus development was assessed ex-vivo at Day 28. Placental parameters were determined by macroscopic and histological evaluations and apoptotic assessments (TUNEL and Caspase-3). The main results of the study showed that, despite MFR altered maternal plasma lipid concentration (P<0.05), there were no effects on maternal bodyweight, plasma leptin concentration or glycemic profile. Fetal crown-rump lengths were reduced in both undernourished groups (P<0.001), but a significant reduction in fetal weight was only observed in the UNDERFED group (P<0.001). Growth in both undernourished groups was asymmetrical, with reduced liver weight (P<0.001) and significantly increased brain: fetal weight-ratio (P<0.001) and brain: liver weight-ratio (P<0.001) when compared to the CONTROL group. A significant reduction in placental weight was only observed in the UNDERFED group (P<0.001), despite both undernourished groups showing higher apoptotic rates at decidua and labyrinth zone (P<0.05) than the CONTROL group. Thus, these groups evidenced signs of placental degeneration, necrosis and stromal collapse. In summary, MFR may encourage the mother to make strategic decisions to safeguard her metabolic status and fitness at the expense of growth reduction in the litter, resulting in enhanced apoptotic and pathological processes at placental level and IUGR.

Topics: Animals; Apoptosis; Blastocyst; Blood Glucose; Body Weight; Crown-Rump Length; Disease Models, Animal; Female; Fetal Growth Retardation; Fetal Weight; Fetus; Leptin; Lipid Metabolism; Malnutrition; Placenta; Pregnancy; Pregnancy Complications; Pregnancy, Animal; Rabbits

Early-life stress (ES) increases the vulnerability to develop psychopathologies and cognitive decline in adulthood. Interestingly, this is often comorbid with metabolic disorders, such as obesity. However, it is unclear whether ES leads to lasting metabolic changes and to what extent this is associated with the ES-induced cognitive impairments. Here, we used an established chronic ES mouse model (from postnatal day (P) 2 to P9) to investigate the short- and long-term effects of ES exposure on parameters of the adipose tissue and the leptin system (i.e. circulating levels and gene expression of leptin and its receptor) in both sexes. Immediately following ES, the offspring exhibited reductions in white adipose tissue (WAT) mass, plasma leptin levels and in leptin mRNA expression in WAT. Furthermore, ES exposure led to increased brown adipose tissue and browning of WAT, which was evident by a drastic increase in uncoupling protein 1 mRNA expression in the inguinal WAT at P9. Notably, the ES-induced reductions in WAT mass, plasma leptin and leptin expression in WAT were sustained into adulthood and were accompanied by changes in body fat distribution, such as a higher ratio between mesenteric WAT and other WATs. Interestingly, while ES exposure increased leptin receptor mRNA expression in the choroid plexus, it was unaltered in the hippocampus. This suggests an adaptation to maintain central leptin homeostasis following ES exposure. In addition, chronic ES exposure resulted in the well-established cognitive impairment in object recognition performance during adulthood, which correlated positively with reductions in WAT mass observed in male, but not in female mice. Finally, to assess if ES leads to a different metabolic phenotype in a moderate obesogenic environment, we measured body fat accumulation of control and ES-exposed mice in response to a moderate western-style diet (WSD) that was provided during adulthood. ES-exposed mice subjected to WSD exhibit a higher increase in adiposity when compared to controls, suggesting that ES exposure might result in a higher vulnerability to develop obesity in a moderate obesogenic environment. To conclude, chronic ES exposure alters parameters of the adipose tissue, leads to central adaptations in leptin regulation and results in higher fat accumulations when exposed to a WSD challenge later in life. A better understanding of these metabolic effects induced by ES might open up new avenues for therapeutic (e.g. nutrit

Topics: Adipose Tissue; Animals; Diet, Western; Disease Models, Animal; Feeding Behavior; Leptin; Mice; Obesity; Stress, Psychological; Uncoupling Protein 1

BACKGROUND Leptin plays a crucial role in bone metabolism, and its level is related to bone callus formation in the fracture repair process. The objective of this study was to evaluate the effect of recombinant leptin on the healing process of femoral fractures in rats. MATERIAL AND METHODS Forty-eight male Sprague Dawley (SD) rats with an average body weight of 389 g (range: 376-398 g) and an average age of 10 weeks were included in this animal research, and all rats were randomly divided into two major groups. Then standardized femur fracture models were implemented in all SD rats. Rats in the control group were treated with only 0.5 mL of physiological saline, and rats in the experimental group were treated with recombinant leptin 5 μg/kg/d along with the same 0.5 mL of physiological saline for 42 days intraperitoneally. At the same time, each major group was evenly divided into three parallel subgroups for each parallel bone evaluation separately at the second, fourth, and sixth weeks. Each subgroup included eight rats. RESULTS The total radiological evaluation results showed that the healing progress of femoral fracture in the experimental group was superior to that in the control group from the fourth week. At the sixth week, experimental group rats began to present significantly better femoral fracture healing progress than that of the control group rats. Results of biomechanics show the ultimate load (N) and deflection ultimate load (mm) of the experimental group rats was significantly increased compared with that of the control group rats from the fourth week. CONCLUSIONS Our results suggest that leptin may have a positive effect on SD rat femur fracture healing.

Topics: Animals; Disease Models, Animal; Femoral Fractures; Fracture Healing; Leptin; Male; Random Allocation; Rats; Rats, Sprague-Dawley; Recombinant Proteins

Obesity can cause or worsen asthma. Compared with common asthma, obese asthma is difficult to control. Statins are effective serum cholesterol-lowering agents in clinical practice, and they also have anti-inflammatory properties, which in theory are potentially beneficial in asthma. Many studies have shown that simvastatin has good therapeutic effect in animal models of asthma. However, the therapeutic effect and action mechanism of simvastatin for obese asthma remain unclear. Leptin, a satiety hormone, is in positive correlation with total body fat mass and may also play a significant role in the pathogenesis of asthma. In this study, we use the method of high-fat diet and ovalbumin (OVA) sensitization and challenge to establish the mouse model of obesity and asthma, and find that obese asthmatic mice has higher levels of glucose, lipid and leptin in serum, and neutrophil percentage in bronchoalveolar lavage fluid (BALF), and more severe airway inflammation and structural changes in lung tissues than non-obese asthmatic mice, and respond poorly to dexamethasone treatment, which indicates that obese asthma might belong to steroid-resistant (SR) asthma. Simvastatin treatment reduces the levels of glucose, lipid, leptin and neutrophil percentage, and improves airway inflammation and remodeling, which can be as a potential therapeutic target used in the treatment of obese asthma in humans. Correlation analysis shows that there is positive correlation between neutrophil percentage and serum leptin/cholesterol level, which indicates that the therapeutic efficacy of simvastatin on obese asthma might be associated with improving dyslipidemia and decreasing leptin level.

Topics: Animals; Asthma; Blood Glucose; Body Weight; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Dyslipidemias; Female; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Leptin; Leukocyte Count; Lipids; Lung; Mice; Mice, Inbred C57BL; Obesity; Simvastatin

The suckling period is a critical phase of development, in which maternal overnutrition may program the susceptibility of developing chronic diseases and disorders, such as obesity and metabolic alterations, in adult life. Here, we questioned whether the consumption of a cafeteria diet throughout lactation in rats affects the macronutrient composition of milk and whether it results in permanent metabolic effects in the offspring.. Nursing rats were fed a control diet or a cafeteria diet during lactation. Milk was obtained at different time points of lactation. Offspring (males and females) were weaned onto a control diet until the age of 6 months. Circulating parameters were measured under ad libitum feeding and under 12-h fasting conditions at weaning and at 3 and 6 months of age. An oral glucose tolerance test (OGTT) was performed at 3 and 6 months of age.. Rats fed a cafeteria diet during lactation consumed an unbalanced diet, with lower protein and higher fat content versus controls, which was reflected in the composition of the milk. The offspring of rats fed a cafeteria diet during lactation showed lower body weight and lower lean mass, but greater fat accumulation, compared with controls. They also displayed hyperleptinaemia, altered lipid profile and impaired response to an OGTT.. Maternal consumption of a cafeteria diet throughout lactation in rats produces lasting effects in the metabolic health of their offspring, which are not associated with a higher body weight but with a greater fat accumulation, similarly to the thin-outside-fat-inside phenotype.

Topics: Adiposity; Animals; Blood Glucose; Body Weight; Diet, Protein-Restricted; Disease Models, Animal; Female; Glucose Tolerance Test; Lactation; Leptin; Male; Maternal Nutritional Physiological Phenomena; Milk; Nutritive Value; Overnutrition; Phenotype; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Thinness; Weaning

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease, resulting not only in liver dysfunction, glucose and lipid metabolism disorder, but also in neuropsychiatric damage. In the present study, a NAFLD rat model was established via feeding of a high-fat diet, and behaviour was observed via the open field test (OFT), the sucrose preference test (SPT), the elevated plus maze (EPM), the forced swimming test (FST) and the Morris water maze (MWM). The plasma concentrations of alanine aminotransferase (ALT), glucose, free fatty acid (FFA), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were detected using chemiluminescence technique. The plasma levels of nesfatin-1, leptin and insulin were measured via enzyme-linked immunosorbent assay, and the protein expressions of p-glycogen synthase kinase-3β (GSK-3β), GSK-3β, p-β-catenin, β-catenin, cyclinD and copine 6 in the hippocampus and prefrontal cortex (PFC) were detected using western blotting. After 4 consecutive weeks of feeding with a high-fat diet, the rats showed obesity; increased plasma concentrations of ALT, glucose, FFA, TC, TG, HDL-C and LDL-C; decreased plasma levels of leptin and insulin; and inflammation and mild hepatocyte steatosis in the liver. Although there was no significant difference between groups with regard to performance in the OFT, EPM or FST, the NAFLD rats showed a decreased sucrose preference index in the SPT and impaired learning and memory in the MWM task. Moreover, the present study provides the first evidence of an increased plasma nesfatin-1 concentration in NAFLD rats, which was significantly correlated with plasma lipid concentrations and behavioural performance. Furthermore, copine 6 and p-β-catenin protein expression decreased and p-GSK-3β increased in the hippocampus and PFC of NAFLD rats. These results suggest that consuming of a high-fat diet for 4 consecutive weeks could successfully induce a NAFLD rat model. More importantly, these results provide the first evidence that impaired learning and memory in NAFLD rats was, at least partly, associated with increased plasma nesfatin-1 concentration and decreased copine 6 expression in the hippocampus and PFC.

Topics: Animals; Behavior, Animal; Calcium-Binding Proteins; Carrier Proteins; Diet, High-Fat; Disease Models, Animal; DNA-Binding Proteins; Hippocampus; Insulin; Learning; Leptin; Lipid Metabolism; Liver; Male; Memory; Nerve Tissue Proteins; Non-alcoholic Fatty Liver Disease; Nucleobindins; Prefrontal Cortex; Rats, Sprague-Dawley

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

The immune system acts on different metabolic tissues that are implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Leptin and linoleic acid have the ability to potentially affect immune cells, whereas curcumin is a known natural polyphenol with antioxidant and anti-inflammatory properties.. This study was designed to evaluate the pro-inflammatory and pro-oxidant effects of leptin and linoleic acid on immune cells from patients with NAFLD and to corroborate the modulatory effects of curcumin and its preventive properties against the progression of NAFLD using a high-fat diet (HFD)-induced NAFLD/nonalcoholic steatohepatitis mouse model.. The ex vivo experiments showed that linoleic acid increased the production of reactive oxygen species in monocytes and liver macrophages, whereas leptin enhanced tumor necrosis factor-α (TNF-α) production in monocytes and interferon-γ production in circulating CD4+ cells. Conversely, oral administration of curcumin prevented HFD-induced liver injury, metabolic alterations, intrahepatic CD4+ cell accumulation and the linoleic acid- and leptin- induced pro-inflammatory and pro-oxidant effects on mouse liver macrophages.. Our findings provide new evidence for the therapeutic potential of curcumin to treat human NAFLD. However, the development of a preventive treatment targeting human circulating monocytes and liver macrophages as well as peripheral and hepatic CD4+ cells requires additional research.

Topics: Animals; Antioxidants; CD4-Positive T-Lymphocytes; Curcumin; Diet, High-Fat; Disease Models, Animal; Fatty Liver; Hepatocytes; Humans; Leptin; Linoleic Acid; Liver; Mice; Non-alcoholic Fatty Liver Disease; Reactive Oxygen Species

Obesity including metabolic syndrome is an independent risk factor of atrial fibrillation (AF). Although hyperleptinemia is usually a characteristic of obese subjects, the relationship with atrial fibrosis and AF is unknown. We tested the hypothesis that high-fat diet (HFD)-induced hyperleptinemia exacerbates atrial fibrosis and AF.. Eight-week-old male C57BL/6 (WT) and leptin-deficient ob/ob (Ob) mice were treated with a normal-fat diet (NFD) or 60% HFD. After 8 weeks, transesophageal burst pacing and electrophysiological study using isolated perfused hearts were performed and left atrial (LA) tissues were collected for histological analysis, hydroxyproline assay, and reverse transcription-polymerase chain reaction. HFD treatment increased body weight in both WT and Ob mice compared with NFD (both P < 0.01). In WT-HFD mice, hyperleptinemia was observed as expected. While transesophageal burst pacing invariably induced AF (8/8, 100%) in WT-HFD mice, AF was induced less frequently (1/8, 12.5%) in Ob-HFD mice (P < 0.01). In isolated perfused hearts, the interatrial conduction time was prolonged in WT-HFD mice, but not in Ob-HFD mice (P < 0.05). Masson's trichrome staining and the hydroxyproline assay revealed interstitial LA fibrosis in WT-HFD mice, which was not observed in Ob-HFD mice (P < 0.05). Upregulation of collagen1, collagen3, α-smooth muscle actin, tumor necrosis factor-α, and monocyte chemoattractant protein-1 mRNA levels was noted in WT-HFD mice LA, but attenuated in Ob-HFD mice LA.. Our findings suggest that hyperleptinemia exacerbates HFD-mediated atrial fibrosis and AF. Inhibition of leptin signaling may become a novel therapeutic target to prevent obesity-related AF.

Topics: Actins; Animals; Atrial Fibrillation; Biomarkers; Cardiac Pacing, Artificial; Chemokine CCL2; Collagen; Diet, High-Fat; Disease Models, Animal; Fibrosis; Heart Atria; Heart Rate; Hydroxyproline; Isolated Heart Preparation; Leptin; Male; Mice, Inbred C57BL; Mice, Obese; Obesity; RNA, Messenger; Time Factors; Tumor Necrosis Factor-alpha; Up-Regulation

Huntington disease is an inherited neurodegenerative disorder characterized by motor, cognitive, psychiatric and metabolic symptoms. We recently published a study describing that the BACHD rat model of HD shows an obesity phenotype, which might affect their motivation to perform food-based behavioral tests. Further, we argued that using a food restriction protocol based on matching BACHD and wild type rats' food consumption rates might resolve these motivational differences. In the current study, we followed up on these ideas in a longitudinal study of the rats' performance in a progressive ratio test. We also investigated the phenotype of reduced food consumption rate, which is typically seen in food-restricted BACHD rats, in greater detail. In line with our previous study, the BACHD rats were less motivated to perform the progressive ratio test compared to their wild type littermates, although the phenotype was no longer present when the rats' food consumption rates had been matched. However, video analysis of food consumption tests suggested that the reduced consumption rate found in the BACHD rats was not entirely based on differences in hunger, but likely involved motoric impairments. Thus, restriction protocols based on food consumption rates are not appropriate when working with BACHD rats. As an alternative, we suggest that studies where BACHD rats are used should investigate how the readouts of interest are affected by motivational differences, and use appropriate control tests to avoid misleading results. In addition, we show that BACHD rats display distinct behavioral changes in their progressive ratio performance, which might be indicative of striatal dysfunction.

Topics: Analysis of Variance; Animal Feed; Animals; Behavior, Animal; Biomarkers; Body Composition; Disease Models, Animal; Disease Progression; Feeding Behavior; Huntington Disease; Leptin; Male; Phenotype; Rats

In the present work, we studied the modulatory effect of Leptin (Lep) against pro-inflammatory cytokines, tumour necrosis factor-alpha (TNFα), interleukin 1-beta (IL1β) and interferon-gamma (IFNγ), in primary glial cell cultures.. Glial cultures were treated with pro-inflammatory cytokines (TNFα, 20ng/ml; IL1β, 20ng/ml; IFNγ 20ng/ml). Cells were pre-treated with Lep 500nM, 1h prior to cytokine treatment. NO released from glial cells was determined using the Griess reaction. Cell viability was determined by the MTT method. Protein expression was determined by western blot.. Pre-treatment with 500nM Lep produced an inhibitory effect on inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production after glial cells exposure to pro-inflammatory cytokines. Anti-inflammatory effect can be related to a decrease in P38 MAP Kinase (MAPK) pathway activity. Treatment of glial cell cultures with Lep also reduced the intrinsic apoptotic pathway (cytochrome c release and caspase-3 activation).. We suggest that Lep would act as an anti-inflammatory factor in glial cells exposed to pro-inflammatory cytokines, exerting its function on p38 MAPK pathway and reducing NO production.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Cell Survival; Cells, Cultured; Cytokines; Disease Models, Animal; Inflammation; Interferon-gamma; Interleukin-1beta; Leptin; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Neuroglia; Nitric Oxide; p38 Mitogen-Activated Protein Kinases; Tumor Necrosis Factor-alpha

Consumption of dietary supplements with green tea extract (GTE) is popular for weight management, but it may be accompanied by various side effects, including interactions with drugs. The aim of the present in vivo study was to evaluate the effect of defined GTE (Polyphenon 60) in three dosage schemes on insulin, leptin and drug-metabolizing enzymes in obese mice.. Experimental obesity was induced by repeated s.c. application of monosodium glutamate to newborn mice. Green tea extract was administered in three dosage schemes in chow diet. The plasmatic levels of insulin and leptin were assayed using enzyme-linked immunosorbent assay. Enzyme activities and mRNA expressions of drug-metabolizing enzymes (totally 13) were analyzed in liver and small intestine using spectrophotometric and HPLC assays and RT-PCR, respectively.. GTE-treatment decreased insulin and leptin levels. Eleven enzymes were significantly affected by GTE-treatment. Long-term administration of 0.01% GTE caused increase in the activity and mRNA level of cytochrome P450 3A4 (CYP3A4) ortholog in the liver as well as in the small intestine. Interestingly, short-term overdose by GTE (0.1%) had more pronounced effects on enzyme activities and mRNA expressions than long-term overdose.. GTE-mediated induction of CYP3A4 ortholog, the main drug-metabolizing enzyme, could result in decreased efficacy of simultaneously or subsequently administered drug in obese individuals.

Topics: Animals; Antioxidants; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP2E1; Cytochrome P-450 CYP3A; Cytochrome P450 Family 2; Dietary Supplements; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Insulin; Leptin; Liver; Male; Mice; Mice, Obese; Obesity; Plant Extracts; RNA, Messenger; Sodium Glutamate; Tea

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

Skeletal fractures are considered a chronic complication of type 2 diabetes mellitus (T2DM), but the etiology of compromised bone quality that develops over time remains uncertain. This study investigated the concurrent alterations in metabolic and skeletal changes in two mouse strains, a responsive (C57BL/6) and a relatively resistant (C3H/HeJ) strain, to high-fat diet-induced glucose intolerance. Four-week-old male C57BL/6 and C3H/HeJ mice were randomized to a control (Con = 10 % kcal fat) or high-fat (HF = 60 % kcal fat) diet for 2, 8, or 16 weeks. Metabolic changes, including blood glucose, plasma insulin and leptin, and glucose tolerance were monitored over time in conjunction with alterations in bone structure and turn over. Elevated fasting glucose occurred in both the C57BL/6 and C3H/HeJ strains on the HF diet at 2 and 8 weeks, but only in the C57BL/6 strain at 16 weeks. Both strains on the HF diet demonstrated impaired glucose tolerance at each time point. The C57BL/6 mice on the HF diet exhibited lower whole-body bone mineral density (BMD) by 8 and 16 weeks, but the C3H/HeJ strain had no evidence of bone loss until 16 weeks. Analyses of bone microarchitecture revealed that trabecular bone accrual in the distal femur metaphysis was attenuated in the C57BL/6 mice on the HF diet at 8 and 16 weeks. In contrast, the C3H/HeJ mice were protected from the deleterious effects of the HF diet on trabecular bone. Alterations in gene expression from the femur revealed that several toll-like receptor (TLR)-4 targets (Atf4, Socs3, and Tlr4) were regulated by the HF diet in the C57BL/6 strain, but not in the C3H/HeJ strain. Structural changes observed only in the C57BL/6 mice were accompanied with a decrease in osteoblastogenesis after 8 and 16 weeks on the HF diet, suggesting a TLR-4-mediated mechanism in the suppression of bone formation. Both the C57BL/6 and C3H/HeJ mice demonstrated an increase in osteoclastogenesis after 8 weeks on the HF diet; however, bone turnover was decreased in the C57BL/6 with prolonged hyperglycemia. Further investigation is needed to understand how hyperglycemia and hyperinsulinemia suppress bone turnover in the context of T2DM and the role of TLR-4 in this response.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Disease Models, Animal; Insulin; Insulin Resistance; Leptin; Mice; Species Specificity; Sprains and Strains; Toll-Like Receptor 4

Pain perception can become altered in individuals with eating disorders and obesity for reasons that have not been fully elucidated. We show that leptin deficiency in ob/ob mice, or leptin insensitivity in the arcuate nucleus of the hypothalamus in mice with high-fat diet (HFD)-induced obesity, are accompanied by elevated orexin-A (OX-A) levels and orexin receptor-1 (OX1-R)-dependent elevation of the levels of the endocannabinoid, 2-arachidonoylglycerol (2-AG), in the ventrolateral periaqueductal gray (vlPAG). In ob/ob mice, these alterations result in the following: (i) increased excitability of OX1-R-expressing vlPAG output neurons and subsequent increased OFF and decreased ON cell activity in the rostral ventromedial medulla, as assessed by patch clamp and in vivo electrophysiology; and (ii) analgesia, in both healthy and neuropathic mice. In HFD mice, instead, analgesia is only unmasked following leptin receptor antagonism. We propose that OX-A/endocannabinoid cross talk in the descending antinociceptive pathway might partly underlie increased pain thresholds in conditions associated with impaired leptin signaling.

Topics: Animals; Arachidonic Acids; Disease Models, Animal; Endocannabinoids; Glycerides; Leptin; Male; Membrane Potentials; Mice, Obese; Neural Pathways; Neurons; Nociceptive Pain; Orexin Receptors; Orexins; Pain Perception; Periaqueductal Gray; Tissue Culture Techniques

Gastric electrical stimulation (GES) has great potential for the treatment of obesity. We investigated the impact of chronic GES on the alteration of adipose tissue and the regulation of neuropeptide Y (NPY), orexin (OX), α-melanocyte-stimulating hormone (α-MSH) and oxytocin (OXT), and their receptors in several tissues.. Most of the experiments included three groups of diet-induced obesity rats: (1) sham-GES (SGES); (2) GL-6mA (GES with 6 mA, 4 ms, 40 Hz, 2 s on, 3 s off at lesser curvature); and (3) SGES-PF (SGES rats receiving pair feeding to match the consumption of GL-6mA rats). Chronic GES was applied for 2 h every day for 4 weeks. During treatment with GES, food intake and body weight were monitored weekly. The alteration of epididymal fat weight, gastric emptying, and expression of peptides and their receptors in several tissues were determined.. GL-6mA was more potent than SGES-PF in decreasing body weight gain, epididymal fat tissue weight, adipocyte size and gastric emptying. Chronic GES significantly altered NPY, OX, α-MSH and OXT and their receptors in the hypothalamus, adipose tissue and stomach.. Chronic GES effectively leads to weight loss by reducing food intake, fat tissue weight and gastric emptying. NPY, α-MSH, orexin and OXT, and their receptors in the hypothalamus, adipose tissue and stomach appear to be involved in the anti-obesity effects of chronic GES.

Topics: Adipocytes; alpha-MSH; Animals; Disease Models, Animal; Eating; Electric Stimulation Therapy; Electrodes, Implanted; Epididymis; Gastric Emptying; Gastric Mucosa; Ghrelin; Hypothalamus; Intra-Abdominal Fat; Leptin; Male; Neuropeptide Y; Obesity; Orexin Receptors; Orexins; Oxytocin; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Receptor, Melanocortin, Type 3; Receptors, G-Protein-Coupled; Receptors, Melanocortin; Receptors, Neuropeptide; Receptors, Neuropeptide Y; Receptors, Oxytocin; RNA, Messenger; Weight Loss

Endocrine disorders have been shown to be a consequence of blast traumatic brain injury in soldiers returning from military conflicts. Hormone deficiency and adrenocorticotropic hormone (ACTH) dysfunction can lead to symptoms such as fatigue, anxiety, irritability, insomnia, sexual dysfunction, and decreased quality of life. Given these changes following blast exposure, the current study focused on investigating chronic pathology within the hypothalamus following blast, in addition to systemic effects. An established rodent model of blast neurotrauma was used to induce mild blast-induced neurotrauma. Adipose tissue, blood, and brain samples were collected at one and three months following a single blast exposure. Adipose tissue and blood were evaluated for changes in ACTH, adiponectin, C-reactive protein, glial fibrillary acidic protein, interleukin (IL)-1β, and leptin. The hypothalamus was evaluated for injury using immunohistochemical techniques. The results demonstrated that the weight of the blast animals was significantly less, compared with the sham group. The slower rate of increase in their weight was associated with changes in ACTH, IL-1β, and leptin levels. Further, histological analysis indicated elevated levels of cleaved caspase-3 positive cells within the hypothalamus. The data suggest that long-term outcomes of brain injury occurring from blast exposure include dysfunction of the hypothalamus, which leads to compromised hormonal function, elevated biological stress-related hormones, and subsequent adipose tissue remodeling.

Topics: Adiponectin; Adipose Tissue; Adrenocorticotropic Hormone; Animals; Blast Injuries; Body Weight; Brain Injuries; Disease Models, Animal; Endocrine System Diseases; Hypothalamic Diseases; Interleukin-1beta; Leptin; Male; Rats; Rats, Sprague-Dawley

Obesity and metabolic syndrome are the major risk factors for cardiovascular disease. Obesity is caused by increased food intake and/or decreased energy expenditure. Leptin potently inhibits food intake and promotes energy expenditure. These effects of leptin involve the activation of proopiomelanocortin (POMC) neurons in the hypothalamus arcuate nucleus (ARC). Disruption of leptin signaling in POMC neuron is considered one of the major causes for obesity.. The present study aimed to examine whether overexpression of interleukin-10 (IL-10) could substitute for the leptin action and ameliorate obesity in leptin-deficient Lep(ob/ob) mice.. Adeno-associated virus (AAV) expressing murine IL-10 (AAV-mIL-10) was injected into the skeletal muscle to overexpress IL-10 in mice. These mice were subsequently subjected to analysis of body weight, food intake, glucose metabolism and underlying mechanisms.. In Lep(ob/ob) mice, AAV-IL-10 ameliorated hyperphagia, obesity, glucose intolerance and insulin resistance, as well as attenuated tumor necrosis factor-α expression. The IL-10 treatment also improved glucose-induced insulin release. Furthermore, IL-10 treatment increased POMC mRNA expression in ARC and phosphorylation of signal transducer and activator of transcription-3 (STAT3) in ARC and white adipose tissue (WAT). In neuron-specific STAT3-null mice that exhibited obesity and hyperphagia, AAV-mIL-10 administration failed to affect food intake, body weight and phosphorylation of STAT3 in WAT.. These results demonstrate that peripheral overexpression of IL-10 induces STAT3 phosphorylation in ARC POMC neurons, and thereby ameliorates hyperphagia and obesity caused by leptin deficiency. IL-10 gene transfer may provide an effective approach for preventing progression of metabolic syndrome due to leptin resistance.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Diabetes Mellitus; Disease Models, Animal; Energy Metabolism; Gene Transfer Techniques; Hyperphagia; Interleukin-10; Leptin; Male; Mice; Obesity; Pro-Opiomelanocortin; Up-Regulation

Fetal overgrowth is common in obese women and is associated with perinatal complications and increased risk for the child to develop metabolic syndrome later in life. Placental nutrient transport capacity has been reported to be increased in obese women giving birth to large infants; however, the underlying mechanisms are not well established. Obesity in pregnancy is characterized by elevated maternal serum insulin and leptin, hormones that stimulate placental amino acid transporters in vitro. We hypothesized that maternal obesity activates placental insulin/IGF-I/mTOR and leptin signaling pathways. We tested this hypothesis in a mouse model of obesity in pregnancy that is associated with fetal overgrowth. C57BL/6J female mice were fed a control (C) or a high-fat/high-sugar (HF/HS) pelleted diet supplemented by ad libitum access to sucrose (20%) solution. Placentas were collected at embryonic day 18.5. Using Western blot analysis, placental mTOR activity was determined along with energy, inflammatory, leptin, and insulin signaling pathways (upstream modulators of mTOR). Phosphorylation of S6 ribosomal protein (S-235/236), 4E-BP1 (T-37/46), Insulin receptor substrate 1 (Y-608), Akt (T-308), and STAT-3 (Y-705) was increased in obese dams. In contrast, expression of placental caspase-1, IкBα, IL-1β, and phosphorylated-JNK(p46/54-T183/Y185) was unaltered. Fetal amino acid availability is a key determinant of fetal growth. We propose that activation of placental insulin/IGF-I/mTOR and leptin signaling pathways in obese mice stimulates placental amino acid transport and contributes to increased fetal growth.

Topics: AMP-Activated Protein Kinases; Animal Nutritional Physiological Phenomena; Animals; Disease Models, Animal; Energy Metabolism; Enzyme Activation; Female; Fetal Nutrition Disorders; Fetal Weight; Gestational Age; Inflammation Mediators; Insulin; Insulin-Like Growth Factor I; Leptin; Maternal-Fetal Exchange; Mice, Inbred C57BL; Nutritional Status; Obesity; Phosphorylation; Placenta; Placental Circulation; Pregnancy; Prenatal Nutritional Physiological Phenomena; Signal Transduction; TOR Serine-Threonine Kinases

Thyroid hormone and leptin are essential regulators of energy homeostasis. Both hormones stimulate energy expenditure but have opposite effects on appetite. The mechanisms behind food intake regulation in thyroid dysfunctions are poorly understood. It has been shown that hypothyroid rats exhibited impaired leptin anorexigenic effect and signaling in total hypothalamus, even though they were hypophagic. It was hypothesized that hypothyroidism modulates the expression of neuropeptides: orexigenic neuropeptide Y (NPY) and anorexigenic proopiomelanocortin (POMC), independently of inducing nuclei-specific changes in hypothalamic leptin signaling.. Adult male rats were rendered hypothyroid by administration of 0.03% methimazole in the drinking water for 21 days. Protein content of NPY, POMC, and leptin signaling (the signal transducer and activator of transcription 3 [STAT3] pathway) were evaluated by Western blot, and mRNA levels by real time reverse transcription polymerase chain reaction in arcuate (ARC), ventromedial (VMN), and paraventricular (PVN) hypothalamic nuclei isolated from euthyroid (eu) and hypothyroid (hypo) rats. Leptin anorexigenic effect was tested by recording food intake for two hours after intracerebroventricular (i.c.v.) administration of leptin. Statistical differences were considered significant at p ≤ 0.05.. Hypothyroidism was confirmed by decreased serum triiodothyronine, thyroxine, and increased thyrotropin, in addition to increased levels of pro-TRH mRNA in PVN and Dio2 mRNA in the ARC of hypo rats. Hypothyroidism decreased body weight and food intake associated with decreased protein content of NPY and increased content of POMC in the ARC. Conversely, hypothyroidism induced central resistance to the acute anorexigenic effect of leptin, since while euthyroid rats displayed reduced food intake after leptin i.c.v. injection, hypothyroid rats showed no response. Hypothyroid rats exhibited decreased leptin receptor (ObRb) protein content in ARC and VMN but not in PVN nucleus. ObRb protein changes were concomitant with decreased phosphorylated STAT3 in the ARC, and decreased total STAT3 in VMN and PVN. However, hypothyroidism did not affect mRNA levels of Lepr or Stat3 in the hypothalamic nuclei.. Experimental hypothyroidism induced a negative energy balance accompanied by decreased NPY and increased POMC protein content in the ARC, resulting in predominance of anorexigenic pathways, despite central leptin resistance and impairment of the leptin signaling cascade in a nuclei-specific manner.

Topics: Animals; Appetite Regulation; Arcuate Nucleus of Hypothalamus; Disease Models, Animal; Eating; Energy Metabolism; Feeding Behavior; Hypothyroidism; Iodide Peroxidase; Iodothyronine Deiodinase Type II; Leptin; Male; Methimazole; Neuropeptide Y; Paraventricular Hypothalamic Nucleus; Phosphorylation; Pro-Opiomelanocortin; Rats, Wistar; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor; Thyrotropin-Releasing Hormone; Ventromedial Hypothalamic Nucleus; Weight Loss

Leptin, one of the typical adipokines, is reported to promote Th17 cell responses and to enhance production of proinflammatory cytokines. To clarify the role of leptin in the regulation of the IL-23/IL-17 axis and the development of kidney disease, we used a murine model of nephrotoxic serum (NTS) nephritis (NTN). Sheep NTS was administered in wild-type C57BL/6J mice and food-restricted, leptin-deficient C57BL/6J-ob/ob(FR-ob/ob) mice after preimmunization with sheep IgG. The profile of mRNA expression relevant to T helper lymphocytes in the kidneys was analyzed by quantitative real-time PCR (qRT-PCR). Cultured murine glomerular podocytes and peritoneal exudate macrophages (PEMs) were used to investigate the direct effect of leptin on IL-23 or MCP-1 production by qRT-PCR. Kidney injury and macrophage infiltration were significantly attenuated in FR-ob/obmice 7 days after NTS injection. The Th17-dependent secondary immune response against deposited NTS in the glomeruli was totally impaired in FR-ob/obmice because of deteriorated IL-17 and proinflammatory cytokine production including IL-23 and MCP-1 in the kidney. IL-23 was produced in glomerular podocytes in NTN mice and cultured murine glomerular podocytes produced IL-23 under leptin stimulation. MCP-1 production in PEMs was also promoted by leptin. Induction of MCP-1 expression was observed in PEMs regardless of Ob-Rb, and the leptin signal was transduced without STAT3 phosphorylation in PEMs. Leptin deficiency impairs the secondary immune response against NTS and down-regulates IL-23 production and Th17 responses in the NTN kidney, which is accompanied by decreased MCP-1 production and macrophage infiltration in the NTN kidney.

Topics: Animals; Biopsy; Cell Line; Chemokine CCL2; Cytokines; Disease Models, Animal; Gene Expression; Immunoglobulin G; Immunophenotyping; Interleukin-23; Kidney Glomerulus; Leptin; Macrophages, Peritoneal; Male; Mice; Mice, Knockout; Nephritis; Podocytes; Severity of Illness Index; Signal Transduction; T-Lymphocyte Subsets

Insulin receptor substrate 2 (IRS2) is one of the 3 major leptin receptor signaling pathways, but its role in mediating the chronic effects of leptin on blood pressure, food intake, and glucose regulation is unclear. We tested whether genetic inactivation of IRS2 in the entire brain (IRS2/Nestin-cre mice) or specifically in proopiomelanocortin (POMC) neurons (IRS2/POMC-cre mice) attenuates the chronic cardiovascular, metabolic, and antidiabetic effects of leptin. Mice were instrumented with telemetry probes for measurement of blood pressure and heart rate and with venous catheters for intravenous infusions. After a 5-day control period, mice received leptin infusion (2 μg/kg per minute) for 7 days. Compared with control IRS2(flox/flox) mice, IRS2/POMC-cre mice had similar body weight and food intake (33±1 versus 35±1 g and 3.6±0.5 versus 3.8±0.2 g per day) but higher mean arterial pressure (MAP) and heart rate (110±2 versus 102±2 mm Hg and 641±9 versus 616±5 bpm). IRS2/Nestin-cre mice were heavier (38±2 g), slightly hyperphagic (4.5±1.0 g per day), and had higher MAP and heart rate (108±2 mm Hg and 659±9 bpm) compared with control mice. Leptin infusion gradually increased MAP despite decreasing food intake by 31% in IRS2(flox/flox) and in Nestin-cre control mice. In contrast, leptin infusion did not change MAP in IRS2/Nestin-cre or IRS2/POMC-cre mice. The anorexic and antidiabetic effects of leptin, however, were similar in all 3 groups. These results indicate that IRS2 signaling in the central nervous system, and particularly in POMC neurons, is essential for the chronic actions of leptin to raise MAP but not for its anorexic or antidiabetic effects.

Topics: Animals; Appetite; Blood Glucose; Blood Pressure; Disease Models, Animal; Energy Metabolism; Hypertension; Insulin Receptor Substrate Proteins; Leptin; Male; Mice; Mice, Transgenic; Neurons; Pro-Opiomelanocortin; Signal Transduction

Increased mitogen-activated protein kinase (MAPK) activity has been found in human osteoarthritis (OA). Dual specificity protein phosphatase 19 (DUSP19), a member of mitogen-activated protein kinase (MAPK) phosphatases (MKPs), controls the activity of various MAPKs. This study was aimed to explore the function of DUSP19 during OA pathogenesis. Here, OA and healthy control data were downloaded from the NCBI Gene Expression Omnibus database (GSE57218). Forty-five patients with OA and 25 healthy donors were enrolled in this study. A rat OA model was induced by anterior cruciate ligament transection. Primary cultured chondrocytes were treated with leptin (10 ng mL(-1)). Cell survival, cell apoptosis and reactive oxygen species (ROS) were identified by CCK-8 and flow cytometry, respectively. In the cartilage of OA patients, DUSP19 was expressed in a lower level than in the cartilage of healthy control. The DUSP19 level was negatively correlated with leptin, which was confirmed by experiments in the rat OA model. Moreover, cell apoptosis and JNK activation in the rat cartilage were increased with the increasing of leptin levels and the decreasing of DUSP19 mRNA levels. In primary culture chondrocytes, exogenous leptin suppressed DUSP19 expression. The ectopic expression of DUSP19 significantly ameliorated leptin-induced apoptosis in damaged chondrocytes, accompanied by the reduced production of ROS. Moreover, the activity of JNK stimulated by leptin was suppressed by DUSP19 overexpression. The present study indicated that DUSP19, a downstream of leptin, inhibited apoptosis of chondrocytes through dephosphorylating JNK.

Topics: Adult; Aged; Animals; Apoptosis; Cartilage, Articular; Cell Survival; Chondrocytes; Disease Models, Animal; Dual-Specificity Phosphatases; HEK293 Cells; Humans; Interleukin-1beta; JNK Mitogen-Activated Protein Kinases; Leptin; Male; Middle Aged; Osteoarthritis; Phosphorylation; Rats, Sprague-Dawley; Reactive Oxygen Species; RNA, Messenger; Signal Transduction; Tumor Necrosis Factor-alpha

Obese patients with asthma respond poorly to conventional asthma medications, resulting in severe symptoms and poor prognosis. Roflumilast, a phosphodiesterase-4 inhibitor that lowers the levels of various substances that are implicated in obese subjects with asthma, may be effective in the treatment of those subjects. We evaluated the potential of roflumilast as a novel therapeutic agent for obese subjects with asthma. We designed three models: diet-induced obesity (DIO); DIO with ovalbumin (OVA); and OVA. We fed C57BL/6J mice a high-fat diet for 3 months with or without OVA sensitization and challenge. Roflumilast or dexamethasone was administered orally three times at 2-day intervals in the last experimental week. Airway hyperresponsiveness resulting from DIO significantly improved in the roflumilast-treated group compared with the dexamethasone-treated groups. Although DIO did not affect the cell proliferation in bronchoalveolar lavage fluid, increased fibrosis was seen in the DIO group, which significantly improved from treatment with roflumilast. DIO-induced changes in adiponectin and leptin levels were improved by roflumilast, whereas dexamethasone aggravated them. mRNA levels and proteins of TNF-α, transforming growth factor-β, IL-1β, and IFN-γ increased in the DIO group and decreased with roflumilast. The reactive oxygen species levels were also increased in the DIO group and decreased by roflumilast. In the DIO plus OVA and OVA models, roflumilast improved Th1 and Th2 cell activation to a greater extent than dexamethasone. Roflumilast is significantly more effective than dexamethasone against airway hyperresponsiveness caused by DIO in the murine model. Roflumilast may represent a promising therapeutic agent for the treatment of obese patients with asthma.

Topics: Adiponectin; Aminopyridines; Animals; Benzamides; Cell Proliferation; Cyclopropanes; Cytokines; Diet; Disease Models, Animal; Leptin; Mice, Inbred C57BL; Models, Biological; Obesity; Ovalbumin; Pulmonary Fibrosis; Reactive Oxygen Species; Respiratory Hypersensitivity; T-Lymphocytes

Studies on peroxisome proliferator-activated receptor (PPAR)-γ ligands have been focused on agonists. However, PPARγ activation may induce obesity and nonalcoholic fatty liver disease (NAFLD), one of the most challenging medical conditions. Here, we identified that isorhamnetin, a naturally occurring compound in fruits and vegetables and the metabolite of quercetin, is a novel antagonist of PPARγ. Isorhamnetin treatment inhibited the adipocyte differentiation induced by the PPARγ agonist rosiglitazone, reduced obesity development and ameliorated hepatic steatosis induced by both high-fat diet treatment and leptin deficiency. Our results suggest that dietary supplement of isorhamnetin may be beneficial to prevent obesity and steatosis and PPARγ antagonists may be useful to treat hepatic steatosis.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Animals; Cell Differentiation; Diet, High-Fat; Dietary Supplements; Disease Models, Animal; Gene Expression Regulation; Humans; Leptin; Metabolic Diseases; Mice; Models, Molecular; Molecular Conformation; Non-alcoholic Fatty Liver Disease; Obesity; PPAR gamma; Protein Binding; Quercetin; Transcriptional Activation

Accumulating evidence from epidemiological studies suggest that type 2 diabetes is linked to an increased risk of Alzheimer's disease (AD). However, the consequences of type 2 diabetes on AD pathologies, such as tau hyperphosphorylation, are not well understood. Here, we evaluated the impact of type 2 diabetes on tau phosphorylation in db/db diabetic mice aged 4 and 26weeks. We found increased tau phosphorylation at the CP13 epitope correlating with a deregulation of c-Jun. N-terminal kinase (JNK) and Protein Phosphatase 2A (PP2A) in 4-week-old db/db mice. 26-week-old db/db mice displayed tau hyperphosphorylation at multiple epitopes (CP13, AT8, PHF-1), but no obvious change in kinases or phosphatases, no cleavage of tau, and no deregulation of central insulin signaling pathways. In contrast to younger animals, 26-week-old db/db mice were hypothermic and restoration of normothermia rescued phosphorylation at most epitopes. Our results suggest that, at early stages of type 2 diabetes, changes in tau phosphorylation may be due to deregulation of JNK and PP2A, while at later stages hyperphosphorylation is mostly a consequence of hypothermia. These results provide a novel link between diabetes and tau pathology, and underlie the importance of recording body temperature to better understand the relationship between diabetes and AD.

Topics: Aging; Analysis of Variance; Animals; Blood Glucose; Body Weight; Brain; Diabetes Mellitus, Type 2; Disease Models, Animal; Gene Expression Regulation; Glycemic Index; Hypothermia, Induced; Insulin Resistance; Leptin; Male; MAP Kinase Kinase 4; Mice; Mice, Mutant Strains; Phosphorylation; Signal Transduction; tau Proteins

High glycemic load diets have been associated with increased breast cancer risk in population-based studies, but the evidence is mixed. This investigation determined whether diets differing in glycemic load affected the carcinogenic process using a preclinical model.. Human diets, formulated to differ 2-fold in glycemic load, were evaluated in the 1-methyl-nitrosourea-induced (37.5 mg/kg) mammary carcinogenesis model. Cancer incidence (23.3 versus 50.0%, p = 0.032), multiplicity, (0.40 versus 1.03, p = 0.030) and burden, (0.62 versus 1.19 g/rat, p = 0.037) were reduced in the low versus high glycemic load diets, respectively. However, the low glycemic protective effect was attenuated when two purified diets that differed in resistant starch and simulated the glycemic effects of the human diets were fed. Protection was associated with alterations in markers of cell growth regulation.. Our findings show that human low or high glycemic load dietary patterns differentially affect the carcinogenic response in a nondiabetic rodent model for breast cancer. However, factors that are associated with these patterns, in addition to dietary carbohydrate availability, appear to account for the differences observed.

Topics: Adiponectin; Animals; Blood Glucose; Breast Neoplasms; Diet; Dietary Carbohydrates; Disease Models, Animal; Female; Glycemic Index; Glycemic Load; Insulin; Leptin; Nitrosourea Compounds; Principal Component Analysis; Rats; Rats, Sprague-Dawley

The pathogenesis of nonalcoholic fatty liver disease (NAFLD) is not fully understood, and experimental models are an alternative to study this issue. We investigated the effects of a simple carbohydrate-rich diet on the development of obesity-related NAFLD and the impact of physical training on the metabolic abnormalities associated with this disorder. Sixty Wistar rats were randomly separated into experimental and control groups, which were fed with sucrose-enriched (18% simple carbohydrates) and standard diet, respectively. At the end of each experimental period (5, 10, 20, and 30 weeks), 6 animals from each group were sacrificed for blood tests and liver histology and immunohistochemistry. From weeks 25 to 30, 6 animals from each group underwent physical training. The experimental group animals developed obesity and NAFLD, characterized histopathologically by steatosis and hepatocellular ballooning, clinically by increased thoracic circumference and body mass index associated with hyperleptinemia, and metabolically by hyperglycemia, hyperinsulinemia, hypertriglyceridemia, increased levels of very low-density lipoprotein- (VLDL-) cholesterol, depletion of the antioxidants liver enzymes superoxide dismutase and catalase, and increased hepatic levels of malondialdehyde, an oxidative stress marker. Rats that underwent physical training showed increased high-density lipoprotein- (HDL-) cholesterol levels. In conclusion, a sucrose-rich diet induced obesity, insulin resistance, oxidative stress, and NAFLD in rats.

Topics: Animals; Biomarkers; Blood Glucose; Body Mass Index; Catalase; Dietary Sucrose; Disease Models, Animal; Exercise Therapy; Insulin; Insulin Resistance; Leptin; Lipids; Liver; Male; Malondialdehyde; Non-alcoholic Fatty Liver Disease; Obesity; Oxidative Stress; Rats, Wistar; Running; Superoxide Dismutase; Time Factors

We previously reported children homozygous for two MC3R sequence variants (C17A+G241A) have greater fat mass than controls. Here we show, using homozygous knock-in mouse models in which we replace murine Mc3r with wild-type human (MC3R(hWT/hWT)) and double-mutant (C17A+G241A) human (MC3R(hDM/hDM)) MC3R, that MC3R(hDM/hDM) have greater weight and fat mass, increased energy intake and feeding efficiency, but reduced length and fat-free mass compared with MC3R(hWT/hWT). MC3R(hDM/hDM) mice do not have increased adipose tissue inflammatory cell infiltration or greater expression of inflammatory markers despite their greater fat mass. Serum adiponectin levels are increased in MC3R(hDM/hDM) mice and MC3R(hDM/hDM) human subjects. MC3R(hDM/hDM) bone- and adipose tissue-derived mesenchymal stem cells (MSCs) differentiate into adipocytes that accumulate more triglyceride than MC3R(hWT/hWT) MSCs. MC3R(hDM/hDM) impacts nutrient partitioning to generate increased adipose tissue that appears metabolically healthy. These data confirm the importance of MC3R signalling in human metabolism and suggest a previously-unrecognized role for the MC3R in adipose tissue development.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Animals; Disease Models, Animal; Eating; Energy Metabolism; Fats; Gene Knock-In Techniques; Humans; Leptin; Mice; Obesity; Receptor, Melanocortin, Type 3

Sleep has a fundamental role in the regulation of energy balance, and it is an essential and natural process whose precise impacts on health and disease have not yet been fully elucidated. The aim of this study was to assess the consequences of different periods of paradoxical sleep deprivation (PSD) and recovery from PSD on lipid profile, oral glucose tolerance test (OGTT) results, and changes in insulin, corticosterone, ghrelin, and leptin concentrations. Three-month-old male Wistar rats weighing 250-350 g were submitted to 24, 96, or 192 h of PSD or 192 h of PSD with 480 h of recovery. The PSD was induced by the multiple platforms method. Subsequently, the animals were submitted to an OGTT. One day later, the animals were killed and the levels of triglycerides, total cholesterol, lipoproteins (low-density lipoprotein, very-low-density lipoprotein, and high-density lipoprotein), insulin, ghrelin, leptin, and corticosterone in plasma were quantified. There was a progressive decrease in body weight with increasing duration of PSD. The PSD induced basal hypoglycemia over all time periods evaluated. Evaluation of areas under the curve revealed progressive hypoglycemia only after 96 and 192 h of PSD. There was an increase in corticosterone levels after 192 h of PSD. We conclude that PSD induces alterations in metabolism that are reversed after a recovery period of 20 days.

Topics: Animals; Appetite Regulation; Biomarkers; Blood Glucose; Body Weight; Corticosterone; Disease Models, Animal; Eating; Energy Metabolism; Ghrelin; Glucose Tolerance Test; Hormones; Insulin; Leptin; Lipids; Male; Rats, Wistar; Recovery of Function; Sleep; Sleep Deprivation; Time Factors

Female mice from independently bred lines previously selected over 50 generations for increased voluntary wheel-running behavior (S1, S2) resist high energy (HE) diet-induced obesity (DIO) at adulthood, even without actual access to running wheels, as opposed to randomly bred controls (CON). We investigated whether adult S mice without wheels remain DIO-resistant when exposed - via the mother - to the HE diet during their perinatal stage (from 2 weeks prior to conception until weaning on post-natal day 21). While S1 and S2 females subjected to HE diet either perinatally or from weaning onwards (post-weaning) resisted increased adiposity at adulthood (as opposed to CON females), they lost this resistance when challenged with HE diet during these periods combined over one single cycle of breeding. When allowed one-week access to wheels (at week 6-8 and at 10 months), however, tendency for increased wheel-running behavior of S mice was unaltered. Thus, the trait for increased wheel-running behavior remained intact following combined perinatal and post-weaning HE exposure, but apparently this did not block HE-induced weight gain. At weaning, perinatal HE diet increased adiposity in all lines, but this was only associated with hyperleptinemia in S lines irrespective of gender. Because leptin has multiple developmental effects at adolescence, we argue that a trait for increased physical activity may advance maturation in times of plenty. This would be adaptive in nature where episodes of increased nutrient availability should be exploited maximally. Associated disturbances in glucose homeostasis and related co-morbidities at adulthood are probably pleiotropic side effects.

Topics: Adaptation, Ocular; Age Factors; Animals; Animals, Newborn; Diet; Disease Models, Animal; Eating; Energy Intake; Fats; Female; Glucose; Leptin; Male; Mice; Motor Activity; Obesity; Physical Exertion; Pregnancy; Prenatal Exposure Delayed Effects; Weaning

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder and is strongly associated with obesity and type 2 diabetes. Currently, there is no approved pharmacological treatment for this disease, but improvement of insulin resistance using peroxisome proliferator-activated receptor-γ (PPARγ) agonists, such as thiazolidinediones (TZDs), has been shown to reduce steatosis and steatohepatitis effectively and to improve liver function in patients with obesity-related NAFLD. However, this approach is limited by adverse effects of TZDs. Recently, we have identified fibroblast growth factor 1 (FGF1) as a target of nuclear receptor PPARγ in visceral adipose tissue and as a critical factor in adipose remodeling. Because FGF1 is situated downstream of PPARγ, it is likely that therapeutic targeting of the FGF1 pathway will eliminate some of the serious adverse effects associated with TZDs. Here we show that pharmacological administration of recombinant FGF1 (rFGF1) effectively improves hepatic inflammation and damage in leptin-deficient ob/ob mice and in choline-deficient mice, two etiologically different models of NAFLD. Hepatic steatosis was effectively reduced only in ob/ob mice, suggesting that rFGF1 stimulates hepatic lipid catabolism. Potentially adverse effects such as fibrosis or proliferation were not observed in these models. Because the anti-inflammatory effects were observed in both the presence and absence of the antisteatotic effects, our findings further suggest that the anti-inflammatory property of rFGF1 is independent of its effect on lipid catabolism. Our current findings indicate that, in addition to its potent glucose-lowering and insulin-sensitizing effects, rFGF1 could be therapeutically effective in the treatment of NAFLD.

Topics: Animals; Choline Deficiency; Disease Models, Animal; Fibroblast Growth Factor 1; Gene Expression; Human Umbilical Vein Endothelial Cells; Humans; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Non-alcoholic Fatty Liver Disease; RAW 264.7 Cells; Recombinant Proteins; Vascular Cell Adhesion Molecule-1

In experimental studies, several parameters, such as body weight, body mass index, adiposity index, and dual-energy X-ray absorptiometry, have commonly been used to demonstrate increased adiposity and investigate the mechanisms underlying obesity and sedentary lifestyles. However, these investigations have not classified the degree of adiposity nor defined adiposity categories for rats, such as normal, overweight, and obese. The aim of the study was to characterize the degree of adiposity in rats fed a high-fat diet using cluster analysis and to create adiposity intervals in an experimental model of obesity. Thirty-day-old male Wistar rats were fed a normal (n=41) or a high-fat (n=43) diet for 15 weeks. Obesity was defined based on the adiposity index; and the degree of adiposity was evaluated using cluster analysis. Cluster analysis allowed the rats to be classified into two groups (overweight and obese). The obese group displayed significantly higher total body fat and a higher adiposity index compared with those of the overweight group. No differences in systolic blood pressure or nonesterified fatty acid, glucose, total cholesterol, or triglyceride levels were observed between the obese and overweight groups. The adiposity index of the obese group was positively correlated with final body weight, total body fat, and leptin levels. Despite the classification of sedentary rats into overweight and obese groups, it was not possible to identify differences in the comorbidities between the two groups.

Topics: Adiposity; Animals; Blood Glucose; Blood Pressure; Body Weight; Cholesterol; Cluster Analysis; Diet, High-Fat; Disease Models, Animal; Fatty Acids, Nonesterified; Insulin; Leptin; Male; Obesity; Rats, Wistar; Sedentary Behavior; Severity of Illness Index; Time Factors; Triglycerides

The neuroprotective effects of liraglutide (200 μg/kg, twice daily, subcutaneous administration) in the hypothalamic arcuate nucleus (ARC) of diet-induced obese mice were investigated.. C57BL/6 mice were separated into groups: standard chow treated with vehicle or liraglutide and the respective liraglutide pair-fed group; high-fat diet treated with vehicle or liraglutide and the respective pair-fed group. Body mass (BM) evolution, carbohydrate metabolism, leptin resistance, proteins involved in energetic balance, apoptosis, and microglia in the ARC were studied.. Obese animals showed glucose intolerance, resistance to insulin and to anorexigenic effect of leptin, and microgliosis accompanied by elevated Bax/Bcl2 ratio in the ARC. Liraglutide improved the carbohydrate metabolism, BM loss, and the activation of pro-opiomelanocortin (POMC) and cocaine and amphetamine-regulated transcript (CART) in the ARC. The liraglutide enhanced leptin sensitivity and diminished the microgliosis with decrease in Bax/Bcl2 ratio.. Liraglutide activates central anorexigenic pathways, thereby diminishing the energy intake of obese mice and improving the metabolic parameters related to obesity. Liraglutide is a relevant neuroprotective agent, which can decrease the microgliosis and stimulate the anti-apoptotic pathway, a significant effect in the treatment of obesity and its comorbidities. Some benefits of liraglutide are independent of the BM loss, which usually accompanies the drug administration.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Diet, High-Fat; Disease Models, Animal; Energy Intake; Hypoglycemic Agents; Hypothalamus; Insulin; Leptin; Liraglutide; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Pro-Opiomelanocortin; RNA, Messenger

Topics: Animals; Anniversaries and Special Events; Disease Models, Animal; Endocrinology; History, 20th Century; History, 21st Century; Hormones; Humans; Leptin; Mice; Obesity; Periodicals as Topic; Receptors, Leptin; Societies, Medical

Emerging data has suggested a high prevalence of osteoarthritis (OA) among obese people. As an important adipokine secreted by white adipose tissue, leptin may be a key mediator in the progression of OA. Leptin exerts a catabolic effect on OA cartilage by increasing the production of metalloproteinase (MMP) enzymes, and contributes to apoptosis in chondrocytes. The current study aimed to explore the role of leptin on the apoptosis of chondrocytes in OA, and its underlying mechanisms. In the in vitro model of OA used in the present study, administration of exogenous leptin induced the generation of reactive oxygen species (ROS) and apoptosis in chondrocytes. It has been demonstrated that leptin is associated with the pathogenesis of OA via the Janus kinase 2 (JAK2)‑signal transducer and activator of transcription 3 (STAT3) signaling pathway, and data gathered in the present study demonstrated that suppression of this signaling pathway using a JAK2 inhibitor, AG490, significantly ameliorated leptin‑induced apoptosis in damaged chondrocytes in vitro, and reduced the generation of ROS. Furthermore, the protein expression levels of MMP‑13 and B‑cell lymphoma 2‑associated X protein were downregulated in the AG490‑treated group. The results of the present study may provide insight into the underlying molecular mechanism by which leptin induces apoptosis in chondrocytes. These findings indicated the importance of leptin as a therapeutic target for the treatment of OA in the overweight population.

Topics: Animals; Anterior Cruciate Ligament; Apoptosis; bcl-2-Associated X Protein; Blotting, Western; Cells, Cultured; Chondrocytes; Disease Models, Animal; Down-Regulation; Janus Kinase 2; Leptin; Male; Matrix Metalloproteinase 13; Osteoarthritis; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Signal Transduction; STAT3 Transcription Factor; Tyrphostins

Despite its therapeutic advantages, chemotherapy can also cause adverse effects, including anorexia and loss of appetite. Although numerous patients with cancer have been reported to suffer from anorexia during or following chemotherapy, treatment options for anorexia remain to be determined. In Asian countries, traditional medicines are widely used to treat problems with appetite; sip-jeon-dea-bo-tang (SJDBT) is one of those medicines used for the treatment of anorexia. The present study demonstrated that SJDBT ameliorated cisplatin-induced anorexia. In a mouse model of chemotherapy-induced anorexia, oral administration of SJDBT prevented the cisplatin-induced reduction of food intake, inhibiting weight loss. The results of multiplex assays showed that SJDBT only altered the levels of interleukin (IL)-6 and leptin in the serum and fat tissue. In addition, SJDBT maintained the serum leptin level and increased the serum IL-6 level, whereas cisplatin reduced the levels of both serum leptin and IL‑6. Furthermore, SJDBT was revealed to increase the levels of leptin and IL-6 in the fat tissue by activating the JAK1/STAT3 signaling pathway. In conclusion, the present results revealed that SJDBT ameliorated cisplatin-induced anorexia, suggesting its usefulness in the prevention of anorexia during chemotherapy.

Topics: Adipose Tissue; Animals; Anorexia; Antineoplastic Agents; Cisplatin; Disease Models, Animal; Drugs, Chinese Herbal; Interleukin-6; Janus Kinase 1; Leptin; Male; Mice; Signal Transduction; STAT3 Transcription Factor

Obesity is a major risk factor for cardiovascular disease in males and females. Whether obesity triggers cardiovascular disease via similar mechanisms in both the sexes is, however, unknown. In males, the adipokine leptin highly contributes to obesity-related cardiovascular disease by increasing sympathetic activity. Females secrete 3× to 4× more leptin than males, but do not exhibit high sympathetic tone with obesity. Nevertheless, females show inappropriately high aldosterone levels that positively correlate with adiposity and blood pressure (BP). We hypothesized that leptin induces hypertension and endothelial dysfunction via aldosterone-dependent mechanisms in females. Leptin control of the cardiovascular function was analyzed in female mice sensitized to leptin via the deletion of protein tyrosine phosphatase 1b (knockout) and in agouti yellow obese hyperleptinemic mice (Ay). Hypersensitivity to leptin (wild-type, 115 ± 2; protein tyrosine phosphatase 1b knockout, 124 ± 2 mm Hg; P<0.05) and obesity elevated BP (a/a, 113 ± 1; Ay, 128 ± 7 mm Hg; P<0.05) and impaired endothelial function. Chronic leptin receptor antagonism restored BP and endothelial function in protein tyrosine phosphatase 1b knockout and Ay mice. Hypersensitivity to leptin and obesity reduced BP response to ganglionic blockade in both strains and plasma catecholamine levels in protein tyrosine phosphatase 1b knockout mice. Hypersensitivity to leptin and obesity significantly increased plasma aldosterone levels and adrenal CYP11B2 expression. Chronic leptin receptor antagonism reduced aldosterone levels. Furthermore, chronic leptin and mineralocorticoid receptor blockade reduced BP and improved endothelial function in both leptin-sensitized and obese hyperleptinemic female mice. Together, these data demonstrate that leptin induces hypertension and endothelial dysfunction via aldosterone-dependent mechanisms in female mice and suggest that obesity leads to cardiovascular disease via sex-specific mechanisms.

Topics: Aldosterone; Analysis of Variance; Animals; Cardiovascular Diseases; Disease Models, Animal; Endothelium, Vascular; Female; Hypertension; Leptin; Male; Mice; Mice, Knockout; Mice, Obese; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Random Allocation; Renin-Angiotensin System; Sensitivity and Specificity; Sex Factors; Statistics, Nonparametric

Notwithstanding compelling contribution of NF-κB to the progression of osteoporosis has been reported, little is known regarding direct inhibition of NF-κB benefiting osteoporosis. In this study, therefore, we evaluated the role of celastrol, an NF-κB inhibitor, in a mouse model of secondary osteoporosis. Animals were divided into three groups as Sham (control), SO (secondary osteoporosis) and SO + CA (secondary osteoporosis treated with celastrol). Significant decreases in body weight and body fat were observed following celastrol treatment in SO group, but leptin levels were much higher. Celastrol also exhibited a significant decrease in urinary calcium excretion. Moreover, other important events were observed after celastrol treatment, covering substantial decrements in serum concentrations of PTH, TRAP-5b, CTX and DPD, improved structure of articular cartilage and cancellous bone (revealed by H&E and safranin-O staining), and significant decline in levels of NF-κB (P65), MMP-1, and MMP-9. These findings demonstrated that celastrol treatment not only improved abnormal lipid metabolism and hypercalciuria in mice subjected to secondary osteoporosis, but also ameliorated articular cartilage lesions. Our results provided evidence of targeted therapy for NF-κB in the clinical treatment of secondary osteoporosis.

Topics: Adipose Tissue; Animals; Body Weight; Cartilage, Articular; Disease Models, Animal; Disease Progression; Hypercalciuria; Leptin; Lipid Metabolism; Male; Mice, Inbred C57BL; Molecular Targeted Therapy; NF-kappa B; Osteoporosis; Parathyroid Hormone; Pentacyclic Triterpenes; Triterpenes

Rats with high-fat diet (HFD)-induced obesity increase daytime eating, suggesting an alteration in circadian food intake mechanisms. Gastric vagal afferents (GVAs) respond to mechanical stimuli to initiate satiety. These signals are dampened in HFD mice and exhibit circadian variations inversely with food intake in lean mice. Furthermore, leptin shows circadian variation in its circulating level and is able to modulate GVA mechanosensitivity. However, whether leptin's ability to modulate GVAs occurs in a circadian manner is unknown. Therefore, we investigated whether changes in the circadian intake of food in HFD-induced obesity is associated with a disruption in GVA circadian rhythms. Eight-week-old male C57BL/6 mice were fed a standard laboratory diet (SLD) or a HFD for 12 weeks. A subgroup of SLD and HFD mice were housed in metabolic cages. After 12 weeks, ex vivo GVA recordings were taken at 3 h intervals starting at zeitgeber time 0 (ZT0) and stomach content was measured. After 12 weeks, HFD mice consumed more food during the light phase through larger and more frequent meals compared with SLD mice. SLD mice exhibited circadian fluctuation in stomach content, which peaked at ZT18 and reached a nadir at ZT9. At these time points, both tension and mucosal receptor mechanosensitivity were the lowest and highest, respectively. HFD mice exhibited little circadian variation in stomach content or GVA mechanosensitivity. Leptin potentiated mucosal receptor mechanosensitivity only in SLD mice and with reduced potency during the dark phase. In conclusion, loss of circadian variation in GVA signaling may underpin changes in eating behavior in HFD-induced obesity.. Appropriate circadian control of food intake is vital for maintaining metabolic health. Diet-induced obesity is associated with strong circadian changes in food intake, but the contributing mechanisms have yet to be determined. Vagal afferents are involved in regulation of feeding behavior, particularly meal size, and have been shown to exhibit circadian fluctuation in mechanosensitivity, potentially allowing for time of day-specific levels of satiety signaling. Our study indicates that, in diet-induced obesity, these circadian fluctuations in gastric vagal afferent mechanosensitivity are lost. This was accompanied by increased light phase eating, particularly increased meal size. This is the first evidence that diet-induced disruption to vagal afferent signaling may cause a perturbation in circadian eating patterns.

Topics: Action Potentials; Afferent Pathways; Animals; Body Weight; Circadian Rhythm; CLOCK Proteins; Diet, High-Fat; Disease Models, Animal; Eating; Energy Metabolism; Ghrelin; Leptin; Male; Mechanoreceptors; Mice; Mice, Inbred C57BL; Obesity; Physical Stimulation; Rats; Stomach; Vagus Nerve

Epidemiological studies suggest that diabetics may be more susceptible to the adverse health effects from exposure to high ambient concentrations of ozone, the primary oxidant gas in photochemical smog. While increased morbidity and mortality from ozone inhalation has been linked to disruption of normal cardiovascular and airway functions, potential effects on glucose and insulin homeostasis are not understood. We tested the hypothesis that ozone exposure would worsen metabolic homeostasis in KKAy mice, a genetic diabetic animal model. Male KKAy mice were exposed to 0.5 ppm ozone for 13 consecutive weekdays, and then assessed for airway, adipose and systemic inflammation, glucose homeostasis, and insulin signaling. Ozone exposure increased plasma TNFα, as well as expression of VCAM-1, iNOS and IL-6 in both pulmonary and adipose tissues. Pro-inflammatory CD11b(+)Gr-1(lo)7/4(hi) macrophages were increased by 200% in adipose tissue, but unchanged in blood. Interestingly, glucose levels were not significantly different in the insulin tolerance test between air- and ozone-exposed mice, whereas fasting insulin levels and HOMA-IR in ozone-exposed animals were significantly reduced. These changes were accompanied by increased insulin signaling in skeletal muscle and liver, but not adipose tissues. Ozone also caused decrease in body weight and plasma leptin. Our results show that in addition to marked local and systemic inflammation, ozone increases insulin sensitivity that may be related to weight loss/leptin sensitization-dependent mechanisms in KKAy mice, warranting further study on the role of hyperglycemia in mediating cardiometabolic effects of ozone inhalation.

Topics: Adiponectin; Adipose Tissue; Administration, Inhalation; Animals; Blood Glucose; Diabetes Mellitus; Disease Models, Animal; Inflammation; Insulin; Insulin Resistance; Leptin; Liver; Male; Mice; Muscle, Skeletal; Sulfuric Acids

Obesity is characterized by increased circulating levels of the adipocyte-derived hormone leptin, which can increase sympathetic nerve activity and raise blood pressure. A previous study revealed that rats fed a high-fat diet (HFD) have an enhanced hypertensive response to subsequent angiotensin II administration that is mediated at least, in part, by increased activity of brain renin-angiotensin system and proinflammatory cytokines. This study tested whether leptin mediates this HFD-induced sensitization of angiotensin II-elicited hypertension by interacting with brain renin-angiotensin system and proinflammatory cytokine mechanisms. Rats fed an HFD for 3 weeks had significant increases in white adipose tissue mass, plasma leptin levels, and mRNA expression of leptin and its receptors in the lamina terminalis and hypothalamic paraventricular nucleus. Central infusion of a leptin receptor antagonist during HFD feeding abolished HFD sensitization of angiotensin II-elicited hypertension. Furthermore, central infusion of leptin mimicked the sensitizing action of HFD. Concomitant central infusions of the angiotensin II type 1 receptor antagonist irbesartan, the tumor necrosis factor-α synthesis inhibitor pentoxifylline, or the inhibitor of microglial activation minocycline prevented the sensitization produced by central infusion of leptin. RT-PCR analysis indicated that either HFD or leptin administration upregulated mRNA expression of several components of the renin-angiotensin system and proinflammatory cytokines in the lamina terminalis and paraventricular nucleus. The leptin antagonist and the inhibitors of angiotensin II type 1 receptor, tumor necrosis factor-α synthesis, and microglial activation all reversed the expression of these genes. The results suggest that HFD-induced sensitization of angiotensin II-elicited hypertension is mediated by leptin through upregulation of central renin-angiotensin system and proinflammatory cytokines.

Topics: Angiotensin II; Animals; Blood Pressure Determination; Cytokines; Diet, High-Fat; Disease Models, Animal; Hypertension; Inflammation; Leptin; Male; Paraventricular Hypothalamic Nucleus; Random Allocation; Rats; Rats, Sprague-Dawley; Reference Values; Renin-Angiotensin System; RNA, Messenger; Up-Regulation

Accumulating evidences suggests that obesity and metabolic syndrome (MetS) contribute towards lower urinary tract symptoms (LUTS) through alterations in the phenotype of bladder and prostate gland. Clinical studies indicate a link between MetS and LUTS. Nevertheless, there is lack of suitable animal model(s) which could illustrate an association linking obesity to LUTS. We examined the lower urinary tract function in an obesity-initiated MetS mouse model.. Male C57BL/6N wild-type and obese B6.V-Lepob/J maintained on regular diet for 28 weeks were subjected to the assessment of body weight (BW), body length (BL), waist circumference (WC), body mass index (BMI), blood glucose (BG), plasma insulin (INS), plasma leptin (LEP), total cholesterol (CHO), free fatty acid (FFA), and measurement of urinary functions. Whole animal peritoneal and subcutaneous adipose tissue measurements as well as prostate and bladder volumes were analyzed by MRI followed by histological evaluation. These parameters were used to draw correlations between MetS and LUTS.. Obesity parameters such as BW, WC, and BMI were significantly higher in B6.V-Lepob/J mice compared to C57BL/6N mice (P < 0.01). Higher levels of total CHO and FFA were noted in B6.V-Lepob/J mice than C57BL/6N mice (P < 0.05). These results were concurrent with frequency, lower average urine volume and other urinary voiding dysfunctions in B6.V-Lepob/J mice. MRI assessments demonstrate marked increase in body fat and prostate volume in these mice. Compared to C57BL/6N mice, histological analysis of the prostate from B6.V-Lepob/J mice showed increased proliferation, gland crowding, and infiltration of immune cells in the stroma; whereas the bladder urothelium was slightly thicker and appears more proliferative in these mice. The regression and correlation analysis indicate that peritoneal fat (R = 0.853; P < 0.02), CHO (R = 0.729; P < 0.001), BG (R = 0.712; P < 0.001) and prostate volume (R = 0.706; P < 0.023) strongly correlate with LUTS whereas BMI, WC, INS, and FFA moderately correlate with the prevalence of bladder dysfunction.. Our results suggest that LUTS may be attributable in part to obesity and MetS. Validation of an in vivo model may lead to understand the underlying pathophysiological mechanisms of obesity-related LUTS in humans. Prostate 76:964-976, 2016. © 2016 Wiley Periodicals, Inc.

Topics: Adipose Tissue; Animals; Biometry; Body Composition; Cholesterol; Disease Models, Animal; Leptin; Lower Urinary Tract Symptoms; Magnetic Resonance Imaging; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Obesity; Peritoneum; Prostate; Urinary Bladder; Urination Disorders

Neonatal growth restriction (nGR) leads to leptin deficiency and increases the risk of hypertension. Previous studies have shown nGR-related hypertension is normalized by neonatal leptin (nLep) and exacerbated by psychological stress. With recent studies linking leptin and angiotensin signaling, we hypothesized that nGR-induced nLep deficiency increases adult leptin sensitivity; leading to leptin- or stress-induced hypertension, through a pathway involving central angiotensin II type 1 receptors.. We randomized mice with incipient nGR, by virtue of their presence in large litters, to vehicle or physiologic nLep supplementation (80 ng/g/d). Adult caloric intake and arterial pressure were monitored at baseline, during intracerebroventricular losartan infusion and during systemic leptin administration.. nGR increased leptin-triggered renal sympathetic activation and hypertension with increased leptin receptor expression in the arcuate nucleus of the hypothalamus; all of those nGR-associated phenotypes were normalized by nLep. nGR mice also had stress-related hyperphagia and hypertension, but only the stress hypertension was blocked by central losartan infusion.. nGR leads to stress hypertension through a pathway that involves central angiotensin II receptors, and nGR-associated leptin deficiency increases leptin-triggered hypertension in adulthood. These data suggest potential roles for preservation of neonatal growth and nLep supplementation in the prevention of nGR-related hypertension.

Topics: Angiotensins; Animals; Blood Pressure; Disease Models, Animal; Growth Disorders; Hypertension; Leptin; Losartan; Male; Mice; Mice, Inbred C57BL; Random Allocation; Receptors, Angiotensin; Renin-Angiotensin System; Signal Transduction; Stress, Psychological; Sympathetic Nervous System

To observe mainfestations of syndrome and biochemical indices of hypertensive model rats with excessive accumulation of phlegm-dampness syndrome (EAPDS), and to explore its possible pathological mechanism.. EAPDS rat model was prepared in 50 Wistar rats by feeding with high fat forage. Meanwhile, a normal control group consisting of 10 Wistar rats was set up by feeding with normal forage. After 25-week continuous feeding, 22 rats with body weight (BW) and blood pressure (BP) exceeding 25% those of the control group were selected as a model group. BW, BP, blood lipids, and related serological indicators were detected in all rats. Morphological changes of target organs were observed. mRNA expression levels of leptin receptor (LepR), Janus kinase2 (Jak2), signal transducer and activator of transcription 3 (Stat3), suppressor of cytokine signaling-3 (Socs3), angiotensin II receptor type 1 (AT1), angiotensin II receptor type 2 (AT2), phosphatidylinositol 3 kinase (P13K), serine threonine kinase (Akt), nuclear factor of kappa B (NF-κBp65), inhibitor of nuclear factor kappa-B kinase α (IKKα), NF-kappa-B inhibitor β (lKKβ), NF-kappa-B inhibitor α (IKBα), and AMP-activated protein kinase (AMPK) were detected by quantitative real-time PCR (qPCR). Expression levels of AT1 and LepR in aorta were detected by immunohistochemical assay and Western blot respectively.. Compared with the control group, BW, BP, and blood lipids increased; serum levels of leptin (Lep) , Ang II, Hcy, ET-1, TNF-α, IL-6, and p2-MG increased, but NO decreased in the model group (P < 0.05, P < 0.01). Aortal endothelial injury and smooth muscle cell proliferation occurred in the model group, accompanied with heart and renal injury. Compared with the control group, mRNA expression levels of LepR, Jak2, Stat3, Socs3, AT1 , PI3K, Akt, NF-κB p65, IKKβ, IKBα, and AMPK in aorta were up-regulated significantly (P < 0.05), while the expression of IKKa decreased (P < 0.05). Immunohistochem- ical staining showed, brownish yellow deposit of AT1 and LepR was obviously increased, with more extensively positive distribution. Western blot results showed, as compared with the control group, protein expression levels of AT1 and LepR obviously increased in the model group (P < 0.05).. Model rats exhibited typical syndromes of EAPDS. They put up weight with fat abdomen, gloomy hair, poor appetite, hypersomnia, lowered activities , reduced food intake, loose stool, dark red tongue, white tongue with white, thick, greasy fur. Lep could be taken as one of objective indicators for evaluating hypertension rat model with EAPDS.

Topics: Animals; Aorta; Cell Proliferation; Disease Models, Animal; Hypertension; I-kappa B Proteins; Interleukin-6; Leptin; NF-kappa B; NF-KappaB Inhibitor alpha; Phosphatidylinositol 3-Kinases; Rats; Rats, Wistar; Suppressor of Cytokine Signaling Proteins; Transcription Factor RelA; Tumor Necrosis Factor-alpha

Chronic inflammation is known to be associated with visceral obesity and insulin resistance and is characterized by altered levels of production of adipokines such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), IL-6, leptin, and adiponectin. Metabolic syndrome (MetS) is a major and escalating public health and clinical challenge worldwide, and patients with MetS have an increased risk of developing cardiovascular disease and type 2 diabetes mellitus. Electroacupuncture (EA) was tested as a means of decreasing inflammation in genetically obese Zucker fatty rats, which serve as a model of MetS. Repeated application of EA at the Zhongwan/Guanyuan acupoints decreased serum TNF-α, but produced no significant alterations in serum leptin, adiponectin, or IL-10. EA had no significant effect on the levels of these four adipokines in white adipose tissue. These findings are consistent with the supposition that EA inhibits proliferation and/or infiltration of macrophages into the adipose tissue of obese rats and stimulates the release of IL-10 from the decreased numbers of macrophages present in adipose tissue. Compared with the control animals, no significant change in body weight occurred. The blood glucose (BG) level over a 30-minute interval in Week 2 was relatively the same as that in Week 1, suggesting that EA treatment does not increase the likelihood of developing hyperglycemia.

Topics: Animals; Disease Models, Animal; Electroacupuncture; Humans; Interleukin-10; Interleukin-6; Leptin; Male; Metabolic Syndrome; Obesity; Rats; Rats, Zucker; Tumor Necrosis Factors

The aim of this study was to assay the effects of Coreopsis tinctoria Nutt. flower extracts on hyperglycemia of diet-induced obese mice and the underlying mechanisms. Coreopsis tinctoria flower was extracted with ethanol and water, respectively. The total phenol, flavonoid levels, and the constituents of the extracts were measured. For the animal experiments, C57BL/6 mice were fed with a chow diet, high-fat diet, or high-fat diet mixed with 0.4% (w/w) water and ethanol extracts of Coreopsis tinctoria flower for 8 weeks. The inhibitory effects of the extracts on α-glucosidase activity and the antioxidant properties were assayed in vitro. We found that the extracts blocked the increase of fasting blood glucose, serum triglyceride (TG), insulin, leptin, and liver lipid levels and prevented the development of glucose tolerance impairment and insulin resistance in the C57BL/6 mice induced by a high-fat diet. The extracts inhibited α-glycosidase activity and increased oxidant activity in vitro. In conclusion, Coreopsis tinctoria flower extracts may ameliorate high-fat diet-induced hyperglycemia and insulin resistance. The underling mechanism may be via the inhibition of α-glucosidase activity. Our data indicate that Coreopsis tinctoria flower could be used as a beverage supplement and a potential source of drugs for treatment of diabetics.

Topics: Animals; Biomarkers; Blood Glucose; Coreopsis; Diet, High-Fat; Disease Models, Animal; Ethanol; Female; Flowers; Glycoside Hydrolase Inhibitors; Hyperglycemia; Insulin; Insulin Resistance; Leptin; Lipids; Liver; Mice, Inbred C57BL; Obesity; Phytotherapy; Plant Extracts; Plants, Medicinal; Solvents; Time Factors; Water

Variants in the gene TBC1D1 have been previously associated with obesity-related traits in several species, including humans, mice, rabbits and chicken. While in humans variants in TBC1D1 were linked to obesity, disruption of the Tbc1d1 gene reduced body weight in mice. TBC1D1 has been identified as a regulator of insulin-dependent glucose transport in skeletal muscle, however, its role in energy homeostasis in the obese state remains unclear. The impact of TBC1D1 deficiency on energy homeostasis, glucose and lipid metabolism in an established mouse model of obesity was examined.. Obese leptin (ob/ob)- and Tbc1d1-double-deficient mice (D1KO-ob/ob) were generated by crossing obese B6.V.Lep(ob/ob)-mice with lean Tbc1d1-deficient mice on a C57BL/6J background. Male mice on either standard (SD) or high-fat diet (HFD) were analyzed for body weight, body composition, food intake, voluntary physical activity and energy expenditure by indirect calorimetry. Glucose and insulin tolerance as well as glucose transport and fatty acid oxidation in skeletal muscle were analyzed.. In obese mice, Tbc1d1 deficiency resulted in reduced body weight on both SD and HFD. However, food intake was unchanged on SD or even increased in HFD-fed Tbc1d1-deficient mice without alterations in voluntary physical activity. Despite substantially reduced insulin-stimulated glucose transport and increased fatty acid oxidation in intact isolated skeletal muscle, obese Tbc1d1-deficient mice showed no gross changes in glycemia and glucose tolerance compared with obese controls. Indirect calorimetry revealed that obese Tbc1d1-deficient mice had a decreased respiratory quotient together with increased daily energy expenditure.. In obese leptin-deficient mice, lack of TBC1D1 has no impact on feeding behavior or energy intake but results in increased energy expenditure, altered energy substrate preference with increased fatty acid oxidation and suppression of obesity. TBC1D1 may have an evolutionary conserved role in regulating energy homeostasis in vertebrates.

Topics: Animals; Biological Transport; Calorimetry, Indirect; Diet, High-Fat; Disease Models, Animal; Energy Metabolism; Fatty Acids; Gene Deletion; Glucose; GTPase-Activating Proteins; Homeostasis; Insulin; Insulin Resistance; Leptin; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mice, Obese; Muscle, Skeletal; Obesity

Visceral leishmaniasis (VL) is caused by the protozoan parasite Leishmania donovani There are no vaccines and available drugs against leishmaniasis are toxic. Immunomodulators that specifically boost the anti-microbial activities of the immune cells could alleviate several of these limitations. Therefore, finding novel immunomodulators for VL therapy is a pressing need. This study is aimed to evaluate the immunomodulatory role of leptin, an adipocyte-derived hormone capable of regulating the immune response, in L. donovani-infected mice. We observed that recombinant leptin treatment reduced splenic parasite burden compared with non-treated infected normal mice. Decrease in parasite burden correlated with an induction of innate immune response in antigen-presenting cells that showed an increase in nitric oxide, enhanced pro-inflammatory cytokine (interferon gamma [IFNγ], interleukin12 [IL]12, and IL1β) response in the splenocytes, indicating host-protecting Th1 response mediated by leptin. Moreover, in infected normal mice, leptin treatment induced IFNγ production from both CD4(+) and CD8(+) T cells, compared with non-treated infected mice. Alternatively, leptin-deficient (Ob/Ob) mice had higher splenic and liver parasite burden compared with the infected normal mice. However, leptin treatment failed to reduce the splenic parasite burden and improve a host-protective cytokine response in these mice. In addition, in contrast to dendritic cells (DCs) from a normal mouse, Ob/Ob mouse-derived DCs showed a defect in the induction of innate immune response on Leishmania infection that could not be reversed by leptin treatment. Therefore, our findings reveal that leptin has a differential immunomodulatory effect in controlling VL in normal and Ob/Ob mice.

Topics: Animals; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Disease Models, Animal; Female; Immunity, Innate; Immunologic Factors; Interferon-gamma; Interleukin-12; Interleukin-1beta; Leishmania donovani; Leishmaniasis, Visceral; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Recombinant Proteins; Spleen

Patients with anorexia nervosa (AN) suffer from neuropsychological deficits including memory impairments. Memory partially depends on 17β-oestradiol (E2), which is reduced in patients with AN. We assessed whether memory functions correlate with E2 plasma levels in the activity-based anorexia (ABA) rat model.. Nine 4-week-old female Wistar rats were sacrificed directly after weight loss of 20-25% (acute starvation), whereas 17 animals had additional 2-week weight-holding (chronic starvation). E2 serum levels and novel object recognition tasks were tested before and after starvation and compared with 21 normally fed controls.. Starvation disrupted menstrual cycle and impaired memory function, which became statistically significant in the chronic state (oestrous cycle (P < 0.001), E2 levels (P = 0.011) and object recognition memory (P = 0.042) compared to controls). E2 reduction also correlated with the loss of memory in the chronic condition (r = 0.633, P = 0.020).. Our results demonstrate that starvation reduces the E2 levels which are associated with memory deficits in ABA rats. These effects might explain reduced memory capacity in patients with AN as a consequence of E2 deficiency and the potentially limited effectiveness of psychotherapeutic interventions in the starved state. Future studies should examine whether E2 substitution could prevent cognitive deficits and aid in earlier readiness for therapy.

Topics: Animals; Anorexia Nervosa; Body Weight; Disease Models, Animal; Estradiol; Estrous Cycle; Female; Humans; Leptin; Memory Disorders; Rats; Rats, Wistar

Children of mothers with gestational diabetes have greater risk of developing hypertension but little is known about the mechanisms by which this occurs. The objective of this study was to test the hypothesis that high maternal concentrations of leptin during pregnancy, which are present in mothers with gestational diabetes and/or obesity, alter blood pressure, vascular structure and vascular function in offspring. Wildtype (WT) offspring of hyperleptinemic, normoglycemic, Leprdb/+ dams were compared to genotype matched offspring of WT-control dams. Vascular function was assessed in male offspring at 6, and at 31 weeks of age after half the offspring had been fed a high fat, high sucrose diet (HFD) for 6 weeks. Blood pressure was increased by HFD but not affected by maternal hyperleptinemia. On a standard diet, offspring of hyperleptinemic dams had outwardly remodeled mesenteric arteries and an enhanced vasodilatory response to insulin. In offspring of WT but not Leprdb/+ dams, HFD induced vessel hypertrophy and enhanced vasodilatory responses to acetylcholine, while HFD reduced insulin responsiveness in offspring of hyperleptinemic dams. Offspring of hyperleptinemic dams had stiffer arteries regardless of diet. Therefore, while maternal hyperleptinemia was largely beneficial to offspring vascular health under a standard diet, it had detrimental effects in offspring fed HFD. These results suggest that circulating maternal leptin concentrations may interact with other factors in the pre- and post -natal environments to contribute to altered vascular function in offspring of diabetic pregnancies.

Topics: Acetylcholine; Animals; Blood Pressure; Disease Models, Animal; Female; Fibrosis; Insulin; Leptin; Lipid Metabolism; Male; Maternal Exposure; Mice; Pregnancy; Prenatal Exposure Delayed Effects; Sex Factors; Vascular Diseases; Vascular Resistance

Disruption of the circadian rhythm contributes to obesity. This study tested the hypothesis that time-restricted feeding (TRF) reduces high-fat diet-induced increase in adiposity. Male C57BL/6 mice were fed the AIN93G or the high-fat diet ad libitum (ad lib); TRF of the high-fat diet for 12 or 8hours during the dark cycle was initiated when high-fat diet-fed mice exhibited significant increases in body weight. Energy intake of the TRF 12-hour group was not different from that of the high-fat ad lib group, although that of the TRF 8-hour group was slightly but significantly lower. Restricted feeding of the high-fat diet reduced body fat mass and body weight compared with mice fed the high-fat diet ad lib. There were no differences in respiratory exchange ratio (RER) among TRF and high-fat ad lib groups, but the RER of these groups was lower than that of the AIN93G group. Energy expenditure of the TRF groups was slightly but significantly lower than that of the high-fat ad lib group. Plasma concentrations of ghrelin were increased in TRF groups compared with both AIN93G and high-fat ad lib groups. Elevations of plasma concentrations of insulin, leptin, monocyte chemoattractant protein-1, and tissue inhibitor metalloproteinase-1 by high-fat ad lib feeding were reduced by TRF to the levels of mice fed the AIN93G diet. In conclusion, TRF during the dark cycle reduces high-fat diet-induced increases in adiposity and proinflammatory cytokines. These results indicate that circadian timing of food intake may prevent obesity and abate obesity-related metabolic disturbance.

Topics: Adiposity; Animals; Body Weight; Chemokine CCL2; Circadian Rhythm; Diet, High-Fat; Disease Models, Animal; Energy Metabolism; Ghrelin; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Time Factors; Tissue Inhibitor of Metalloproteinase-1

Upon activation, T cells require energy for growth, proliferation, and function. Effector T (Teff) cells, such as Th1 and Th17 cells, utilize high levels of glycolytic metabolism to fuel proliferation and function. In contrast, Treg cells require oxidative metabolism to fuel suppressive function. It remains unknown how Teff/Treg-cell metabolism is altered when nutrients are limited and leptin levels are low. We therefore examined the role of malnutrition and associated hypoleptinemia on Teff versus Treg cells. We found that both malnutrition-associated hypoleptinemia and T cell-specific leptin receptor knockout suppressed Teff-cell number, function, and glucose metabolism, but did not alter Treg-cell metabolism or suppressive function. Using the autoimmune mouse model EAE, we confirmed that fasting-induced hypoleptinemia altered Teff-cell, but not Treg-cell, glucose metabolism, and function in vivo, leading to decreased disease severity. To explore potential mechanisms, we examined HIF-1α, a key regulator of Th17 differentiation and Teff-cell glucose metabolism, and found HIF-1α expression was decreased in T cell-specific leptin receptor knockout Th17 cells, and in Teff cells from fasted EAE mice, but was unchanged in Treg cells. Altogether, these data demonstrate a selective, cell-intrinsic requirement for leptin to upregulate glucose metabolism and maintain function in Teff, but not Treg cells.

Topics: Animals; Cell Differentiation; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Glycolysis; Hypoxia-Inducible Factor 1, alpha Subunit; Leptin; Malnutrition; Mice; Mice, Inbred C57BL; Mice, Knockout; T-Lymphocytes, Regulatory; Th17 Cells

Myoinositol and D-chiroinositol improve insulin resistance in women with obesity and gestational diabetes and in postmenopausal women with metabolic syndrome. We previously reported that offspring born to hypertensive dams lacking endothelial nitric oxide synthase and fed a high-fat diet develop metabolic-like syndrome phenotype.. The objective of the study was to investigate the effect of a mixture of myoinositol/D-chiroinositol supplementation during pregnancy on the maternal metabolic profile in pregnancies complicated by the metabolic-like syndrome and obesity using a pregnant mouse model.. Female heterozygous endothelial nitric oxide synthase(-/+) mice with moderate hypertension were placed on a high-fat diet for 4 weeks to induce a metabolic-like syndrome phenotype. Similarly, wild-type C57BL/6 mice were placed on a high-fat diet for 4 weeks to induce a murine obesity model. Mice were then bred with wild-type males. On gestational day 1, dams were randomly allocated to receive either a mixture of myoinositol/D-chiroinositol in water (7.2/0.18 mg/mL, respectively) or water as control (placebo). At term (gestational day 18), maternal weights, systolic blood pressure, and a glucose tolerance test were obtained. Dams were then killed; pups and placentas were weighed and maternal blood collected. Serum levels of metabolic biomarkers relevant to diabetes and obesity (ghrelin, gastric inhibitory peptide, glucagon-like peptide 1, glucagon, insulin, leptin, resistin) were measured by a multiplex enzyme-linked immunosorbent assay. Analysis was done comparing metabolic-like syndrome-myoinositol/D-chiroinositol-treated vs metabolic-like syndrome-nontreated mice and obese-myoinositol/D-chiroinositol-treated vs obese nontreated mice.. Mean systolic blood pressure was lower in metabolic-like syndrome pregnant mice treated with myoinositol/D-chiroinositol compared with placebo (P = .04), whereas there was no difference in systolic blood pressure between treated and placebo-treated obese pregnant mice. Pregnant metabolic-like syndrome mice treated with myoinositol/D-chiroinositol showed lower glucose values during the glucose tolerance test and in the area under the curve (myoinositol/D-chiroinositol: 17512.5 ± 3984.4 vs placebo: 29687.14 ± 8258.7; P = .003), but no differences were seen in the obese pregnant mice. Leptin serum levels were lower in the metabolic-like syndrome-myoinositol/D-chiroinositol-treated mice compared with the placebo group (myoinositol/D-chiroinositol: 16985 ± 976.4 pg/dL vs placebo: 24181.9 ± 3128.2 pg/dL, P = .045). No other differences were seen in any of the remaining serum metabolic biomarkers studied in metabolic-like syndrome and in obese pregnant mice. Maternal weight gain was not different in the pregnant metabolic-like syndrome dams, whereas it was lower in the obese myoinositol/D-chiroinositol-treated dams compared with the placebo group (myoinositol/D-chiroinositol: 10.9 ± 0.5 g vs 12.6 ± 0.6 g, P = .04). Fetal and placental weights did not differ between myoinositol/D-chiroinositol-treated and nontreated pregnant dams with metabolic-like syndrome and obesity.. Combined inositol treatment during pregnancy improves blood pressure, glucose levels at the glucose tolerance test, and leptin levels in pregnant dams with metabolic-like syndrome phenotype but not in obese pregnant dams. In addition, inositol treatment was associated with lower gestational weight gain in the obese but not in the metabolic-like syndrome pregnant dams.

Topics: Animals; Biomarkers; Blood Glucose; Dietary Supplements; Disease Models, Animal; Female; Gastric Inhibitory Polypeptide; Gestational Age; Ghrelin; Glucose Tolerance Test; Inositol; Insulin; Insulin Resistance; Leptin; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide Synthase Type III; Obesity; Pregnancy; Pregnancy Complications; Weight Gain

Although leptin receptors are found in hypothalamic nuclei classically associated with homeostatic feeding mechanisms, they are also present in brain regions known to regulate hedonic-based feeding, natural reward processing, and responses to drugs of abuse. The ob/ob mouse is deficient in leptin signaling, and previous work has found altered mesolimbic dopamine signaling and sensitivity to the locomotor activating effects of amphetamine in these mice.. We directly assessed responses to three drugs of abuse and non-drug rewards in the leptin-deficient ob/ob mouse.. Ob/ob mice were tested in assays of sweet preference, novelty seeking, and drug reward/reinforcement.. In assays of novelty seeking, novel open field activity and operant sensation seeking were reduced in ob/ob mice, although novel object interaction and novel environment preference were comparable to wild types. We also found that ob/ob mice had specific phenotypes in regard to cocaine: conditioned place preference for 2.5 mg/kg was increased, while the locomotor response to 10 mg/kg was reduced, and cocaine self-administration was the same as wild types. Ob/ob mice also acquired self-administration of the potent opioid remifentanil, but breakpoints for the drug were significantly reduced. Finally, we found significant differences in ethanol drinking in ob/ob mice that correlated negatively with body weight and positively with operant sensation seeking.. In conclusion, ob/ob mice displayed task-specific deficits in novelty seeking and dissociable differences in reward/reinforcement associated with cocaine, remifentanil, and ethanol.

Topics: Amphetamine; Animals; Behavior, Animal; Central Nervous System Depressants; Cocaine; Conditioning, Operant; Disease Models, Animal; Dopamine Uptake Inhibitors; Ethanol; Exploratory Behavior; Feeding Behavior; Illicit Drugs; Leptin; Locomotion; Male; Mice; Motor Activity; Piperidines; Remifentanil; Taste

Metabolic syndrome (MetS) is associated with nephropathy. Along with common risk factors such as hypertension and hyperglycemia, adipocytokines released from perirenal adipose tissue (PRAT) are implicated in the pathogenesis of MetS nephropathy. The study was designed to elucidate the adverse effects of PRAT-derived leptin on nephropathy and to determine whether the angiotensin II type 1 receptor antagonist telmisartan exerts a renoprotective effect by decreasing the PRAT-derived leptin level in the high-fat diet-induced MetS rat. In MetS rats, PRAT-derived leptin expression increased concomitant with dysfunction of adipogenesis, and the activities of the angiotensin II-angiotensin II type 1 receptor and the angiotensin-converting enzyme 2-angiotensin (1-7)-Mas receptor axes were imbalanced in PRAT. PRAT-derived leptin from MetS rats promoted proliferation of rat glomerular endothelial cells (GERs) by activating the p38 MAPK (mitogen-activated protein kinase) pathway, thereby contributing to the development of nephropathy. Long-term telmisartan treatment improved metabolic parameters and renal function, decreased the amount of PRAT, promoted adipogenesis, increased the expression of angiotensin-converting enzyme 2, restored balanced activities of the angiotensin II-AT1R and angiotensin-converting enzyme 2-angiotensin (1-7)-Mas axes, and exerted an indirect renoprotective effect on MetS rats by decreasing PRAT-derived leptin release. Our results demonstrate a novel link between nephropathy and PRAT in MetS and show that telmisartan confers an underlying protective effect on visceral adipose tissue and the kidney, suggesting that it has potential as a therapeutic agent for the treatment of MetS-associated nephropathy.

Topics: Adipogenesis; Angiotensin II Type 1 Receptor Blockers; Animals; Benzimidazoles; Benzoates; Disease Models, Animal; Intra-Abdominal Fat; Kidney Diseases; Leptin; Male; Metabolic Syndrome; Protective Agents; Rats; Rats, Wistar; Telmisartan

Spinal cord injury (SCI) causes long-term disability and has no clinically effective treatment. After SCI, adenosine triphosphate (ATP) may be released from neuronal cells and astrocytes in large amounts. Our previous studies have shown that the extracellular release of ATP increases the phosphorylation of cytosolic phospholipase A2 (cPLA2 ) and triggers the rapid release of arachidonic acid (AA) and prostaglandin E2 (PGE2) via the stimulation of epidermal growth factor receptor (EGFR) and the downstream phosphorylation of extracellular-regulated protein kinases 1 and 2. Leptin, a glycoprotein, induces the activation of the Janus kinase (JAK2)/signal transducers and activators of transcription-3 (Stat3) pathway via the leptin receptor. In this study, we found that 1) prolonged leptin treatment suppressed the ATP-stimulated release of AA and PGE2 from cultured spinal cord astrocytes; 2) leptin elevated the expression of caveolin-1 (Cav-1) via the JAK2/Stat3 signaling pathway; 3) Cav-1 blocked the interaction between Src and EGFR, thereby inhibiting the phosphorylation of EGFR and cPLA2 and attenuating the release of AA or PGE2; 4) pretreatment with leptin decreased ;he level of apoptosis and the release of interleukin-6 from cocultured neurons and astrocytes; and 5) leptin improved the recovery of locomotion in mice after SCI. Our results highlight leptin as a promising therapeutic agent for SCI. © 2016 Wiley Periodicals, Inc.

Topics: Adenosine Triphosphate; Animals; Astrocytes; Calcium-Binding Proteins; Caveolin 1; Cells, Cultured; Culture; Disease Models, Animal; ErbB Receptors; Leptin; Mice; Mice, Inbred C57BL; Microfilament Proteins; Motor Activity; Nerve Tissue Proteins; Neurons; Receptors, Leptin; Signal Transduction; Spinal Cord; Spinal Cord Injuries; Up-Regulation

LEPTIN (LEP) is a circulating hormone released primarily from white adipocytes and is crucial for regulating satiety and energy homeostasis in humans and animals. Using the CRISPR technology, we created a set of Lep mutant rats that carry either null mutations or a deletion of the 14(th) Ile (LEP(∆I14)) in the mature LEP protein. We examined the potential off-target sites (OTS) by whole-genome high-throughput sequencing and/or Sanger-sequencing analysis and found no OTS in mutant rats. Mature LEP(∆I14) is incessantly produced and released to blood at a much elevated level due to the feedback loop. Structure modeling of binding conformation between mutant LEP(∆I14) and LEPTIN receptor (LEPR) suggests that the conformation of LEP(∆I14) impairs its binding with LEPR, consistent with its inability to activate STAT3-binding element in the luciferase reporter assay. Phenotypic study demonstrated that Lep(∆I14) rats recapitulate phenotypes of Lep-null mutant rats including obesity, hyperinsulinemia, hepatic steatosis, nephropathy, and infertility. Compared to the existing ob/ob mouse models, this Lep(∆I14/∆I14) rat strain provides a robust tool for further dissecting the roles of LEP in the diabetes related kidney disease and reproduction problem, beyond its well established function in regulating energy homeostasis.

Topics: Adipose Tissue; Animals; Binding Sites; CRISPR-Cas Systems; Disease Models, Animal; Energy Metabolism; Female; Homeostasis; Isoleucine; Leptin; Male; Mice, Obese; Models, Molecular; Mutation; Obesity; Protein Binding; Rats; Receptors, Leptin; Signal Transduction; Whole Genome Sequencing

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

The cellular processes that cause high caloric diet (HCD)-induced infertility are poorly understood but may involve upregulation of suppressor of cytokine signaling (SOCS-3) proteins that are associated with hypothalamic leptin resistance. Deletion of SOCS-3 from brain cells is known to protect mice from diet-induced obesity, but the effects on HCD-induced infertility are unknown. We used neuron-specific SOCS3 knock-out mice to elucidate this and the effects on regional hypothalamic leptin resistance. As expected, male and female neuron-specific SOCS3 knock-out mice were protected from HCD-induced obesity. While female wild-type mice became infertile after 4 months of HCD feeding, infertility onset in knock-out females was delayed by 4 weeks. Similarly, knock-out mice had delayed leptin resistance development in the medial preoptic area and anteroventral periventricular nucleus, regions important for generation of the surge of GnRH and LH that induces ovulation. We therefore tested whether the suppressive effects of HCD on the estradiol-induced GnRH/LH surge were overcome by neuron-specific SOCS3 knock-out. Although only 20% of control HCD-mice experienced a preovulatory-like LH surge, LH surges could be induced in almost all neuron-specific SOCS3 knock-out mice on this diet. In contrast to females, HCD-fed male mice did not exhibit any fertility decline compared with low caloric diet-fed males despite their resistance to the satiety effects of leptin. These data show that deletion of SOCS3 delays the onset of leptin resistance and infertility in HCD-fed female mice, but given continued HCD feeding this state does eventually occur, presumably in response to other mechanisms inhibiting leptin signal transduction.. Obesity is commonly associated with infertility in humans and other animals. Treatments for human infertility show a decreased success rate with increasing body mass index. A hallmark of obesity is an increase in circulating leptin levels; despite this, the brain responds as if there were low levels of leptin, leading to increased appetite and suppressed fertility. Here we show that leptin resistant infertility is caused in part by the leptin signaling molecule SOCS3. Deletion of SOCS3 from brain neurons delays the onset of diet-induced infertility.

Topics: Age Factors; Animals; Body Weight; Calcium-Calmodulin-Dependent Protein Kinase Kinase; Diet, High-Fat; Disease Models, Animal; Estrous Cycle; Female; Gene Expression Regulation; Hypothalamus; Infertility; Leptin; Luteinizing Hormone; Male; Mice; Mice, Inbred DBA; Mice, Transgenic; Neurons; Obesity; Prosencephalon; Suppressor of Cytokine Signaling 3 Protein

Adipose tissue (AT) expansion is the result of two processes: hyperplasia and hypertrophy; and both, directly or indirectly, depend on the adipogenic potential of adipocyte precursor cells (APCs). Glucocorticoids (GCs) have a potent stimulatory effect on terminal adipogenesis; while their effects on early stages of adipogenesis are largely unknown. In the present work, we study, in a model of high GC levels, the adipogenic potential of APCs from retroperitoneal AT (RPAT) and its relationship with RPAT mass expansion. We employed a model of hyper-adiposity (30- and 60-day-old rats) due to high endogenous GC levels induced by neonatal treatment with l-monosodium glutamate (MSG). We found that the RPAT APCs from 30-day-old MSG rats showed an increased adipogenic capacity, depending on the APCs' competency, but not in their number. Analyses of RPAT adipocyte diameter revealed an increase in cell size, regardless of the rat age, indicating the prevalence of a hypertrophic process. Moreover, functional RPAT alterations worsened in 60-day-old rats, suggesting that the hyperplastic AT expansion found in 30-day-old animals might have a protective role. We conclude that GCs chronic excess affects APCs' adipogenic capacity, modifying their competency. This change would modulate the hyperplastic/hypertrophic balance determining healthy or unhealthy RPAT expansion and, therefore, its functionality.

Topics: Adipocytes; Adipogenesis; Adiposity; Animals; Cell Differentiation; Cell Proliferation; Cells, Cultured; Corticosterone; Disease Models, Animal; Glucocorticoids; Hyperplasia; Hypertrophy; Insulin; Intra-Abdominal Fat; Leptin; Male; Malonates; Obesity; Rats; Rats, Sprague-Dawley

It has been suggested that food components such as ω-3 polyunsaturated fatty acids (ω-3 PUFAs) and (poly)phenols counteract diet-induced metabolic alterations by common or complementary mechanisms. To examine the effects of a combination of ω-3 PUFAs and (poly)phenols on such alterations, adult Wistar-Kyoto rats were fed an obesogenic high-fat high-sucrose diet supplemented, or not, for 24 weeks with: eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) 1 : 1 (16.6 g kg(-1) feed); proanthocyanidin-rich grape seed extract (GSE, 0.8 g kg(-1) feed); or EPA/DHA 1 : 1 + GSE. Body weight, feed intake, and plasma glucose were evaluated every 6 weeks, while adipose tissue weight, insulin, glucagon, ghrelin, leptin, adiponectin, cholesterol, and triglycerides were evaluated at the end of the experiment. ω-3 PUFAs reduced plasma leptin and cholesterol levels, but did not modify diet-induced perigonadal fat or plasma insulin levels; while GSE increased plasma triglyceride levels. The combined action of ω-3 PUFAs and the proanthocyanidins reduced plasma insulin and leptin, as well as partially prevented perigonadal fat accumulation. While separate supplementation with ω-3 PUFAs or grape proanthocyanidins may not counteract all the key metabolic changes induced by a high-energy-dense diet, the combination of both supplements reverts altered insulin, leptin and triglyceride levels to normal.

Topics: Adiponectin; Adiposity; Animals; Blood Glucose; Body Weight; Cholesterol; Diet; Dietary Supplements; Disease Models, Animal; Docosahexaenoic Acids; Eicosapentaenoic Acid; Female; Ghrelin; Glucagon; Insulin; Leptin; Metabolic Syndrome; Proanthocyanidins; Rats; Rats, Inbred WKY; Triglycerides; Vitis

To evaluate the effect of leptin combined with CoCl2 on rat femur fracture healing. 48 male Sprague Dawley rats were randomly divided into two main groups. Then standardized femur fractures were created to all rats. Control group rats were treated with 0.5 mL physiological saline, and experimental group rats were treated with 5 μg/Kg.d leptin and 15 mg/Kg.d CoCl2 along with 0.5 mL physiological saline for 42 days intraperitoneally. Each main group was divided into three subgroups for each evaluation at second, fourth and sixth weeks, each subgroup included eight rats. The radiological evaluation showed that the fracture healing progress of experimental group was superior to control group from second week. At fourth week, experimental group had better fracture healing progress than control group significantly. Results of biomechanics show the ultimate load (N) and deflection ultimate load (mm) of experimental group was significantly increased than that in control group from fourth week. The present result demonstrated that leptin combined with CoCl2 significantly increased the mRNA expression levels of HIF1A, Vegfa, Runx2, Bmp2, Bglap and Alpl. It suggested that leptin combined with CoCl2 have a positive effect on rat femur fracture healing by activating the HIF1A pathway.

Topics: Animals; Cobalt; Core Binding Factor Alpha 1 Subunit; Disease Models, Animal; Drug Therapy, Combination; Femoral Fractures; Fracture Healing; Hypoxia-Inducible Factor 1, alpha Subunit; Injections, Intraperitoneal; Leptin; Male; Random Allocation; Rats; Rats, Sprague-Dawley; Treatment Outcome; Up-Regulation; Vascular Endothelial Growth Factor A

Determine whether voluntary wheel running triggers compensatory changes in nonexercise activity in lean and high-fat diet fed mice.. C57Bl/6 mice received a control (C) or a high-fat diet (H) and half of them had free access to a running wheel 5days/week (CE and HE, respectively) for 10weeks. Energy intake, nonexercise activity (global activity, distance covered and average speed of displacement in the home cage) and energy expenditure (EE) were evaluated at weeks 5 and 10 during the 2days without the wheels.. High-fat diet increased weight gain in H (110%) and HE (60%) groups compared to C and CE groups, respectively, with no effect of exercise. Wheel running increased energy intake (26% CE, 11% HE in week 5; 7% CE, 45% HE in week 10) and decreased distance covered (26% for both CE and HE in week 5; 35% CE and 13% HE in week 10) and average speed (35% CE and 13% HE in week 5; 45% CE and 18% HE in week 10) compared to the respective nonexercised groups. In week 10 there was an interaction between diet and exercise for global activity, which was reduced nearly 18% in CE, H, and HE groups compared to C. Access to a running wheel increased EE in week 5 (11% CE and 16% HE) but not in week 10, which is consistent with the period of highest running (number of turns: weeks 1-5 nearly 100%>weeks 6-10 for CE and HE groups). EE was reduced in H (19%) and HE (12%) groups compared to C and CE, in week 10.. Voluntary running causes a compensatory decrease in nonexercise activity and an increase in energy intake, both contributing to the lack of effect of exercise on body mass.

Topics: Adipose Tissue; Animals; Body Weight; Calorimetry; Diet, High-Fat; Disease Models, Animal; Energy Intake; Energy Metabolism; Leptin; Mice; Mice, Inbred C57BL; Obesity; Physical Conditioning, Animal; Time Factors

Travel into outer space is fraught with risk of exposure to energetic heavy ion radiation such as (56)Fe ions, which due to its high linear energy transfer (high-LET) characteristics deposits higher energy per unit volume of tissue traversed and thus more damaging to cells relative to low-LET radiation such as γ rays. However, estimates of human health risk from energetic heavy ion exposure are hampered due to lack of tissue specific in vivo molecular data. We investigated long-term effects of (56)Fe radiation on adipokines and insulin-like growth factor 1 (IGF1) signaling axis in mouse intestine and colon. Six- to eight-week-old C57BL/6J mice were exposed to 1.6 Gy of (56)Fe ions. Serum and tissues were collected up to twelve months post-irradiation. Serum was analyzed for leptin, adiponectin, IGF1, and IGF binding protein 3. Receptor expressions and downstream signaling pathway alterations were studied in tissues. Irradiation increased leptin and IGF1 levels in serum, and IGF1R and leptin receptor expression in tissues. When considered along with upregulated Jak2/Stat3 pathways and cell proliferation, our data supports the notion that space radiation exposure is a risk to endocrine alterations with implications for chronic pathophysiologic changes in gastrointestinal tract.

Topics: Adiponectin; Animals; Cell Proliferation; Colon; Disease Models, Animal; Heavy Ions; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Intestinal Mucosa; Intestines; Iron Isotopes; Leptin; Mice; Mice, Inbred C57BL; Radiation Exposure; Receptor, IGF Type 1; Receptors, Leptin; Receptors, Somatomedin; Signal Transduction

We previously reported that offspring heterozygous mice partially lacking endothelial nitric oxide synthase (eNOS) gene, and born to hypertensive eNOS-/- Knockout mother, are hypertensive. We hypothesized that those offspring when placed on high-fat diet (HFD) will undergo altered metabolic programming increasing their risk for developing metabolic syndrome.. eNOS-/-KO and wild-type mice (eNOS+/+WT) were cross-bred to produce heterozygous offspring: maternal heterozygous (Mat, eNOS-/+), born from hypertensive eNOS-/-KO mothers; and paternal heterozygous (Pat, eNOS-/+), born from normotensive WT mothers. Mat, eNOS-/+ and Pat, eNOS-/+ female were allocated to HFD or control diet (CD) until 8 weeks of age. Then a metabolic profile was obtained: weight, glucose/insulin tolerance test (GTT, ITT), systolic blood pressure (SBP), serum fasting levels of insulin, adiponectin, leptin, and a lipid panel.. Weight was not different between all offspring within each diet. GTT curve was higher in Mat, eNOS-/+ vs. Pat, eNOS-/+ offspring on both diet (P < 0.001). In ITT, glucose level at 15 minutes was higher in Mat, eNOS-/+ on HFD. Insulin level was increased in Mat, eNOS-/+ vs. Pat, eNOS-/+ on either diet. SBP was elevated in Mat, eNOS-/+ vs. Pat, eNOS-/+ on CD and was further raised in Mat, eNOS-/+ offspring on HFD (P < 0.001). No other differences were seen except for lower high-density lipoprotein levels in Mat, eNOS-/+ fed HFD (P < 0.003).. Mat, eNOS-/+ offspring exposed in utero to maternal hypertension and fed HFD postnatally have increased susceptibility for metabolic abnormalities. Thus, maternal HTN is a risk factor for altered fetal metabolic programming.

Topics: Adiponectin; Animals; Biomarkers; Blood Glucose; Blood Pressure; Diet, High-Fat; Disease Models, Animal; Female; Genetic Predisposition to Disease; Heterozygote; Hypertension; Insulin; Leptin; Lipids; Metabolic Syndrome; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide Synthase Type III; Phenotype; Pregnancy; Prenatal Exposure Delayed Effects; Risk Factors; Time Factors; Weight Gain

Time-restricted feeding ameliorates the deleterious effects of a high-fat diet on body weight and metabolism in young adult mice. Because obesity is highly prevalent in the middle-aged population, this study tested the hypothesis that time-restricted feeding alleviates the adverse effects of a high-fat diet in male middle-aged (12months) mice. C57BL6/J mice were fed one of three diets for 21-25weeks: 1) high-fat diet (60% total calories from fat) ad-libitum (HFD-AL), 2) HFD, time-restricted feeding (HFD-TRF), and 3) low-fat diet (10% total calories from fat) ad-libitum (LFD-AL) (n=15 each). HFD-TRF mice only had food access for 8h/day during their active period. HFD-TRF mice gained significantly less weight than HFD-AL mice (~20% vs 55% of initial weight, respectively). Caloric intake differed between these groups only during the first 8weeks and accounted for most but not all of their body weight difference during this time. TRF of a HFD lowered glucose tolerance in terms of incremental area under the curve (iAUC) (p<0.02) to that of LFD-AL mice. TRF of a HFD lowered liver weight (p<0.0001), but not retroperitoneal or epididymal fat pad weight, to that of LFD-AL mice. Neither HFD-AL nor HFD-TRF had any effect on performance in the novel object recognition or object location memory tests. Circulating corticosterone levels either before or after restraint stress were not affected by diet. In conclusion, TRF without caloric restriction is an effective strategy in middle-aged mice for alleviating the negative effects of a HFD on body weight, liver weight, and glucose tolerance.

Topics: Activities of Daily Living; Analysis of Variance; Animals; Blood Glucose; Body Weight; Corticosterone; Diet, High-Fat; Disease Models, Animal; Eating; Energy Intake; Exploratory Behavior; Feeding Behavior; Food Deprivation; Glucose Tolerance Test; Insulin; Leptin; Liver; Male; Metabolic Diseases; Mice; Mice, Inbred C57BL; Recognition, Psychology; Stress, Physiological

Leptin is an adipocytokine that plays a key role in the modulation of immune responses and the development and maintenance of inflammation. Circulating levels of leptin are elevated in systemic lupus erythematosus (SLE) patients, but it is not clear whether this association can reflect a direct influence of leptin on the propathogenic events that lead to SLE. To investigate this possibility, we compared the extent of susceptibility to SLE and lupus manifestations between leptin-deficient (ob/ob) and H2-matched leptin-sufficient (wild-type, WT) mice that had been treated with the lupus-inducing agent pristane. Leptin deficiency protected ob/ob mice from the development of autoantibodies and renal disease and increased the frequency of immunoregulatory T cells (Tregs) compared with leptin-sufficient WT mice. The role of leptin in the development of SLE was confirmed in the New Zealand Black (NZB) × New Zealand White (NZW)F1 (NZB/W) mouse model of spontaneous SLE, where elevated leptin levels correlated with disease manifestations and the administration of leptin accelerated development of autoantibodies and renal disease. Conversely, leptin antagonism delayed disease progression and increased survival of severely nephritic NZB/W mice. At the cellular level, leptin promoted effector T-cell responses and facilitated the presentation of self-antigens to T cells, whereas it inhibited the activity of regulatory CD4 T cells. The understanding of the role of leptin in modulating autoimmune responses in SLE can open possibilities of leptin-targeted therapeutic intervention in the disease.

Topics: Animals; Autoantibodies; Autoimmunity; Disease Models, Animal; Humans; Immunity, Innate; Inflammation; Leptin; Lupus Erythematosus, Systemic; Mice; Mice, Inbred NZB; T-Lymphocytes, Regulatory; Terpenes

Previous studies have shown that rats fed a high calorie diet rich in saturated fat for 12weeks exhibit peripheral insulin resistance and impairments of behavioural flexibility when switched from an operant delayed matching to place (DMTP) schedule to a delayed non-matching to place (DNMTP) schedule. However, the metabolic changes evoked by feeding a high fat (HF) diet can be observed within two weeks of commencing the diet. The current study has confirmed that 4weeks exposure to an HF diet resulted in increased body weight, peripheral insulin resistance and plasma leptin. Studies performed during weeks 3 and 4 on the HF diet revealed suppressed lever pressing rates and impaired behavioural flexibility in the operant DMTP/DNMTP task. When animals fed the HF diet were then returned to a standard chow (SC) diet for 5weeks their weight and blood biochemistry no longer differed from those measured in animals that had never been exposed to the HF diet. The animals restored to the SC diet exhibited a clear ability to acquire the DNMTP schedule of reinforcement although these animals continued to lever press at a lower rate when compared with animals that received the SC diet throughout. The data suggest that exposure to an HF diet diminishes the motivation to respond for a reward and, thus, the capacity to adapt behavioural performance. This deficit was ameliorated, but not totally reversed, by the dietary intervention. If also true for humans, the results suggest that deficits in behavioural flexibility develop after only a short period on a high calorie diet but may be largely reversible through simple dietary intervention, at least in the early stages of deficit development. However, the putative effects of short-term exposure to an HF diet on behavioural motivation may persist for some time after switching to a healthier low fat diet and remain a problem for those seeking to adopt a healthier diet.

Topics: Analysis of Variance; Animals; Blood Glucose; Body Weight; Conditioning, Operant; Diet, High-Fat; Disease Models, Animal; Fasting; Insulin; Leptin; Male; Mental Disorders; Metabolic Diseases; Rats; Rats, Wistar; Reinforcement, Psychology; Time Factors

What is the central question of this study? This study addresses the relative impact of obesity and intermittent hypoxia in the pathophysiological process of obstructive sleep apnoea by investigating the metabolic, inflammatory and cardiovascular consequences of intermittent hypoxia in lean and obese Zucker rats. What is the main finding and its importance? We found that obesity and intermittent hypoxia have mainly distinct consequences on the investigated inflammatory and cardiometabolic parameters in Zucker rats. This suggests that, for a given severity of sleep apnea, the association of obesity and obstructive sleep apnoea may not necessarily be deleterious. Obstructive sleep apnoea is associated with obesity with a high prevalence, and both co-morbidities are independent cardiovascular risk factors. Intermittent hypoxia (IH) is thought to be the main factor responsible for the obstructive sleep apnoea-related cardiometabolic alterations. The aim of this study was to assess the respective impact of obesity and IH on the inflammatory and cardiometabolic state in rats. Lean and obese Zucker rats were exposed to normoxia or chronic IH, and we assessed metabolic and inflammatory parameters, such as plasma lipids and glucose, serum leptin and adiponectin, liver cytokines, nuclear factor-κB activity and cardiac endothelin-1 levels. Myocardial infarct size was also evaluated following in vitro ischaemia-reperfusion. Circulating lipids, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), leptin and adiponectin levels were higher in obese versus lean rats. Chronic IH did not have a significant impact on metabolic parameters in lean rats. In obese rats, IH increased glycaemia and HOMA-IR. Liver interleukin-6 and tumour necrosis factor-α levels were elevated in lean rats exposed to IH; obesity prevented the increase in interleukin-6 but not in tumour necrosis factor-α. Finally, IH exposure enhanced myocardial sensitivity to infarction in both lean and obese rats and increased cardiac endothelin-1 in lean but not obese rats. In conclusion, this study shows that the dyslipidaemia and insulin resistance induced by obesity of genetic origin does not enhance the deleterious cardiovascular response to IH and may even partly protect against IH-induced inflammation.

Topics: Adiponectin; Animals; Blood Glucose; Cardiovascular Diseases; Cytokines; Disease Models, Animal; Endothelin-1; Hypoxia; Inflammation; Insulin; Interleukin-6; Leptin; Lipids; Liver; Male; Myocardium; NF-kappa B; Obesity; Rats; Rats, Zucker; Tumor Necrosis Factor-alpha

This study was designed to investigate the antiobesity effects of Salvia plebeia R. Br. ethanolic extracts (SPE) in mice fed high-fat diets (HFD). Male C57BL/6J mice were randomly assigned to four groups: normal diet (Chow), high-fat diet (HFD, 45% fat), HFD+SPE 200 (200 mg/kg b.w.), and HFD+SPE 400 (400 mg/kg b.w.). Extracts were administered orally every day for 8 weeks. Increases in body/fat weight and feed efficiency ratio were monitored in all mice. In addition, obesity resulting from feeding HFD to the mice was confirmed by the increase of glucose level, aspartate transaminase, alanine transaminase, triglyceride (TG), high-density lipoprotein cholesterol, very low-density lipoprotein-c, leptin, and adiponectin in blood. The SPE-treated mice gained less body and mesenteric/subcutaneous adipose tissues weights and had lower TG, very low-density lipoprotein cholesterol, leptin, and glucose level in serum, compared to the HFD group. Moreover, histopathological examinations revealed that the size of adipocytes in liver and adipose tissue was significantly decreased by SPE, compared to the HFD group. The expression of adipogenesis transcription factors (e.g., peroxisome proliferator activated receptor γ and CCAAT/enhancer binding protein α) and lipogenesis-related target genes (adipocyte fatty acid-binding protein 2, lipoprotein lipase, fatty acid synthase, and sterol regulatory element-binding transcription factor 1c) in HFD-induced obese mice was decreased by SPE treatment. These results suggest that SPE attenuates the fat accumulation in HFD-induced obese mice by suppressing the expressions of genes related to adipogenesis and lipogenesis activity. Therefore, SPE could be developed as a potential therapy for reduction of body weight and antiobesity intervention.

Topics: Adiponectin; Adipose Tissue; Animals; Anti-Obesity Agents; Body Weight; Cell Differentiation; Diet, High-Fat; Disease Models, Animal; Leptin; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Organ Size; Plant Extracts; Random Allocation; Salvia

Leptin plays a key role in the pathogenesis of obesity and depression via the long form of leptin receptor (LepRb). An animal model of comorbid obesity and depression induced by high-fat diet (HFD) combined with chronic unpredictable mild stress (CUMS) was developed to study the relationship between depression/anxiety-like behavior, levels of plasma leptin and LepRb in the brains between four groups of rats, the combined obesity and CUMS (Co) group, the obese (Ob) group, the CUMS group and controls. Our results revealed that the Co group exhibited most severe depression-like behavior in the open field test (OFT), anxiety-like behavior in elevated plus maze test (EMT) and cognitive impairment in the Morris water maze (MWM). The Ob group had the highest weight and plasma leptin levels while the Co group had the lowest levels of protein of LepRb in the hypothalamus and hippocampus. Furthermore, depressive and anxiety-like behaviors as well as cognitive impairment were positively correlated with levels of LepRb protein and mRNA in the hippocampus and hypothalamus. The down-regulation of leptin/LepRb signaling might be associated with depressive-like behavior and cognitive impairment in obese rats facing chronic mild stress.

Topics: Animals; Anxiety; Behavior, Animal; Depression; Depressive Disorder, Major; Diet, High-Fat; Disease Models, Animal; Down-Regulation; Hippocampus; Hypothalamus; Leptin; Male; Obesity; Rats; Rats, Wistar; Receptors, Leptin; RNA, Messenger; Stress, Psychological

Obesity causes multiorgan dysfunction, specifically metabolic abnormalities in the liver. Obese patients are opioid-sensitive and have high rates of respiratory complications after surgery. Obesity also has been shown to cause resistance to leptin, an adipose-derived hormone that is key in regulating hunger, metabolism, and respiratory stimulation. We hypothesized that obesity and leptin deficiency impair opioid pharmacokinetics (PK) independently of one another.. Morphine PK were characterized in C57BL/6J wild-type (WT), diet-induced obese (DIO), and leptin-deficient (ob/ob) mice, and in ob/ob mice given leptin-replacement (LR) therapy. WT mice received several dosing regimens of morphine. Obese mice (30 g) received one 80 mg/kg bolus of morphine. Blood was collected at fixed times after morphine injection for quantification of plasma morphine and morphine 3-glucuronide (M3G) levels. PK parameters used to evaluate morphine metabolism included area-under the curve (AUC150), maximal morphine concentration (CMAX), and M3G-to-morphine ratio, and drug elimination was determined by clearance (Cl/F), volume of distribution, and half-life (T1/2). PK parameters were compared between mouse groups by the use of 1-way analysis of variance, with P values less than .05 considered significant.. DIO compared with WT mice had significantly decreased morphine metabolism with lower M3G-to-morphine ratio (mean difference [MD]: -4.9; 95% confidence interval [CI]: -8.8 to -0.9) as well as a decreased Cl/F (MD: -4.0; 95% CI: -8.9 to -0.03) Ob/ob compared with WT mice had a large increase in morphine exposure with a greater AUC150 (MD: 980.4; 95% CI: 630.1-1330.6), CMAX (MD: 6.8; 95% CI: 2.7-10.9), and longer T1/2 (MD: 23.1; 95% CI: 10.5-35.6), as well as a decreased Cl/F (MD: -7.0; 95% CI: -11.6 to -2.7). Several PK parameters were significantly greater in ob/ob compared with DIO mice, including AUC150 (MD: 636.4; 95% CI: 207.4-1065.4), CMAX (MD: 5.3; 95% CI: 3.2-10.3), and T1/2 (MD: 18.3; 95% CI: 2.8-33.7). When leptin was replaced in ob/ob mice, PK parameters began to approach DIO and WT levels. LR compared with ob/ob mice had significant decreases in AUC150 (MD: -779.9; 95% CI: -1229.8 to -330), CMAX (MD: -6.1; 95% CI: -11.4 to -0.9), and T1/2 (MD: -19; 95% CI: -35.1 to -2.8). Metabolism increased with LR, with LR mice having a greater M3G-to-morphine ratio compared with DIO (MD: 5.3; 95% CI: 0.3-10.4).. Systemic effects associated with obesity decrease morphine metabolism and excretion. A previous study from our laboratory demonstrated that obesity and leptin deficiency decrease the sensitivity of central respiratory control centers to carbon dioxide. Obesity and leptin deficiency substantially decreased morphine metabolism and clearance, and replacing leptin attenuated the PK changes associated with leptin deficiency, suggesting leptin has a direct role in morphine metabolism.

Topics: Analgesics, Opioid; Analysis of Variance; Animals; Area Under Curve; Diet, High-Fat; Disease Models, Animal; Genetic Predisposition to Disease; Half-Life; Leptin; Male; Metabolic Clearance Rate; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Models, Biological; Morphine; Morphine Derivatives; Obesity; Phenotype

Melanocortin-4 receptor (Mc4r)-expressing neurons in the autonomic nervous system, particularly in the paraventricular nucleus of the hypothalamus (PVH), play an essential role in blood pressure (BP) control. Mc4r-deficient (Mc4rKO) mice are severely obese but lack obesity-related hypertension; they also show a reduced pressor response to salt loading. We have previously reported that lean juvenile offspring born to diet-induced obese rats (OffOb) exhibit sympathetic-mediated hypertension, and we proposed a role for postnatally raised leptin in its etiology. Here, we test the hypothesis that neonatal hyperleptinemia due to maternal obesity induces persistent changes in the central melanocortin system, thereby contributing to offspring hypertension. Working on the OffOb paradigm in both sexes and using transgenic technology to restore Mc4r in the PVH of Mc4rKO (Mc4rPVH) mice, we have now shown that these mice develop higher BP than Mc4rKO or WT mice. We have also found that experimental hyperleptinemia induced in the neonatal period in Mc4rPVH and WT mice, but not in the Mc4rKO mice, leads to heightened BP and severe renal dysfunction. Thus, Mc4r in the PVH appears to be required for early-life programming of hypertension arising from either maternal obesity or neonatal hyperleptinemia. Early-life exposure of the PVH to maternal obesity through postnatal elevation of leptin may have long-term consequences for cardiovascular health.

Topics: Animals; Blood Pressure; Diet; Disease Models, Animal; Female; Humans; Hypertension; Leptin; Male; Maternal-Fetal Relations; Mice, Knockout; Neurons; Obesity; Paraventricular Hypothalamic Nucleus; Pregnancy; Prenatal Exposure Delayed Effects; Receptor, Melanocortin, Type 4; Sympathetic Nervous System

Strong epidemiologic evidence links colon cancer to obesity. The increasing worldwide incidence of colon cancer has been linked to the spread of the Western lifestyle, and in particular consumption of a high-fat Western diet. In this study, our objectives were to establish mouse models to examine the effects of high-fat Western diet-induced obesity on the growth of human colon cancer tumor xenografts, and to examine potential mechanisms driving obesity-linked human colon cancer tumor growth. We hypothesize that mice rendered insulin resistant due to consumption of a high-fat Western diet will show increased and accelerated tumor growth. Homozygous Rag1

Topics: Adipose Tissue, White; Animals; Chemokine CCL2; Colonic Neoplasms; Diet, High-Fat; Diet, Western; Dietary Fats; Disease Models, Animal; Epididymis; Heterografts; Humans; Inflammation; Insulin; Insulin Resistance; Intra-Abdominal Fat; JNK Mitogen-Activated Protein Kinases; Leptin; Male; Mice, Inbred Strains; Obesity; Phosphorylation; Receptor Protein-Tyrosine Kinases; Signal Transduction

Postmenopausal diabetes is exacerbated by estrogen deficiency. Ovariectomized (OVX) animal models can be used to develop strategies for preventing or treating postmenopausal symptoms. We previously found that a diet containing kudzu (Pueraria lobata) vine ethanol extract (PVEE) suppressed weight gain in OVX mice. Therefore, this study further elucidated how PVEE affected OVX mice. Ten-week-old OVX or sham-operated mice were fed diets containing either no PVEE (control) or 20 mg•kg

Topics: Adiponectin; Adipose Tissue; Animals; Blood Glucose; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Disease Models, Animal; Female; Hypoglycemic Agents; Insulin; Isoflavones; Leptin; Mice; Organ Size; Ovariectomy; Phytotherapy; Plant Extracts; Postmenopause; Pueraria; Triglycerides; Uterus; Weight Gain

Topics: Animals; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Fatty Acids; Fatty Liver; Gene Expression; Glycated Hemoglobin; Humans; Leptin; Liver; Mice; Mice, Obese; Mutation; NF-kappaB-Inducing Kinase; Non-alcoholic Fatty Liver Disease; Obesity; Peptide Hormones; Protein Serine-Threonine Kinases; Signal Transduction; Sterol Regulatory Element Binding Protein 1; Transcription Factors

The mechanisms linking obesity and osteoarthritis (OA) are not fully understood and have been generally attributed to increased weight, rather than metabolic or inflammatory factors. Here, we examined the influence of fatty acids, adipokines, and body weight on OA following joint injury in an obese mouse model.. Mice were fed high-fat diets rich in various fatty acids (FA) including saturated FAs (SFAs), ω-6 polyunsaturated FAs (PUFAs), and ω-3 PUFAs. OA was induced by destabilising the medial meniscus. Wound healing was evaluated using an ear punch. OA, synovitis and wound healing were determined histologically, while bone changes were measured using microCT. Activity levels and serum cytokines were measured at various time-points. Multivariate models were performed to elucidate the associations of dietary, metabolic and mechanical factors with OA and wound healing.. Using weight-matched mice and multivariate models, we found that OA was significantly associated with dietary fatty acid content and serum adipokine levels, but not with body weight. Furthermore, spontaneous activity of the mice was independent of OA development. Small amounts of ω-3 PUFAs (8% by kcal) in a high-fat diet were sufficient to mitigate injury-induced OA, decreasing leptin and resistin levels. ω-3 PUFAs significantly enhanced wound repair, SFAs or ω-6 PUFAs independently increased OA severity, heterotopic ossification and scar tissue formation.. Our results indicate that with obesity, dietary FA content regulates wound healing and OA severity following joint injury, independent of body weight, supporting the need for further studies of dietary FA supplements as a potential therapeutic approach for OA.

Topics: Animals; Body Weight; Bone and Bones; Diet, High-Fat; Dietary Fats; Disease Models, Animal; Ear Auricle; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Femur; Leg Injuries; Leptin; Mice; Obesity; Osteoarthritis; Osteoarthritis, Knee; Resistin; Stifle; Synovitis; Tibia; Tibial Meniscus Injuries; Wound Healing; X-Ray Microtomography

Obesity is a risk factor for episodic migraine to develop into chronic migraine; hence, it is speculated that obesity and hyperleptinemia are associated with migraine. We hypothesized that leptin is involved in the mechanisms of cortical spreading depression (CSD). Therefore, we examined whether leptin affected a rat model of CSD to clarify the relationship between leptin and migraine.. We evaluated the effect of intracerebroventricular (ICV) administration of leptin on a rat CSD model. We then examined whether once-a-day intraperitoneal administration of leptin for seven days (as a chronic hyperleptinemia model) affected rat CSD models. Finally, we induced CSD in Zucker fatty (ZF) rats, which is a well-known model of obesity.. In the parietal cortex, the percent change in cerebral blood flow and direct current (DC) potential decreased after ICV administration of leptin. A similar decrease in DC potential was observed in rats treated with intraperitoneal leptin. The number of CSDs increased significantly in rats given intraperitoneal leptin and in ZF rats.. The present study suggests that leptin is involved in the mechanisms of CSD.

Topics: Animals; Cerebral Cortex; Cerebrovascular Circulation; Cortical Spreading Depression; Disease Models, Animal; Injections, Intraperitoneal; Injections, Intraventricular; Leptin; Migraine Disorders; Obesity; Rats; Rats, Sprague-Dawley; Rats, Zucker

Compelling evidence supports the important role of the glutamatergic system in the pathophysiology of major depression and also as a target for rapid-acting antidepressants. However, the functional role of glutamate release/transmission in behavioral processes related to depression and antidepressant efficacy remains to be elucidated. In this study, glutamate release and behavioral responses to tail suspension, a procedure commonly used for inducing behavioral despair, were simultaneously monitored in real time. The onset of tail suspension stress evoked a rapid increase in glutamate release in hippocampal field CA3, which declined gradually after its offset. Blockade of N-methyl-D-aspartic acid (NMDA) receptors by intra-CA3 infusion of MK-801, a non-competitive NMDA receptor antagonist, reversed behavioral despair. A subpopulation of granule neurons that innervated the CA3 region expressed leptin receptors and these cells were not activated by stress. Leptin treatment dampened tail suspension-evoked glutamate release in CA3. On the other hand, intra-CA3 infusion of NMDA blocked the antidepressant-like effect of leptin in reversing behavioral despair in both the tail suspension and forced swim tests, which involved activation of Akt signaling in DG. Taken together, these results suggest that the DG-CA3 glutamatergic pathway is critical for mediating behavioral despair and antidepressant-like responses to leptin.

Topics: Animals; Antidepressive Agents; CA3 Region, Hippocampal; Dentate Gyrus; Depression; Disease Models, Animal; Enzyme Inhibitors; Excitatory Amino Acid Agents; Gene Expression Regulation; Glutamic Acid; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Motor Activity; N-Methylaspartate; Receptors, Leptin; RNA, Untranslated; Synapses; Synaptic Transmission; Wakefulness

In addition to the amount of ingested calories, both timing of food intake and meal composition are determinants of body weight gain. However, at present, it is unknown if the inappropriate timing of diet components is responsible for body weight gain. In the present study, we therefore studied a time-dependent effect of the diet composition on energy homeostasis. Male Wistar rats were subjected to chow ad libitum (chow group) or a choice diet with saturated fat, a 30% sugar solution, chow and tap water. The choice diet was provided either with all components ad libitum (AL), with ad libitum access to chow, tap water and a 30% sugar solution, but with access to saturated fat only during the light period (LF), or with ad libitum access to chow, tap water and saturated fat, but access to a 30% sugar solution only during the light period (LS). Caloric intake and body weight gain were monitored during 31 days. Energy expenditure was measured in the third week in calorimetric cages. All rats on a choice diet showed hyperphagia and gained more body weight compared to the chow group. Within the choice diet groups, rats on the LS diet were most food efficient (i.e. gained most body weight per ingested calorie) and showed a lower respiratory exchange ratio (RER) with an anti-phasic pattern, whereas no differences in locomotor activity or heat production were found. Collectively these data indicate that the timing of the diet composition affects food efficiency, most likely due to a shifted oxidation pattern, which can predispose for obesity. Further studies are underway to assess putative mechanisms involved in this dysregulation.

Topics: Animals; Body Composition; Body Weight; Calorimetry; Circadian Rhythm; Diabetes Mellitus, Type 2; Diet; Dietary Fats; Dietary Sucrose; Disease Models, Animal; Eating; Energy Intake; Feeding Behavior; Homeostasis; Leptin; Light; Male; Obesity; Oxygen; Rats; Rats, Wistar; Time Factors; Weight Gain

The pathophysiology of non-alcoholic fatty liver disease remains to be elucidated, and the currently available treatments are not entirely effective. Polydatin, a stilbenoid compound derived from the rhizome of Polygonum cuspidatum, has previously been demonstrated to possess hepatoprotective effects. The present study aimed to determine the effects of polydatin supplementation on hepatic fat accumulation and injury in rats fed a high-fat diet. In addition, the mechanisms underlying the protective effects of polydatin were examined. Male Sprague Dawley rats were randomly divided into four groups and received one of four treatment regimes for 12 weeks: Control diet, control diet supplemented with polydatin, high-fat diet, or high-fat diet supplemented with polydatin. Polydatin was supplemented in the drinking water at a concentration of 0.3% (wt/vol). The results of the present study showed that long-term high-fat feeding resulted in fatty liver in rats, which was manifested by excessive hepatic neutral fat accumulation and elevated plasma alanine aminotransferase and aspartate aminotransferase levels. Polydatin supplementation alleviated the hepatic pathological changes, and attenuated the insulin resistance, as shown by an improved homeostasis model assessment of basal insulin resistance values and a glucose tolerance test. Polydatin supplementation also corrected abnormal leptin and adiponectin levels. Specifically, polydatin supplementation enhanced insulin sensitivity in the liver, as shown by improved insulin receptor substrate 2 expression levels and Akt phosphorylation in the rat liver, following high-fat diet feeding. The results of the present study suggest that polydatin protects rats against high-fat feeding-induced insulin resistance and hepatic steatosis. Polydatin may be an effective hepatoprotective agent and a potential candidate for the prevention of fatty liver disease and insulin resistance.

Topics: Adiponectin; Animals; Body Weight; Diet; Dietary Supplements; Disease Models, Animal; Fatty Liver; Gene Expression; Glucose Tolerance Test; Glucosides; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Leptin; Liver; Male; Rats; Stilbenes

Weight regain contributes to the therapeutic failure in 15-20% of type 2 diabetic patients after Roux-en-Y gastric bypass surgery (RYGB), and the mechanism remains largely unknown. This study was conducted to explore the mechanism of weight regain.. Wild-type (WT) diet-induced obese (DIO) mice were used to mimic human obesity, and ob/ob mice were used for leptin deficiency-induced obesity. Two groups of mice were compared in weight regain for 10 months after RYGB. Weight loss, food intake, fecal energy loss and energy expenditure were monitored in the study of weight regain. Fasting insulin, insulin tolerance and homeostatic model assessment-insulin resistance were tested for insulin sensitivity under the weight regain. Weight loss from RYGB and calorie restriction was compared for the impact in insulin sensitivity.. In WT mice, RYGB induced a sustained weight loss and insulin sensitization over the sham operation in this 10-month study. However, RYGB failed to generate the same effects in leptin-deficient ob/ob mice, which suffered a weight regain over the pre-surgery level. In ob/ob mice, body weight was reduced by RYGB transiently in the first week, recovered in the second week and increased over the baseline thereafter. Weight loss was induced by RYGB relative to that of sham mice, but the loss was not sufficient to keep body weight below the pre-surgery levels. In addition, insulin sensitivity was not improved by the weight loss. The response to RYGB was improved in ob/ob mice by 2 weeks of leptin treatment. Weight loss from calorie restriction had an equivalent effect on insulin sensitization compared with that of RYGB.. Those data demonstrate that ob/ob mice and DIO mice responded differently to RYGB surgery, suggesting that leptin may be one of the factors required for RYGB to prevent weight regain and diabetes recurrence.

Topics: Animals; Diet, High-Fat; Disease Models, Animal; Gastric Bypass; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Reproducibility of Results; Weight Gain; Weight Loss

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

The aim of this study was to evaluate the effects of maternal obesity on pancreas structure and carbohydrate metabolism in early adult life, focusing on the F1 and F2 generations after F0 maternal pregestational, gestation, and lactation high-fat diet (HF).. C57 BL/6 female mice (F0) were fed standard chow (SC) or an HF diet for 8 wk before mating and during the gestation and lactation periods to provide the F1 generation (F1-SC and F1-HF). At 3 mo old, F1 females were mated to produce the F2 generation (F2-SC and F2-HF). The male offspring from all groups were evaluated at 3 mo old.. F0-HF and F1-HF dams were overweight before gestation and had a higher body mass gain and energy intake during gestation, although only F0-HF dams presented pregestational hyperglycemia. The F1-HF offspring had higher body mass, energy intake, fasting glucose levels, and were glucose intolerant compared with F1-SC offspring. These parameters were not significantly altered in F2-HF offspring. Both F1-HF and F2-HF offspring showed hyperinsulinemia, hyperleptinemia, decreased adiponectin levels, increased pancreatic mass, and islet volume density with elevated α- and β-cell mass, hypertrophied islet characterized by an altered distribution of α- and β-cells and weak pancreatic-duodenal homeobox (Pdx)1 immunoreactivity.. Maternal HF diet consumed during the preconception period and throughout the gestation and lactation periods in mice promotes metabolism and pancreatic programming in F1 and F2 male offspring, implying intergenerational effects.

Topics: Adiponectin; Animals; Blood Glucose; Body Mass Index; Diet, High-Fat; Disease Models, Animal; Energy Intake; Female; Hyperglycemia; Hyperinsulinism; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Lactation; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Pregnancy; Prenatal Exposure Delayed Effects

Stress is a widely recognized risk factor for psychiatric and metabolic disorders. A number of animal models utilizing various stressors have been developed to facilitate our understanding in the pathophysiology of stress-related dysfunctions. The most commonly used chronic stress paradigms include the unpredictable chronic mild stress paradigm, the social defeat paradigm and the social deprivation paradigm. Here we assess the potential of social crowding as an alternative chronic stress model to study the effects on affective behaviors and metabolic disturbances. Ten-week-old male C57BL/6 mice were housed in groups of four (control) or eight (social crowding; SC) in standard cage for 9 weeks. Exploration, anxiety- and depressive-like behaviors were assessed in the open field test, the elevated T-maze, the novelty-suppressed feeding test and the forced swim test. SC mice exhibited a modest anxiety-like phenotype without change in depressive-like behaviors. Nine weeks of social crowding did not affect the body weight, but robustly increased adiposity as determined by increased mass of fat depots. Consistent with the increased fat content, serum leptin was markedly elevated in the SC mice. Specific changes in gene expression were also observed in the hypothalamus and the white adipose tissue following SC housing. Our study demonstrates the potential of social crowding as an alternative model for the study of stress-related metabolic and behavioral dysfunctions.

Topics: Adiponectin; Adiposity; Animals; Anxiety; Behavior, Animal; Body Weight; Corticosterone; Crowding; Depression; Disease Models, Animal; Eating; Environment; Exploratory Behavior; Housing, Animal; Insulin-Like Growth Factor I; Leptin; Male; Mice; Motor Activity; Stress, Psychological

Hypothalamic fatty acid (FA) sensing neurons alter their activity utilizing the FA translocator/receptor, FAT/CD36. Depletion of ventromedial hypothalamus (VMH) CD36 with adeno-associated viral vector expressing CD36 shRNA (AAV CD36 shRNA) leads to redistribution of adipose stores and insulin resistance in outbred rats. This study assessed the requirement of VMH CD36-mediated FA sensing for the regulation of energy and glucose homeostasis in postnatal day 5 (P5) and P21 selectively bred diet-induced obese (DIO) and diet-resistant (DR) rats using VMH AAV CD36 shRNA injections. P5 CD36 depletion altered VMH neuronal FA sensing predominantly in DIO rats. After 10 wk on a 45% fat diet, DIO rats injected with VMH AAV CD36 shRNA at P21 ate more and gained more weight than DIO AAV controls, while DR AAV CD36 shRNA-injected rats gained less weight than DR AAV controls. VMH CD36 depletion increased inguinal fat pad weights and leptin levels in DIO and DR rats. Although DR AAV CD36 shRNA-injected rats became as obese as DIO AAV controls, only DIO control and CD36 depleted rats became insulin-resistant on a 45% fat diet. VMH CD36 depletion stunted linear growth in DIO and DR rats. DIO rats injected with AAV CD36 shRNA at P5 had increased fat mass, mostly due to a 45% increase in subcutaneous fat. They were also insulin-resistant with an associated 71% increase of liver triglycerides. These results demonstrate that VMH CD36-mediated FA sensing is a critical factor in the regulation of energy and glucose homeostasis and fat deposition in DIO and DR rats.

Topics: Adipose Tissue; Animal Feed; Animals; Blood Glucose; Body Weight; CD36 Antigens; Disease Models, Animal; Energy Intake; Fatty Acids; Homeostasis; Insulin; Leptin; Male; Obesity; Rats

Hepatic fibrosis in nonalcoholic steatohepatitis (NASH) is the common pathophysiological process resulting from chronic liver inflammation and oxidative stress. Although significant research has been carried out on the role of leptin-induced NADPH oxidase in fibrogenesis, the molecular mechanisms that connect the leptin-NADPH oxidase axis in upregulation of transforming growth factor (TGF)-β signaling have been unclear. We aimed to investigate the role of leptin-mediated upregulation of NADPH oxidase and its subsequent induction of micro-RNA 21 (miR21) in fibrogenesis. Human NASH livers and a high-fat (60% kcal) diet-fed chronic mouse model, where hepatotoxin bromodichloromethane was used to induce NASH, were used for this study. To prove the role of the leptin-NADPH oxidase-miR21 axis, mice deficient in genes for leptin, p47phox, and miR21 were used. Results showed that wild-type mice and human livers with NASH had increased oxidative stress, increased p47phox expression, augmented NF-κB activation, and increased miR21 levels. These mice and human livers showed increased TGF-β, SMAD2/3-SMAD4 colocalizations in the nucleus, increased immunoreactivity against Col1α, and α-SMA with a concomitant decrease in protein levels of SMAD7. Mice that were deficient in leptin or p47phox had decreased activated NF-κB and miR21 levels, suggesting the role of leptin and NADPH oxidase in inducing NF-κB-mediated miR21 expression. Further miR21 knockout mice had decreased colocalization events of SMAD2/3-SMAD4 in the nucleus, increased SMAD7 levels, and decreased fibrogenesis. Taken together, the studies show the novel role of leptin-NADPH oxidase induction of miR21 as a key regulator of TGF-β signaling and fibrogenesis in experimental and human NASH.

Topics: Animals; Case-Control Studies; Cell Nucleus; Diet, High-Fat; Disease Models, Animal; Humans; Leptin; Liver; Male; Membrane Glycoproteins; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs; NADPH Oxidase 2; NADPH Oxidases; NF-kappa B; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Peroxynitrous Acid; RNA Interference; Signal Transduction; Smad Proteins, Receptor-Regulated; Smad4 Protein; Smad7 Protein; Transforming Growth Factor beta; Trihalomethanes

Obesity is characterized by an increased production of inflammatory markers. High levels of circulating free fatty acids and chronic inflammation lead to increased oxidative stress, contributing to the development of insulin resistance (IR). Recent studies have focused on the potential use of flavonoids for obesity management due to their antioxidant and anti-inflammatory properties. This study was designed to investigate the antioxidant and anti-inflammatory effects of helichrysum and grapefruit extracts in overweight insulin-resistant rats. Thirty-eight male Wistar rats were randomly distributed in two groups: control group (n=8) and high-fat sucrose (HFS) group (n=30). After 22 days of ad libitum water and food access, the rats fed HFS diet changed to standard diet and were reassigned into three groups (n=10 each group): nonsupplemented, helichrysum extract (2 g/kg bw), and grapefruit extract (1 g/kg bw) administered for 5 weeks. Rats supplemented with both extracts gained less body weight during the 5-week period of treatment, showed lower serum insulin levels and liver TBARS levels. Leptin/adiponectin ratio, as an indicator of IR, was lower in both extract-administered groups. These results were accompanied by a reduction in TNFα gene expression in epididymal adipose tissue and intestinal mucosa, and TLR2 expression in intestinal mucosa. Helichrysum and grapefruit extracts might be used as complement hypocaloric diets in weight loss treatment. Both extracts helped to reduce weight gain, hyperinsulinemia, and IR, improved inflammation markers, and decreased the HFS diet-induced oxidative stress in insulin-resistant rats.

Topics: Adiponectin; Animals; Antioxidants; Blood Glucose; Body Weight; Citrus paradisi; Diet, High-Fat; Dietary Supplements; Disease Models, Animal; Helichrysum; Inflammation; Insulin; Insulin Resistance; Leptin; Male; Overweight; Plant Extracts; Rats; Rats, Wistar; Thiobarbituric Acid Reactive Substances; Treatment Outcome; Weight Loss

We have previously demonstrated that a number of rats fed a moderately high-fat diet (MHFD) become obese and hypertensive and had compromised sympathoinhibitory and vasodilator responses to the gut hormones cholecystokinin (CCK) and gastric leptin. This has implications for increased resistance in vascular beds that attract a large proportion of cardiac output after a meal and may be an important mechanism underlying the development of hypertension in obesity in which food consumption is greatly increased. The aim of this study was to determine whether swapping a MHFD for a low-fat diet (LFD) would induce weight loss in obese animals, reverse the signs of hypertension and restore sympathoinhibitory reflexes. Male Sprague-Dawley rats were placed on a LFD (controls; n = 8) or a MHFD (n = 24) for 11 weeks after which the latter displayed either an obesity-prone (OP) or obesity-resistant (OR) phenotype. All animals were fed a LFD for a further 6 weeks after which they were anaesthetised with isoflurane and artificially ventilated for evaluation of resting arterial pressure (AP) and renal sympathetic nerve responses to CCK (0.1-4 μg/kg) and leptin (15 μg/kg). Weight gain in OP animals remained higher than OR or controls following diet switch (P < 0.05 for both). Resting AP was not significantly different between OP (103 ± 4 mmHg), OR (102 ± 3 mmHg) or control (104 ± 3 mmHg) animals and sympathoinhibitory responses to CCK or leptin were not different between the groups (P > 0.05). These results demonstrate that diet modification can have beneficial effects on sympathetic function and restore normotension without the need for weight reduction.

Topics: Animals; Arterial Pressure; Autonomic Agents; Body Weight; Cholecystokinin; Diet, Fat-Restricted; Diet, High-Fat; Disease Models, Animal; Gastrointestinal Agents; Genetic Predisposition to Disease; Hypertension; Leptin; Male; Obesity; Rats, Sprague-Dawley; Sympathetic Nervous System

The aim of this study was to characterize Carioca High-conditioned Freezing rats (CHF) regarding their endocrine and metabolic backgrounds. We found an increase in serum corticosterone (CTRL: 96.7 ± 21.65 vs CHF: 292.0 ± 4 0.71 ng/ml) and leptin (CTRL: 9.5 ± 1.51 vs CHF: 19.2 ± 4.32 ng/ml). Serum testosterone (CTRL: 3.3 ± 0.29 vs CHF: 2.0 ± 0.28 ng/ml) and T3 (CTRL: 52.4 ± 2.74 vs CHF: 42.7 ± 2.94 ng/dl) were decreased in the CHF group, but serum TSH and T4 were unaffected. Body weight and food intake were unchanged, nevertheless retroperitoneal fat (CTRL: 2.2 ± 0.24 vs CHF: 4.8 ± 0.64 g) and epididymal fat (CTRL: 2.6 ± 0.20 vs CHF: 4.8 ± 0.37 g) depot weights were around 2-fold higher in CHF animals. BAT weight was similar in both groups. Serum triglycerides (CTRL: 41.4 ± 6.03 vs CHF: 83.2 ± 17.09 mg/dl) and total cholesterol (CTRL: 181.6 ± 5.61 vs CHF: 226.4 ± 13.04 mg/dl) were higher in the CHF group. Fasting glycemia (CTRL: 68.7 ± 3.04 vs CHF: 82.3 ± 2.99 mg/dl) was also higher in the CHF group, however glucose tolerance test response and serum insulin levels were similar between the groups. Oxygen consumption (CTRL: 10.5 ± 0.40 vs CHF: 7.9 ± 0.58 VO2ml/min/kg(0.75)) and BAT D2 activity (CTRL: 0.7 ± 0.17 vs CHF: 0.3 ± 0.04 fmolT4/min/mg ptn) were lower in the CHF group. Our data show that anxiety could impair endocrine and metabolic functions and may contribute to the development of metabolic diseases.

Topics: Adipose Tissue, Brown; Animals; Anxiety Disorders; Body Weight; CD3 Complex; CD4 Antigens; Cholesterol; Corticosterone; Disease Models, Animal; Fasting; Insulin; Intra-Abdominal Fat; Leptin; Male; Oxygen Consumption; Rats, Wistar; Species Specificity; Testosterone; Thyrotropin; Triglycerides

To investigate whether and how human chorionic gonadotropin (HCG) treatment ameliorates endometriosis in an endometriotic rat model.. Twenty-four endometriosis rats were established and were randomly divided into four groups, and then the rats were treated with 19.4, 25.8, and 51.6 IU/100 g weight/day of HCG, respectively. The control group was treated with 0.9% NaCl. After 15 days (3 estrous cycles), the ectopic lesion volume and the expression of leptin protein in eutopic and ectopic endometrium were investigated.. After HCG treatment, the volumes of endometriotic lesions were significantly smaller than those before treatment. During endometriosis development, the expression of leptin protein in eutopic and ectopic endometrium was remarkably increased. HCG administration reversed leptin upregulation in endometriotic tissues.. HCG therapy appears to be an effective treatment for endometriosis in rats through down-regulation of leptin expression in eutopic and ectopic endometrium.

Topics: Animals; Blotting, Western; Chorionic Gonadotropin; Disease Models, Animal; Down-Regulation; Endometriosis; Endometrium; Female; Fluorescent Antibody Technique; Humans; Leptin; Rats; Rats, Sprague-Dawley

Laparoscopic sleeve gastrectomy (SG) and gastric banding (GB) are popular bariatric procedures for treating morbid obesity. This study aimed to investigate changes in the hypothalamic feeding center after these surgeries in a diet-induced obese rat model.. Obesity was induced in 60 Sprague-Dawley rats using a high-energy diet for 6 weeks. These rats were divided into four groups: the sham-operated (SO) control, pair-fed (PF) control, SG and GB groups. Six weeks after the surgery, metabolic parameters, the plasma levels of leptin, ghrelin, peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) and the hypothalamic mRNA expressions of neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) were measured.. Compared with those observed in the SO group, the body and fat tissue weights were significantly decreased and the metabolic parameters were significantly improved in the PF, SG and GB groups 6 weeks after surgery. The plasma ghrelin levels were significantly lower and the PYY and GLP-1 levels were significantly higher in the SG group than in the PF, GB and SO groups. Compared with that seen in the PF and GB groups, the hypothalamic mRNA expression of NPY was significantly lower and the expression of POMC was significantly higher in the SG group.. SG may affect the neurological pathway associated with appetite in the hypothalamus and thereby control ingestive behavior.

Topics: Animals; Bariatric Surgery; Disease Models, Animal; Feeding Behavior; Gastrectomy; Ghrelin; Glucagon-Like Peptide 1; Hypothalamus; Leptin; Male; Neuropeptide Y; Obesity, Morbid; Peptide YY; Pro-Opiomelanocortin; Rats, Sprague-Dawley; RNA, Messenger

Excessive proliferation of pulmonary arterial smooth muscle cells (PA-SMCs) and perivascular inflammation lead to pulmonary arterial hypertension (PAH) progression, but they are not specifically targeted by the current therapies. Since leptin (Ob) and its main receptor ObR-b contribute to systemic vascular cell proliferation and inflammation, we questioned whether targeting Ob/ObR-b axis would be an effective antiproliferative and anti-inflammatory strategy against PAH. In idiopathic PAH (iPAH), using human lung tissues and primary cell cultures (early passages ≤5), we demonstrate that pulmonary endothelial cells (P-ECs) over produce Ob and that PA-SMCs overexpress ObR-b. Furthermore, we obtain evidence that Ob enhances proliferation of human PA-SMCs in vitro and increases right ventricular systolic pressure in Ob-treated mice in the chronic hypoxia-induced pulmonary hypertension (PH) model. Using human cells, we also show that Ob leads to monocyte activation and increases cell adhesion molecule expression levels in P-ECs. We also find that Ob/ObR-b axis contributes to PH susceptibility by using ObR-deficient rats, which display less severe hypoxia-induced PH (pulmonary haemodynamics, arterial muscularisation, PA-SMC proliferation and perivascular inflammation). Importantly, we demonstrate the efficacy of two curative strategies using a soluble Ob neutraliser and dichloroacetate in hypoxia-induced PH. We demonstrate here that Ob/ObR-b axis may represent anti-proliferative and anti-inflammatory targets in PAH.

Topics: Adult; Animals; Blotting, Western; Case-Control Studies; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Familial Primary Pulmonary Hypertension; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Hypoxia; Leptin; Male; Mice; Mice, Inbred C57BL; Middle Aged; Molecular Targeted Therapy; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Signal Transduction; Up-Regulation; Vascular Remodeling

Cigarette smoking, which is a well-known major risk factor for chronic obstructive pulmonary disease (COPD), causes both pulmonary and extrapulmonary abnormalities. Ghrelin is a gastric peptide that regulates energy homeostasis. In the present study, we investigated the effects of ghrelin on the catabolic changes, respiratory function and emphysema in an animal model of COPD induced by chronic exposure to cigarette smoke. Rats were exposed to cigarette smoke, and they were administered human ghrelin (0.1 or 1 mg/kg, subcutaneous, twice daily) for 12 weeks. Compared with air-exposed rats, body weight gain, food intake, food efficiency, tidal volume, peak expiratory flow rate, and forced expiratory volume at 100 ms were significantly lower, while functional residual capacity, lung capacity, and neutrophils in bronchoalveolar lavage fluid were significantly higher in cigarette smoke-exposed rats. These indicated that the systemic abnormalities associated with COPD developed after the exposure to cigarette smoke. Ghrelin significantly and dose-dependently increased the body weight gain and food efficiency in cigarette smoke-exposed rats. In ghrelin-treated rats, skeletal muscle strength, which tended to be lowered by cigarette smoke exposure, was improved. Ghrelin ameliorated respiratory function and emphysema in a dose-dependent manner, but did not inhibit the increase in neutrophils in the bronchoalveolar lavage fluid. The respiratory functional parameters and lung capacity were significantly correlated with body weight gain. These results suggest that ghrelin inhibited the development of the catabolic changes, respiratory dysfunction, and emphysema that were induced by cigarette smoke exposure in rats, at least in part, through the amelioration of nutritional status.

Topics: Animals; Bronchoalveolar Lavage Fluid; C-Reactive Protein; Cell Count; Disease Models, Animal; Forced Expiratory Volume; Forelimb; Ghrelin; Hand Strength; Leptin; Lung; Male; Nicotiana; Peak Expiratory Flow Rate; Pulmonary Disease, Chronic Obstructive; Rats, Wistar; Smoke; Tidal Volume

Leptin, a 16 kDa anti-obesity hormone, exhibits various physiological properties. Interestingly, skin wound healing was proven to delay in leptin-deficient ob/ob mice. However, little is known on the mechanisms of this phenomenon. In this study, we attempted to elucidate a role of leptin in wound healing of skin.. Immunohistochemical analysis was performed to confirm the expression of the leptin receptor (Ob-R) in human and mouse skin. Leptin was topically administered to chemical wounds created in mouse back skin along with sustained-release absorbable hydrogel. The process of wound repair was histologically observed and the area of ulceration was measured over time. The effect of leptin on the proliferation, differentiation and migration of human epidermal keratinocytes was investigated.. Ob-R was expressed in epidermal cells of human and mouse skin. Topical administration of leptin significantly promoted wound healing. Histological analysis showed more blood vessels in the dermal connective tissues in the leptin-treated group. The proliferation, differentiation/function and migration of human epidermal keratinocytes were enhanced by exogenous leptin.. Topically administered leptin was proven to promote wound healing in the skin by accelerating proliferation, differentiation/function and migration of epidermal keratinocytes and enhancing angiogenesis around the wounded area. These results strongly suggest that topical administration of leptin may be useful as a treatment to promote wound healing in the skin.

Topics: Administration, Topical; Angiogenesis Inducing Agents; Animals; Cell Differentiation; Cell Movement; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Humans; Keratinocytes; Leptin; Mice; Neovascularization, Physiologic; Receptors, Leptin; Skin; Wound Healing

The combinatorial peptidergic therapy of islet amyloid polypeptide (IAPP) and leptin (LEP) analogues was once an optimistic option in treating obese animals and patients. However, the need for frequent administrations and its negative side effects prevent it from being a viable choice. Here, we developed a combinatorial gene therapy of IAPP and LEP, where two genes are inserted into a single plasmid with self-cleaving furin and 2A sites to treat diet-induced obese (DIO) mice. The developed plasmid DNA (pDNA) individually produced both IAPP and LEP peptides in vitro and in vivo. The pDNA was delivered with a non-viral polymeric carrier, and its once-a-week administrations demonstrated a synergistic loss of body weight and significant reductions of fat mass, blood glucose, and lipid levels in DIO mice. The results suggest that the combinatorial gene therapy would have higher potential than the peptidergic approach for future translation due to its improved practicability.

Topics: Adiposity; Animals; Blood Glucose; Diet, High-Fat; Disease Models, Animal; Eating; Gene Transfer Techniques; Genetic Therapy; HEK293 Cells; Humans; Islet Amyloid Polypeptide; Leptin; Lipids; Male; Mice, Inbred C57BL; Obesity; Plasmids; Polymers; Time Factors; Transfection; Weight Loss

It is well established that obesity-related hormones can have modulatory effects associated with the immune response. Ghrelin, a hormone mainly derived from endocrine cells of the gastric mucosa, regulates appetite, energy expenditure and body weight counteracting leptin, a hormone mainly derived from adipocytes. Additionally, receptors of both have been detected on immune cells and demonstrated an immune regulatory function during sepsis.. In the present study, the effect of peripheral ghrelin administration on early immune response and survival was investigated with lean mice and mice with diet-induced obesity using cecal ligation and puncture to induce sepsis.. In the obese group, we found that ghrelin treatment improved survival, ameliorated hypothermia, and increased hyperleptinemia as compared to the lean controls. We also observed that ghrelin treatment divergently regulated serum IL-1ß and TNF-α concentrations in both lean and obese septic mice. Ghrelin treatment initially decreased but later resulted in increased bacteriaemia in lean mice while having no impact upon obese mice. Similarly, ghrelin treatment increased early neutrophil oxidative burst while causing a decrease 48 hours after sepsis inducement.. In conclusion, as the immune response to sepsis temporally changes, ghrelin treatment differentially mediates this response. Specifically, we observed that ghrelin conferred protective effects during the early phase of sepsis, but during the later phase deteriorated immune response and outcome. These adverse effects were more pronounced upon lean mice as compared to obese mice.

Topics: Animals; Disease Models, Animal; Ghrelin; Interleukin-1beta; Leptin; Mice; Mice, Obese; Neutrophils; Obesity; Sepsis; Survival Analysis; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

To observe the effect of electroacupuncture (EA) stimulation of "Housanli" (ST 36) and "Zhongwan" (CV 12) on serum leptin level and expression of phosphorylated Janus kinase 2 (p-JAK 2) and phosphorylated signal transducer and activator of transcription 3 (p-STAT 3) proteins in the liver tissue of obese rats.. Thirty-two male Wistar rats were randomly divided into control group, model group, manual acupuncture (MA) group and EA group (n = 8 in each group). The obese model was induced by high fat diet for 8 weeks. MA or EA (20 Hz, 1.5 V) stimulation was applied to bilateral "Housanli" (ST 36) and "Zhongwan" (CV 12) for 20 min, once daily for 4 weeks. The animals' body weight and length were recorded, and Lee's index was calculated. Serum leptin level and liver p-JAK 2 and p-STAT 3 protein expression levels were detected using radioimmunoassay and Western blot, respectively.. In comparison with the control group, the rats' body weight, Lee's index, and serum leptin content were remarkably increased in the model group (P<0.05), while hepatocellular p-JAK 2 and p-STAT 3 protein expression levels were significantly down-regulated in the model group (P<0.05). After treatment for 4 weeks, the levels of body weight, Lee's index, serum leptin were significantly reduced (P<0.05), and hepatocellular p-JAK 2 and p-STAT 3 protein expression in the MA and EA groups were considerably up-regulated compared with the model group (P<0.05). The effect of EA was apparently superior to that of MA in up-regulating p-JAK 2 and p-STAT 3 protein expression (P<0.05).. Both EA and MA stimulation can reduce the obese rats' body weight, and Lee's index, which may be closely associated with their effects in down-regulating serum leptin and in enhancing hepatocellular p-JAK 2 and p-STAT 3 protein expression.

Topics: Acupuncture Points; Animals; Disease Models, Animal; Electroacupuncture; Humans; Janus Kinase 2; Leptin; Male; Obesity; Phosphorylation; Rats; Rats, Wistar; Signal Transduction; STAT3 Transcription Factor; Up-Regulation

To characterize mechanisms responsible for fat accumulation we used a selectively bred obesity-prone (OP) and obesity-resistant (OR) rat model where the rats were fed a Western diet for 76 days. Body composition was assessed by magnetic resonance imaging scans, and as expected, the OP rats developed a higher degree of fat accumulation compared with OR rats. Indirect calorimetry showed that the OP rats had higher respiratory exchange ratio (RER) compared with OR rats, indicating an impaired ability to oxidize fat. The OP rats had lower expression of carnitine palmitoyltransferase 1b in intra-abdominal fat, and higher expression of stearoyl-CoA desaturase 1 in subcutaneous fat compared with OR rats, which could explain the higher fat accumulation and RER values. Basal metabolic parameters were also examined in juvenile OP and OR rats before and during the introduction of the Western diet. Juvenile OP rats likewise had higher RER values, indicating that this trait may be a primary and contributing factor to their obese phenotype. When the adult obese rats were exposed to the orexigenic and adipogenic hormone ghrelin, we observed increased RER values in both OP and OR rats, while OR rats were more sensitive to the orexigenic effects of ghrelin as well as ghrelin-induced attenuation of activity and energy expenditure. Thus increased fat accumulation characterizing obesity may be caused by impaired oxidative capacity due to decreased carnitine palmitoyltransferase 1b levels in the white adipose tissue, whereas ghrelin sensitivity did not seem to be a contributing factor.

Topics: Adiposity; Animals; Calorimetry, Indirect; Carnitine O-Palmitoyltransferase; Diet, High-Fat; Disease Models, Animal; Down-Regulation; Eating; Energy Metabolism; Gene Expression Regulation; Ghrelin; Hypothalamus; Insulin; Intra-Abdominal Fat; Leptin; Magnetic Resonance Imaging; Male; Muscle, Skeletal; Obesity; Oxidation-Reduction; Rats; Subcutaneous Fat; Time Factors; Weight Gain

Piper nigrum Linn (Piperaceae) (PnL) is used in traditional medicine to treat gastric ailments, dyslipidemia, diabetes, and hypertension.. The present study explores the possible protective effects of P. nigrum extracts on high-fat diet-induced obesity in rats.. High-fat diet-induced obese rats were treated orally with 200 mg/kg bw of different extracts (hexane, ethylacetate, ethanol, and aqueous extracts) of PnL for 42 d. The effects of PnL extracts on body composition, insulin resistance, biochemical parameters, leptin, adiponectin, lipid profile, liver marker enzymes, and antioxidants were studied.. The HFD control group rats showed a substantial raise in body weight (472.8 ± 9.3 g), fat% (20.8 ± 0.6%), and fat-free mass (165.9 ± 2.4 g) when compared with normal control rats whose body weight, fat%, and fat-free mass were 314.3 ± 4.4 g, 6.4 ± 1.4%, and 133.8 ± 2.2 g, respectively. Oral administration of ethyl acetate or aqueous extracts of PnL markedly reduced the body weight, fat%, and fat-free mass of HFD-fed rats. In contrast to the normal control group, a profound increase in plasma glucose, insulin resistance, lipid profile, leptin, thiobarbituric acid reactive substance (TBARS), and the activities of lipase and liver marker enzymes, and a decrease in adiponectin and antioxidant enzymes were noted in HFD control rats. Administration of PnL extracts to HFD-induced obese rats significantly (p < 0.05) restored the above profiles.. PnL extracts significantly reduced the body weight, fat%, and ameliorated HFD-induced hyperlipidemia and its constituents.

Topics: Adiponectin; Adiposity; Animals; Antioxidants; Biomarkers; Blood Glucose; Diet, High-Fat; Disease Models, Animal; Hyperlipidemias; Hypoglycemic Agents; Hypolipidemic Agents; Insulin; Insulin Resistance; Leptin; Lipids; Male; Oxidative Stress; Phytotherapy; Piper nigrum; Plant Extracts; Plants, Medicinal; Rats, Sprague-Dawley; Solvents; Thiobarbituric Acid Reactive Substances; Weight Loss

Prader-Willi syndrome (PWS) is a multigene disorder associated with neonatal failure to thrive, developmental delay and endocrine abnormalities suggestive of hypothalamic dysfunction. Children with PWS typically develop overt hyperphagia and obesity ∼8 years of age, later than children with other genetic forms of obesity. This suggests a postnatal developmental or degenerative component to PWS-associated obesity. De novo inactivating mutations in one PWS candidate gene, MAGEL2, have been identified in children with features of PWS. Adult mice lacking Magel2 are insensitive to the anorexic effect of leptin treatment, and their hypothalamic pro-opiomelanocortin (POMC) neurons fail to depolarize in response to leptin. However, it is unclear whether this leptin insensitivity is congenital, or whether normal leptin sensitivity in neonatal Magel2-null mice is lost postnatally. We used in vitro cytosolic calcium imaging to follow the postnatal development of leptin responses in POMC neurons in these mice. Leptin caused an activation of POMC neurons in wild-type acute hypothalamic slice preparations at all ages, reflecting their normal leptin-invoked depolarization. Normal leptin responses were found in Magel2-null mice up to 4 weeks of age, but the proportion of leptin-responsive POMC neurons was reduced in 6-week-old Magel2-null mice. The number of α-melanocyte-stimulating hormone immunoreactive fibers in the paraventricular hypothalamic nucleus was also reduced in mutant mice at 6 weeks of age. A similar progressive loss of leptin sensitivity caused by loss of MAGEL2 in children with PWS could explain the delayed onset of increased appetite and weight gain in this complex disorder.

Topics: Animals; Antigens, Neoplasm; Arcuate Nucleus of Hypothalamus; Disease Models, Animal; Humans; Hypothalamus; Leptin; Mice; Neurons; Prader-Willi Syndrome; Pro-Opiomelanocortin; Proteins; Weight Gain

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

Relations of the 25 mammalian selenoprotein genes with obesity and the associated inflammation remain unclear.. This study explored impacts of high-fat diet-induced obesity on inflammation and expressions of selenoprotein and obesity-related genes in 10 tissues of pigs.. Plasma and 10 tissues were collected from pigs (n = 10) fed a corn-soy-based control diet or that diet containing 3-7% lard from weanling to finishing (180 d). Plasma concentrations (n = 8) of cytokines and thyroid hormones and tissue mRNA abundance (n = 4) of 25 selenoprotein genes and 16 obesity-related genes were compared between the pigs fed the control and high-fat diets. Stepwise regression was applied to analyze correlations among all these measures, including the previously reported body physical and plasma biochemical variables.. The high-fat diet elevated (P < 0.05) plasma concentrations of tumor necrosis factor α, interleukin-6, leptin, and leptin receptor by 29-42% and affected (P < 0.05-0.1) tissue mRNA levels of the selenoprotein and obesity-related genes in 3 patterns. Specifically, the high-fat diet up-regulated 12 selenoprotein genes in 6 tissues, down-regulated 13 selenoprotein genes in 7 tissues, and exerted no effect on 5 genes in any tissue. Body weights and plasma triglyceride concentrations of pigs showed the strongest regressions to tissue mRNA abundances of selenoprotein and obesity-related genes. Among the selenoprotein genes, selenoprotein V and I were ranked as the strongest independent variables for the regression of phenotypic and plasma measures. Meanwhile, agouti signaling protein, adiponectin, and resistin genes represented the strongest independent variables of the obesity-related genes for the regression of tissue selenoprotein mRNA.. The high-fat diet induced inflammation in pigs and affected their gene expression of selenoproteins associated with thioredoxin and oxidoreductase systems, local tissue thyroid hormone activity, endoplasmic reticulum protein degradation, and phosphorylation of lipids. This porcine model may be used to study interactive mechanisms between excess fat intake and selenoprotein function.

Topics: Adiponectin; Agouti Signaling Protein; Animals; Body Weight; Diet, High-Fat; Disease Models, Animal; Down-Regulation; Inflammation; Interleukin-6; Leptin; Obesity; Receptors, Leptin; Resistin; RNA, Messenger; Selenoproteins; Swine; Thyroid Hormones; Tumor Necrosis Factor-alpha; Up-Regulation

Experimental models of intermittent hypoxia (IH) have been developed during the last decade to investigate the consequences of obstructive sleep apnea. IH is usually associated with detrimental metabolic and vascular outcomes. However, paradoxical protective effects have also been described depending of IH patterns and durations applied in studies. We evaluated the impact of short-term IH on vascular and metabolic function in a diet-induced model of metabolic syndrome (MS).. Mice were fed either a standard diet or a high fat diet (HFD) for 8 weeks. During the final 14 days of each diet, animals were exposed to either IH (1 min cycle, FiO2 5% for 30s, FiO2 21% for 30s; 8 h/day) or intermittent air (FiO2 21%). Ex-vivo vascular reactivity in response to acetylcholine was assessed in aorta rings by myography. Glucose, insulin and leptin levels were assessed, as well as serum lipid profile, hepatic mitochondrial activity and tissue nitric oxide (NO) release.. Mice fed with HFD developed moderate markers of dysmetabolism mimicking MS, including increased epididymal fat, dyslipidemia, hepatic steatosis and endothelial dysfunction. HFD decreased mitochondrial complex I, II and IV activities and increased lactate dehydrogenase (LDH) activity in liver. IH applied to HFD mice induced a major increase in insulin and leptin levels and prevented endothelial dysfunction by restoring NO production. IH also restored mitochondrial complex I and IV activities, moderated the increase in LDH activity and liver triglyceride accumulation in HFD mice.. In a mouse model of MS, short-term IH increases insulin and leptin levels, restores endothelial function and mitochondrial activity and limits liver lipid accumulation.

Topics: Animals; Diet, High-Fat; Disease Models, Animal; Endothelium, Vascular; Glycolysis; Hypoxia; Insulin; Leptin; Lipid Metabolism; Liver; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mitochondria, Liver; Nitric Oxide; Sleep Apnea, Obstructive

Reduced cardiac β-adrenoceptor (β-AR) expression and cardiovascular dysfunction occur in models of hyperglycemia and hypoinsulinemia. Cardiac β-AR expression in type-2 diabetes models of hyperglycemia and hyperinsulinemia, remain less clear. This study investigates cardiac β-AR expression in type-2 diabetic Zucker diabetic fatty (ZDF) rats.. Ex vivo biodistribution experiments with [3H]CGP12177 were performed in Zucker lean (ZL) and ZDF rats at 10 and 16 weeks of age as diabetes develops. Blood glucose, body mass, and diet consumption were measured. Western blotting of β-AR subtypes was completed in parallel. Echocardiography was performed at 10 and 16 weeks to assess systolic and diastolic function. Fasted plasma insulin, free fatty acids (FFA), leptin and fed-state insulin were also measured.. At 10 weeks, myocardial [3H]CGP12177 was normal in hyperglycemic ZDF (17±4.1mM) compared to ZL, but reduced 16-25% at 16 weeks of age as diabetes and hyperglycemia (22±2.4mM) progressed. Reduced β-AR expression not apparent at 10 weeks also developed by 16 weeks of age in ZDF brown adipose tissue. In the heart, Western blotting at 10 weeks indicated normal β1-AR (98±9%), reduced β2-AR (76±10%), and elevated β3-AR (108±6). At 16 weeks, β1-AR expression became reduced (69±16%), β2-AR expression decreased further (68±14%), and β3-AR remained elevated, similar to 10 weeks (112±9%). While HR was reduced at 10 and 16 weeks in ZDF rats, no significant changes were observed in diastolic or systolic function.. Cardiac β-AR are reduced over 6 weeks of sustained hyperglycemia in type-2 diabetic ZDF rats. This indicates cardiac [3H]CGP12177 retention and β1- and β2-AR expression are inversely correlated with the progression of type-2 diabetes.

Topics: Animals; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Disease Models, Animal; Disease Progression; Echocardiography; Fatty Acids, Nonesterified; Gene Expression Regulation; Heart Diseases; Hyperglycemia; Insulin; Leptin; Male; Myocardium; Rats; Rats, Zucker; Receptors, Adrenergic, beta

Obesity can cause insulin resistance and type 2 diabetes. Moderate elevations in bilirubin levels have anti-diabetic effects. This study is aimed at determining the mechanisms by which bilirubin treatment reduces obesity and insulin resistance in a diet-induced obesity (DIO) mouse model. DIO mice were treated with bilirubin or vehicle for 14 days. Body weights, plasma glucose, and insulin tolerance tests were performed prior to, immediately, and 7 weeks post-treatment. Serum lipid, leptin, adiponectin, insulin, total and direct bilirubin levels were measured. Expression of factors involved in adipose metabolism including sterol regulatory element-binding protein (SREBP-1), insulin receptor (IR), and PPARγ in liver were measured by RT-PCR and Western blot. Compared to controls, bilirubin-treated mice exhibited reductions in body weight, blood glucose levels, total cholesterol (TC), leptin, total and direct bilirubin, and increases in adiponectin and expression of SREBP-1, IR, and PPARγ mRNA. The improved metabolic control achieved by bilirubin-treated mice was persistent: at two months after treatment termination, bilirubin-treated DIO mice remained insulin sensitive with lower leptin and higher adiponectin levels, together with increased PPARγ expression. These results indicate that bilirubin regulates cholesterol metabolism, adipokines and PPARγ levels, which likely contribute to increased insulin sensitivity and glucose tolerance in DIO mice.

Topics: Adipokines; Adiponectin; Animals; Bilirubin; Blood Glucose; Body Weight; Cholesterol; Diet, High-Fat; Disease Models, Animal; Glucose Tolerance Test; Insulin Resistance; Leptin; Lipid Metabolism; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; PPAR gamma; Receptor, Insulin; Sterol Regulatory Element Binding Protein 1

Leptin alleviates metabolic conditions such as insulin resistance and obesity, although the precise mechanism of action is unclear. Mitochondrial fusion/fission states affect energy balance, but the association between mitochondrial fusion and lipid metabolism is also unknown. The aim of this study was to determine whether mitochondrial fusion/fission state regulates lipid accumulation and to understand the role of leptin in mitochondrial function and its mechanism of action in metabolic regulation.. Primary mouse hepatocytes were isolated from C57BL/6J mice and treated with leptin (25 ng ml(-1)) for 3 days before determinations of mitochondrial morphology and fatty acid accumulation. Hyperglycemia in C57BL/6J mice was induced by providing a 30% fructose-rich diet (FRD) for 6 months, followed by intraperitoneal injections of leptin (1 mg kg(-1) per body weight) for 6 weeks (twice per week).. Leptin triggered mitochondrial fusion and alleviated high glucose-induced fatty acid accumulation in primary hepatocytes by promoting mitochondrial fusion-associated transcription factor peroxisome proliferative-activated receptor-α and co-activator peroxisome proliferative-activated receptor-γ co-activator (PGC)-1α. In turn, these activate the fusion protein mitofusin 1 (Mfn-1). RNA silencing of Mfn-1 or PGC-1 blocked the inhibitory effect of leptin. Leptin treatment also elevated liver Mfn-1 and PGC-1α and improved lipid profiles in FRD mice.. Mitochondrial fusion has a critical role in alleviating hepatic fatty acid accumulation. Leptin switches mitochondrial morphology via a PGC-1α-dependent pathway to improve hyperlipidemia.

Topics: Animals; Blotting, Western; Cells, Cultured; Disease Models, Animal; Fatty Liver; Gene Expression Regulation; Hepatocytes; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Mitochondrial Dynamics

The rewarding value of palatable foods contributes to overconsumption, even in satiated subjects. Midbrain dopaminergic activity in response to reward-predicting environmental stimuli drives reward-seeking and motivated behavior for food rewards. This mesolimbic dopamine (DA) system is sensitive to changes in energy balance, yet it has thus far not been established whether reward signaling of DA neurons in vivo is under control of hormones that signal appetite and energy balance such as ghrelin and leptin.. We trained rats (n=11) on an operant task in which they could earn two different food rewards. We then implanted recording electrodes in the ventral tegmental area (VTA), and recorded from DA neurons during behavior. Subsequently, we assessed the effects of mild food restriction and pretreatment with the adipose tissue-derived anorexigenic hormone leptin or the orexigenic hormone ghrelin on VTA DA reward signaling.. Animals showed an increase in performance following mild food restriction (P=0.002). Importantly, food-cue induced DA firing increased when animals were food restricted (P=0.02), but was significantly attenuated after leptin pretreatment (P=0.00). While ghrelin did affect baseline DA activity (P=0.025), it did not affect cue-induced firing (P⩾0.353).. Metabolic signals, such as leptin, affect food seeking, a process that is dependent on the formation of cue-reward outcomes and involves midbrain DA signaling. These data show that food restriction engages the encoding of food cues by VTA DA neurons at a millisecond level and leptin suppresses this activity. This suggests that leptin is a key in linking metabolic information to reward signaling.

Topics: Animals; Appetite; Cues; Disease Models, Animal; Dopamine; Dopaminergic Neurons; Feeding Behavior; Ghrelin; Leptin; Male; Obesity; Overnutrition; Rats; Rats, Wistar; Reward; Signal Transduction; Ventral Tegmental Area

To clarify metabolic syndrome induced stone formation mechanisms we investigated the metabolic and immunohistochemical characteristics associated with renal crystal deposition using a model of mice with metabolic syndrome administered a high fat diet and ethylene glycol.. Ob/Ob mice with Leptin gene deficiencies and metabolic syndrome related characteristics were compared with wild heterozygous lean mice. Four study groups were fed standard food and water (control group), a high fat diet and normal water (high fat diet group), 1% ethylene glycol and standard food (ethylene glycol group) or a high fat diet and 1% ethylene glycol (high fat diet plus ethylene glycol group). Blood, urine and kidney samples were taken after 14 days.. Ob/Ob mice in the high fat diet plus ethylene glycol group showed diffuse renal crystal depositions. Lean and Ob/Ob mice in the high fat diet plus ethylene glycol group showed significant excretion of urinary calcium oxalate crystals. Ob/Ob mice had significant hypercalciuria, hyperphosphaturia and hyperlipidemia, massive lipid fragments in tubular lumina and fat droplets in renal tubular cells. Ob/Ob mice in the high fat diet plus ethylene glycol group had markedly increased expression of osteopontin, monocyte chemoattractant protein-1, interleukin-6 and tumor necrosis factor-α. In Ob/Ob mice the number of proinflammatory macrophages was considerably elevated.. We induced renal crystal deposition in mice with metabolic syndrome using a high fat diet and ethylene glycol. Increases in luminal mineral and lipid density, and proinflammatory adipocytokines and macrophages facilitated renal crystal formation in mice with metabolic syndrome.

Topics: Adipokines; Animals; Calcium Oxalate; Cell Count; Diet, High-Fat; Disease Models, Animal; Ethylene Glycol; Inflammation Mediators; Kidney Calculi; Leptin; Macrophages; Male; Metabolic Syndrome; Mice; Mice, Obese

An experimental study to investigate the role of enhanced central leptin activity in a bipedal mouse scoliosis model.. To investigate the influence of enhanced central leptin activity on the development of scoliosis in mice, and to support Burwell's hypothesis that central leptin dysfunction is involved in the etiopathogenesis of idiopathic scoliosis.. Significantly lower level of circulating leptin and higher level of soluble leptin receptor have been reported in adolescent idiopathic scoliosis compared with healthy adolescents, suggesting possible association between abnormal central leptin level and dysfunction.. Amputation of forelimbs and tail was performed on 50 male C3H/HeJ mice at the age of 3 weeks. Then, the mice were randomly divided into 2 groups: Group A consisted of 25 mice treated with injection into the hypothalamus with lentivirus vectors that overexpressed leptin; and Group B involved the remaining 25 mice receiving intracerebral injection with the control vectors. Radiographs were obtained at 20th week to determine the presence of spinal deformity. The incidence of scoliosis and curve magnitude were compared between groups.. The body weight was initially found to be slightly lower in mice of Group A when compared with Group B. Significantly higher peripheral serum leptin level was found in leptin-overexpressing mice than control mice. Scoliosis developed in 23 mice of Group A (92%), with an average Cobb angle of 30.2°, and in 13 of Group B (52%), with an average Cobb angle of 18.4°, respectively. A higher incidence (P = 0.002) and more severe curve (P <0.001) were observed in Group A.. In this bipedal mouse scoliosis model, enhanced central leptin activity might not only increase the risk of developing a scoliosis, but also contribute to the progression of scoliosis.. N/A.

Topics: Amputation, Surgical; Animals; Body Weight; Disease Models, Animal; Disease Progression; Leptin; Male; Mice; Mice, Inbred C3H; Receptors, Leptin; Risk; Scoliosis

To identify possible mechanisms linking obesity in pregnancy to increased fetal adiposity and growth, a unique mouse model of maternal obesity associated with fetal overgrowth was developed, and the hypothesis that maternal obesity causes up-regulation of placental nutrient transporter expression and activity was tested.. C57BL/6J female mice were fed a control (C) or a high-fat/high-sugar (HF/HS) pelleted diet supplemented by ad libitum access to sucrose (20%) solution, mated, and studied at embryonic day 18.5.. HF/HS diet increased maternal fat mass by 2.2-fold (P < 0.01) and resulted in glucose intolerance with normal fasting glucose. Maternal circulating insulin, leptin, and cholesterol were increased (P < 0.05) whereas total and high-molecular-weight adiponectin was decreased (P < 0.05). HF/HS diet increased fetal weight (+18%, P = 0.0005). In trophoblast plasma membranes (TPM) isolated from placentas of HF/HS-fed animals, protein expression of glucose transporter (GLUT) 1 and 3, sodium-coupled neutral amino acid transporter (SNAT) 2, and large neutral amino acid transporter 1 (LAT1) was increased. TPM System A and L amino acid transporter activity was increased in the HF/HS group.. Up-regulation of specific placental nutrient transporter isoforms may constitute a mechanism underlying fetal overgrowth in maternal obesity.

Topics: Animals; Disease Models, Animal; Female; Fetal Weight; Insulin; Leptin; Mice; Mice, Inbred C57BL; Mothers; Obesity; Pregnancy; Up-Regulation; Weight Gain

New evidance highlights the importance of food timing. Recently, we showed that a low-calorie diet with carbohydrates eaten mostly at dinner changed diurnal hormone secretion and led to greater weight loss and improved metabolic status in obese people. Herein, we set out to test whether concentrated-carbohydrates diet (CCD), in which carbohydrates are fed only before sleep, leads to an improved metabolic status in mouse hypothalamus and peripheral tissues. Diet-induced obese mice were given concentrated or distributed carbohydrate diet for 6 weeks. Obese mice fed CCD ate 8.3% less, were 9.3% leaner and had 39.7% less fat mass. Leptin, ghrelin and adiponectin displayed altered secretion. In addition, these mice exhibited an improved biochemical and inflammatory status. In the hypothalamus, anorexigenic signals were up-regulated and orexigenic signals were down-regulated. In peripheral tissues, CCD promoted adiponectin signaling, repressed gluconeogenesis, enhanced lipid oxidation and lowered inflammation, thus ameliorating the major risk factors of obesity.

Topics: Adiponectin; Animals; Appetite Regulation; Body Weight; Dietary Carbohydrates; Disease Models, Animal; Feeding Behavior; Gene Expression Regulation; Ghrelin; Gluconeogenesis; Hypothalamus; Inflammation; Leptin; Lipid Peroxidation; Male; Mice; Mice, Inbred C57BL; Obesity; Sleep

Hydrocellular foam dressing (HCF) absorbs excessive wound fluid, which contains various cytokines and growth factors, and ensures a moist environment to promote wound healing. However, the molecular mechanisms underlying the wound fluid component changes induced by HCF are poorly understood. In the present study, we examined the effect of HCF on wound healing and the associated regulatory mechanisms in relation to variations in cytokine levels in the wound fluid. We created full-thickness wounds on the dorsolateral skin of rats and collected the resulting wound fluid samples. HCF was immersed in a plate containing the wound fluids. HCF was then removed and the excess wound fluid remaining in the plate was examined by cytokine array and enzyme-linked immunosorbent assay. We also used a rat model and human dermal fibroblast cultures to examine the effect of wound fluid component changes during the wound healing process. Upon treatment with HCF, leptin levels were upregulated in the wound fluid. Fibroblast proliferation was enhanced and the effect was suppressed in the presence of leptin antagonist. In our in vivo model, HCF increased wound contraction compared with film dressings and this positive effect of HCF was suppressed by addition of leptin antagonist. Our results suggest that dermal fibroblast proliferation is upregulated by HCF due to increased leptin level at the wound surface, and these effects promote wound healing. We believe that the present study contributes to furthering the understanding of the mechanisms underlying the effects of HCF-induced wound healing.

Topics: Animals; Bandages, Hydrocolloid; Body Fluids; Cell Proliferation; Cells, Cultured; Cytokines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Immunoblotting; Leptin; Male; Rats; Rats, Wistar; Skin; Wound Healing; Wounds and Injuries

Diabesity-associated metabolic stresses modulate the development of Alzheimer's disease (AD). For further insights into the underlying mechanisms, we examine whether the genetic background of APPswe/PS1dE9 at the prodromal stage of AD affects peripheral metabolism in the context of diabesity. We characterized APPswe/PS1dE9 transgenic mice treated with a combination of high-fat diet with streptozotocin (HFSTZ) in the early stage of AD. HFSTZ-treated APPswe/PS1dE9 transgenic mice exhibited worse metabolic stresses related to diabesity, while serum β-amyloid levels were elevated and hepatic steatosis became apparent. Importantly, two-way analysis of variance shows a significant interaction between HFSTZ and genetic background of AD, indicating that APPswe/PS1dE9 transgenic mice are more vulnerable to HFSTZ treatment. In addition, body weight gain, high hepatic triglyceride, and hyperglycemia were positively associated with serum β-amyloid, as validated by Pearson's correlation analysis. Our data suggests that the interplay between genetic background of AD and HFSTZ-induced metabolic stresses contributes to the development of obesity and hepatic steatosis. Alleviating metabolic stresses including dysglycemia, obesity, and hepatic steatosis could be critical to prevent peripheral β-amyloid accumulation at the early stage of AD.

Topics: Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Disease Models, Animal; Fatty Acids, Nonesterified; Fatty Liver; Humans; Leptin; Lipids; Liver; Male; Mice, Inbred C57BL; Mice, Transgenic; Obesity; Peptide Fragments; Presenilin-1; Stress, Physiological; Triglycerides; Weight Gain

Leptin is an adipocytokine produced by adipocytes and controlling body weight. It is unclear whether leptin works as a proinflammatory or an anti-inflammatory cytokine. We investigated the effects of hyperleptinemia on leptin transgenic (LepTg) mice in terms of cartilage destruction, bone destruction, joint synovitis, and serum cytokine levels by using a mouse model of collagen-antibody-induced arthritis (CAIA).. CAIA was induced for female age-matched 6- to 8-week-old C57BL/6 J control mice and LepTg mice. Mice were injected intraperitoneally with 5 mg of a combination of monoclonal antibody specific for type II collagen on day 0 and 12.5 mg of lipopolysaccharide (LPS) on day 3. Clinical evaluation of arthritis was monitored for 14 days, and hind paws were examined clinically and histologically. Serum cytokine levels of interleukin (IL)-1β, IL-6, IL-10, and IL-17 and tumor necrosis factor alpha (TNF-α) were also analyzed on days 0 and 5. Moreover, THP-1 cells, which are human monocytic cell line derived from an acute monocytic leukemia patient, were cultured and differentiated into macrophages. The effects of leptin on messenger RNA (mRNA) expression of IL-6 were examined by real-time quantitative polymerase chain reaction (RT-PCR).. Serum leptin concentrations were approximately ninefold higher in LepTg mice (62.0 ± 20.7 ng/ml) than in control mice (7.2 ± 0.5 ng/ml). Severity of clinical paw swelling, arthritis score, synovial hyperplasia, and cartilage damage were suppressed in LepTg mice with CAIA. Although serum cytokine levels of IL-1β, IL-17, and IL-10 and TNF-α showed no significant changes in two mice, serum levels of IL-6 in LepTg mice were suppressed at day 5. Moreover, in vitro study showed that IL-6 elevation following LPS exposure in THP-1 cells was suppressed with high leptin concentrations.. Our finding suggests that hyperleptinemia suppress IL-6 responses and progression of joint inflammation. Leptin may play an anti-inflammatory role under hyperleptinemia.

Topics: Animals; Arthritis, Experimental; Biopsy, Needle; Cartilage, Articular; Collagen Type II; Cytokines; Disease Models, Animal; Disease Progression; Enzyme-Linked Immunosorbent Assay; Female; Immunohistochemistry; Interleukin-6; Leptin; Mice; Mice, Inbred C57BL; Mice, Transgenic; Random Allocation; Real-Time Polymerase Chain Reaction; Sensitivity and Specificity

Leptin is widely distributed in many tissues, including the nervous system. However, the ontogeny of leptin expression in the dorsal root ganglion (DRG) is unclear. Recent studies have shown that leptin is involved in the regulation of neuropathic pain induced by nerve injury. Our previous results showed that exogenous leptin administration alleviated the pain behaviors induced by chronic constriction sciatic nerve injury. In the present study, the ontogenic expression of leptin was detected in the DRG of the mouse embryo at days 15.5 (E15.5), E17.5, and E19.5 of gestation and in the postnatal mouse at days 5 (P5), P15, and P25, and in the adult mouse. Leptin immunoreactivity and mRNA were not found in DRG at E15.5. The percentage of leptin immunopositive (leptin) neurons was about 27% at E17.5. It continued to increase to about 70% at P5. From P5 to P15, there was no significant change. The proportion of DRG neurons positive for leptin decreased after P15 and there were about 41% leptin neurons in adults. The expression profile of leptin mRNA is similar to leptin immunoreactivity. Oxaliplatin (OXA) is an effective platinum-based drug used as first-line chemotherapy for advanced colorectal cancer. However, it may induce neuropathic pain. In the current study, we found that the expression of leptin was increased in the lumbar 4-6 DRG of OXA-treated mice. These results indicate that leptin is involved in the regulation of DRG development and OXA-induced neuropathic pain.

Topics: Animals; Animals, Newborn; Cold Temperature; Disease Models, Animal; Ganglia, Spinal; Hyperalgesia; Leptin; Lumbar Vertebrae; Male; Mice, Inbred C57BL; Neuralgia; Neurons; Organoplatinum Compounds; Oxaliplatin; Random Allocation; RNA, Messenger; Touch

In this study, we aimed to establish a chronic intermittent hypoxia model in rats and explore the possible role of vaspin in insulin sensitivity.. Healthy male Wistar rats were randomly divided into two groups: normal control group (NC) and chronic intermittent hypoxia group (CIH). The NC group was raised under physiological conditions and the CIH group was kept in the plexiglass chamber between 9 am and 5 pm undergoing intermittent hypoxic challenge for 8 hours/day for 8 weeks. Arterial blood pressure of rats (tail cannulation) was measured before and after the study. Fasting plasma glucose (FPG), total cholesterol (TC), triglycerides (TG), fasting insulin (FINS), vaspin, and leptin levels were measured. Vaspin mRNA expression in visceral adipose tissues was measured with Real Time-PCR. The protein levels of vaspin, Akt and phospho-Akt in visceral tissues were determined by Western-blot.. At baseline, all the measurements in the CIH and NC groups were comparable. By the end of the experiment, the blood pressure of the CIH group was significantly higher than the NC group. The levels of FPG, FINS, TG, TC, leptin, and vaspin in the CIH group were significantly higher than in NC group. Plasma vaspin levels were correlated with FINS, HOMA-IR, and TG levels. Vaspin expression in both mRNA and protein levels in visceral adipose tissues of the CIH group were clearly higher than the NC group. Phospho-Akt protein level was decreased in visceral adipose tissues of the CIH group compared to the NC group.. In the chronic intermittent hypoxia rat model, the expression of vaspin in visceral adipose tissues and plasma were increased, which were correlated with insulin resistance.

Topics: Animals; Arterial Pressure; Biomarkers; Blood Glucose; Cholesterol; Disease Models, Animal; Hypoxia; Insulin; Insulin Resistance; Intra-Abdominal Fat; Leptin; Male; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats, Wistar; RNA, Messenger; Serpins; Sleep Apnea, Obstructive; Time Factors; Triglycerides; Up-Regulation

Undernutrition during brain development causes long lasting alterations in different neurotransmitter systems that may alter responses to psychoactive drugs. Despite the recognized effects of early undernutrition on the cholinergic system, no evidence that demonstrates the influence of this insult on nicotine susceptibility has been reported. We investigated the effects of protein/calorie restriction during lactation on the susceptibility to nicotine in adolescent mice. Dams were randomly assigned to one of the following groups: Control (C, 20 litters)--free access to standard laboratory diet (23% protein); Protein Restricted (PR, 12 litters)--free access to a isoenergetic, 8% protein diet; Calorie Restricted (CR, 12 litters)--access to standard laboratory diet in restricted quantities (mean ingestion of PR: pair-fed group). Undernutrition extended from postnatal day 2 (PN2) to weaning (PN21). At PN30, animals either received an i.p. injection of nicotine (0.5mg/Kg) or saline and were immediately placed in open field (OF). After the OF, adrenal glands and serum were collected for the analyses of stress-related endocrine parameters and leptin concentration. PR and CR offspring showed less body mass gain and visceral fat mass. PR offspring presented reduced serum leptin concentration. In the OF, nicotine increased locomotor activity of C and PR, but not of CR. CR and PR offspring showed decreased adrenal catecholamine content, which was not dependent on nicotine exposure. Our results indicate that early undernutrition interferes with nicotine-elicited locomotor effects in adolescent mice and suggest that endocrine parameters alterations in malnourished animals do not influence the behavioral response to nicotine.

Topics: Adrenal Medulla; Animals; Animals, Newborn; Body Mass Index; Caloric Restriction; Catecholamines; Diet, Protein-Restricted; Disease Models, Animal; Eating; Exploratory Behavior; Fats; Female; Hormones; Lactation; Leptin; Locomotion; Male; Malnutrition; Mice; Nicotine; Nicotinic Agonists

The involvement of the opioid system in energy balance has been known for several decades but many questions remain unanswered. Therefore, this study was designed to investigate the effect of the non-selective opioid receptor antagonist (LY255582) on high fat diet (HFD)-induced obesity.. Twenty-four adult male albino rats were divided into 4 groups: Control, HFD non-treated, HFD+LY255582 treated during the first 4 weeks and Obese-LY255582- treated groups during the following 4 weeks after the induction of obesity. LY255582 (0.31 mg/kg, s.c.) was administrated daily with HFD feeding. Blood samples were collected for measurement of lipid profile, glucose, insulin, and leptin. Body weight, body mass index (BMI), and food intake were also measured.. Consumption of HFD resulted in a significant increase in body weight, body mass index (BMI), glucose, insulin, leptin levels, and induced a state of dyslipideamia. Opioid antagonist LY255582 administration with HFD decreased food intake, body weight and BMI, in addition to the improvement of HFD related metabolic abnormalities (dyslipidemia and insulin resistance) during the dynamic phase of obesity development than in animals with already developed dietary obesity.. The use of opioid antagonist may be a promising approach in treatment of HFD-induced obesity.

Topics: Animals; Anti-Obesity Agents; Biomarkers; Blood Glucose; Body Mass Index; Cyclohexanes; Diet, High-Fat; Disease Models, Animal; Eating; Insulin; Leptin; Lipids; Male; Narcotic Antagonists; Obesity; Piperidines; Rats, Sprague-Dawley; Receptors, Opioid; Time Factors

The potential of natural products to prevent obesity have been investigated, with evidence to suggest that chitosan has anti-obesity effects. The current experiment investigated the anti-obesity potential of prawn shell derived chitosan on a range of variables relevant to obesity in a pig model. The two dietary treatment groups included in this 63 day study were: T1) basal diet and T2) basal diet plus 1000 ppm chitosan (n = 20 gilts per group (70 ± 0.90 kg). The parameter categories which were assessed included: performance, nutrient digestibility, serum leptin concentrations, nutrient transporter and digestive enzyme gene expression and gut microbial populations. Pigs offered chitosan had reduced feed intake and final body weight (P< 0.001), lower ileal digestibility of dry matter (DM), gross energy (GE) (P< 0.05) and reduced coefficient of apparent total tract digestibility (CATTD) of gross energy and nitrogen (P<0.05) when compared to the basal group. Fatty acid binding protein 2 (FABP2) gene expression was down-regulated in pigs offered chitosan (P = 0.05) relative to the basal diet. Serum leptin concentrations increased (P< 0.05) in animals offered the chitosan diet compared to pigs offered the basal diet. Fatness traits, back-fat depth (mm), fat content (kg), were significantly reduced while lean meat (%) was increased (P<0.05) in chitosan supplemented pigs. Pigs offered chitosan had decreased numbers of Firmicutes in the colon (P <0.05), and Lactobacillus spp. in both the caecum (P <0.05) and colon (P <0.001). Bifidobacteria populations were increased in the caecum of animals offered the chitosan diet (P <0.05). In conclusion, these findings suggest that prawn shell chitosan has potent anti-obesity/body weight control effects which are mediated through multiple biological systems in vivo.

Topics: Animal Shells; Animals; Body Weight; Chitosan; Dietary Supplements; Disease Models, Animal; Eating; Gastrointestinal Tract; Leptin; Microbiota; Nephropidae; Obesity; Swine

αMUPA transgenic mice spontaneously consume less food compared with their wild type (WT) ancestors due to endogenously increased levels of the satiety hormone leptin. αMUPA mice share many benefits with mice under caloric restriction (CR) including an extended life span. To understand mechanisms linked to cardiac aging, we explored the response of αMUPA hearts to ischemic conditions at the age of 6, 18, or 24 months. Mice were subjected to myocardial infarction (MI) in vivo and to ischemia/reperfusion ex vivo. Compared to WT mice, αMUPA showed functional and histological advantages under all experimental conditions. At 24 months, none of the WT mice survived the first ischemic day while αMUPA mice demonstrated 50% survival after 7 ischemic days. Leptin, an adipokine decreasing under CR, was consistently ~60% higher in αMUPA sera at baseline. Leptin levels gradually increased in both genotypes 24h post MI but were doubled in αMUPA. Pretreatment with leptin neutralizing antibodies or with inhibitors of leptin signaling (AG-490 and Wortmannin) abrogated the αMUPA benefits. The antibodies also reduced phosphorylation of the leptin signaling components STAT3 and AKT specifically in the αMUPA myocardium. αMUPA mice did not show elevation in adiponectin, an adipokine previously implicated in CR-induced cardioprotection. WT mice treated for short-term CR exhibited cardioprotection similar to that of αMUPA, however, along with increased adiponectin at baseline. Collectively, the results demonstrate a life-long increased ischemic tolerance in αMUPA mice, indicating the attenuation of cardiac aging. αMUPA cardioprotection is mediated through endogenous leptin, suggesting a protective pathway distinct from that elicited under CR.

Topics: Adipokines; Animals; Biomarkers; Cellular Senescence; Disease Models, Animal; Echocardiography; Heart Ventricles; Kaplan-Meier Estimate; Leptin; Mice; Mice, Transgenic; Myocardial Infarction; Myocardium; Proto-Oncogene Proteins c-akt; Signal Transduction; STAT3 Transcription Factor; Tyrphostins; Ventricular Function

Maternal stress exerts long-lasting postnatal growth on offspring, which persist into adulthood. However, the effect of maternal stress on appetizing system has not been widely reported. In this study, we found that maternal immobilization stress (IS) during lactation resulted in low body weight and food intake. Immunohistochemistry showed an increase in stomach ghrelin protein expression. The central regulation of body weight and food intake occurs in the hypothalamus, which contains multiple neuronal systems that play important roles in the regulation of energy homeostasis. These systems including multiple neuropeptides involve in the ghrelin pathway of appetite regulation. Therefore, real time reverse transcription polymerase chain reaction (RT-PCR) was used to measure the change of mRNA expression of ghrelin pathway related hormones in order to explore the mechanisms involved in the appetite regulation. Expression levels of the hypothalamic 5-hydroxytryptamine 2c receptor (5-HT2cR) and 5-HT2bR, which are essential for the development and function of ghrelin and leptin, were decreased, as well as those of corticotrophin releasing factor (CRF) and pro-opiomelanocortin (POMC). While the expression of growth hormone secretagogue receptor (GHSR), neuropeptide-Y (NPY) and agouti-related protein (AgRP) showed an increase with significant difference. These results suggest that stress in a postpartum mother has persistent effects on the body weight of their offspring. Increased ghrelin and decreased leptin expression in the stomach may play a role in these effects.

Topics: Agouti Signaling Protein; Animals; Appetite Regulation; Corticotropin-Releasing Hormone; Disease Models, Animal; Eating; Feeding Behavior; Female; Gastric Mucosa; Ghrelin; Hypothalamus; Lactation; Leptin; Maternal Exposure; Mice, Inbred ICR; Neuropeptide Y; Postpartum Period; Pro-Opiomelanocortin; Receptor, Serotonin, 5-HT2B; Receptor, Serotonin, 5-HT2C; Receptors, Ghrelin; Restraint, Physical; Stress, Psychological; Time Factors; Weight Gain

Reduced growth hormone (GH) action is associated with extended longevity in many vertebrate species. GH receptor (GHR) null (GHR(-)(/-)) mice, which have a disruption in the GHR gene, are a well-studied example of mice that are insulin sensitive and long lived yet obese. However, unlike other mouse lines with reduced GH action, GH receptor antagonist (GHA) transgenic mice have reduced GH action yet exhibit a normal, not extended, life span. Understanding why GHA mice do not have extended life span though they share many physiological attributes with GHR(-)(/-) mice will help provide clues about how GH influences aging. For this study, we examined age- and sex-related changes in body composition, glucose homeostasis, circulating adipokines, and tissue weights in GHA mice and littermate controls. Compared with previous studies with GHR(-)(/-) mice, GHA mice had more significant increases in fat mass with advancing age. The increased obesity resulted in significant adipokine changes. Euglycemia was maintained in GHA mice; however, hyperinsulinemia developed in older male GHA mice. Overall, GHA mice experience a more substantial, generalized obesity accompanied by altered adipokine levels and glucose homeostasis than GHR(-)(/-) mice, which becomes more exaggerated with advancing age and which likely contributes to the lack of life-span extension in these mice.

Topics: Adiponectin; Adiposity; Animals; Blood Glucose; Disease Models, Animal; Female; Growth Hormone; Insulin; Insulin-Like Growth Factor I; Leptin; Longevity; Male; Mice; Mice, Transgenic; Receptors, Somatotropin; Sex Factors

Aging leads to increased insulin resistance and arterial dysfunction, with oxidative stress playing an important role. This study explored the metabolic and arterial effects of a chronic treatment with resveratrol, an antioxidant polyphenol compound that has been shown to restore insulin sensitivity and decrease oxidative stress, in old mice with or without a high-protein diet renutrition care. High-protein diet tended to increase insulin resistance and atheromatous risk. Resveratrol improved insulin sensitivity in old mice fed standard diet by decreasing homeostasis model of assessment-insulin resistance and resistin levels. However, resveratrol did not improve insulin resistance status in old mice receiving the high-protein diet. In contrast, resveratrol exhibited deleterious effects by increasing inflammation state and superoxide production and diminishing aortic distensibility. In conclusion, we demonstrate that resveratrol has beneficial or deleterious effects on insulin sensitivity and arterial function, depending on nutritional status in our models.

Topics: Aging; Animals; Antioxidants; Aorta; Blood Glucose; Chemokine CCL5; Chemokine CXCL1; Dietary Proteins; Disease Models, Animal; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Nutritional Status; Oxidative Stress; Phenols; Resistin; Resveratrol; Ribonucleotide Reductases; Serum Albumin; Stilbenes; Superoxides; Tumor Necrosis Factor-alpha; Vascular Capacitance; Vascular Diseases; Vasodilation

In this study, to evaluate the anti-obesity effects of fermented red ginseng (FG), levan (L), and their combination (FGL), we investigated their effects on the weights of body, liver and white adipose tissue, lipid profiles, and biomarkers for insulin resistance in high fat diet (HFD)-induced obese C57BL/6J male mice. Furthermore, the levels of leptin in the serum were measured. FG (150 mg/kg/d), L (100 mg/kg/d), and FGL (150 mg/kg/d of FG plus 100 mg/kg/d of L) were administered orally to mice daily for 11 weeks. After 11 weeks feeding, FGL showed significantly lower body weight and fat mass with decreasing food efficiency ratio than the HFD control mice. In addition, the FGL group was significantly lower in the levels of total cholesterol and fasting blood glucose and score of the homeostatic model assessment of insulin resistance. Furthermore, FGL decreased serum leptin levels compared to the HFD control group. Taken together, FGL showed a significant anti-obesity effect in HFD-induced obese mice and prevent insulin and leptin resistance. FGL may be potentially useful for the prevention of obesity.

Topics: Adipose Tissue, White; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Cholesterol; Diet, High-Fat; Disease Models, Animal; Fermentation; Fructans; Hyperlipidemias; Insulin; Insulin Resistance; Leptin; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Panax; Plant Extracts

Anxiety and depression are common in diabetics. Diabetes also may cause reduced leptin levels in the blood. We investigated the relation between diabetes induced anxiety- and depression-like behavior, and leptin and leptin receptor expression levels in diabetic rats. The anxiety- and depression-like behaviors of rats were assessed 4 weeks after intraperitoneal injection of streptozotocin. Diabetic rats exhibited greater anxiety-like behavior; they spent more time in closed branches of the elevated plus maze test and less time in the center cells of the open field arena. Increased depression-like behavior was observed in diabetic rats using the Porsolt swim test. Prefrontal cortex (PFC), blood leptin levels and PFC neuron numbers were decreased, and leptin receptor expression and apoptosis were increased in diabetic rats. Blood corticosterone levels also were increased in diabetic rats. These results indicate that reduction of leptin up-regulates leptin receptor expression and may affect PFC neurons, which eventually triggers anxiety- and depression-like behaviors in diabetic rats.

Topics: Animals; Anxiety; Behavior, Animal; Corticosterone; Depression; Diabetes Mellitus, Experimental; Disease Models, Animal; Leptin; Male; Neurons; Prefrontal Cortex; Rats, Wistar; Receptors, Leptin; Streptozocin

Short sleep confers a higher risk of obesity in humans. Restricted sleep increases appetite, promotes higher calorie intake from fat and carbohydrate sources, and induces insulin resistance. However, the effects of fragmented sleep (SF), such as occurs in sleep apnea, on body weight, metabolic rates, and adipose tissue distribution are unknown.. C57BL/6 mice were exposed to SF for 8 weeks. Their body weight, food consumption, and metabolic expenditure were monitored over time, and their plasma leptin levels measured after exposure to SF for 1 day as well as for 2 weeks. In addition, adipose tissue distribution was assessed at the end of the SF exposure using MRI techniques.. Chronic SF-induced obesogenic behaviors and increased weight gain in mice by promoting increased caloric intake without changing caloric expenditure. Plasma leptin levels initially decreased and subsequently increased. Furthermore, increases in both visceral and subcutaneous adipose tissue volumes occurred.. These results suggest that SF, a frequent occurrence in many disorders and more specifically in sleep apnea, is a potent inducer of obesity via activation of obesogenic behaviors and possibly leptin resistance, in the absence of global changes in energy expenditure.

Topics: Animals; Body Fat Distribution; Calorimetry, Indirect; Disease Models, Animal; Energy Intake; Homeostasis; Intra-Abdominal Fat; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Sleep Deprivation; Subcutaneous Fat; Weight Gain

Recruitment of alveolar microvascular reserves, assessed from the relationship between pulmonary diffusing capacity (DLCO) and perfusion (Q˙c), is critical to the maintenance of arterial blood oxygenation. Leptin-resistant ZDF fatty diabetic (fa/fa) rats exhibit restricted cardiopulmonary physiology under anesthesia. To assess alveolar microvascular function in conscious, non-sedated, non-instrumented, and minimally restrained animals, we adapted a rebreathing technique to study fa/fa and control non-diabetic (+/+) rats (4-5 and 7-11mo old) at rest and during mild spontaneous activity. Measurements included O2 uptake, lung volume, Q˙c, DLCO, membrane diffusing capacity (DMCO), capillary blood volume (Vc) and septal tissue-blood volume. In older fa/fa than +/+ animals, DLCO and DMCO at a given Q˙c were lower; Vc was reduced in proportion to Q˙c. Results demonstrate the consequences of alveolar microangiopathy in the metabolic syndrome: lung volume restriction, reduced Q˙c, and elevated membrane resistance to diffusion. At a given Q˙c, DLCO is lower in rats and guinea pigs than dogs or humans, consistent with limited alveolar microvascular reserves in small animals.

Topics: Age Factors; Animals; Capillaries; Consciousness; Disease Models, Animal; Leptin; Male; Obesity; Pulmonary Alveoli; Pulmonary Circulation; Pulmonary Diffusing Capacity; Pulmonary Gas Exchange; Rats; Rats, Transgenic

The arcuate nucleus (ARC) of the hypothalamus plays a key role in sensing metabolic feedback and regulating energy homeostasis. Recent studies revealed activation of microglia in mice with high-fat diet (HFD)-induced obesity (DIO), suggesting a potential pathophysiological role for inflammatory processes within the hypothalamus. To further investigate the metabolic causes and molecular underpinnings of such glial activation, we analyzed the microglial activity in wild-type (WT), monogenic obese ob/ob (leptin deficient), db/db (leptin-receptor mutation), and Type-4 melanocortin receptor knockout (MC4R KO) mice on either a HFD or on standardized chow (SC) diet. Following HFD exposure, we observed a significant increase in the total number of ARC microglia, immunoreactivity of ionized calcium binding adaptor molecule 1 (iba1-ir), cluster of differentiation 68 (CD68-ir), and ramification of microglial processes. The ob/ob mice had significantly less iba1-ir and ramifications. Leptin replacement rescued these phenomena. The db/db mice had similar iba1-ir comparable with WT mice but had significantly lower CD68-ir and more ramifications than WT mice. After 2 weeks of HFD, ob/ob mice showed an increase of iba1-ir, and db/db mice showed increase of CD68-ir. Obese MC4R KO mice fed a SC diet had comparable iba1-ir and CD68-ir with WT mice but had significantly more ramifications than WT mice. Intriguingly, treatment of DIO mice with glucagon-like peptide-1 receptor agonists reduced microglial activation independent of body weight. Our results show that diet type, adipokines, and gut signals, but not body weight, affect the presence and activity levels of hypothalamic microglia in obesity.

Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Body Weight; Cytokinins; Diet, High-Fat; Disease Models, Animal; Exenatide; Hormones; Leptin; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Obesity; Peptides; Receptor, Melanocortin, Type 4; Receptors, Interleukin-8A; Receptors, Leptin; Signal Transduction; Supraoptic Nucleus; Venoms

The role of leptin in the mucosal immune response to Clostridium difficile colitis, a leading cause of nosocomial infection, was studied in humans and in a murine model. Previously, a mutation in the receptor for leptin (LEPR) was shown to be associated with susceptibility to infectious colitis and liver abscess due to Entamoeba histolytica as well as to bacterial peritonitis. Here we discovered that European Americans homozygous for the same LEPR Q223R mutation (rs1137101), known to result in decreased STAT3 signaling, were at increased risk of C. difficile infection (odds ratio, 3.03; P = 0.015). The mechanism of increased susceptibility was studied in a murine model. Mice lacking a functional leptin receptor (db/db) had decreased clearance of C. difficile from the gut lumen and diminished inflammation. Mutation of tyrosine 1138 in the intracellular domain of LepRb that mediates signaling through the STAT3/SOCS3 pathway also resulted in decreased mucosal chemokine and cell recruitment. Collectively, these data support a protective mucosal immune function for leptin in C. difficile colitis partially mediated by a leptin-STAT3 inflammatory pathway that is defective in the LEPR Q223R mutation. Identification of the role of leptin in protection from C. difficile offers the potential for host-directed therapy and demonstrates a connection between metabolism and immunity.

Topics: Animals; Chemokines; Clostridioides difficile; Clostridium Infections; Colitis; Cytokines; Disease Models, Animal; Flow Cytometry; Genetic Predisposition to Disease; Intestinal Mucosa; Intestines; Leptin; Logistic Models; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Odds Ratio; Polymorphism, Genetic; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor; Tyrosine

Leptin's in vivo effect on the rodent skeleton depends on the model used and the mode of administration. Superactive mouse leptin antagonist (SMLA) was produced and then pegylated (PEG) to prolong and enhance its in vivo activity. We blocked leptin signaling by injecting this antagonist peripherally into normal mice at various time points and studied their metabolic and skeletal phenotypes. Subcutaneous PEG-SMLA injections into 4-wk-old female C57BL/6J mice increased weight gain and food consumption significantly after only 1 mo, and the effect lasted for the 3 mo of the experiment, proving its central inhibiting activity. Mice showed a significant increase in serum glucose, cholesterol, triglycerides, insulin, and HOMA-IR throughout the experiment. Quantification of gene expression in "metabolic" tissues also indicated the development of insulin resistance. Bone analyses revealed a significant increase in trabecular and cortical parameters measured in both the lumbar vertebrae and tibiae in PEG-SMLA-treated mice in the 1st and 3rd months as well as a significant increase in tibia biomechanical parameters. Interestingly, 30 days of treatment with the antagonist in older mice (aged 3 and 6 mo) affected body weight and eating behavior, just as they had in the 1-mo-old mice, but had no effect on bone parameters, suggesting that leptin's effect on bones, either directly or through its obesogenic effect, is dependent upon stage of skeletal development. This potent and reversible antagonist enabled us to study leptin's in vivo role in whole body and bone metabolism and holds potential for future therapeutic use in diseases involving leptin signaling.

Topics: Animals; Biomechanical Phenomena; Blood Glucose; Body Weight; Bone and Bones; Cholesterol; Diabetes Mellitus, Type 2; Disease Models, Animal; Eating; Female; Gene Expression; Insulin; Insulin Resistance; Leptin; Metabolic Syndrome; Metabolism; Mice; Mice, Inbred C57BL; Triglycerides

Obesity is characterized by an increased recruitment of proinflammatory macrophages to the adipose tissue (AT), leading to systemic inflammation and metabolic disease. The pathogenesis of this AT inflammation, however, remains to be elucidated. The circulating adipokine leptin is increased in obesity and is involved in immune cell function and activation. In the present study, we investigated the role of leptin in the induction of obesity-associated inflammation. We generated radiation chimeric C57BL/6J mice reconstituted with either leptin receptor-deficient (db/db) or wild-type (WT) bone marrow and challenged them with a high-fat diet (HFD) for 16 weeks. Mice reconstituted with db/db bone marrow (WT/db), had significantly lower body weight and adiposity compared with mice with WT bone marrow (WT/WT). Gonadal AT in WT/db mice displayed a 2-fold lower expression of the inflammatory genes Tnfa, Il6, and Ccl2. In addition, gonadal fat of WT/db mice contained significantly fewer crown-like structures compared with WT/WT mice, and most of their AT macrophages expressed macrophage galactose-type C type lectin 1 (MGL1) and were C-C chemokine receptor type 2 (CCR2)-negative, indicative of an anti-inflammatory phenotype. Moreover, WT/db mice exhibited greater insulin sensitivity compared with WT/WT mice. These data show that disrupted leptin signaling in bone marrow-derived cells attenuates the proinflammatory conditions that mediate many of the metabolic complications that characterize obesity. Our findings establish a novel mechanism involved in the regulation of obesity-associated systemic inflammation and support the hypothesis that leptin is a proinflammatory cytokine.

Topics: Adipose Tissue; Animal Feed; Animals; Body Composition; Bone Marrow; Diet, High-Fat; Disease Models, Animal; Gene Expression Profiling; Gene Expression Regulation; Immunohistochemistry; Inflammation; Leptin; Macrophages; Male; Mice; Mice, Inbred C57BL; Obesity; Receptors, Leptin; Signal Transduction

In the present study, the ability of metformin to inhibit skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA) was analyzed in mice maintained on either an overweight control diet or an obesity-inducing diet. Rapamycin was included for comparison, and a combination of metformin and rapamycin was also evaluated. Metformin (given in the drinking water) and rapamycin (given topically) inhibited development of both papillomas and squamous cell carcinomas in overweight and obese mice in a dose-dependent manner. A low-dose combination of these two compounds displayed an additive inhibitory effect on tumor development. Metformin treatment also reduced the size of papillomas. Interestingly, all treatments seemed to be at least as effective for inhibiting tumor formation in obese mice, and both metformin and rapamycin were more effective at reducing tumor size in obese mice compared with overweight control mice. The effect of metformin on skin tumor development was associated with a significant reduction in TPA-induced epidermal hyperproliferation. Furthermore, treatment with metformin led to activation of epidermal AMP-activated protein kinase (AMPK) and attenuated signaling through mTOR complex (mTORC)-1 and p70S6K. Combinations of metformin and rapamycin were more effective at blocking epidermal mTORC1 signaling induced by TPA consistent with the greater inhibitory effect on skin tumor promotion. Collectively, the current data demonstrate that metformin given in the drinking water effectively inhibited skin tumor promotion in both overweight and obese mice and that the mechanism involves activation of epidermal AMPK and attenuated signaling downstream of mTORC1.

Topics: Adenylate Kinase; Adiponectin; Animals; Body Weight; Carcinogenesis; Carcinoma, Squamous Cell; Diet; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Insulin; Insulin-Like Growth Factor I; Leptin; Mechanistic Target of Rapamycin Complex 1; Metformin; Mice; Mice, Obese; Multiprotein Complexes; Neoplasms, Experimental; Obesity; Overweight; Papilloma; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; Skin Neoplasms; Tetradecanoylphorbol Acetate; TOR Serine-Threonine Kinases

Adipose tissue secretes various proteins referred to as adipokines, being involved in inflammation. It was recognized that mesenteric adipose tissue (MAT) is altered by inflammation, and pathologies such as inflammatory bowel disease (IBD). The aim of this study was to investigate the alterations of the mesenteric adipose tissue in two experimental colitis models in mice adapted to obtain moderate colonic inflammation.. Colonic inflammation was obtained using two models, either DSS dissolved in drinking water or intra-colonic instillation of DNBS. The expression of adipokines (leptin and adiponectin) and inflammatory markers (IL-6, MCP-1, F4/80) was studied by qRT-PCR in the MAT of treated and control mice.. Observations of the colon and IL-6 plasma level determination demonstrated that DNBS treatment led to stronger inflammation. Colitis induced a decrease of mRNA encoding to leptin and adiponectin in MAT. In contrast, colonic inflammation led to an increase of mRNA encoding to IL-6, MCP-1 and F4/80, a specific marker of macrophages.. The mesenteric adipose tissue, in two models of moderate colitis, shows a loss of adipose profile and a strong increase of inflammatory pattern, close to the observations made in MAT of IBD patients. These data suggest that these pro-inflammatory modifications of MAT have to be taken into account in the pathophysiology of IBD.

Topics: Adiponectin; Adipose Tissue; Animals; Colitis; Dextran Sulfate; Dinitrofluorobenzene; Disease Models, Animal; Inflammation; Inflammation Mediators; Inflammatory Bowel Diseases; Leptin; Male; Mice; Mice, Inbred BALB C; Proteasome Endopeptidase Complex; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Parkinson's disease (PD) patients frequently display loss of body fat mass and increased energy expenditure, and several studies have outlined a relationship between these metabolic abnormalities and disease severity, yet energy metabolism is largely unstudied in mouse models of PD. Here we characterize metabolic and physiologic responses to a high calorie diet (HCD) in mice expressing in neurons a mutant form of human α-synuclein (A53T) that causes dominantly inherited familial forms of the disease. A53T (SNCA) and wild type (WT) littermate mice were placed on a HCD for 12 weeks and evaluated for weight gain, food intake, body fat, blood plasma leptin, hunger, glucose tolerance, and energy expenditure. Results were compared with both SNCA and WT mice on a control diet. Despite consuming similar amounts of food, WT mice gained up to 66% of their original body weight on a HCD, whereas SNCA mice gained only 17%. Further, after 12 weeks on a HCD, magnetic resonance imaging analysis revealed that WT mice had significantly greater total and visceral body fat compared with SNCA mice (p < 0.007). At the age of 24 weeks SNCA mice displayed significantly increased hunger compared with WT (p < 0.03). At the age of 36 weeks, SNCA mice displayed significant hypoleptinemia compared with WT, both on a normal diet and a HCD (p < 0.03). The HCD induced insulin insensitivity in WT, but not SNCA mice, as indicated by an oral glucose tolerance test. Finally, SNCA mice displayed greater energy expenditure compared with WT, as measured in a Comprehensive Laboratory Animal Monitoring System, after 12 weeks on a HCD. Thus, SNCA mice are resistant to HCD-induced obesity and insulin resistance and display reduced body fat, increased hunger, hypoleptinemia and increased energy expenditure. Our findings reveal a profile of metabolic dysfunction in a mouse model of PD that is similar to that of human PD patients, thus providing evidence that α-synuclein pathology is sufficient to drive such metabolic abnormalities and providing an animal model for discovery of the underlying mechanisms and potential therapeutic interventions.

Topics: Adipose Tissue; alpha-Synuclein; Animals; Disease Models, Animal; Energy Intake; Energy Metabolism; Insulin Resistance; Leptin; Male; Mice; Mutation; Parkinson Disease

Endometriosis pain is a very common and extremely disabling condition whose mechanism is still poorly understood. While increased levels of leptin have been reported in patients with endometriosis, their contribution to endometriosis pain has not been explored. Using a rodent model of endometriosis we provide evidence for an estrogen-dependent contribution of leptin in endometriosis-induced pain. Rats implanted with autologous uterine tissue onto the gastrocnemius muscle developed endometriosis-like lesions and local chronic pain. Compared to eutopic uterine tissue, leptin mRNA and protein were up-regulated in the endometriosis-like lesions. Intramuscular injection of recombinant leptin in naive rats produced dose-dependent local mechanical hyperalgesia and nociceptor sensitization to mechanical stimulation. Ovariectomy attenuated the mechanical hyperalgesia induced by recombinant leptin, in rats treated with vehicle compared to those treated with 17β-estradiol replacement, at 1 and 24 h after leptin injection. Finally, intralesional injections of a pegylated leptin receptor (Ob-R) antagonist or of an inhibitor of Janus kinase2, which transduces the Ob-R signal, markedly attenuated pain in the endometriosis model. Taken together these data support the hypothesis that leptin, generated in ectopic endometrial lesions produces mechanical hyperalgesia by acting on nociceptors innervating the lesion. This sensitivity to leptin is dependent on estrogen levels. Thus, interventions targeting leptin signaling, especially in combination with interventions that lower estrogen levels, might be useful for the treatment of endometriosis pain.

Topics: Animals; Chronic Pain; Disease Models, Animal; Endometriosis; Endometrium; Enzyme Inhibitors; Estradiol; Estrogens; Female; Hyperalgesia; Janus Kinase 2; Leptin; Muscle, Skeletal; Nociceptors; Ovariectomy; Rats; Rats, Sprague-Dawley; Receptors, Leptin; RNA, Messenger; Touch; Uterus

In postmenopausal women the mechanisms responsible for hypertension have not been completely elucidated, and there are no gender-specific guidelines for women despite studies showing that blood pressure is not as well controlled to goal in women as in men. In the present study we tested the hypotheses that the sympathetic nervous system and the renal sympathetic nerves contribute to hypertension in aging female rats, that sympathetic activation may be mediated by the melanocortin 3/4 receptor (MC3/4R), and that MC3/4R activation may be due to increases in leptin. α-1, β-1,2-Adrenergic blockade reduced blood pressure in both young (3-4 mo) and old (18-19 mo) female spontaneously hypertensive rats (SHR). Renal denervation attenuated the hypertension more in old females than young females. MC3/4R antagonism with SHU-9119 given intracerebroventricularly had no effect on blood pressure in either young or old females but significantly reduced blood pressure in old males. Plasma leptin levels were similar in old male and female SHR and in old versus young females. These data suggest that the hypertension in old female SHR is in part due to activation of the sympathetic nervous system, that the renal nerves contribute to the hypertension, and that the mechanism responsible for sympathetic activation in old females is independent of the MC3/4R.

Topics: Age Factors; Animals; Blood Pressure; Denervation; Disease Models, Animal; Female; Hypertension; Kidney; Leptin; Melanocyte-Stimulating Hormones; Postmenopause; Rats; Rats, Inbred SHR; Receptor, Melanocortin, Type 2; Receptor, Melanocortin, Type 3; Sympathetic Nervous System

Obesity induced by high-fat (HF) diets increases bone resorption, decreases trabecular bone mass, and reduces bone strength in various animal models. This study investigated whether N-acetylcysteine (NAC), an antioxidant and a glutathione precursor, alters glutathione status and mitigates bone microstructure deterioration in mice fed an HF diet. Forty-eight 6-wk-old male C57BL/6 mice were randomly assigned to 4 treatment groups (n = 12 per group) and fed either a normal-fat [NF (10% energy as fat)] or an HF (45% energy as fat) diet ad libitum with or without NAC supplementation at 1 g/kg diet for 17 wk. Compared with the NF groups, mice in the HF groups had higher body weight, greater serum leptin concentrations and osteoclast differentiation, and lower trabecular bone volume, trabecular number, and connectivity density (P < 0.05). NAC supplementation increased the serum-reduced glutathione concentration and bone volume and decreased osteoclast differentiation in HF-fed mice (P < 0.05). We further demonstrated that osteoclast differentiation was directly regulated by glutathione status. NAC treatment of murine macrophage RAW 264.7 cells in vitro increased glutathione status and decreased osteoclast formation. These results show that NAC supplementation increases the bone mass of obese mice induced by an HF diet through elevating glutathione status and decreasing bone resorption.

Topics: Acetylcysteine; Animals; Antioxidants; Body Weight; Bone Density; Bone Resorption; Cell Differentiation; Cell Line, Tumor; Diet, High-Fat; Dietary Fats; Dietary Supplements; Disease Models, Animal; Glutathione; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Osteoclasts

Maternal undernutrition leads to an increased risk of metabolic disorders in offspring including obesity and insulin resistance, thought to be due to a programmed thrifty phenotype which is inappropriate for a subsequent richer nutritional environment. In a rat model, both male and female offspring of undernourished mothers are programmed to become obese, however postnatal leptin treatment gives discordant results between males and females. Leptin treatment is able to rescue the adverse programming effects in the female offspring of undernourished mothers, but not in their male offspring. Additionally, in these rats, postnatal leptin treatment of offspring from normally-nourished mothers programmes their male offspring to develop obesity in later life, while there is no comparable effect in their female offspring.. We show by microarray analysis of the female liver transcriptome that both maternal undernutrition and postnatal leptin treatment independently induce a similar thrifty transcriptional programme affecting carbohydrate metabolism, amino acid metabolism and oxidative stress genes. Paradoxically, however, the combination of both stimuli restores a more normal transcriptional environment. This demonstrates that "leptin reversal" is a global phenomenon affecting all genes involved in fetal programming by maternal undernourishment and leptin treatment. The thrifty transcriptional programme was associated with pro-inflammatory markers and downregulation of adaptive immune mediators, particularly MHC class I genes, suggesting a deficit in antigen presentation in these offspring.. We propose a revised model of developmental programming reconciling the male and female observations, in which there are two competing programmes which collectively drive liver transcription. The first element is a thrifty metabolic phenotype induced by early life growth restriction independently of leptin levels. The second is a homeostatic set point calibrated in response to postnatal leptin surge, which is able to over-ride the metabolic programme. This "calibration model" for the postnatal leptin surge, if applicable in humans, may have implications for understanding responses to catch-up growth in infants. Additionally, the identification of an antigen presentation deficit associated with metabolic thriftiness may relate to a previously observed correlation between birth season (a proxy for gestational undernutrition) and infectious disease mortality in rural African communities.

Topics: Amino Acids; Animals; Carbohydrate Metabolism; Diet; Disease Models, Animal; Female; Fetal Development; Fetal Nutrition Disorders; Histocompatibility Antigens Class I; Inflammation Mediators; Leptin; Liver; Male; Obesity; Oxidative Stress; Phenotype; Pregnancy; Rats; Rats, Wistar; Transcriptome

Leptin, an adipocyte-derived hormone, has well-established anorexigenic effects but is also able to regulate glucose homeostasis independent of body weight. Until recently, the ob/ob mouse was the only animal model of global leptin deficiency. Here we report the effects of leptin deficiency on glucose homeostasis in male and female leptin knockout (KO) rats. Leptin KO rats developed obesity by 6 to 7 weeks of age, and lipid mass was increased by more than 2-fold compared with that of wild-type (WT) littermates at 18 weeks of age. Hyperinsulinemia and insulin resistance were evident in both males and females and were sustained with aging. Male KO rats experienced transient mild fasting hyperglycemia between 14 and 25 weeks of age, but thereafter fasting glucose levels were comparable to those of WT littermates up to 36 weeks of age. Fasting glucose levels of female KO rats were similar to those of WT littermates. Male KO rats exhibited a 3-fold increase in the proportion of β-cell area relative to total pancreas at 36 weeks of age. Islets from 12-week-old KO rats secreted more insulin when stimulated than islets from WT littermates. Leptin replacement via miniosmotic pump (100 μg/d) reduced food intake, attenuated weight gain, normalized glucose tolerance, and improved glucose-stimulated insulin secretion and insulin sensitivity. Together, these data demonstrate that the absence of leptin in rats recapitulates some of the phenotype previously observed in ob/ob mice including development of hyperinsulinemia, obesity, and insulin resistance.

Topics: Animals; Blood Glucose; Body Composition; Body Weight; Disease Models, Animal; Female; Glucose Tolerance Test; Homeostasis; Hyperinsulinism; Insulin; Insulin Resistance; Islets of Langerhans; Leptin; Liver; Male; Muscles; Obesity; Phenotype; Rats; Rats, Sprague-Dawley; Rats, Transgenic

Osteoporosis and overweight/obesity constitute major worldwide public health burdens that are associated with aging. A high proportion of women develop osteoporosis and increased intraabdominal adiposity after menopause. which leads to bone fractures and metabolic disorders. There is no efficient treatment without major side effects for these 2 diseases. We previously showed that the administration of oxytocin (OT) normalizes ovariectomy-induced osteopenia and bone marrow adiposity in mice. Ovariectomized mice, used as an animal model mimicking menopause, were treated with OT or vehicle. Trabecular bone parameters and fat mass were analyzed using micro-computed tomography. Herein, we show that this effect on trabecular bone parameters was mediated through the restoration of osteoblast/osteoclast cross talk via the receptor activator of nuclear factor-κB ligand /osteoprotegerin axis. Moreover, the daily administration of OT normalized body weight and intraabdominal fat depots in ovariectomized mice. Intraabdominal fat mass is more sensitive to OT that sc fat depots, and this inhibitory effect is mediated through inhibition of adipocyte precursor's differentiation with a tendency to lower adipocyte size. OT treatment did not affect food intake, locomotors activity, or energy expenditure, but it did promote a shift in fuel utilization favoring lipid oxidation. In addition, the decrease in fat mass resulted from the inhibition of the adipose precursor's differentiation. Thus, OT constitutes an effective strategy for targeting osteopenia, overweight, and fat mass redistribution without any detrimental effects in a mouse model mimicking the menopause.

Topics: Adipocytes; Adipose Tissue; Animals; Body Weight; Bone Diseases, Metabolic; Cell Culture Techniques; Coculture Techniques; Disease Models, Animal; Female; Leptin; Lipids; Menopause; Mice; Mice, Inbred C57BL; Osteoblasts; Osteoclasts; Osteoporosis; Ovariectomy; Oxygen; Oxytocin; Weight Gain; X-Ray Microtomography

The pathogenesis of diabetic retinopathy (DR) in metabolic syndrome (MetS) and type 2 diabetes (T2D) is not well studied, partly because an appropriate model has not been developed. Recently, we introduced a novel model of spontaneous T2D and MetS that replicates the relevant features of the human disease. In the current study, we investigated the retinal vascular changes in these animals. Experimental DR in streptozotocin (STZ)-injected rodents is described as an inflammatory disease, in which intercellular adhesion molecule 1 (ICAM-1) plays a key role. In comparison, advanced diabetes (HbA1c>10%) in the Nile grass rat (NGR) was associated with lower ICAM-1 protein expression when compared with that in normal or moderately diabetic animals. Vascular cell adhesion molecule 1 (VCAM-1) expression, however, was unaffected by the disease state. As opposed to the STZ-induced model of DR, in diabetic NGRs, most leukocytes accumulated in the retinal arteries. Consistent with the ICAM-1 reduction, leukocyte accumulation was significantly reduced in advanced disease. Similarly, leukocyte adhesions were significantly lower, with elevated plasma triglycerides (>200 mg/dl), and cholesterol (>240 mg/dl). However, these adhesions were significantly higher in animals with higher plasma insulin (>5 μIU/ml) and leptin (>20 ng/ml), suggesting a role for these hormones in diabetic retinal leukostasis. Diabetic NGRs showed substantial retinal endothelial injury, primarily in the microvessels, including vascular tortuosity, obliterated acellular capillaries, and pericyte ghosts. The NGR provides a convenient and realistic model for investigation of retinal changes in MetS/T2D with convincing advantages over the commonly used STZ-induced T1D.

Topics: Adiponectin; Animals; Blood-Retinal Barrier; Cell Adhesion; Diabetes Complications; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Disease Models, Animal; Female; Glycated Hemoglobin; Inflammation; Insulin; Intercellular Adhesion Molecule-1; Leptin; Leukocytes; Lipids; Male; Metabolic Syndrome; Rats; Retina; Retinal Vessels; Streptozocin; Triglycerides; Vascular Cell Adhesion Molecule-1

Obesity is a risk factor for sepsis morbidity and mortality, whereas the hypothalamic-pituitary-adrenal (HPA) axis plays a protective role in the body's defence against sepsis. Sepsis induces a profound systemic immune response and cytokines serve as excellent markers for sepsis as they act as mediators of the immune response. Evidence suggests that the adipokine leptin may play a pathogenic role in sepsis. Mouse endotoxaemic models present with elevated leptin levels and exogenously added leptin increased mortality whereas human septic patients have elevated circulating levels of the soluble leptin receptor (Ob-Re). Evidence suggests that leptin can inhibit the regulation of the HPA axis. Thus, leptin may suppress the HPA axis, impairing its protective role in sepsis. We hypothesised that leptin would attenuate the HPA axis response to sepsis. We investigated the direct effects of an i.p. injection of 2 mg/kg leptin on the HPA axis response to intraperitoneally injected 25 μg/kg lipopolysaccharide (LPS) in the male Wistar rat. We found that LPS potently activated the HPA axis, as shown by significantly increased plasma stress hormones, ACTH and corticosterone, and increased plasma interleukin 1β (IL1β) levels, 2 h after administration. Pre-treatment with leptin, 2 h before LPS administration, did not influence the HPA axis response to LPS. In turn, LPS did not affect plasma leptin levels. Our findings suggest that leptin does not influence HPA function or IL1β secretion in a rat model of LPS-induced sepsis, and thus that leptin is unlikely to be involved in the acute-phase endocrine response to bacterial infection in rats.

Topics: Adrenocorticotropic Hormone; Animals; Disease Models, Animal; Humans; Hypothalamo-Hypophyseal System; Leptin; Lipopolysaccharides; Male; Pituitary-Adrenal System; Rats; Rats, Wistar; Sepsis

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

Exposure to sex steroids is associated with increased breast cancer risk, and adipokines, leptin and adiponectin have been implicated in cancer progression. However, it is not known whether sex steroids affect adipokine secretion in breast tissue.. To elucidate the role of estrogen and tamoxifen on adipokine release in normal human breast tissue and breast cancer.. Microdialysis sampling was used to collect extracellular in vivo leptin and adiponectin from normal human breast tissue in premenopausal healthy volunteers during the menstrual cycle and in postmenopausal women before tamoxifen treatment and after 6 weeks of treatment. In women with breast cancer, microdialysis was performed intratumorally before surgery. In addition, whole normal breast tissue biopsies were cultured ex vivo, and murine breast cancer models were evaluated.. In normal breast tissue, plasma estradiol negatively correlated with local extracellular adiponectin levels (r = -0.34; P < .05) and positively correlated with leptin (r = 0.37; P < .05) and leptin:adiponectin ratio (r = 0.38; P < .05). In postmenopausal women, tamoxifen treatment increased adiponectin (P < 0.05) and decreased leptin (P < .01) and the leptin:adiponectin ratio (P < .01). These in vivo results were confirmed in breast tissue biopsies cultured ex vivo. In patients with breast cancer, extracellular leptin was higher (P < .01) and adiponectin lower (P < .05) in tumors than in normal adjacent breast tissue. In a murine model of breast cancer, estrogen exposure increased leptin secretion (P < .05).. Estrogen exposure may have a critical role in the regulation of adipokines in human breast tissue and may serve as therapeutic targets for treatment and prevention.

Topics: Adiponectin; Adult; Aged; Animals; Antineoplastic Agents, Hormonal; Breast; Breast Neoplasms; Cells, Cultured; Disease Models, Animal; Estradiol; Estrogens; Extracellular Space; Female; Humans; Leptin; Mice; Mice, Inbred BALB C; Mice, Nude; Microdialysis; Middle Aged; Postmenopause; Premenopause; Subcutaneous Fat; Tamoxifen; Young Adult

Adipose tissue has a critical role in energy and metabolic homeostasis, but it is challenging to adapt techniques to modulate adipose function in vivo. Here we develop an in vivo, systemic method of gene transfer specifically targeting adipose tissue using adeno-associated virus (AAV) vectors. We constructed AAV vectors containing cytomegalovirus promoter-regulated reporter genes, intravenously injected adult mice with vectors using multiple AAV serotypes, and determined that AAV2/8 best targeted adipose tissue. Altering vectors to contain adiponectin promoter/enhancer elements and liver-specific microRNA-122 target sites restricted reporter gene expression to adipose tissue. As proof of efficacy, the leptin gene was incorporated into the adipose-targeted expression vector, package into AAV2/8 and administered intravenously to 9- to 10-week-old ob/ob mice. Phenotypic changes were measured over an 8-week period. Leptin mRNA and protein were expressed in adipose and leptin protein was secreted into plasma. Mice responded with reversal of weight gain, decreased hyperinsulinemia and improved glucose tolerance. AAV2/8-mediated systemic delivery of an adipose-targeted expression vector can replace a gene lacking in adipose tissue and correct a mouse model of human disease, demonstrating experimental application and therapeutic potential in disorders of adipose.

Topics: 3' Untranslated Regions; Adiponectin; Adipose Tissue; Animals; Dependovirus; Disease Models, Animal; Gene Targeting; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Humans; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; MicroRNAs; Obesity; Organ Specificity

Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disease that causes death of motor neurons. ALS patients and mouse models of familial ALS display organismal level metabolic dysfunction, which includes increased energy expenditure despite decreased lean mass. The pathophysiological relevance of abnormal energy homeostasis to motor neuron disease remains unclear. Leptin is an adipocyte-derived hormone that regulates whole-animal energy expenditure. Here, we report that placing mutant superoxide dismutase 1 (SOD1) mice in a leptin-deficient background improves energy homeostasis and slows disease progression. Leptin-deficient mutant SOD1 mice possess increased bodyweight and fat mass, as well as decreased energy expenditure. These observations coincide with enhanced survival, improved strength and decreased motor neuron loss. These results suggest that altering whole-body energy metabolism in mutant SOD1 mice can mitigate disease progression. We propose that manipulations that increase fat mass and reduce energy expenditure will be beneficial in the setting of motor neuron disease.

Topics: Amyotrophic Lateral Sclerosis; Animals; Body Weight; Disease Models, Animal; Energy Metabolism; Humans; Leptin; Male; Mice; Motor Neurons; Muscle, Skeletal; Superoxide Dismutase; Superoxide Dismutase-1

Type 1 diabetes is associated with subfertility in humans. The current treatment for type 1 diabetes, insulin monotherapy, is suboptimal to fully stabilize glycemia, potentially leading to this subfertility. Recent work has demonstrated that treatment with the energy-regulating hormone leptin, alone or in combination with insulin, can more effectively control glycemia in mouse models of type 1 diabetes. Here, we sought to determine whether the fertility defects in a type 1 diabetic mouse model, the Akita mouse, can be rescued with leptin monotherapy in the absence of any exogenous insulin. Akita homozygous mice treated with leptin alone had a larger total body size, testes, and seminal vesicles than their untreated siblings. Leptin treatment prevented testicular degeneration and rescued sperm motility to wild-type levels. Furthermore, sperm obtained from leptin-treated mice could successfully fertilize ooctyes in vitro. Despite completely rescuing spermatogenesis, the critical reproductive hormones LH and testosterone were only modestly higher than in untreated mice, indicating that a minimum threshold of these hormones must be met to maintain spermatogenesis. Cumulatively, these findings implicate the importance of leptin in maintaining fertility and support the use of leptin therapy in the treatment of type 1 diabetes.

Topics: Adiposity; Animals; Atrophy; Diabetes Mellitus, Type 1; Disease Models, Animal; Genetic Carrier Screening; Homozygote; Infertility, Male; Leptin; Luteinizing Hormone; Male; Mice; Spermatogenesis; Testosterone

The principal goal of this study was to determine the effect of the photoperiod on oxidative damage biomarkers in rats submitted to different light/darkness patterns, in a hyperlipidemic nephropathy model (induced by adriamycin), as well as its possible relationship with melatonin and leptin secretion rhythms. To test this hypothesis, six different groups were used (N = 6 rats per group): control (12 h/12h light:dark); exposure to permanent illumination (24 h light); exposure to darkness (22 h dark); injected with adriamycin, 12h/12h light:dark; injected with adriamycin + exposure to permanent illumination and injected with adriamycin + exposure to darkness (22 h dark). The different photoperiods were begun two weeks prior to medication and were maintained up to the day of the animal's sacrifice, ten days after medication. The following parameters were analysed: i) weight evolution; ii) in plasma: urea, creatinine, uric acid, total proteins, albumen, lactate dehydrogenase, creatinine-quinase, aspartate aminotransferase, alanine aminotransferase and total cholesterol; iii) in urine: urea, creatinine, total proteins and microalbumen; iv) biomarkers of oxidative damage in kidneys, heart, liver and brain: lipoperoxides, total glutathione, reduced glutathione, catalase, glutathione peroxidase, glutathione reductase and glutathione transferase; v) melatonin (pineal gland tissue and plasma) and leptin (plasma). From the results obtained it was concluded that the administration of adriamycin generated oxidative stress in renal, cerebral, hepatic and cardiac tissue. Additionally, in the healthy animal, but of a lesser relevance in the adriamycin animal, permanent light worsened the oxidative stress, whereas darkness improved it. This could be related to the circadian rhythm of the inverse release shown by melatonin and leptin, accentuating the release of melatonin in the darkness phase and that of leptin in the light phase. The correlation between melatonin and leptin in the healthy animal seemed to confirm the relationship between both variables and their influence on oxidative damage biomarkers.

Topics: Animals; Antibiotics, Antineoplastic; Disease Models, Animal; Doxorubicin; Hyperlipidemias; Kidney Diseases; Leptin; Male; Melatonin; Nephrons; Oxidative Stress; Photoperiod; Rats, Wistar

The time course of metabolic and cardiovascular changes with weight gain and subsequent weight loss has not been elucidated. The goal of the present study was to determine how weight gain, weight loss and altered body fat distribution affected metabolic and cardiovascular changes in an obese dog model. Testing was performed when the dogs were lean (scores 4-5 on a nine-point scale), after ad libitum feeding for 12 and 32 weeks to promote obesity (>5 score), and after weight loss. Measurements included serum glucose and insulin, plasma leptin, adiponectin and C-reactive protein, echocardiography, flow-mediated dilation and blood pressure. Body fat distribution was assessed by computed tomography. Fasting serum glucose concentrations increased significantly with obesity (P< 0·05). Heart rate increased by 22 (SE 5) bpm after 12 weeks of obesity (P= 0·003). Systolic left ventricular free wall thickness increased after 12 weeks of obesity (P= 0·002), but decreased after weight loss compared with that observed in the lean phase (P= 0·03). Ventricular free wall thickness was more strongly correlated with visceral fat (r 0·6, P= 0·001) than with total body fat (r 0·4, P= 0·03) and was not significantly correlated with subcutaneous body fat (r 0·3, P= 0·1). The present study provides evidence that metabolic and cardiovascular alterations occur within only 12 weeks of obesity in an obese dog model and are strongly predicted by visceral fat. These results emphasise the importance of obesity prevention, as weight loss did not result in the return of all metabolic indicators to their normal levels. Moreover, systolic cardiac muscle thickness was reduced after weight loss compared with the pre-obesity levels, suggesting possible acute adverse cardiovascular effects.

Topics: Adiponectin; Adiposity; Animals; Blood Glucose; C-Reactive Protein; Diet, Reducing; Disease Models, Animal; Disease Progression; Dogs; Female; Heart Rate; Heart Ventricles; Hypertrophy, Left Ventricular; Insulin; Intra-Abdominal Fat; Leptin; Male; Obesity; Ultrasonography; Weight Gain; Weight Loss

Modification of hydrophilic proteins with amphiphilic block copolymers capable of crossing cell membranes is a new strategy to improve protein delivery to the brain. Leptin, a candidate for the treatment of epidemic obesity, has failed in part because of impairment in its transport across the blood-brain barrier (BBB) that develops with obesity. We posit that modification of leptin with poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide), Pluronic P85 (P85) might permit this protein to penetrate the BBB independently of its transporter, thereby overcoming peripheral leptin resistance. Here we report that peripherally administered leptin-P85 conjugates exhibit biological activity by reducing food intake in mouse models of obesity (ob/ob, and diet-induced obese mouse). We further generated two new leptin-P85 conjugates: one, Lep(ss)-P85(L), containing one P85 chain and another, Lep(ss)-P85(H), containing multiple P85 chains. We report data on their purification, analytical characterization, peripheral and brain pharmacokinetics (PK). Lep(ss)-P85(L) crosses the BBB using the leptin transporter, and exhibits improved peripheral PK along with increased accumulation in the brain compared to unmodified leptin. Lep(ss)-P85(H) also has improved peripheral PK but in a striking difference to the first conjugate penetrates the BBB independently of the leptin transporter via a non-saturable mechanism. The results demonstrate that leptin analogs can be developed through chemical modification of the native leptin with P85 to overcome leptin resistance at the level of the BBB, thus improving the potential for the treatment of obesity.

Topics: Animals; Anti-Obesity Agents; Blood-Brain Barrier; Body Weight; Cells, Cultured; Chemistry, Pharmaceutical; Disease Models, Animal; Drug Carriers; Drug Stability; Eating; Feeding Behavior; Injections, Intravenous; Injections, Subcutaneous; Leptin; Male; Mice; Obesity; Permeability; Poloxalene; Technology, Pharmaceutical

The main role of early nutritional programming in the current rise of obesity and associated diseases is well known. However, translational studies are mostly based in postnatal food excess and, thus, there is a paucity of information on the phenotype of individuals with prenatal deficiencies but adequate postnatal conditions. Thus, we assessed the effects of prenatal programming (comparing descendants from females fed with a diet fulfilling 100 or only 50% of their nutritional requirements for pregnancy) on gene expression, patterns of growth and fattening, metabolic status and puberty attainment of a swine model of obesity/leptin resistance with controlled postnatal nutrition and opportunity of exercise. Maternal restriction was related to changes in the relationships among gene expression of positive (insulin-like growth factors 1 and 2) and negative (myostatin) regulators of muscle growth, with negative correlations in gilts from restricted pregnancies and positive relationships in the control group. In spite of these differences, the patterns of growth and fattening and the metabolic features during juvenile growth were similar in control gilts and gilts from restricted pregnancies. Concomitantly, there was a lack of differences in the timing of puberty attainment. However, after reaching puberty and adulthood, females from restricted pregnancies were heavier and more corpulent than control gilts, though such increases in weight and size were not accompanied by increases in adiposity. In conclusion, in spite of changes in gene expression induced by developmental programming, the propensity for higher weight and adiposity of individuals exposed to prenatal malnutrition may be modulated by controlled food intake and opportunity of physical exercise during infant and juvenile development.

Topics: Adiposity; Animals; Animals, Newborn; Body Weight; Disease Models, Animal; Female; Leptin; Male; Obesity; Physical Conditioning, Animal; Pregnancy; Prenatal Exposure Delayed Effects; Prenatal Nutritional Physiological Phenomena; Swine

Type 2 diabetes, obesity, and metabolic syndrome are pathologies where insulin resistance plays a central role, and that affect a large population worldwide. These pathologies are usually associated with a dysregulation of insulin secretion leading to a chronic exposure of the tissues to high insulin levels (i.e. hyperinsulinemia), which diminishes the concentration of key downstream elements, causing insulin resistance. The complexity of the study of insulin resistance arises from the heterogeneity of the metabolic states where it is observed. To contribute to the understanding of the mechanisms triggering insulin resistance, we have developed a zebrafish model to study insulin metabolism and its associated disorders. Zebrafish larvae appeared to be sensitive to human recombinant insulin, becoming insulin-resistant when exposed to a high dose of the hormone. Moreover RNA-seq-based transcriptomic profiling of these larvae revealed a strong downregulation of a number of immune-relevant genes as a consequence of the exposure to hyperinsulinemia. Interestingly, as an exception, the negative immune modulator protein tyrosine phosphatase nonreceptor type 6 (ptpn6) appeared to be upregulated in insulin-resistant larvae. Knockdown of ptpn6 was found to counteract the observed downregulation of the immune system and insulin signaling pathway caused by hyperinsulinemia. These results indicate that ptpn6 is a mediator of the metabolic switch between insulin-sensitive and insulin-resistant states. Our zebrafish model for hyperinsulinemia has therefore demonstrated its suitability for discovery of novel regulators of insulin resistance. In addition, our data will be very useful in further studies of the function of immunological determinants in a non-obese model system.

Topics: Animals; Disease Models, Animal; Gene Knockdown Techniques; Humans; Hyperinsulinism; Immunity; Insulin; Insulin Resistance; Larva; Leptin; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Signal Transduction; Transcriptome; Up-Regulation; Zebrafish

Mid-life obesity and type 2 diabetes mellitus (T2DM) confer a modest, increased risk for Alzheimer's disease (AD), though the underlying mechanisms are unknown. We have created a novel mouse model that recapitulates features of T2DM and AD by crossing morbidly obese and diabetic db/db mice with APPΔNL/ΔNLx PS1P264L/P264L knock-in mice. These mice (db/AD) retain many features of the parental lines (e.g. extreme obesity, diabetes, and parenchymal deposition of β-amyloid (Aβ)). The combination of the two diseases led to additional pathologies-perhaps most striking of which was the presence of severe cerebrovascular pathology, including aneurysms and small strokes. Cortical Aβ deposition was not significantly increased in the diabetic mice, though overall expression of presenilin was elevated. Surprisingly, Aβ was not deposited in the vasculature or removed to the plasma, and there was no stimulation of activity or expression of major Aβ-clearing enzymes (neprilysin, insulin degrading enzyme, or endothelin-converting enzyme). The db/AD mice displayed marked cognitive impairment in the Morris Water Maze, compared to either db/db or APPΔNLx PS1P264L mice. We conclude that the diabetes and/or obesity in these mice leads to a destabilization of the vasculature, leading to strokes and that this, in turn, leads to a profound cognitive impairment and that this is unlikely to be directly dependent on Aβ deposition. This model of mixed or vascular dementia provides an exciting new avenue of research into the mechanisms underlying the obesity-related risk for age-related dementia, and will provide a useful tool for the future development of therapeutics.

Topics: Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Blood Pressure; Cognition Disorders; Dementia, Vascular; Diabetes Mellitus; Disease Models, Animal; Glucose Tolerance Test; Humans; Insulin; Leptin; Maze Learning; Mice; Mice, Transgenic; Mutation; Neprilysin; Obesity, Morbid; Presenilin-1; Receptors, Leptin

Leptin is a neuroendocrine peptide released by adipose tissue that enhances metabolism and acts on the hypothalamus to suppress appetite. Leptin also regulates aspects of cardiovascular function and low serum leptin has been associated with increased mortality in humans. We hypothesized that leptin deficiency alters the structure and function of the pulmonary vasculature.. We examined two groups of C57BL/6 male mice aged 12 weeks: five ob/ob (B6.VLepob/ob) leptin-deficient and five wild type (WT) (C57BL/6) control mice. As expected, weight was significantly greater in ob/ob mice relative to WT mice [weight (g), Mean±SD): ob/ob 52±2.5 g, wild type 30±2.5 g; p<0.001]. The pulmonary vasculature of ob/ob mice and WT control animals was examined by histology, immunohistochemistry and immunofluorescence staining.. Pulmonary arterial wall thickness was significantly increased in ob/ob mice relative to WT littermates [median (interquartile range) distance in pixels: ob/ob 0.13 (0.05-0.18), wild type 0.03 (0.02-0.04); p=0.001]. The ob/ob mice also exhibited significant right ventricular hypertrophy in comparison to control animals [RV thickness (Mean±SD): ob/ob 0.75±0.19, wild type; 0.58±0.13 p<0.001]. We observed substantial macrophage infiltration and abundant proliferation of myofibroblasts and fibroblasts in histological sections of pulmonary arterioles of ob/ob mice. In addition, we noted increased hyaluronan deposition, colocalizing with SMC-actin in the pulmonary vasculature of ob/ob mice relative to WT controls.. The pulmonary pathology of leptin deficiency in ob/ob mice recapitulates many of the histological features of pulmonary vascular diseases, including pulmonary hypertension, suggesting that leptin deficiency is associated to the pathogenesis of pulmonary vascular disease.

Topics: Actins; Animals; Cell Proliferation; Disease Models, Animal; Hyaluronic Acid; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Leptin; Macrophages; Male; Mice, Inbred C57BL; Mice, Knockout; Myofibroblasts; Pulmonary Artery; Vascular Remodeling

Weight loss is a prominent early feature of Alzheimer's disease (AD) that often precedes the cognitive decline and clinical diagnosis. While the exact pathogenesis of AD remains unclear, accumulation of amyloid-β (Aβ) derived from the amyloid precursor protein (APP) in the brain is thought to lead to the neuronal dysfunction and death underlying the dementia. In this study, we examined whether transgenic mice overexpressing the Swedish mutation of APP (Tg2576), recapitulating selected features of AD, have hypothalamic leptin signaling dysfunction leading to early body weight deficits. We found that 3-month-old Tg2576 mice, before amyloid plaque formation, exhibit decreased weight with markedly decreased adiposity, low plasma leptin levels, and increased energy expenditure without alterations in feeding behavior. The expression of the orexigenic neuropeptide Y (NPY) in the hypothalamus to the low leptin state was abnormal at basal and fasting conditions. In addition, arcuate NPY neurons exhibited abnormal electrophysiological responses to leptin in Tg2576 hypothalamic slices or wild-type slices treated with Aβ. Finally, the metabolic deficits worsened as Tg2576 mice aged and amyloid burden increased in the brain. These results indicate that excess Aβ can potentially disrupt hypothalamic arcuate NPY neurons leading to weight loss and a pathologically low leptin state early in the disease process that progressively worsens as the amyloid burden increases. Collectively, these findings suggest that weight loss is an intrinsic pathological feature of Aβ accumulation and identify hypothalamic leptin signaling as a previously unrecognized pathogenic site of action for Aβ.

Topics: Adiposity; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Arcuate Nucleus of Hypothalamus; Brain; Brain Chemistry; Disease Models, Animal; Disease Progression; Fasting; Feeding Behavior; Female; Genes, Reporter; Humans; Hypothalamus; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Neurons; Neuropeptide Y; Patch-Clamp Techniques; Plaque, Amyloid; Weight Loss

Opioid analgesics are commonly used in chronic pain management despite a potential risk of rewarding. However, it remains unclear whether opioid analgesia would enhance the opioid rewarding effect thereby contributing to opioid rewarding. Utilizing a rat paradigm of conditioned place preference (CPP) combined with ankle monoarthritis as a condition of persistent nociception, we showed that analgesia induced by either morphine or the nonsteroid anti-inflammatory drug ibuprofen increased CPP scores in arthritic rats, suggesting that analgesia itself had a rewarding effect. However, arthritic rats exhibited a significantly higher CPP score in response to morphine than ibuprofen. Thus, the rewarding effect of morphine was enhanced in the presence of persistent nociception, producing a phenomenon of analgesia-enhanced opioid reward. At the cellular level, administration of morphine activated a cascade of leptin expression, glial activation, and dopamine receptor upregulation in the nucleus accumbens (NAc), while administration of ibuprofen decreased glial activation with no effect on leptin expression in the NAc. Furthermore, the morphine rewarding effect was blocked in leptin deficient ob/ob mice or by neutralizing leptin or interleukin-1β in the NAc without diminishing morphine analgesia. The data indicate that systemic opioid can activate a leptin-mediated central mechanism in the NAc that led to the enhanced opioid rewarding effect. These findings provide evidence for an interaction between opioid analgesia and opioid rewarding, which may have implications in clinical opioid dose escalation in chronic pain management.

Topics: Analgesics, Opioid; Animals; Animals, Newborn; Arthritis, Experimental; Astrocytes; Cerebral Cortex; Conditioning, Operant; Disease Models, Animal; Gene Expression Regulation; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Morphine; Mutation; Pain; Pain Measurement; Pain Threshold; Rats; Rats, Sprague-Dawley; Reward

Obesity is a public health problem that increases the risk of metabolic disease, infertility, and other chronic health problems. The present study aimed to develop a new rat model for sex hormone disorder with overweight and Ca loss by intramuscular injection of exogenous leptin (LEP). Thirty female Sprague-Dawley (SD) rats (40 days old) were injected thrice intramuscularly with LEP or keyhole limpet hemocyanin immunogen. The following analyses were performed to determine the development of appetite, overweight, reproductive related-hormones, and calcium (Ca)/phosphorus (Pi) in SD rats: measurement of Lee's index, body weight, food intake; serum Ca, Pi, and hormone tests by enzyme-linked immunosorbent analysis; histological analysis of abdominal fat; real-time polymerase chain reaction analysis of neuropeptide Y, pro-opiomelanocortin, gonadotropin-releasing hormone (Gnrh) mRNA, and gonadotropin-releasing hormone receptor (Gnrhr) mRNA expression; and western blotting analysis of enzyme phosphatidylinositol-3-kinase (PI3K). Rats injected with LEP immunogen displayed significantly increased body weight, food intake, Lee's index, serum LEP, serum cortisol, fat deposition in the abdomen, and decreased hormones including follicle stimulating hormone, luteinizing hormone, estradiol, cholecystokinin, and Ca. Exogenous LEP administered intramuscularly also downregulate Gnrh and PI3K. In conclusion, exogenous LEP administered intramuscularly is a novel animal model for sex hormones disorder with overweight and Ca loss in SD rats. The downregulation of PI3K and Gnrh may be involved in the development of this animal model.

Topics: Animals; Calcium; Disease Models, Animal; Down-Regulation; Female; Gene Expression; Gonadal Steroid Hormones; Gonadotropin-Releasing Hormone; Injections, Intramuscular; Leptin; Overweight; Phosphatidylinositol 3-Kinases; Rats, Sprague-Dawley

Recent evidence has indicated that polyunsaturated fatty acids (PUFA), such as omega-3 PUFA, have protective effects on a range of chronic inflammatory conditions, including obesity, and may play a role in the reversal of steatohepatitis. However, the effects of omega-3 PUFA on adipokine expression and hepatic lipid metabolism have not been well evaluated. Thus, the aim of our study was to investigate the effects of PUFAs on adipokines, as well as lipid and glycometabolism, in a rat model of non-alcoholic steatohepatitis (NASH).. Male Sprague-Dawley rats were divided into control, model and therapy groups. The control group received a normal diet, while the model and therapy groups received a high-fat diet. On the eighth week of high-fat diet, the therapy group was treated with omega-3 PUFA (1.0 g/d) daily. At the end of 20 weeks, serum biochemistry indices were measured and adipokine levels in serum and liver samples were detected with ELISA, Western blotting and real time fluorescence quantitative PCR (qRT-PCR).. The weight, biochemical parameters and adipokine levels in serum of the model group were elevated compared to the control group (P < 0.05). In addition, the protein and mRNA expression levels of adipokines in the liver were significantly altered compared to the control group (P < 0.01). The therapy group was characterized by decreased weight and biochemical indices (P < 0.05) compared with the model group. Supplementing high-fat diet with omega-3 PUFA decreased serum levels of leptin and resistin, while adiponectin levels were slightly elevated. In liver tissue samples, the protein and mRNA expression levels of adipokines were significantly improved (P < 0.01) in the therapy group compared to the model group.. Omega-3 PUFA improved lipid and glycometabolism in NASH rats and regulated adipokine expression, indicating that omega-3 PUFA may have a therapeutic benefit for patients with NASH.

Topics: Adipokines; Adiponectin; Animals; Diet, High-Fat; Disease Models, Animal; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Leptin; Liver; Male; Non-alcoholic Fatty Liver Disease; Rats; Rats, Sprague-Dawley; Resistin; RNA, Messenger

Both sexes of mice were fed a high fat diet (HFD) for 10 weeks without and with polyphenolic-rich potato extracts (PRPE) of cultivars Onaway and Russet Burbank. PRPE attenuated weight gain in male and female mice by as much as 63.2%, which was associated mostly with a reduction in adiposity. Mice receiving PRPE showed enhanced capacity for blood glucose clearance. Sex differences regarding the impact of HFD and PRPE on plasma levels of insulin, ghrelin, leptin, gastric inhibitory peptide, and resistin were noted. PRPE may serve as part of a preventative dietary strategy against the development of obesity and type 2 diabetes.

Topics: Adiposity; Animals; Blood Glucose; Diet, High-Fat; Disease Models, Animal; Female; Gastric Inhibitory Polypeptide; Ghrelin; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Plant Extracts; Polyphenols; Resistin; Solanum tuberosum; Weight Gain

Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are known to critically influence brain development and functions. Dietary supplementation with n-3 PUFAs has been suggested as a non-pharmacological therapy for a number of developmental disorders, e.g., autistic spectrum disorders (ASD), but human studies so far have led to conflicting results. Furthermore, it has been hypothesized that the therapeutic impact of n-3 PUFAs on these disorders might be explained by their anti-inflammatory properties and their promoting effects on synaptic function and plasticity, but no clear evidence has been produced in this direction. We evaluated the impact of n-3 PUFA dietary supplementation in a mouse model of fragile X syndrome (FXS), i.e., a major developmental disease and the most frequent monogenic cause of ASD. Fmr1-KO and wild-type mice were provided with a diet enriched or not with n-3 PUFAs from weaning until adulthood when they were tested for multiple FXS-like behaviors. The brain expression of several cytokines and of brain-derived neurotrophic factor (BDNF) was concomitantly assessed as inflammatory and synaptic markers. n-3 PUFA supplementation rescued most of the behavioral abnormalities displayed by Fmr1-KO mice, including alterations in emotionality, social interaction and non-spatial memory, although not their deficits in social recognition and spatial memory. n-3 PUFAs also rescued most of the neuroinflammatory imbalances of KOs, but had a limited impact on their BDNF deficits. These results demonstrate that n-3 PUFAs dietary supplementation, although not a panacea, has a considerable therapeutic value for FXS and potentially for ASD, suggesting a major mediating role of neuroinflammatory mechanisms.

Topics: Animals; Biomarkers; Body Composition; Body Weight; Brain; Brain-Derived Neurotrophic Factor; Cytokines; Dietary Supplements; Disease Models, Animal; Eating; Fatty Acids, Omega-3; Female; Fragile X Mental Retardation Protein; Fragile X Syndrome; Leptin; Male; Mice; Mice, Knockout; Phenotype

Anorexia nervosa is a primary psychiatric disorder, with non-negligible rates of mortality and morbidity. Some of the related alterations could participate in a vicious cycle limiting the recovery. Animal models mimicking various physiological alterations related to anorexia nervosa are necessary to provide better strategies of treatment.. To explore physiological alterations and recovery in a long-term mouse model mimicking numerous consequences of severe anorexia nervosa.. C57Bl/6 female mice were submitted to a separation-based anorexia protocol combining separation and time-restricted feeding for 10 weeks. Thereafter, mice were housed in standard conditions for 10 weeks. Body weight, food intake, body composition, plasma levels of leptin, adiponectin, IGF-1, blood levels of GH, reproductive function and glucose tolerance were followed. Gene expression of several markers of lipid and energy metabolism was assayed in adipose tissues.. Mimicking what is observed in anorexia nervosa patients, and despite a food intake close to that of control mice, separation-based anorexia mice displayed marked alterations in body weight, fat mass, lean mass, bone mass acquisition, reproductive function, GH/IGF-1 axis, and leptinemia. mRNA levels of markers of lipogenesis, lipolysis, and the brown-like adipocyte lineage in subcutaneous adipose tissue were also changed. All these alterations were corrected during the recovery phase, except for the hypoleptinemia that persisted despite the full recovery of fat mass.. This study strongly supports the separation-based anorexia protocol as a valuable model of long-term negative energy balance state that closely mimics various symptoms observed in anorexia nervosa, including metabolic adaptations. Interestingly, during a recovery phase, mice showed a high capacity to normalize these parameters with the exception of plasma leptin levels. It will be interesting therefore to explore further the central and peripheral effects of the uncorrected hypoleptinemia during recovery from separation-based anorexia.

Topics: Adipocytes, Brown; Adiponectin; Adipose Tissue; Animals; Anorexia Nervosa; Anxiety, Separation; Body Composition; Disease Models, Animal; Eating; Estrous Cycle; Feeding Behavior; Female; Gene Expression Regulation; Glucose Tolerance Test; Growth Hormone; Insulin-Like Growth Factor I; Leptin; Lipid Metabolism; Mice, Inbred C57BL; Oxidation-Reduction; Phenotype; Reproduction; Time Factors; Weight Loss

The number of patients with Alzheimer's disease (AD) is increasing worldwide, and available drugs have shown limited efficacy. Hence, preventive interventions and treatments for presymptomatic AD are currently considered very important. Obesity rates have also been increasing dramatically and it is an independent risk factor of AD. Therefore, for the prevention of AD, it is important to elucidate the pathomechanism between obesity and AD. We generated high calorie diet (HCD)-induced obese tauopathy model mice (PS19), which showed hyperleptinemia but limited insulin resistance. HCD enhanced tau pathology and glial activation. Conversely, voluntary exercise with a running wheel normalized the serum leptin concentration without reducing body weight, and restored the pathological changes induced by HCD. Thus, we speculated that persistent hyperleptinemia played an important role in accelerating pathological changes in PS19 mice. Leptin primarily regulates food intake and body weight via leptin receptor b (LepRb). Interestingly, the nuclear staining for p-STAT3, which was activated by LepRb, was decreased in hippocampal neurons in HCD PS19 mice, indicating leptin resistance. Meanwhile, astroglial activation and the astrocytic expression of a short LepR isoform, LepRa, were enhanced in the hippocampus of HCD PS19 mice. Real-time PCR analysis demonstrated that leptin increased mRNA levels for pro-inflammatory cytokines including IL-1β and TNF-α in primary cultured astrocytes from wild type and LepRb-deficient mice. These observations suggest that persistent hyperleptinemia caused by obesity induces astrocytic activation, astrocytic leptin hypersensitivity with enhanced LepRa expression, and enhanced inflammation, consequently accelerating tau pathology in PS19 mice.

Topics: Age Factors; Animals; Astrocytes; Body Weight; Cells, Cultured; Cerebral Cortex; Diet, High-Fat; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Exercise Therapy; Humans; Hyperlactatemia; Leptin; Membrane Proteins; Mice; Mice, Transgenic; Mutation; Nerve Tissue Proteins; Obesity; Phosphorylation; Receptors, Leptin; RNA, Messenger; STAT3 Transcription Factor; tau Proteins; Tauopathies

The metabolic syndrome is a worldwide problem mainly caused by obesity. FTO was found to be a obesity-risk gene in humans and FTO deficiency in mice led to reduction in adipose tissue. Thus, FTO is an important factor for the development of obesity. Leptin-deficient mice are a well characterized model for analysing the metabolic syndrome. To determine the relevance of FTO for the development of the metabolic syndrome we analysed different parameters in combined homozygous deficient mice (Lep(ob/ob);Fto(-/-)). Lep(ob/ob);Fto(-/-) mice showed an improvement in analysed hallmarks of the metabolic syndrome in comparison to leptin-deficient mice wild type or heterozygous for Fto. Lep(ob/ob);Fto(-/-) mice did not develop hyperglycaemia and showed an improved glucose tolerance. Furthermore, extension of beta-cell mass was prevented in Lep(ob/ob);Fto(-/-)mice and accumulation of ectopic fat in the liver was reduced. In conclusion this study demonstrates that FTO deficiency has a protective effect not only on the development of obesity but also on the metabolic syndrome. Thus, FTO plays an important role in the development of metabolic disorders and is an interesting target for therapeutic agents.

Topics: Adipose Tissue; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Animals; Body Weight; Disease Models, Animal; Fatty Liver; Female; Genetic Predisposition to Disease; Hepatocytes; Hyperglycemia; Islets of Langerhans; Leptin; Lipid Metabolism; Male; Metabolic Syndrome; Mice; Mice, Knockout; Mixed Function Oxygenases; Oxo-Acid-Lyases

Leptin may reduce pancreatic lipid deposition, which increases with progression of obesity and can impair β-cell function. The insulinotropic effect of glucagon-like peptide-1 (GLP-1) and the efficacy of GLP-1 receptor agonist are reduced associated with impaired β-cell function. In this study, we examined whether leptin could restore the efficacy of exenatide, a GLP-1 receptor agonist, in type 2 diabetes with increased adiposity. We chronically administered leptin (500 μg·kg⁻¹·day⁻¹) and/or exenatide (20 μg·kg⁻¹·day⁻¹) for 2 wk in a mouse model of type 2 diabetes with increased adiposity induced by streptozotocin and high-fat diet (STZ/HFD mice). The STZ/HFD mice exhibited hyperglycemia, overweight, increased pancreatic triglyceride level, and reduced glucose-stimulated insulin secretion (GSIS); moreover, the insulinotropic effect of exenatide was reduced. However, leptin significantly reduced pancreatic triglyceride level, and adding leptin to exenatide (LEP/EX) remarkably enhanced GSIS. These results suggested that the leptin treatment restored the insulinotropic effect of exenatide in the mice. In addition, LEP/EX reduced food intake, body weight, and triglyceride levels in the skeletal muscle and liver, and corrected hyperglycemia to a greater extent than either monotherapy. The pair-feeding experiment indicated that the marked reduction of pancreatic triglyceride level and enhancement of GSIS by LEP/EX occurred via mechanisms other than calorie restriction. These results suggest that leptin treatment may restore the insulinotropic effect of exenatide associated with the reduction of pancreatic lipid deposition in type 2 diabetes with increased adiposity. Combination therapy with leptin and exenatide could be an effective treatment for patients with type 2 diabetes with increased adiposity.

Topics: Adiposity; Animals; Anti-Obesity Agents; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Drug Implants; Drug Synergism; Drug Therapy, Combination; Exenatide; Glucagon-Like Peptide 1; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Leptin; Male; Mice, Inbred C57BL; Overweight; Pancreas; Peptides; Recombinant Proteins; Streptozocin; Triglycerides; Venoms

Prematurity and neonatal growth restriction (GR) are risk factors for autism and attention deficit hyperactivity disorder (ADHD). Leptin production is suppressed during periods of undernutrition, and we have shown that isolated neonatal leptin deficiency leads to adult hyperactivity while neonatal leptin supplementation normalizes the brain morphology of GR mice. We hypothesized that neonatal leptin would prevent the development of GR-associated behavioral abnormalities. From postnatal day 4-14, C57BL/6 mice were randomized to daily injections of saline or leptin (80ng/g), and GR was identified by a weanling weight below the tenth percentile. The behavioral phenotypes of GR and control mice were assessed beginning at 4 months. Within the tripartite chamber, GR mice had significantly impaired social interaction. Baseline escape times from the Barnes maze were faster for GR mice (65+/-6s vs 87+/-7s for controls, p<0.05), but GR mice exhibited regression in their escape times on days 2 and 3 (56% regressed vs 22% of control saline mice, p<0.05). Compared to controls, GR mice entered the open arms of the elevated plus maze more often and stayed there longer (72+/-10s vs 36+/-5s, p<0.01). Neonatal leptin supplementation normalized the behavior of GR mice across all behavioral assays. In conclusion, GR alters the social interactions, learning and activity of mice, and supplementation with the neurotrophic hormone leptin mitigates these effects. We speculate neonatal leptin deficiency may contribute to the adverse neurodevelopmental outcomes associated with postnatal growth restriction, and postnatal leptin therapy may be protective.

Topics: Analysis of Variance; Animals; Animals, Newborn; Anxiety; Behavior, Animal; Developmental Disabilities; Disease Models, Animal; Drug Administration Schedule; Fear; Frontal Lobe; Interpersonal Relations; Leptin; Mice; Mice, Inbred C57BL; Restraint, Physical; Spatial Learning

Diabetic gastroparesis (DG) is a common clinical complication of diabetes mellitus. Leptin may cause delayed gastric emptying in the central and peripheral pathways. Microcirculatory disturbances in the stomach make gastric smooth muscles and nerves hypoxic-ischemic, thereby impairing gastric motility. Irbesartan is an angiotensin II (ATII) receptor blocker that indirectly decreases serum leptin levels and improves blood vessel endothelia. This study examined the effect of irbesartan on DG and its relationship with serum leptin levels and microcirculatory disturbances of the stomach. Sprague-Dawley rats were injected with streptozotocin to induce diabetes and were then treated with or without 0.012 g·kg(-1)·d(-1) irbesartan by gavage. After six weeks of treatment, the gastric evacuation rate (GER) was measured using phenol red. Serum leptin levels were detected using enzyme-linked immunosorbent assays. Endothelin (ET) in the stomach tissue was examined using a radioimmunoassay, whereas chemical colorimetry was used to measure the nitric oxide synthase (NOS) activity of stomach tissues. The mRNA expression of the ATII receptor (AT1R) was assessed using reverse transcription-polymerase chain reaction. Treatment with irbesartan significantly increased the GER of diabetic rats and reduced the serum leptin levels, as well as decreased the ET content and AT1R mRNA expression in the stomach (P<0.05). Changes in the cNOS activity after irbesartan intervention were not significant (P>0.05), whereas iNOS activity was significantly decreased (P<0.05). Irbesartan can alleviate hyperglycemia-induced delayed gastric emptying, which is associated with decreased serum leptin levels and improved microcirculation in the stomach.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Biphenyl Compounds; Blood Glucose; Diabetes Complications; Diabetes Mellitus, Experimental; Disease Models, Animal; Gastric Emptying; Gastroparesis; Gene Expression; Irbesartan; Leptin; Male; Microcirculation; Nitric Oxide Synthase; Rats; Receptor, Angiotensin, Type 2; Stomach; Tetrazoles; Triglycerides

To observe the effect of Pi transportation, dampness resolving and phlegm expelling herbs (PTDRPEH) on the obesity degree, fat hormones, and leptin resistance in diet-induced obesity (DIO) rats.. Among the 120 Wister rats, 10 were recruited as the blank control group (fed with basal forage), and the remaining 110 were administered with high-fat high-nutrition forage for 17 weeks. According to weight, we obtained 40 DIO rats and 10 diet-induced obesity resistance (DIO-R) rats. DIO rats were further divided into four groups, i.e., the DIO model group (normal saline, at the daily dose of 2 mL), the sibutramine group (at the daily dose of 1.6 mg/kg), the dampness resolving and phlegm expelling group (DRPE, at the daily dose of 3.2 g/kg), and the Pi transportation group (PT, at the daily dose of 3.2 g/kg). All were given by gastrogavage. Normal saline (2 mL) was given by gastrogavage to rats in the blank control group and the DIO-R group. The basal forage was administered to rats in the blank control group, while high fat forage was continually given to rats in the remaining five groups. Their body weights and body lengths were measured after 16 weeks of gastrogavage. All intra-abdominal fat was taken out to measure the degree of obesity and fat contents. Insulin resistance index (IRI), blood glucose, triglycerides, cholesterol, leptin, neuropeptide Y (NPY), tumor necrosis factor alpha (TNF-alpha), and adiponectin were detected after blood withdrawing. Leptin, TNF-alpha, adiponectin, suppressors of cytokine signaling-3 (SOCS-3), and other relevant adipose hormones and inflammatory cytokines were examined in the fat homogenate.. Compared with the blank control group, DIO model rats' body weight, body mass index (BMI), fat factor, IRI, serum leptin, TNF-alpha, and SOCS-3 significantly increased (P < 0.05, P < 0.01); serum NPY, serum leptin, and adiponectin decreased (P < 0.05). Leptin increased and NPY decreased in DIO-R model rats. Compared with the DIO group, DIO-R model rats' body weight, BMI, fat factor, IRI, serum NPY, TNF-alpha, and SOCS-3 all decreased (P < 0.05, P < 0.01); leptin and adiponectin in serum and the fat homogenate all increased (P < 0.05, P < 0.01). After intervention with Sibutramine, rats' body weight, BMI, fat factor, and TNF-alpha in the fat homogenate obviously decreased (P < 0.05, P < 0.01). Serum TNF-alpha decreased, leptin and adiponectin increased in rats of the DRPE group (P < 0.05, P < 0.01). BMI, fat factor, IRI, leptin, and SOCS-3 showed a decreasing tendency, but with no statistical difference (P > 0.05). The body weight, BMI, fat factor, IRI, TNF-alpha, and SOCS-3 all decreased in the PT group (P < 0.05, P < 0.01); leptin and adiponectin in the serum and the fat homogenate increased (P < 0.05, P < 0.01).. Sibutramine could reduce body weight and TNF-alpha in the adipose tissue. Herbs of PT could inhibit fat diet-induced obesity and insulin resistance (IR), with superior effect to herbs of DRPE. Its mechanism might be closely related to promoting leptin and adiponectin secreted by fat, reducing leptin resistance, and elevating serum levels of leptin and adiponectin.

Topics: Adiponectin; Animals; Diet, High-Fat; Disease Models, Animal; Drugs, Chinese Herbal; Insulin Resistance; Leptin; Male; Obesity; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Studies in both humans and rodents suggest that maternal diabetes leads to a higher risk of the fetus developing impaired glucose tolerance and obesity during adulthood. However, the impact of hyperinsulinemia in the mother on glucose homeostasis in the offspring has not been fully explored. We aimed to determine the consequences of maternal insulin resistance on offspring metabolism and endocrine pancreas development using the LIRKO mouse model, which exhibits sustained hyperinsulinemia and transient increase in blood glucose concentrations during pregnancy. We examined control offspring born to either LIRKO or control mothers on embryonic days 13.5, 15.5, and 17.5 and postpartum days 0, 4, and 10. Control offspring born to LIRKO mothers displayed low birth weights and subsequently rapidly gained weight, and their blood glucose and plasma insulin concentrations were higher than offspring born to control mothers in early postnatal life. In addition, concentrations of plasma leptin, glucagon, and active GLP-1 were higher in control pups from LIRKO mothers. Analyses of the endocrine pancreas revealed significantly reduced β-cell area in control offspring of LIRKO mothers shortly after birth. β-Cell proliferation and total islet number were also lower in control offspring of LIRKO mothers during early postnatal days. Together, these data indicate that maternal hyperinsulinemia and the transient hyperglycemia impair endocrine pancreas development in the control offspring and induce multiple metabolic alterations in early postnatal life. The relatively smaller β-cell mass/area and β-cell proliferation in these control offspring suggest cell-autonomous epigenetic mechanisms in the regulation of islet growth and development.

Topics: Animals; Animals, Newborn; Blood Glucose; Cell Proliferation; Diabetes, Gestational; Disease Models, Animal; Female; Glucagon; Glucagon-Like Peptide 1; Hyperglycemia; Hyperinsulinism; Insulin; Insulin Resistance; Insulin-Secreting Cells; Islets of Langerhans; Leptin; Mice; Organ Size; Phenotype; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Weight Gain

The intestines of obese humans and mice are enriched with Erysipelotrichi, a class within the Firmicutes. Clostridium ramosum, a member of the Erysipelotrichi, is associated with symptoms of the metabolic syndrome in humans. To clarify the possible obesogenic potential of this bacterial species and to unravel the underlying mechanism, we investigated the role of C. ramosum in obesity development in gnotobiotic mice. Mice were associated with a simplified human intestinal (SIHUMI) microbiota of eight bacterial species, including C. ramosum, with the SIHUMI microbiota except C. ramosum (SIHUMIw/oCra), or with C. ramosum only (Cra) and fed a high-fat diet (HFD) or a low-fat diet (LFD). Parameters related to the development of obesity and metabolic diseases were compared. After 4 weeks of HFD feeding, the mouse groups did not differ in energy intake, diet digestibility, gut permeability, and parameters of low-grade inflammation. However, SIHUMI and Cra mice fed the HFD gained significantly more body weight and body fat and displayed higher food efficiency than SIHUMIw/oCra mice fed the HFD. Gene expression of glucose transporter 2 (Glut2) in jejunal mucosa and of fatty acid translocase (CD36) in ileal mucosa was significantly increased in the obese SIHUMI and Cra mice compared with the less obese SIHUMIw/oCra mice. The data demonstrate that the presence of C. ramosum in SIHUMI and Cra mice enhanced diet-induced obesity. Upregulation of small intestinal glucose and fat transporters in these animals may contribute to their increased body fat deposition.. Obesity is a growing health problem worldwide. Changes in the proportions of Bacteroidetes and Firmicutes, the two dominant phyla in the human and the murine intestinal tract, link the intestinal microbiota to obesity. Erysipelotrichi, a class within the Firmicutes, increase in response to high-fat feeding in mice. Clostridium ramosum, a member of the Erysipelotrichi, has been linked to symptoms of the metabolic syndrome. We hypothesized that C. ramosum promotes obesity development and related pathologies. Our experiments in gnotobiotic mice show that C. ramosum promoted diet-induced obesity, probably by enhancing nutrient absorption. Identification of obesogenic bacteria and understanding their mode of action enable the development of novel strategies for the treatment of this epidemic disease. Pharmaceuticals that target obesogenic bacteria or their metabolism could help to prevent and treat obesity and related disorders in the future.

Topics: Adipose Tissue; Animals; Body Composition; Body Weight; Clostridium; Diet, High-Fat; Disease Models, Animal; Energy Intake; Germ-Free Life; Glucose Transporter Type 2; Humans; Intestinal Mucosa; Intestines; Leptin; Male; Mice; Mice, Inbred C3H; Microbiota; Obesity; Transcription, Genetic; Up-Regulation

Pulmonary hypoplasia (PH), characterized by alveolar immaturity, is one of the leading causes of respiratory insufficiency in newborns with congenital diaphragmatic hernia (CDH). Leptin (Lep) and its receptor (Lep-R) play an important role in fetal lung growth by stimulating alveolar differentiation and maturation. Lep and Lep-R are strongly expressed by alveolar cells during the saccular stage of fetal lung development. Lep-deficient mice exhibit decreased alveolarization with reduced pulmonary surfactant phospholipid synthesis, similar to human and nitrofen-induced PH. Prenatal administration of all-trans retinoic acid (ATRA) has been shown to stimulate alveolarization in nitrofen-induced PH. Recent studies have demonstrated that Lep and Lep-R expression in developing lungs is regulated by ATRA. We hypothesized that prenatal treatment with ATRA increases pulmonary Lep and Lep-R expression in the nitrofen model of CDH-associated PH.. Time-mated rats received either 100 mg nitrofen or vehicle via oral-gastric lavage on embryonic day 9.5 (E9.5). Control and nitrofen-exposed dams were randomly assigned to either intraperitoneal ATRA (5 mg/kg/d) or placebo administration on E18.5, E19.5 and E20.5. Fetal lungs were harvested on E21.5, and divided into Control+Placebo, Control+ATRA, Nitrofen+Placebo and Nitrofen+ATRA. Alveolarization was assessed using stereo- and morphometric analysis techniques. Surfactant phospholipid synthesis was analyzed by labeling for surfactant protein B (SP-B). Pulmonary gene expression levels of Lep and Lep-R were determined using quantitative real-time polymerase chain reaction. Immunohistochemical staining for Lep and Lep-R was performed to evaluate alveolar protein expression and localization.. In vivo administration of ATRA resulted in significantly increased lung-to-body weight ratio with enhanced radial alveolar count and decreased mean linear intercept compared to placebo treatment. Immunofluorescence analysis demonstrated markedly increased pulmonary SP-B expression in Nitrofen+ATRA compared to Nitrofen+Placebo. Relative mRNA expression of Lep and Lep-R was significantly increased in Nitrofen+ATRA compared to Nitrofen+Placebo. Lep and Lep-R immunoreactivity was markedly increased in interstitial and alveolar epithelial cells of Nitrofen+ATRA compared to Nitrofen+Placebo.. Increased Lep and Lep-R expression after prenatal administration of ATRA in nitrofen-induced PH suggests that ATRA may have therapeutic potential in attenuating CDH-associated PH by stimulating alveolarization and de novo surfactant production.

Topics: Animals; Disease Models, Animal; Female; Hernias, Diaphragmatic, Congenital; Immunohistochemistry; Leptin; Lung; Organogenesis; Pregnancy; Pregnancy, Animal; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Tretinoin; Up-Regulation

In systemic lupus erythematosus (SLE), the availability of self-antigen promotes and fuels self-reactive immune responses. Apoptotic cells represent a major source of self-antigens, and an impairment of the removal of apoptotic material containing self-antigen can contribute to the development of autoimmunity. To address whether the adipocytokine leptin--which favors autoimmune responses through little understood mechanisms--could modulate the handling of apoptotic cells in SLE, we evaluated the ability of leptin to modulate the capacity of macrophages to phagocytose apoptotic bodies in (NZB × NZW)F1 lupus mice. It was found that leptin promoted phagocytosis of apoptotic cells by macrophages by modulating cAMP levels in macrophages. This finding associated with an increased availability of antigen that favored the development of T cell responses to apoptotic-derived antigen. As leptin promotes macrophage phagocytosis of apoptotic bodies in SLE and subsequent availability of apoptotic-derived antigen to T cells, an inhibition of this process via leptin blockade might have a therapeutic potential in SLE.

Topics: Animals; Apoptosis; Autoantigens; Autoimmunity; Cell Line; Cyclic AMP; Disease Models, Animal; Female; Leptin; Lupus Erythematosus, Systemic; Lymphocyte Activation; Macrophages; Mice; Mice, Transgenic; Phagocytosis; T-Lymphocytes

Leptin acts on its receptor (ObR) in the hypothalamus to inhibit food intake and energy expenditure. Leptin and ObR are also expressed in the gastrointestinal tract; however, the physiological significance of leptin signaling in the gut remains uncertain. Suppressor of cytokine signaling 3 (SOCS3) is a key negative feedback regulator of ObR-mediated signaling in the hypothalamus. We now show that gastrointestinal epithelial cell-specific SOCS3 conditional knockout (T3b-SOCS3 cKO) mice developed gastric tumors by enhancing leptin production and the ObRb/signal transducer and activator of transcription 3 (STAT3) signaling pathway. All T3b-SOCS3 cKO mice developed tumors in the stomach but not in the bowels by 2 months of age, even though the SOCS3 deletion occurred in both the epithelium of stomach and bowels. The tumors developed in the absence of the inflammatory response and all cKO mice died within 6 months. These tumors displayed pathology and molecular alterations, such as an increase in MUC2 (Mucin 2, oligomeric mucus/gel-forming) and TFF3 (trefoil factor 3), resembling human intestinal-type gastric tumors. Administration of antileptin antibody to T3b-SOCS3 cKO mice reduced hyperplasia of gastric mucosa, which is the step of the initiation of gastric tumor. These data suggest that SOCS3 is an antigastric tumor gene that suppresses leptin overexpression and ObRb/STAT3 hyperactivation, supporting the hypothesis that the leptin/ObRb/STAT3 axis accelerates tumorigenesis and that it may represent a new therapeutic target for the treatment of gastric cancer.

Topics: Adenocarcinoma; Animals; Antibodies; Antineoplastic Agents; Carcinogenesis; Cells, Cultured; Disease Models, Animal; Drug Evaluation, Preclinical; Gastric Mucosa; Humans; Injections, Intraperitoneal; Intestinal Mucosa; Leptin; Mice; Mice, Transgenic; Neoplasms, Experimental; Protein Kinases; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor; Stomach; Stomach Neoplasms; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins

We showed that early weaned rats developed obesity, hyperleptinemia, leptin and insulin resistance at adulthood. Here, we studied the potential beneficial effects of Ilex paraguariensis aqueous solution upon body composition, glycemia, lipid and hormonal profiles, leptin signaling and NPY content.. To induce early weaning, lactating rats' teats were blocked with a bandage to interrupt lactation during the last 3 days (EW group), while control offspring had free access to milk throughout lactation (C group). In postnatal day (PN) 150, EW offspring were subdivided into: EW and EW+ mate groups treated, respectively, with water or yerba mate aqueous solution (1 g/kg BW/day, gavage) during 30 days. C offspring received water for gavage. In PN180, offspring were killed.. EW+ mate group presented lower body weight (-10 %), adipose mass (retroperitoneal:-40 % and epididymal:-44 %), total body fat (-43 %), subcutaneous fat (-46 %), visceral adipocyte area (-21 %), triglyceridemia (-31 %) and hypothalamic NPY content (-37 %) compared to EW group. However, hyperglycemia and lower HDL-c levels observed in EW group were not reverted with mate treatment. Although the hyperleptinemia, lower hypothalamic JAK2 and pSTAT3 content of EW group were not corrected by mate treatment, the hyperphagia and higher hypothalamic SOCS-3 content were normalized in EW+ mate group, indicating that the central leptin resistance could be restored.. Thus, the therapy with yerba mate solution was capable to reverse abdominal obesity, leptin resistance and hypertriglyceridemia, suggesting an important role of this bioactive component in the management of obesity in this programming model.

Topics: Animals; Blood Glucose; Body Composition; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Disease Models, Animal; Dyslipidemias; Female; Hyperglycemia; Hypothalamus; Ilex paraguariensis; Insulin Resistance; Janus Kinase 2; Lactation; Leptin; Neuropeptide Y; Obesity; Plant Extracts; Rats; STAT3 Transcription Factor; Subcutaneous Fat; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Weaning

We examined the hypothesis that leptin signaling contributes to the atrial fibrosis and atrial fibrillation (AF) evoked by angiotensin II (AngII).. Eight-week-old male CL57/B6 (CNT) and leptin-deficient ob/ob mice (Ob) were subcutaneously infused with AngII (2.0 mg/kg per day). Two weeks later, transesophageal burst pacing and an electrophysiological study using isolated perfused hearts were performed. Left-atrial tissues were collected to determine interstitial fibrosis by Masson trichrome staining, and the expressions of mRNAs related to inflammatory profibrotic signals were assessed. Left-atrial fibroblasts were isolated from adult Sprague-Dawley and Zucker rats. The effects of leptin (100 ng/mL) or AngII (100 nmol/L) treatment were evaluated. In CNT-AngII mice, leptin expression in the left atrium was upregulated (P<0.01). Transesophageal burst pacing induced atrial fibrillation in 88% (7/8) of CNT-AngII mice, but not in Ob-AngII mice (0/8; P<0.01). In isolated perfused hearts, atrial fibrillation was induced only in CNT-AngII mice (4/6; 67%). Interatrial conduction time was prolonged in CNT-AngII mice (P<0.01), but not in Ob-AngII mice. The upregulation of collagen 1, collagen 3, transforming growth factor-β1, α-smooth muscle actin, MCP-1, F4/80, and RANTES mRNA, which was seen in CNT-AngII mice, was attenuated in Ob-AngII mice. In cultured Sprague-Dawley rat atrial fibroblasts, AngII treatment increased leptin expression (P<0.01). Addition of leptin increased transforming growth factor-β1, α-smooth muscle actin, MCP-1, and RANTES expressions in Sprague-Dawley rat atrial fibroblasts, but not in Zucker rat atrial fibroblasts.. Our results demonstrate for the first time that leptin signaling is essential for the development of atrial fibrosis and atrial fibrillation evoked by AngII.

Topics: Angiotensin II; Animals; Atrial Fibrillation; Disease Models, Animal; Fibroblasts; Fibrosis; Heart Atria; Leptin; Male; Mice; Mice, Inbred C57BL; Myocardium; Rats; Rats, Sprague-Dawley; Rats, Zucker; Signal Transduction

In rabbits, mean arterial pressure (MAP) increases in response to fat feeding, but does not increase further with progressive weight gain. We documented the progression of adiposity and the alterations in endocrine/cardiovascular function in response to fat feeding in rabbits, to determine whether stabilization of MAP after 3 weeks could be explained by stabilization of neurohormonal factors. Rabbits were fed a control diet or high-fat diet for 9 weeks (n=23). Fat feeding progressively increased body mass and adiposity. Heart rate (HR) was elevated by week 3 (15±3%) but changed little thereafter. The effects of fat feeding on MAP were dependent on baseline MAP and peaked at 3 weeks. From baseline, MAP 80 mm Hg, MAP had increased by 8.1±1.3, 4.7±1.7 and 5.6±1.2 mm Hg, respectively, 3, 6 and 9 weeks after commencing the high-fat diet, but by only 2.6±1.5, 3.0±1.7 and 3.9±1.4 mm Hg, respectively, in control rabbits. Fat feeding did not increase MAP from a baseline >80 mm Hg. Plasma concentrations of leptin and insulin increased during the first 3-6 weeks of fat feeding and then stabilized (increasing by 111±17% and 731±302% by week 9, respectively), coinciding with the pattern of changes in MAP and HR. Plasma total cholesterol, triglycerides, renin activity, aldosterone and atrial natriuretic peptide were not significantly altered by fat feeding. Given that the changes in plasma leptin and insulin mirrored the changes in MAP and HR, leptin and insulin may be important factors in the development of hypertension and tachycardia in the rabbit model of obesity.

Topics: Animals; Blood Glucose; Body Composition; Body Weight; Cardiovascular Diseases; Disease Models, Animal; Endocrine System Diseases; Hemodynamics; Insulin; Leptin; Male; Obesity; Rabbits; Renin-Angiotensin System

The recently identified G protein-coupled receptor GPRC6A is activated by dietary amino acids and expressed in multiple tissues. Although the receptor is hypothesised to exert biological impact on metabolic and endocrine-related parameters, the role of the receptor in obesity and metabolic complications is still elusive. In the present study, we investigated the impact of GPRC6A deficiency in a murine model of diet-induced obesity (DIO). Male Gprc6a knockout (KO) mice and WT littermates were subjected to a high-fat diet (HFD) for 25 weeks and exposed to comprehensive metabolic phenotyping. A significant increase in body weight, corresponding to a selective increase in body fat, was observed in Gprc6a KO mice exposed to an HFD relative to WT controls. The obese phenotype was linked to subtle perturbations in energy homoeostasis as GPRC6A deficiency resulted in chronic hyperphagia and decreased locomotor activity. Moreover, diet-induced obese Gprc6a KO mice had increased circulating insulin and leptin levels relative to WT animals, thereby demonstrating that endocrine abnormalities associate with the reported disturbances in energy balance. The phenotype was further accompanied by disruptions in glucose metabolism showing that Gprc6a KO mice on an HFD display increased susceptibility to develop metabolic-related disorders. Altogether, these data suggest that the amino acid sensing receptor GPRC6A plays an important role in resistance to DIO and metabolic complications. Future studies will illuminate the underlying molecular mechanisms mediating the herein reported findings and potentially facilitate the development of novel therapeutic compounds targeting the GPRC6A receptor.

Topics: Animals; Body Composition; Diet, High-Fat; Disease Models, Animal; Eating; Energy Metabolism; Genetic Predisposition to Disease; Glucose; Insulin; Leptin; Male; Mice; Mice, Knockout; Obesity; Phenotype; Receptors, G-Protein-Coupled

To investigate the expressions of leptin and its receptor in the epididymis of experimental varicocele (EV) rats.. Forty male Sprague-Dawley rats were randomly divided into four groups: 4-week EV (n = 12), 8-week EV (n = 12), 4-week control (n = 8), and 8-week control (n = 8). EV models were established by partial ligation of the left renal vein. The expressions of leptin and its receptor in the rat epididymis were measured by immunohistochemistry, and their mRNA expressions determined by real-time quantitative PCR.. The expressions of leptin and its receptor in the epididymis were significantly higher in the 4- and 8-week EV groups than in the 4- and 8-week control groups (P < 0.01), with no significant difference between the two EV groups (P > 0.05). So were their mRNA expressions in the former two than in the latter two groups (P < 0.01), with no significant difference between the former two (P > 0.05).. The expressions of leptin and its receptor are markedly increased in the epididymis of varicocele rats. Leptin may be involved in the mechanisms of varicocele inducing male infertility.

Topics: Animals; Disease Models, Animal; Epididymis; Leptin; Male; Rats; Rats, Sprague-Dawley; Receptors, Leptin; Varicocele

Th17 CD4(+) cells promote inflammation and autoimmunity. In this study, we report that Th17 cell frequency is reduced in ob/ob mice (that are genetically deficient in the adipokine leptin) and that the administration of leptin to ob/ob mice restored Th17 cell numbers to values comparable to those found in wild-type animals. Leptin promoted Th17 responses in normal human CD4(+) T cells and in mice, both in vitro and in vivo, by inducing RORγt transcription. Leptin also increased Th17 responses in (NZB × NZW)F1 lupus-prone mice, whereas its neutralization in those autoimmune-prone mice inhibited Th17 responses. Because Th17 cells play an important role in the development and maintenance of inflammation and autoimmunity, these findings envision the possibility to modulate abnormal Th17 responses via leptin manipulation, and they reiterate the link between metabolism/nutrition and susceptibility to autoimmunity.

Topics: Animals; CD4-Positive T-Lymphocytes; Disease Models, Animal; Gene Expression Regulation; Humans; Leptin; Lupus Erythematosus, Systemic; Mice; Mice, Knockout; Nuclear Receptor Subfamily 1, Group F, Member 3; Receptors, Leptin; Th17 Cells; Transcription, Genetic

Impaired mitochondrial biogenesis causes skeletal muscle damage in diabetes. However, whether and how mitochondrial biogenesis is impaired in the diabetic heart remains largely unknown. Whether adiponectin (APN), a potent cardioprotective molecule, regulates cardiac mitochondrial function has also not been previously investigated. In this study, electron microscopy revealed significant mitochondrial disorders in ob/ob cardiomyocytes, including mitochondrial swelling and cristae disorientation and breakage. Moreover, mitochondrial biogenesis of ob/ob cardiomyocytes is significantly impaired, as evidenced by reduced Ppargc-1a/Nrf-1/Tfam mRNA levels, mitochondrial DNA content, ATP content, citrate synthase activity, complexes I/III/V activity, AMPK phosphorylation, and increased PGC-1α acetylation. Since APN is an upstream activator of AMPK and APN plasma levels are significantly reduced in ob/ob mice, we further tested the hypothesis that reduced APN in ob/ob mice is causatively related to mitochondrial biogenesis impairment. One week of APN treatment of ob/ob mice activated AMPK, reduced PGC-1α acetylation, increased mitochondrial biogenesis, and attenuated mitochondrial disorders. In contrast, knocking out APN inhibited AMPK-PGC-1α signaling and impaired both mitochondrial biogenesis and function. The ob/ob mice exhibited lower survival rates and exacerbated myocardial injury after MI, when compared to controls. APN supplementation improved mitochondrial biogenesis and attenuated MI injury, an effect that was almost completely abrogated by the AMPK inhibitor compound C. In high glucose/high fat treated neonatal rat ventricular myocytes, siRNA-mediated knockdown of PGC-1α blocked gAd-enhanced mitochondrial biogenesis and function and attenuated protection against hypoxia/reoxygenation injury. In conclusion, hypoadiponectinemia impaired AMPK-PGC-1α signaling, resulting in dysfunctional mitochondrial biogenesis that constitutes a novel mechanism for rendering diabetic hearts more vulnerable to enhanced MI injury.

Topics: Acetylation; Adenosine Triphosphate; Adiponectin; AMP-Activated Protein Kinases; Animals; Animals, Newborn; Cells, Cultured; Diabetes Complications; Disease Models, Animal; DNA-Binding Proteins; DNA, Mitochondrial; Electron Transport Chain Complex Proteins; Energy Metabolism; High Mobility Group Proteins; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Electron; Mitochondria, Heart; Mitochondrial Swelling; Mitochondrial Turnover; Myocardial Infarction; Myocardium; Nuclear Respiratory Factor 1; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Rats; Rats, Sprague-Dawley; RNA Interference; RNA-Binding Proteins; RNA, Messenger; Signal Transduction; Time Factors; Trans-Activators; Transcription Factors; Transfection

The effects of oral delivery of exenatide or pramlintide acetate in dodecyl maltoside (DDM) on energy balance and glycemic control in insulin-resistant obese db/db mice are enhanced when given in combination with [D-Leu-4]-OB3. To examine the anti-hyperglycemic influence of [D-Leu-4]-OB3 in a non-obese insulin-deficient animal model, we compared the effects of metformin (200mg/kg) and [D-Leu-4]-OB3 (40 mg/kg) on energy balance and glycemic control in streptozotocin (STZ)-induced diabetic male Swiss Webster (SW) mice. Diabetic mice were given insulin (Levemir(®), sc) alone, or in combination with metformin or [D-Leu-4]-OB3 orally in DDM, for 14 days. Body weight and food and water intake were measured daily. Fasting blood glucose levels were determined every other day. Serum C-peptide was measured by ELISA. Diabetic mice receiving insulin alone for 14 days gained significantly more weight than DDM-treated control mice, or mice given insulin in combination with metformin or [D-Leu-4]-OB3. The weight gain seen in mice given insulin alone was accompanied by significant increases in both food and water intake. Mice treated with insulin in combination with metformin or [D-Leu-4]-OB3, consumed significantly less food and water. Blood glucose levels in STZ-treated mice receiving insulin alone were reduced to 65.3% of initial levels, while mice receiving insulin with metformin or [D-Leu-4]-OB3 were reduced to 44.5% and 38.9%, respectively. Our results indicate that [D-Leu-4]-OB3 is as effective as metformin in preventing the body weight gain associated with insulin therapy, and on a molar basis, that the efficacy of [D-Leu-4]-OB3 as an insulin sensitizer may equal or surpass that of metformin.

Topics: Administration, Oral; Animals; Biological Availability; Blood Glucose; Disease Models, Animal; Energy Metabolism; Hypoglycemic Agents; Insulin; Leptin; Male; Metformin; Mice; Peptide Fragments

Previous studies have demonstrated that both curcumin and leptin are protective factors against acute injuries. Here, we investigated whether leptin and its signaling pathway mediate the protective effects of curcumin.. A solid dispersion of curcumin-polyvinylpyrrolidone K30 was prepared and administered intraperitoneally. In vivo intestinal ischemia/reperfusion (I/R) injury in mice determined the effects of curcumin administration on inflammation, oxygen radical production, and leptin expression. In vitro studies using the venous epithelial cell line ECV-304 examined hypoxia/reoxygenation-induced leptin expression and release after curcumin administration. Furthermore, the effects on the leptin-regulated ERK1/2 and p38 MAPK signaling pathways were also explored.. Intestinal I/R induced marked bowel injuries. Curcumin treatment significantly improved animal survival and reduced the pathologic injuries in the intestines. Furthermore, the elevated intestinal water content and levels of malondialdehyde, interleukin 1β (IL-1β) and IL-6 were significantly decreased, but levels of superoxide dismutase increased. Interestingly, we found that the decreased leptin and its receptor Ob-Rb were restored by curcumin administration. In addition, in vitro studies showed that curcumin increased leptin expression and release after hypoxia/reoxygenation-induced cell injuries. Moreover, curcumin treatment restored decreased ERK1/2 phosphorylation (p-ERK1/2) and inhibited overactive p38 (p-p38) after injuries, and the effect was reversed by a leptin-specific antibody or Ob-R blocker.. These data suggest that leptin and Ob-Rb-dependent ERK and p38 MAPK signaling pathways may be involved in curcumin protection against intestinal I/R injury, and leptin may be a potential target of curcumin in intestinal I/R injury and other related acute diseases.

Topics: Acute Disease; Animals; Curcumin; Disease Models, Animal; Enzyme Inhibitors; Epithelial Cells; Intestines; Leptin; Male; Mice; Phosphorylation; Reperfusion Injury; Signal Transduction

The common marmoset as a model of early obesity was assessed. The hypotheses that juvenile marmosets with excess adipose tissue will display higher fasting glucose, decreased insulin sensitivity, and decreased ability to clear glucose from the blood stream were tested.. Normal and obese (body fat > 14%) common marmoset infants (N = 39) were followed up from birth until 1 year. Body fat was measured by quantitative magnetic resonance. Circulating glucose was measured by glucometer and insulin, adiponectin, and leptin by commercial assays. The quantitative insulin sensitivity check index (QUICKI; a measure of insulin sensitivity) was calculated for subjects with fasting glucose and insulin measures. Oral glucose tolerance tests (OGTTs) were conducted at 12 months on 35 subjects.. At 6 months, obese subjects already had significantly lower insulin sensitivity (mean QUICKI = 0.378 ± 0.029 vs. 0.525 ± 0.019, N = 11, P = 0.003). By 12 months, obese subjects also had higher fasting glucose (129.3 ± 9.1 mg/dL vs. 106.1 ± 6.5 mg/dL, P = 0.042), and circulating adiponectin tended to be lower (P = 0.057). Leptin was associated with percent body fat; however, birth weight also influenced circulating leptin. The OGTT results demonstrated that obese animals had a decreased ability to clear glucose.. Early-onset obesity in marmosets results in impaired glucose homeostasis by 1 year.

Topics: Adiponectin; Adipose Tissue; Animals; Blood Glucose; Body Composition; Callithrix; Disease Models, Animal; Female; Glucose Tolerance Test; Insulin; Insulin Resistance; Leptin; Male; Obesity

The aim of the present study was to compare leptin and interleukin (IL)-6 expression in patients and rat models with chronic obstructive pulmonary disease (COPD). Leptin and IL-6 levels were determined in patients with an acute exacerbation of COPD (AECOPD), stable COPD and in healthy controls. Rat models of COPD were developed, histological and immunohistochemical analyses were performed and leptin and IL-6 levels were determined. Leptin and IL-6 levels in the serum and sputum were higher in patients with AECOPD compared with stable COPD and control patients. In rats, leptin and IL-6 were expressed in bronchial epithelial and inflammatory cells, while leptin expression was observed in alveolar cells and IL-6 expression in blood vessel cells only. Serum levels of leptin and IL-6 were significantly higher in COPD1 and COPD2 rats compared with the control rats, and were even higher in COPD1 rats than COPD2 rats. In conclusion, leptin and IL-6 levels were demonstrated to be associated with the severity of COPD.

Topics: Adult; Animals; Body Weight; Disease Models, Animal; Humans; Immunohistochemistry; Interleukin-6; Leptin; Lung; Male; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Sprague-Dawley; Severity of Illness Index; Sputum

We sought to determine a role for NPY overexpression in the dorsomedial hypothalamus (DMH) in obesity etiology using the rat model of adeno-associated virus (AAV)-mediated expression of NPY (AAVNPY) in the DMH. Rats received bilateral DMH injections of AAVNPY or control vector and were fed on regular chow. Five-week postviral injection, half the rats from each group were switched to access to a high-fat diet for another 11 weeks. We examined variables including body weight, food intake, energy efficiency, meal patterns, glucose tolerance, fat mass, plasma insulin, plasma leptin, and hypothalamic gene expression. Rats with DMH NPY overexpression had increased food intake and body weight and lowered metabolic efficiency. The hyperphagia was mediated through increased meal size during the dark. Although these rats had normal blood glucose, their plasma insulin levels were increased in both basal and glucose challenge conditions. While high-fat diet induced hyperphagia, obesity, and hyperinsulinemia, these effects were amplified in rats with DMH NPY overexpression. Arcuate Npy, agouti-related protein and proopiomelanocortin expression was appropriately regulated in response to positive energy balance. These results indicate that DMH NPY overexpression can cause hyperphagia and obesity and DMH NPY may have actions in glucose homeostasis.

Topics: Agouti-Related Protein; Animals; Body Weight; Dependovirus; Diet, High-Fat; Disease Models, Animal; Energy Metabolism; Gene Expression Regulation; Glucose; Glucose Tolerance Test; Homeostasis; Hyperphagia; Hypothalamus; Leptin; Male; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley

This study was done to investigate whether chronic intermittent hypoxia (CIH) induced changes in leptin and leptin receptor protein levels, and known downstream mediators of leptin receptor signaling in the carotid body. Rats were subjected to CIH (120s normoxia, 80s hypoxia) or normoxia for 8h/day to either short term (7 days) or long term CIH exposure (95 days). After both 7 and 95 days of CIH, carotid body leptin protein expression was decreased, while protein levels of the long form leptin receptor (OB-Rb) were elevated. On the other hand, protein expression levels of the short form leptin receptor (OB-R100) were unchanged. Furthermore, phosphorylated signal transducer and activator of transcription 3 (pSTAT3) protein levels were found to be significantly decreased at only the 7 day period. On the other hand, suppressor of cytokine signaling 3 (SOCS3) protein levels were elevated at only the 7 day period, while phosphorylated extracellular-signal-regulated kinase 1/2 (pERK1/2) was elevated only at the 95 day period. In both the normoxia and the CIH groups, carotid body leptin was decreased at the 95 day period compared to 7 days. However, OB-Rb or Ob-R100 protein levels were not changed in the normoxic or CIH group at either time point. Furthermore, pSTAT3 protein levels were found to be significantly higher, while SOCS3 levels were significantly lower in the 95 day CIH group compared to the 7 day CIH group. Taken together, these data indicate that CIH induces changes in leptin and leptin downstream signaling proteins within the carotid bodies which may contribute to alterations in carotid chemoreceptor sensitivity.

Topics: Animals; Carotid Body; Disease Models, Animal; Gene Expression Regulation; Hypoxia; Leptin; Male; MAP Kinase Signaling System; Rats; Rats, Sprague-Dawley; Receptors, Leptin; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Time Factors

The metabolic syndrome (MS) leads to myocardial fibrosis (MF) and diastolic dysfunction. Statins have proven beneficial effects in MS, but their impact on cardiac remodelling is uncertain. We examined the effects and mechanisms of chronic statin treatment on cardiac remodelling, e.g. fibrosis and diastolic properties.. We used a mouse model deficient in leptin and the LDL-receptor (DKO) that reproduces this MS phenotype. DKO mice (12 weeks) were treated with rosuvastatin (R) for 6 months vs. placebo. Morphometric and echocardiographic measurements showed that R reduced cardiac mass and increased left-ventricular end-diastolic diameter despite unchanged cardiomyocyte dimensions. Similarly, R had no effect on the hypertrophic response to neurohormones in isolated cardiomyocytes. Conversely, R reversed the age-dependent development of MF as well as mRNA expression of TGF-β1 and several pro-fibrotic markers (procollagen type I, its carboxy-terminal proteinase, Lysyl oxidase). R similarly inhibited the pro-fibrotic effects of TGF-β1 on procollagen type I, alpha Smooth Muscle Actin expression and migratory properties of cardiac fibroblasts in vitro. In parallel, R increased the activation of AMP-activated protein kinase (AMPK), a known inhibitor of fibrosis, in vivo and in vitro, and the anti-fibrotic effects of R were abrogated in fibroblasts transfected with AMPKα1/α2 siRNA. The reversal of MF by R in DKO mice was accompanied with improved diastolic properties assessed by P-V loop analysis (slope of EDPVR, dP/dt min and cardiac output).. In this model of MS, statin treatment reverses myocardial remodelling and improves ventricular relaxation through AMPK-mediated anti-fibrotic effects.

Topics: Actins; AMP-Activated Protein Kinases; Animals; Cells, Cultured; Collagen Type I; Diastole; Disease Models, Animal; Enzyme Activation; Fibroblasts; Fibrosis; Fluorobenzenes; Heart Diseases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Leptin; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardium; Procollagen; Pyrimidines; Rats; Receptors, LDL; Recovery of Function; Rosuvastatin Calcium; Signal Transduction; Sulfonamides; Time Factors; Transfection; Transforming Growth Factor beta1; Ventricular Function, Left; Ventricular Remodeling

Obesity is currently a worldwide pandemic. Leptin resistance is a main mechanism of obese human and rodents. The downregulation of the long form of the leptin receptor (Lrb) was involved in leptin resistance in diet-induced obese rats. In the studies, we investigated whether arcuate nucleus (ARC) silencing of Lrb would promote diet-induced obesity in rats. Lentiviral vectors expressing Lrb-shRNA were administered to 5-week-old male rats by ARC injection. Following viral delivery, the rats were provided with a high-fat diet (HFD) or a chow diet (CD). After 8 weeks of the diet, serum leptin, and insulin concentrations were measured by RIA, gene expression of Lrb in the ARC was detected by a real-time RT-PCR, and leptin signaling was examined by western blot. The Lrb-shRNA knocked down the expression of Lrb mRNA in infected regions by 54% for the HFD rats and 47% for the CD rats respectively. The Lrb knockdown reduced Stats3 activation and increased expression of Npy mRNA. The rats with reduced Lrb in the ARC showed a significant increase in energy intake and body weight (BW) again when fed with a HFD. By contrast, there were no effects of Lrb reduction on energy intake or BW when rats maintained on a low-fat chow. Our results provide evidence that Lrb knockdown selectively in the ARC promotes diet-induced obesity and associated metabolic complications in rats.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Diet, High-Fat; Disease Models, Animal; Gene Expression Regulation; Gene Knockdown Techniques; Genetic Vectors; Lentivirus; Leptin; Male; Neuropeptide Y; Obesity; Rats; Receptors, Leptin; RNA Interference; RNA, Small Interfering; Signal Transduction; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous autosomal recessive disorder characterized by obesity, retinal degeneration, polydactyly, hypogenitalism and renal defects. Recent findings have associated the etiology of the disease with cilia, and BBS proteins have been implicated in trafficking various ciliary cargo proteins. To date, 17 different genes have been reported for BBS among which BBS1 is the most common cause of the disease followed by BBS10, and BBS4. A murine model of Bbs4 is known to phenocopy most of the human BBS phenotypes, and it is being used as a BBS disease model. To better understand the in vivo localization, cellular function, and interaction of BBS4 with other proteins, we generated a transgenic BBS4 mouse expressing the human BBS4 gene under control of the beta actin promoter. The transgene is expressed in various tissues including brain, eye, testis, heart, kidney, and adipose tissue. These mice were further bred to express the transgene in Bbs4 null mice, and their phenotype was characterized. Here we report that despite tissue specific variable expression of the transgene, human BBS4 was able to complement the deficiency of Bbs4 and rescue all the BBS phenotypes in the Bbs4 null mice. These results provide an encouraging prospective for gene therapy for BBS related phenotypes and potentially for other ciliopathies.

Topics: Animals; Bardet-Biedl Syndrome; Cilia; Disease Models, Animal; Female; Gene Expression; Genotype; Humans; Hydrocephalus; Infertility, Male; Kidney; Leptin; Male; Mice; Mice, Knockout; Mice, Transgenic; Microtubule-Associated Proteins; Obesity; Phenotype; Proteins; Retinal Diseases; Sympathetic Nervous System; Testis; Transgenes

Although primary cilia are well established as important sensory and signaling structures, their function in most tissues remains unknown. Obesity is a feature associated with some syndromes of cilia dysfunction, such as Bardet-Biedl syndrome (BBS) and Alström syndrome, as well as in several cilia mutant mouse models. Recent data indicate that obesity in BBS mutant mice is due to defects in leptin receptor trafficking and leptin resistance. Furthermore, induction of cilia loss in leptin-responsive proopiomelanocortin neurons results in obesity, implicating cilia on hypothalamic neurons in regulating feeding behavior. Here, we directly test the importance of the cilium as a mediator of the leptin response. In contrast to the current dogma, a longitudinal study of conditional Ift88 cilia mutant mice under different states of adiposity indicates that leptin resistance is present only when mutants are obese. Our studies show that caloric restriction leads to an altered anticipatory feeding behavior that temporarily abrogates the anorectic actions of leptin despite normalized circulating leptin levels. Interestingly, preobese Bbs4 mutant mice responded to the anorectic effects of leptin and did not display other phenotypes associated with defective leptin signaling. Furthermore, thermoregulation and activity measurements in cilia mutant mice are inconsistent with phenotypes previously observed in leptin deficient ob/ob mice. Collectively, these data indicate that cilia are not directly involved in leptin responses and that a defect in the leptin signaling axis is not the initiating event leading to hyperphagia and obesity associated with cilia dysfunction.

Topics: Animals; Bardet-Biedl Syndrome; Body Composition; Cilia; Disease Models, Animal; Feeding Behavior; Leptin; Mice; Mice, Obese; Mice, Transgenic; Motor Activity; Mutation; Neurons; Obesity; Phenotype; Signal Transduction; Temperature

Polychlorinated biphenyls (PCBs) are persistent environmental pollutants that are detectable in the serum of all American adults. Amongst PCB congeners, PCB 153 has the highest serum level. PCBs have been dose-dependently associated with obesity, metabolic syndrome and nonalcoholic fatty liver disease (NAFLD) in epidemiological studies.. The purpose of this study is to determine mechanisms by which PCB 153 worsens diet-induced obesity and NAFLD in male mice fed a high-fat diet (HFD).. Male C57BL6/J mice were fed either control or 42% milk fat diet for 12 weeks with or without PCB 153 coexposure (50 mg/kg ip ×4). Glucose tolerance test was performed, and plasma and tissues were obtained at necropsy for measurements of adipocytokine levels, histology and gene expression.. In control diet-fed mice, addition of PCB 153 had minimal effects on any of the measured parameters. However, PCB 153 treatment in high-fat-fed mice was associated with increased visceral adiposity, hepatic steatosis and plasma adipokines including adiponectin, leptin, resistin and plasminogen activator inhibitor-1 levels. Likewise, coexposure reduced expression of hepatic genes implicated in β-oxidation while increasing the expression of genes associated with lipid biosynthesis. Regardless of diet, PCB 153 had no effect on insulin resistance or tumor necrosis factor alpha levels.. PCB 153 is an obesogen that exacerbates hepatic steatosis, alters adipocytokines and disrupts normal hepatic lipid metabolism when administered with HFD but not control diet. Because all US adults have been exposed to PCB 153, this particular nutrient-toxicant interaction potentially impacts human obesity/NAFLD.

Topics: Adiponectin; Animals; Diet, High-Fat; Disease Models, Animal; Environmental Pollutants; Fatty Liver; Glucose Tolerance Test; Insulin Resistance; Leptin; Lipogenesis; Liver; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity; Plasminogen Activator Inhibitor 1; Polychlorinated Biphenyls; Resistin

The reversibility of diabetic nephropathy remains controversial. Here, we tested whether replacing leptin could reverse the advanced diabetic nephropathy modeled by the leptin-deficient BTBR ob/ob mouse. Leptin replacement, but not inhibition of the renin-angiotensin-aldosterone system (RAAS), resulted in near-complete reversal of both structural (mesangial matrix expansion, mesangiolysis, basement membrane thickening, podocyte loss) and functional (proteinuria, accumulation of reactive oxygen species) measures of advanced diabetic nephropathy. Immunohistochemical labeling with the podocyte markers Wilms tumor 1 and p57 identified parietal epithelial cells as a possible source of regenerating podocytes. Thus, the leptin-deficient BTBR ob/ob mouse provides a model of advanced but reversible diabetic nephropathy for further study. These results also suggest that restoration of lost podocytes is possible but is not induced by RAAS inhibition, possibly explaining the limited efficacy of RAAS inhibitors in promoting repair of diabetic nephropathy.

Topics: Animals; Diabetic Nephropathies; Disease Models, Animal; Immunohistochemistry; Leptin; Mice; Mice, Inbred Strains; Podocytes; Renin-Angiotensin System

The ventral hypothalamus acts to integrate visceral and systemic information to control energy balance. The basic helix-loop-helix transcription factor neurogenin-3 (Ngn3) is required for pancreatic β-cell development and has been implicated in neuronal development in the hypothalamus. Here, we demonstrate that early embryonic hypothalamic inactivation of Ngn3 (also known as Neurog3) in mice results in rapid post-weaning obesity that is associated with hyperphagia and reduced energy expenditure. This obesity is caused by loss of expression of Pomc in Pomc- and Cart-expressing (Pomc/Cart) neurons in the arcuate nucleus, indicating an incomplete specification of anorexigenic first order neurons. Furthermore, following the onset of obesity, both the arcuate and ventromedial hypothalamic nuclei become insensitive to peripheral leptin treatment. This conditional mouse mutant therefore represents a novel model system for obesity that is associated with hyperphagia and underactivity, and sheds new light upon the roles of Ngn3 in the specification of hypothalamic neurons controlling energy balance.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Basic Helix-Loop-Helix Transcription Factors; Cell Count; Disease Models, Animal; Energy Metabolism; Feeding Behavior; Gene Deletion; Hyperphagia; Hypothalamus; Insulin Resistance; Integrases; Leptin; Mice; Mice, Knockout; Mice, Mutant Strains; Motor Activity; Nerve Tissue Proteins; Neurons; Nuclear Proteins; Obesity; Pro-Opiomelanocortin; Thyroid Nuclear Factor 1; Transcription Factors; Viscera

Obesity is a critical risk factor for the development of metabolic syndrome, and many obese animal models are used to investigate the mechanisms responsible for the appearance of symptoms. To establish a new obese mouse model, we screened ∼13,000 ICR mice and discovered a mouse demonstrating spontaneous obesity. We named this mouse "Daruma" after a traditional Japanese ornament. Following the fixation of the genotype, these animals exhibited obese phenotypes according to Mendel's law of inheritance. In the Daruma mouse, the leptin receptor gene sequence carried two base mutations that are good candidates for the variation(s) responsible for the obese phenotype. The Daruma mice developed characteristic visceral fat accumulation at 4 wk of age, and the white adipose and liver tissues exhibited increases in cell size and lipid droplets, respectively. No histological abnormalities were observed in other tissues of the Daruma mice, even after the mice reached 25 wk of age. Moreover, the onset of impaired leptin signaling was early and manifested as hyperleptinemia and hyperinsulinemia. Pair feeding completely inhibited obesity, although these mice rapidly developed hyperphagia and obesity followed by hyperleptinemia when pair feeding ceased and free-access feeding was permitted. Therefore, the Daruma mice exhibited unique characteristics and may be a good model for studying human metabolic syndrome.

Topics: Adipose Tissue; Animals; Body Weight; Cholesterol; Diabetes Mellitus, Type 2; Disease Models, Animal; Eating; Ghrelin; Glucose Tolerance Test; Hemodynamics; Hyperphagia; Leptin; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mutation; Obesity; Real-Time Polymerase Chain Reaction; Receptors, Leptin; Tomography, X-Ray Computed; Triglycerides

Recent epidemiological studies provide strong evidence suggesting obesity is a risk factor in several cancers, including thyroid cancer. However, the molecular mechanisms by which obesity increases the risk of thyroid cancer are poorly understood. In this study, we evaluated the effect of diet-induced obesity on thyroid carcinogenesis in a mouse model that spontaneously develops thyroid cancer (Thrb(PV/PV)Pten(+/-) mice). These mice harbor a mutated thyroid hormone receptor-β (denoted as PV) and haplodeficiency of the Pten gene. A high-fat diet (HFD) efficiently induced the obese phenotype in Thrb(PV/PV)Pten(+/-) mice after 15 weeks. Thyroid tumor growth was markedly greater and survival was significantly lower in Thrb(PV/PV)Pten(+/-) mice fed an HFD than in controls fed a low-fat diet (LFD). The HFD increased thyroid tumor cell proliferation by increasing the protein levels of cyclin D1 and phosphorylated retinoblastoma protein to propel cell cycle progression. Histopathological analysis showed that the frequency of anaplasia of thyroid cancer was significantly greater (2.6-fold) in the HFD group than the LFD group. The HFD treatment led to an increase in parametrial/epididymal fat pad and elevated serum leptin levels in Thrb(PV/PV)Pten(+/-) mice. Further molecular analyses indicated that the HFD induced more aggressive pathological changes that were mediated by increased activation of the Janus kinase 2-signaling transducer and activator of transcription 3 (STAT3) signaling pathway and induction of STAT3 target gene expression. Our findings demonstrate that diet-induced obesity exacerbates thyroid cancer progression in Thrb(PV/PV)Pten(+/-) mice and suggest that the STAT3 signaling pathway could be tested as a potential target for the treatment of thyroid cancer.

Topics: Animals; bcl-X Protein; Cell Cycle; Cell Proliferation; Cyclin D1; Diet, High-Fat; Disease Models, Animal; Female; Heterozygote; Janus Kinase 2; Leptin; Male; Mice; Mutation; Obesity; Phosphorylation; Proto-Oncogene Proteins c-myc; PTEN Phosphohydrolase; Retinoblastoma Protein; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; STAT3 Transcription Factor; Thyroid Gland; Thyroid Hormone Receptors beta; Thyroid Neoplasms

Obesity is a chronic inflammatory disease and a risk factor for disorders such as heart disease, diabetes, and cancer. A high-fat diet (HFD), a risk factor for obesity, has also been associated with inflammatory bowel disease (IBD). A proinflammatory state characterized by systemic and local increases in cytokine and chemokine levels are noted in both obesity and IBD, but it is unclear whether obesity is a risk factor for IBD. To examine any association between obesity and IBD, we chose FVB.129P2- Abcb1a(tm1Bor)N7 (Mdr1a(-/-)) mice, because this strain develops IBD spontaneously with age without a chemical or bacterial "trigger." In addition, its background strain, FVB, has been used for diet-induced obesity studies. Mdr1a(-/-) mice and wild-type (WT) mice were fed a HFD (∼60% calories from fat) or a low-fat diet (LFD; ∼11% calories from fat) for 12 wk. Obesity phenotypes examined included body weight measurements, glucose metabolism changes, and adiposity at termination of the study. IBD was determined by clinical signs, necropsy, and histopathology. We found that compared with those fed the LFD, both the Mdr1a(-/-) and WT mice fed the HFD had greater weight gains and elevated plasma leptin concentrations (P < 0.0001). When all mice were analyzed, weight gain was also associated with inflammation in mesenteric fat (R(2) = 0.5; P < 0.0001) and mesenteric lymph nodes (R(2) = 0.4; P < 0.0001). In contrast, the HFD was not associated with IBD in WT mice, whereas it exacerbated spontaneous IBD in Mdr1a(-/-) mice (P = 0.012; Fisher's exact test). Although a HFD and obesity were not associated with IBD in WT mice, our studies suggest that they are likely risk factors for IBD in a genetically susceptible host, such as Mdr1a(-/-) mice.

Topics: Adipose Tissue; Adiposity; Animals; Diet; Diet, Fat-Restricted; Diet, High-Fat; Disease Models, Animal; Energy Intake; Fatty Liver; Glucose Tolerance Test; Inflammatory Bowel Diseases; Insulin Resistance; Leptin; Male; Mice; Mice, Knockout; Obesity; Weight Gain

Leptin is one of the key molecules in maintaining energy homeostasis. Although genetically leptin-deficient Lep(ob)/Lep(ob) mice have greatly contributed to elucidating leptin physiology, the use of more than one species can improve the accuracy of analysis results. Using the N-ethyl-N-nitrosourea mutagenesis method, we generated a leptin-deficient Lep(mkyo)/Lep(mkyo) rat that had a nonsense mutation (Q92X) in leptin gene. Lep(mkyo)/Lep(mkyo) rats showed obese phenotypes including severe fatty liver, which were comparable to Lep(ob)/Lep(ob) mice. To identify genes that respond to leptin in the liver, we performed microarray analysis with Lep(mkyo)/Lep(mkyo) rats and Lep(ob)/Lep(ob) mice. We sorted out genes whose expression levels in the liver of Lep(mkyo)/Lep(mkyo) rats were changed from wild-type (WT) rats and were reversed toward WT rats by leptin administration. In this analysis, livers were sampled for 6 h, a relatively short time after leptin administration to avoid the secondary effect of metabolic changes such as improvement of fatty liver. We did the same procedure in Lep(ob)/Lep(ob) mice and selected genes whose expression patterns were common in rat and mouse. We verified their gene expressions by real-time quantitative PCR. Finally, we identified eight genes that primarily respond to leptin in the liver commonly in rat and mouse. These genes might be important for the effect of leptin in the liver.

Topics: Animals; Codon, Nonsense; Disease Models, Animal; Ethylnitrosourea; Fatty Liver; Gene Expression; Leptin; Lipid Metabolism; Liver; Male; Mice, Mutant Strains; Mutagenesis; Obesity; Rats, Mutant Strains; Real-Time Polymerase Chain Reaction

Since pancreatic cancer is a lethal disease, developing prevention strategies is an important goal. We determined whether calorie restriction would prevent the development and delay progression of pancreatic intraepithelial neoplasms to pancreatic ductal adenocarcinoma (PDA) in LSL-KrasG12D/+; Pdx-1/Cre mice that develop all the precursor lesions that progress to PDA. Eight-week-old LSL-KrasG12D; Pdx-1/Cre mice were assigned to three groups: (1) ad libitum (AL) fed the AIN93M diet or (2) intermittently calorie restricted (ICR) a modified AIN93M at 50% of AL intake followed by one week intervals at 100% of AL intake, or (3) chronically calorie restricted (CCR) an AIN93M diet at 75% of AL intake. AL fed mice had a greater percentage of pancreatic ducts with PanIN-2 (13.6%) than did the ICR (1.0%) and CCR groups (1.6%), P < 0.0001. Calorie restriction (ICR [0%] and CCR [0.7%]) reduced the percentage of ducts with PanIN-3 lesions compared to the AL group (7.0%), P < 0.0001. The incidence of PanIN-2 or more lesions was significantly reduced in both ICR (27%; n = 16) and CCR (40%) mice (n = 15; P < 0.001) compared to AL (70%) fed mice (n = 11). The delayed progression of lesions in ICR and CCR mice was associated with reduced proliferation measured by proliferating cell nuclear antigen staining, reduced protein expression of Glut1, increased protein expression of Sirt1, increased serum adiponectin, and decreased serum leptin. CCR resulted in decreased phosphorylated mammalian target of rapamycin and decreased serum insulin-like growth factor-1. In summary, this is the first study to show in LSL-KrasG12D; Pdx-1/Cre mice that ICR and CCR delay the progression of lesions to PDA.

Topics: Adiponectin; Animals; Blood Glucose; Body Weight; Caloric Restriction; Cell Proliferation; Cell Survival; Disease Models, Animal; Disease Progression; Feeding Behavior; Homeodomain Proteins; Humans; Insulin-Like Growth Factor I; Integrases; Leptin; Mice; Mice, Transgenic; Organ Size; Pancreas; Pancreatic Ducts; Pancreatic Neoplasms; Phosphorylation; Proliferating Cell Nuclear Antigen; Proto-Oncogene Proteins p21(ras); Signal Transduction; Sirtuin 1; Trans-Activators

Leptin is reported to be involved in acute lung injury (ALI). However, the role and underlying mechanisms of leptin in ALI remain unclear. The aim of this study was to determine whether leptin deficiency promoted the development of ALI. LPS or oleic acid (OA) were administered to wild-type and leptin deficient (ob/ob) mice to induce ALI. Leptin level, survival rate, and lung injury were examined. Results showed that leptin levels were predominantly increased in the lung, but also in the heart, liver, kidney, and adipose tissue after LPS adminiatration. Compared with wild-type mice, LPS- or OA-induced lung injury was worse and the survival rate was lower in ob/ob mice. Moreover, leptin deficiency promoted the release of proinflammatory cytokines. Exogenous administration of leptin reduced lethality in ob/ob mice and ameliorated lung injury partly through inhibiting the activation of NF-κB, p38, and ERK pathways. These results indicated that leptin deficiency contributed to the development of lung injury by enhancing inflammatory response, and a high level of leptin improved survival and protected against ALI.

Topics: Acute Lung Injury; Animals; Cytokines; Disease Models, Animal; Female; Inflammation Mediators; Leptin; Lipopolysaccharides; Lung; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mice, Obese; NF-kappa B; Oleic Acid; Up-Regulation

Obesity is prevalent worldwide and is a major risk factor for many diseases including renal complications. Thrombospondin 1 (TSP1), a multifunctional extracellular matrix protein, plays an important role in diabetic kidney diseases. However, whether TSP1 plays a role in obesity-related kidney disease is unknown. In the present studies, the role of TSP1 in obesity-induced renal dysfunction was determined by using a diet-induced obese mouse model. The results demonstrated that TSP1 was significantly upregulated in the kidney from obese mice. The increased TSP1 was localized in the glomerular mesangium as well as in the tubular system from obese wild-type mice. Obese wild-type mice developed renal hypertrophy and albuminuria, which was associated with increased kidney macrophage infiltration, augmented kidney inflammation, and activated transforming growth factor (TGF)-β signaling and renal fibrosis. In contrast, obese TSP1-deficient mice did not develop these kidney damages. Furthermore, in vitro studies demonstrated that leptin treatment stimulated the expression of TSP1, TGF-β1, fibronectin, and collagen type IV in mesangial cells isolated from wild-type mice. These leptin-stimulated effects were abolished in TSP1-deficient mesangial cells. Taken together, these data suggest that TSP1 is an important mediator for obesity- or hyperleptinemia-induced kidney dysfunction.

Topics: Animals; Cells, Cultured; Collagen Type IV; Diabetic Nephropathies; Diet, High-Fat; Disease Models, Animal; Fibronectins; Fibrosis; Kidney; Leptin; Male; Mice; Nephritis; Obesity; Thrombospondin 1; Transforming Growth Factor beta

Obesity, a state of imbalance between lean mass and fat mass, is important for the etiology of diseases affected by the interplay of multiple genetic and environmental factors. Although genome-wide association studies have repeatedly associated genes with obesity and body weight, the mechanisms underlying the interaction between the muscle and adipose tissues remain unknown. Using 351 mice (at 10 wk of age) of an intercross population between Berlin Fat Mouse Inbred (BFMI) and C57BL/6NCrl (B6N) mice, we examined the causal relationships between genetic variations and multiple traits: body lean mass and fat mass, adipokines, and bone mineral density. Furthermore, evidence from structural equation modeling suggests causality among these traits. In the BFMI model, juvenile obesity affects lean mass and impairs bone mineral density via adipokines secreted from the white adipose tissues. While previous studies have indicated that lean mass has a causative effect on adiposity, in the Berlin Fat Mouse model that has been selected for juvenile obesity (at 9 wk of age) for >90 generations, however, the causality is switched from fat mass to lean mass. In addition, linkage studies and statistical modeling have indicated that quantitative trait loci on chromosomes 5 and 6 affect both lean mass and fat mass. These lines of evidence indicate that the muscle and adipose tissues interact with one another and the interaction is modulated by genetic variations that are shaped by selections. Experimental examinations are necessary to verify the biological role of the inferred causalities.

Topics: Adiponectin; Adipose Tissue; Adiposity; Animals; Body Weight; Bone Density; Crosses, Genetic; Disease Models, Animal; Female; Genetic Association Studies; Genetic Linkage; Genetic Variation; Leptin; Male; Mice; Mice, Inbred C57BL; Muscles; Obesity; Phenotype; Quantitative Trait Loci

Although pregnancies associated with hyperinsulinemia and altered placental angiogenic and inflammatory factors are at increased risk for developing preeclampsia, the effects of euglycemic hyperinsulinemia on placental factors and blood pressure regulation during pregnancy are unclear. We hypothesized that chronic hyperinsulinemia results in increased placental soluble fms-like tyrosine kinase 1(sFlt-1) and tumor necrosis factor α (TNF- α) levels and hypertension in pregnant rats.. On gestational day (GD) 14, Sprague-Dawley rats were assigned as normal pregnant or pregnant + insulin. Insulin was infused subcutaneously by osmotic minipump for 5 days at a dose of 1.5 mU/kg/min. Those rats receiving insulin were supplemented with 20% glucose in drinking water to maintain euglycemia. On GD 19, mean arterial pressure (MAP) and heart rate (HR) were assessed in conscious rats by indwelling carotid catheters, followed by collections of blood, placentas, and fetuses. In addition to placental sFlt-1 and TNF-α levels, circulating insulin, glucose, leptin, cholesterol, triglyceride, and free fatty acid concentrations were measured.. MAP was higher in pregnant + insulin vs. normal pregnant rats; however, HR was similar between groups. Although litter size and placental weight were comparable, fetuses from pregnant + insulin rats were heavier. Importantly, circulating insulin concentration was elevated in the pregnant + insulin group, with no change in glucose level. Moreover, circulating leptin, cholesterol, triglyceride, and free fatty acid concentrations were increased in the pregnant + insulin group. There were no differences in placental sFlt-1 and TNF-α concentrations between groups.. In summary, sustained euglycemic hyperinsulinemia, comparable with insulin levels in preeclamptic women, can raise blood pressure in pregnancy independent of recognized placental factors associated with preeclampsia.

Topics: Animals; Biomarkers; Blood Pressure; Cholesterol; Disease Models, Animal; Female; Glucose; Heart Rate; Hyperinsulinism; Hypertension; Insulin; Leptin; Placenta; Pre-Eclampsia; Pregnancy; Random Allocation; Rats; Rats, Sprague-Dawley; Triglycerides; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor Receptor-1

Maternal obesity (MO) remains a serious obstetric problem with acute and chronic morbidities for both mothers and offspring. The mechanisms underlying these adverse consequences of MO remain unknown. Endocannabinoids (ECB) are neuromodulatory lipids released from adipocytes and other tissues. Metabolic crosstalk between placenta and adipocytes may mediate sequelae of MO. The goal of this study was to elucidate placental and systemic ECB in MO.. Placentas, sera, and subcutaneous fat were collected at Cesarean sections performed near term (0.9 G) in four non-obese (nOB) and four obese (OB) baboons (Papio spp.). Concentrations of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) were measured by liquid chromatography coupled to tandem mass spectrometry. AEA and 2-AG pathways were characterized in placentas by Q-RT-PCR, Western blot and immunohistochemistry.. Placental 2-AG levels were lower and maternal fat AEA levels were higher in OB (1254.1 ± 401.3 nmol/kg and 17.3 ± 4 nmol/kg) vs. nOB (3124.2 ± 557.3 nmol/kg and 3.1 ± 0.6 nmol/kg) animals. Concentrations of 2-AG correlated positively between maternal fat and placenta (r = 0.82, p = 0.013), but correlated negatively with maternal leptin concentrations (r = -0.72, p = 0.04 and r = -0.83, p = 0.01, respectively).. This is the first study to demonstrate differential ECB pathway regulation in maternal fat and placenta in MO. Differential regulation and function exist for AEA and 2-AG as the major ECB pathways in placenta.

Topics: Animals; Arachidonic Acids; Biological Transport; Chromatography, High Pressure Liquid; Disease Models, Animal; Endocannabinoids; Female; Gene Expression Regulation, Developmental; Glycerides; Leptin; Obesity; Papio; Placenta; Polyunsaturated Alkamides; Pregnancy; Pregnancy Complications; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid; Subcutaneous Fat, Abdominal; Tandem Mass Spectrometry

This study was done to investigate the effects of acute intermittent hypoxia (IH) on metabolic factors associated with energy balance and body weight, and on hypothalamic satiety-inducing pathways. Adult male Sprague-Dawley rats were exposed to either 8h IH or normoxic control conditions. Food intake, locomotion and body weights were examined after IH. Additionally, plasma levels of leptin, adiponectin corticosterone, insulin and blood glucose were measured following exposure to IH. Furthermore, adipose tissue was removed and analyzed for leptin and adiponectin content. Finally, the hypothalamic arcuate nucleus (ARC) was assessed for alterations in protein signaling associated with satiety. IH reduced body weight, food intake and active cycle locomotion without altering adipose tissue mass. Leptin protein content was reduced while adiponectin content was elevated in adipose tissue after IH. Plasma concentration of leptin was significantly increased while adiponectin decreased after IH. No changes were found in plasma corticosterone, insulin and blood glucose. In ARC, phosphorylation of signal transducer and activator of transcription-3 and pro-opiomelanocortin (POMC) expression were elevated. In addition, POMC-expressing neurons were activated as determined by immediate early gene FRA-1/2 expression. Finally, ERK1/2 and its phosphorylation were reduced in response to IH. These data suggest that IH induces significant alterations to body energy balance through changes in the secretion of leptin which exert effects on satiety-inducing pathways within the hypothalamus.

Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Disease Models, Animal; Drinking; Energy Metabolism; Feeding Behavior; Hypothalamus; Hypoxia; Leptin; Locomotion; Male; Nerve Tissue Proteins; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Receptors, Leptin; Signal Transduction; Transcription Factors

Neuropeptide Y (NPY) neurons in both the arcuate nucleus of the hypothalamus (ARH) and the dorsomedial hypothalamus (DMH) have been implicated in food intake and obesity. However, while ARH NPY is highly expressed in the lean animal, DMH NPY mRNA expression is observed only after diet-induced obesity (DIO). Furthermore, while ARH NPY neurons are inhibited by leptin, the effect of this adipokine on DMH NPY neurons is unknown. In this study we show that in contrast to the consistent expression in the ARH, DMH NPY mRNA expression was undetectable until after 10 weeks in mice fed a high-fat diet, and peaked at 20 weeks. Surprisingly, electrophysiological experiments demonstrated that leptin directly depolarized and increased the firing rate of DMH NPY neurons in DIO mice. To further differentiate the regulation of DMH and ARH NPY populations, fasting decreased expression of DMH NPY expression, while it increased ARH NPY expression. However, treatment with a leptin receptor antagonist failed to alter DMH NPY expression, indicating that leptin may not be the critical factor regulating mRNA expression. Importantly, we also demonstrated that DMH NPY neurons coexpress cocaine amphetamine-regulated transcript (CART); however, CART mRNA expression in the DMH peaked earlier in the progression of DIO. This study demonstrates novel and important findings. First, NPY and CART are coexpressed in the same neurons within the DMH, and second, leptin stimulates DMH NPY neurons. These studies suggest that during the progression of DIO, there is an unknown signal that drives the expression of the orexigenic NPY signal within the DMH, and that the chronic hyperleptinemia increases the activity of these NPY/CART neurons.

Topics: Action Potentials; Analysis of Variance; Animals; Diet; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression Regulation; Green Fluorescent Proteins; Hypothalamus; In Vitro Techniques; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Tissue Proteins; Neurons; Neuropeptide Y; Obesity; Patch-Clamp Techniques; Proto-Oncogene Proteins c-fos; Radioimmunoassay; RNA, Messenger; STAT3 Transcription Factor; Time Factors

Insulin resistance, dyslipidemia and hypertension are independent mediators of endothelial dysfunction. It is incompletely defined whether dyslipidemia and hypertension in addition to diabetes mellitus type II (DMII), as seen in the metabolic syndrome (MS), worsen diabetes-induced endothelial dysfunction. Furthermore, it is unclear whether treatment influences endothelial dysfunction similarly in MS and DMII. Therefore, we studied vascular reactivity and the effect of in vivo treatment with angiotensin-converting enzyme inhibition (ACE-I) or hypocaloric diet in LDL receptor- and leptin-deficient (ob/ob), double knockout mice (DKO), featuring MS and in ob/ob mice with DMII.. Vascular reactivity was studied in isolated aortic ring segments. Maximum vasorelaxant response to acetylcholine (Ach) was more depressed in DKO than in ob/ob mice, whereas response to bradykinin (BK) was equally attenuated in both genotypes (52 ± 3 and 23 ± 9% reversal of preconstriction induced by 10(-7) M phenylephrine in DKO vs. 76 ± 3 and 23 ± 8% reversal of preconstriction in ob/ob mice, respectively). ACE-I and hypocaloric diet improved ACh-induced vasorelaxation significantly (89 ± 2 and 59 ± 2% reversal of preconstriction in DKO vs. 80 ± 3 and 84 ± 4% in ob/ob mice, respectively), but not the response to BK.. These results indicate a differential impact of DMII and MS on endothelial function. ACE-I and hypocaloric diet improved ACh-, but not BK-induced vasorelaxation in these mouse models of DMII and MS.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Biomarkers; Blood Glucose; Caloric Restriction; Captopril; Combined Modality Therapy; Diabetes Mellitus, Type 2; Disease Models, Animal; Dose-Response Relationship, Drug; Dyslipidemias; Endothelium, Vascular; Female; Hypertension; Leptin; Lipids; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Nitric Oxide; Receptors, LDL; Time Factors; Vasodilation; Vasodilator Agents; Weight Loss

Conjugated linoleic acid (CLA) is found naturally in meat and dairy products, and represents a potential therapeutic functional nutrient. However, given the discrepancies in isomer composition and concentration, controversy surrounds its proposed antidiabetic, antiobesity effects. This study focused on the effects of CLA-enriched beef (composed predominantly of c9, t11-CLA) in two separate models of metabolic disease: proatherosclerotic ApoE(-/-) mice and diabetic, leptin-deficient ob/ob mice. Animals were fed CLA-enriched beef for 28 days, and markers of the metabolic syndrome and atherosclerosis were assessed. Comprehensive hepatic transcriptomic analysis was completed to understand divergent metabolic effects of CLA. CLA-enriched beef significantly reduced plasma glucose, insulin, nonesterified fatty acid and triacylglycerol and increased adiponectin levels in ob/ob mice. In contrast, plasma lipid profiles and glucose homeostasis deteriorated and promoted atherosclerosis following the CLA-enriched beef diet in ApoE(-/-) mice. Hepatic transcriptomic profiling revealed divergent effects of CLA-enriched beef on insulin signaling and lipogenic pathways, which were adversely affected in ApoE(-/-) mice. This study demonstrated clear divergence in the effects of CLA. CLA-enriched beef improved metabolic flexibility in ob/ob mice, resulting in enhanced insulin sensitivity. However, CLA-enriched diet increased expression of lipogenic genes, resulting in inefficient fatty acid storage which increases lipotoxicity in peripheral organs, and led to profound metabolic dysfunction in ApoE(-/-) mice. While CLA may have potential health effects, in some circumstances, caution must be exercised in presenting this bioactive lipid as a potential functional food for the treatment of metabolic disease.

Topics: Adipose Tissue; Animals; Apolipoproteins E; Atherosclerosis; Cattle; Diet; Disease Models, Animal; Fatty Acids, Unsaturated; Gene Expression Profiling; Gene Expression Regulation; Glucose; Insulin; Leptin; Linoleic Acids, Conjugated; Lipids; Liver; Meat Products; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese

Mesenchymal stem cells (MSCs) are multipotent adult stem cells capable of differentiating along the osteoblast, adipocyte, and chondrocyte lineages. Regulation of MSCs differentiation may be a useful tool for regenerative medicine and cell-based therapy. The discovery of small molecule that activates the osteogenic differentiation of MSCs could aid in the development of a new anabolic drug for osteoporosis treatment. We identified CW008, a derivative of pyrazole-pyridine, that stimulates osteoblast differentiation of human MSCs and increases bone formation in ovariectomized mice. CW008 promotes osteogenesis by activating cAMP/PKA/CREB signaling pathway and inhibiting leptin secretion. These results suggest that CW008 is an agonist of cAMP/PKA/CREB pathway in osteogenic differentiation and that application of CW008 may be useful for the treatment of bone-related diseases and for the study of bone biology.

Topics: Adult Stem Cells; Animals; Cell Differentiation; Cells, Cultured; Cyclic AMP; Cyclic AMP Response Element-Binding Protein; Cyclic AMP-Dependent Protein Kinases; Disease Models, Animal; Female; Humans; Leptin; Mesenchymal Stem Cells; Mice; Osteogenesis; Osteoporosis; Pyrazoles; Pyridines; Signal Transduction

Early weaning is associated with changes in the developmental plasticity. Here, we studied the adipocytes morphology, adipokines expression or content in adipose tissue as well as adrenal and thyroid function of neonate and adult offspring primed by early weaning. After birth, lactating rats were divided into 2 groups: EW (early weaning)--dams were wrapped with a bandage to block access to milk during the last 3 days of lactation, and Control--dams whose pups had free access to milk throughout lactation (21 days). At postnatal day (PN) 21, EW pups had lower visceral and subcutaneous adipocyte area (-67.7% and -62%, respectively), body fat mass (-26%), and leptin expression in visceral adipocyte (-64%) but higher leptin expression in subcutaneous adipocyte (2.9-fold increase). Adrenal evaluations were normal, but neonate EW pups presented lower serum T3 (-55%) and TSH (-44%). At PN 180, EW offspring showed higher food intake, higher body fat mass (+21.6%), visceral and subcutaneous adipocyte area (both 3-fold increase), higher leptin (+95%) and ADRβ3 (2-fold increase) content in visceral adipose tissue, and higher adiponectin expression in subcutaneous adipose tissue (+47%) but lower in visceral adipose tissue (-40%). Adult EW offspring presented higher adrenal catecholamine content (+31%), but no changes in serum corticosterone or thyroid status. Thus, early weaning primed for hypothyroidism at weaning, which can be associated with the adipocyte hypertrophy at adulthood. The marked changes in catecholamine adrenal content and visceral adipocyte ADRB3 are generally found in obesity, contributing to the development of other cardiovascular and metabolic disturbances.

Topics: Absorptiometry, Photon; Adiposity; Adrenal Glands; Animals; Animals, Newborn; Disease Models, Animal; Endocrine System Diseases; Gene Expression Regulation; Growth and Development; Intra-Abdominal Fat; Leptin; Obesity; Rats; Rats, Wistar; Receptors, Adrenergic, beta-3; Subcutaneous Fat; Thyroid Function Tests; Weaning

Leptin, originally identified as an anti-obesity hormone, also has an important role in the regulation of mood and emotion. The present study was designed to monitor effects of injected leptin on immobilization stress-induced anorexia, behavioral deficits, and plasma corticosterone secretion in rats. Exposure to 2 h immobilization stress decreased food intake and body weight in saline-injected animals. Animals exposed to open field, elevated plus maze, and light-dark transition tests the day following immobilization exhibited anxiety-like behavior. Leptin injected at doses of 0.1 and 0.5 mg/kg also decreased food intake and body weight in unstressed animals and elicited anxiolytic effects at dose of 0.5 mg/kg, monitored on the following day. Immobilization-induced decreases in food intake, body weight, as well as stress-induced behavioral deficits in the open field, elevated plus maze, and light-dark transition test were reversed by exogenous leptin in a dose-dependent (0.1-0.5 mg/kg) manner. Acute exposure to 2 h immobilization produced a fourfold rise in plasma levels of corticosterone. Animals injected with leptin at a dose of 0.1 mg/kg, but not at dose of 0.5 mg/kg, exhibited a marginal increase in plasma corticosterone. Immobilization-induced increases of plasma corticosterone were reversed by leptin injected at doses of 0.1 or 0.5 mg/kg. The data suggest that exogenous leptin can reduce stress perception, resulting in an inhibition of stress effects on the activity of hypothalamic-pituitary-adrenal axis and behavior. The reported pharmacological effects of leptin represent an innovative approach for the treatment of stress-related disorders.

Topics: Animals; Anorexia; Behavior, Animal; Biomarkers; Body Weight; Corticosterone; Disease Models, Animal; Dose-Response Relationship, Drug; Eating; Hypothalamo-Hypophyseal System; Injections, Intraperitoneal; Leptin; Male; Motor Activity; Pituitary-Adrenal System; Rats; Rats, Wistar; Restraint, Physical; Stress, Psychological; Time Factors; Up-Regulation

In this study, we evaluated the effect of an analogue of l-carnitine on parameters involved with Metabolic Syndrome in obese Zucker rats. Twenty-four rats were treated for 5 weeks with l-carnitine (300 mg/kg) and its analogue at two concentrations (100 and 250 mg/kg) to assess their impact on glucose, triglycerides and cholesterol in liver and blood samples, as well as the amount of liver glycogen. Liver slices were also analysed. The analogue reduced the levels of glucose, triglycerides and cholesterol in liver and the level of triglycerides in serum. At 100 mg/kg, the analogue proved more effective than l-carnitine in improving the biochemical alterations present in liver. The amount of liver glycogen content was higher in obese animals treated with both l-carnitine and the analogue. No changes on insulin and leptin were observed in animals treated. l-carnitine and its analogue reduced the microvesicular fatty infiltration in liver. This study demonstrated that the analogue tested is more potent and efficient than l-carnitine and improves the pharmacological profile of l-carnitine.

Topics: Animals; Carnitine; Cholesterol; Disease Models, Animal; Dose-Response Relationship, Drug; Glucose; Glycogen; Insulin; Leptin; Liver; Male; Metabolic Syndrome; Obesity; Rats; Rats, Zucker; Triglycerides

Dyslipidemia has been identified as an important pathogenic risk factor for diabetic neuropathy, but current animal models do not adequately reproduce the lipid profile observed in human diabetics (increased triglycerides with an elevated LDL-cholesterol and reduced HDL-cholesterol). High fat feeding of mice produces hyperlipidemia, but mice are resistant to increases in the LDL to HDL ratio, reducing the potential for peripheral lipid deposits to impact neuropathy, as is postulated to occur in human subjects. Genetic manipulations provide an alternative approach to reproducing a neuropathic plasma lipid profile. Based on findings from the atherosclerosis literature, we began with knockout of ApoE. Since knockout of ApoE alone only partially mimics the human diabetic lipid profile, we examined the impact of its combination with a well-characterized model of type 2 diabetes exhibiting neuropathy, the db/db mouse. We added further gene manipulations to increase hyperlipidemia by using mice with both ApoE and ApoB48 knockout on the ob/+ (leptin mutation) mice. In all of these models, we found that either the db/db or ob/ob genotypes had increased body weight, hyperlipidemia, hyperglycemia, and evidence of neuropathy compared with the control groups (db/+ or ob/+, respectively). We found that ApoE knockout combined with leptin receptor knockout produced a lipid profile most closely modeling human dyslipidemia that promotes neuropathy. ApoE knockout combined with additional ApoB48 and leptin knockout produced similar changes of smaller magnitude, but, notably, an increase in HDL-cholesterol. Our data suggest that the overall effects of ApoE knockout, either directly upon nerve structure and function or indirectly on lipid metabolism, are insufficient to significantly alter the course of diabetic neuropathy. Although these models ultimately do not deliver optimal lipid profiles for translational diabetic neuropathy research, they do present glycemic and lipid profile properties of value for future therapeutic investigations.

Topics: Animals; Apolipoproteins E; Behavior, Animal; Blood Glucose; Body Weight; Cholesterol; Data Interpretation, Statistical; Disease Models, Animal; Dyslipidemias; Electrophysiological Phenomena; Leptin; Lipids; Lipoproteins; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Pain Measurement; Peripheral Nervous System Diseases; Triglycerides

The aim of this study was to investigate the syste-matic changes in ghrelin and leptin expression, as well as their correlation with insulin resistance (IR) during the development of type 2 diabetes mellitus (T2DM) in a rat model. T2DM was induced in rats fed a high-fat (HF)-diet followed by the intraperitoneal injection of low-dose streptozotocin (STZ, 35 mg/kg). Sixty male Sprague-Dawley rats were divided into 4 groups: the control, HF-4W (HF diet for 4 weeks), HF-8W (HF diet for 8 weeks) and the T2DM group. During the development of T2DM, the production of ghrelin in the stomach and leptin in adipose tissue, the blood levels of ghrelin and leptin, and the expression of leptin and ghrelin receptors (OB-Rb and GHS-R1a) in the hypothalamus were measured by enzyme-linked immunosorbent assay (ELISA), radioimmunology assay (RIA), immunohistochemistry (IHC) and real-time reverse transcription-polymerase chain reaction (real-time RT-PCR). IR was assessed using the hyperinsulinemic-euglycemic clamp technique. The production of ghrelin in the stomach, the plasma ghrelin levels and the expression of GHS-R1a in the hypothalamus were significantly reduced in the HF-4W and HF-8W rats compared with the control rats; however, no significant difference was found between the HF-8W and T2DM group rats. Comparing the control to the T2DM group, the production of leptin in the adipose tissue and the serum leptin levels increased, whereas the expression of OB-Rb in the hypothalamus decreased. At the same time, the glucose infusion rate (GIR), indicating the insulin sensitivity, decreased significantly; GIR positively correlated with plasma ghrelin and negatively correlated with serum leptin levels. In conclusion, increased leptin levels are associated with obesity and T2DM, while decreased ghrelin levels are associated with obesity/IR rather than T2DM.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Disease Models, Animal; Gene Expression Regulation; Ghrelin; Insulin; Leptin; Lipids; Male; Rats

Dietary obesity is usually characterized by leptin resistance and abnormal lipid metabolism. Lithocarpus polystachyus Rehd.(Sweet Tea) leaf is a kind of Chinese folkloric medicine, and it has been widely used for obesity, diabetes, and hypertension in South China. The present study is aimed at investigating the pharmacological mechanism of the anti-hyperleptinaemia effects of Sweet Tea leaves extract in high fat diet-induced obese rats.. We induced high fat diet obesity for 14 weeks to test the corrective effects of three ST doses (75, 150 and 300 mg/kg per day) for 8 weeks. At the end of the experiment, body weight, fasting blood glucose and serum lipids, superoxide dismutase (SOD), malondialdehyde (MDA), fasting serum insulin and leptin, C-reactive protein, adiponectin and resistin levels were measured, Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) was also calculated. mRNA gene expression of PPARγ (peroxisome proliferator-activated receptor γ) and C/EBPα(CCAAT/enhancer-binding protein α) in epididymal adipose tissue of DIO control and experimental groups were evaluated.. Sweet Tea leaves extract could significantly decrease the levels of serum lipids, attenuate body weight gain and lower circulating leptin and insulin levels, ameliorate the state of oxidative stress, raise serum adiponectin, reduce circulating CRP and resistin levels, and depress the expression of PPARγ and C/EBPα in epididymal adipose tissue of obese rats.. The present findings suggest that ST can effectively attenuate the leptin resistance at least through anti-hyperlipidemic activity and thus has the therapeutic potential in treating hyperlipidemia and hyperleptinaemia related to dietary obesity.

Topics: Adiponectin; Adipose Tissue; Animals; Beverages; Blood Glucose; Body Weight; C-Reactive Protein; CCAAT-Binding Factor; Diet, High-Fat; Disease Models, Animal; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Fagaceae; Gene Expression; Insulin; Insulin Resistance; Leptin; Lipid Metabolism; Male; Malondialdehyde; Obesity; Plant Leaves; PPAR gamma; Rats; Rats, Sprague-Dawley; Resistin; Superoxide Dismutase

Leptin is a potent AMP kinase (AMPK) inhibitor that induces neuroprotection, neurogenesis, and angiogenesis when administered immediately after stroke. To dissociate these effects, we explored the effects of delayed administration of leptin, at 10 days after stroke onset, on neurogenesis and angiogenesis after stroke. Sabra mice underwent photothrombotic stroke and were treated with vehicle or leptin given either as a single dose or in triple dosing, 10 days later. Newborn cells were labeled with bromodeoxyuridine. Functional outcome was studied with the neurological severity score for 90 days poststroke, and the brains were then evaluated via immunohistochemistry. Final infarct volumes did not differ between the groups. Exogenous leptin led to significant increments in the number of proliferating BrdU(+) cells in the subventricular zone and in the cortex abutting the lesion (2.5-fold and 1.4-fold, respectively). There were significant increments in the number of newborn neurons and glia (4- and 3.4-fold, respectively) in leptin-treated animals. Leptin also significantly increased the number of blood vessels in the perilesioned cortex. However, animals treated with leptin failed to demonstrate significantly better functional states. In conclusion, leptin induces neurogenesis and angiogenesis even when given late after stroke but does not lead to better functional outcome in this delayed-treatment paradigm. These results suggest that the main beneficial effects of leptin after stroke are associated with its early neuroprotective role rather than with its proneurogenic or proangiogenic effects.

Topics: Animals; Blood Vessels; Brain Infarction; Bromodeoxyuridine; Cell Proliferation; Disease Models, Animal; Drug Administration Schedule; Glial Fibrillary Acidic Protein; Leptin; Male; Mice; Neovascularization, Physiologic; Neurogenesis; Neuroprotective Agents; Phosphopyruvate Hydratase; Platelet Endothelial Cell Adhesion Molecule-1; Stroke; Time Factors

Major depression is a complex multi-factorial disorder with a lifetime diagnosis of nearly 1 out of 6. We used the Flinders Sensitive Line (FSL) of rats, a model of depression, and the parent Sprague-Dawley (SD) rats to identify genes, gene ontology categories and pathways associated with depression. Depression-like behavior was verified in the FSL line by forced swim testing, with FSL animals exhibiting greater immobility compared to SD rats. RNA samples from the hippocampus were isolated from a group of experimentally naïve FSL and SD rats for microarray analysis. Microarray analysis yielded a total of 361 genes that were differentially regulated between FSL and SD rats, with catechol-O-methyltransferase (COMT) being the most up-regulated. The genes that were differentially regulated between FSL and SD rats were subjected to bioinformatic analysis using the Database for Annotation, Visualization and Integrated Discovery (DAVID), which yielded several gene ontology categories that were overrepresented. Subsequent pathway analysis indicated dysregulation of the adipocytokine signaling pathway. To test the translational impact of this pathway, metabolic factors and psychiatric symptoms were evaluated in a sample of human research participants. Results from our human subjects indicated that anxiety and a subset of depressive symptoms were correlated with adiponectin levels (but not leptin levels). Our results and those of others suggest that disruption of the adipocytokine signaling pathway may be a critical component of the depressive-like behaviors observed in the FSL rats and may also be an important indicator of depressive and anxiety symptoms in humans.

Topics: Adiponectin; Adult; Animals; Anxiety; Catechol O-Methyltransferase; Databases, Genetic; Depression; Disease Models, Animal; Female; Gene Expression Regulation; Hippocampus; Humans; Immobility Response, Tonic; Leptin; Male; Microarray Analysis; Psychiatric Status Rating Scales; Rats; Rats, Inbred Strains; Rats, Sprague-Dawley; Signal Transduction; Up-Regulation

Progression from steatosis to steatohepatitic lesions is hypothesized to require a second hit. These lesions have been associated with increased oxidative stress, often ascribed to high levels of leptin and other proinflammatory mediators. Here we have examined the role of leptin in inducing oxidative stress and Kupffer cell activation in CCl4-mediated steatohepatitic lesions of obese mice.. Male C57BL/6 mice fed with a high-fat diet (60%kcal) at 16 weeks were administered CCl₄ to induce steatohepatitic lesions. Approaches included use of immuno-spin trapping for measuring free radical stress, gene-deficient mice for leptin, p47 phox, iNOS and adoptive transfer of leptin primed macrophages in vivo.. Diet-induced obese (DIO) mice, treated with CCl4 increased serum leptin levels. Oxidative stress was significantly elevated in the DIO mouse liver, but not in ob/ob mice, or in DIO mice treated with leptin antibody. In ob/ob mice, leptin supplementation restored markers of free radical generation. Markers of free radical formation were significantly decreased by the peroxynitrite decomposition catalyst FeTPPS, the iNOS inhibitor 1400W, the NADPH oxidase inhibitor apocynin, or in iNOS or p47 phox-deficient mice. These results correlated with the decreased expression of TNF-alpha and MCP-1. Kupffer cell depletion eliminated oxidative stress and inflammation, whereas in macrophage-depleted mice, the adoptive transfer of leptin-primed macrophages significantly restored inflammation.. These results, for the first time, suggest that leptin action in macrophages of the steatotic liver, through induction of iNOS and NADPH oxidase, causes peroxynitrite-mediated oxidative stress thus activating Kupffer cells.

Topics: Animals; Cytokines; Disease Models, Animal; Fatty Liver; Inflammation Mediators; Kupffer Cells; Leptin; Male; Mice; Mice, Inbred C57BL; NADPH Oxidases; Nitric Oxide Synthase Type II; Non-alcoholic Fatty Liver Disease; Obesity; Oxidative Stress; Peroxynitrous Acid

Leptin promotes atherosclerosis and vessel wall remodeling. As abdominal aortic aneurysm (AAA) formation involves tissue remodeling, we hypothesized that local leptin synthesis initiates and promotes this process.. Human surgical AAA walls were analyzed for antigen and mRNA levels of leptin and leptin receptor, as well as mRNA for matrix metalloproteinases (MMP)-9 and MMP-12. Leptin and leptin receptor antigen were evident in all AAAs, and leptin, MMP-9, and MMP-12 mRNA was increased relative to age-matched nondilated controls. To simulate in vivo local leptin synthesis, ApoE(-/-) mice were subjected to a paravisceral periaortic application of low-dose leptin. Leptin-treated aortas exhibited decreased transforming growth factor-β and increased MMP-9 mRNA levels 5 days after surgery, and leptin receptor mRNA was upregulated by day 28. Serial ultrasonography demonstrated accelerated regional aortic diameter growth after 28 days, correlating with local medial degeneration, increased MMP-9, MMP-12, and periadventitial macrophage clustering. Furthermore, the combination of local periaortic leptin and systemic angiotensin II administration augmented medial MMP-9 synthesis and aortic aneurysm size.. Leptin is locally synthesized in human AAA wall. Paravisceral aortic leptin in ApoE(-/-) mice induces local medial degeneration and augments angiotensin II-induced AAA, thus suggesting novel mechanistic links between leptin and AAA formation.

Topics: Angiotensin II; Animals; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Apolipoproteins E; Delayed-Action Preparations; Dilatation, Pathologic; Disease Models, Animal; Humans; Leptin; Macrophages; Male; Matrix Metalloproteinase 12; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Leptin; RNA, Messenger; Time Factors; Transforming Growth Factor beta; Ultrasonography

The molecular mechanism underlying adipogenesis and the physiological functions of adipose tissue are not fully understood. We describe here a unique mouse model of severe lipodystrophy. Ablation of Ptpn11/Shp2 in adipocytes, mediated by aP2-Cre, led to premature death, lack of white fat, low blood pressure, compensatory erythrocytosis, and hepatic steatosis in Shp2(fat-/-) mice. Fat transplantation partially rescued the lifespan and blood pressure in Shp2(fat-/-) mice, and administration of leptin also restored partially the blood pressure of mutant animals with endogenous leptin deficiency. Consistently, homozygous deletion of Shp2 inhibited adipocyte differentiation from embryonic stem (ES) cells. Biochemical analyses suggest a Shp2-TAO2-p38-p300-PPARγ pathway in adipogenesis, in which Shp2 suppresses p38 activation, leading to stabilization of p300 and enhanced PPARγ expression. Inhibition of p38 restored adipocyte differentiation from Shp2(-/-) ES cells, and p38 signaling is also suppressed in obese patients and obese animals. These results illustrate an essential role of adipose tissue in mammalian survival and physiology and also suggest a common signaling mechanism involved in adipogenesis and obesity development.

Topics: Adipogenesis; Adipose Tissue; Animals; Blood Pressure; Disease Models, Animal; DNA Primers; E1A-Associated p300 Protein; Gene Deletion; Leptin; Lipodystrophy; Mice; Mice, Knockout; p38 Mitogen-Activated Protein Kinases; PPAR gamma; Protein Kinases; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Real-Time Polymerase Chain Reaction; Signal Transduction

We hypothesized that leptin is expressed in a specific time sequence during fracture healing, and its deficiency leads to impaired healing.. Control (C57BL/6) mice and leptin -/- obese (ob/ob) mice were used. ARM 1:: Fracture callus was harvested at 1, 3, 5, 7, 10, 14, and 21 days (n = 8/time point) after closed middiaphyseal femur fractures were created in 56 C57BL/6 mice, and reverse transcriptase polymerase chain reaction analysis was then performed. Levels of leptin were tracked at each time point listed. ARM 2:: Forty-two C57BL/6 controls and 42 ob/ob mice underwent open stabilized middiaphyseal femur fractures, and tissues were harvested at 14, 21, and 42 days and radiographic, histologic, and quantitative computerized tomography analyses were performed. ARM 3:: Murine recombinant leptin was applied directly at the newly created fracture site in 2 separate groups (10 or 100 μg of leptin) of 42 ob/ob mice. Two-factor analysis of variance and the Student t-test were used for statistical analysis.. The time course of Leptin mRNA expression within a fracture callus was detected. Delay in callus maturation was demonstrated radiographically and histologically in the ob/ob mice. ob/ob fractures had an increase in total callus volume by quantitative computerized tomography (P < 0.05). Application of local leptin at both doses reversed the delay in healing.. Leptin is expressed in a unique time course during fracture healing and leptin deficiency leads to impaired fracture healing that reverses by local application of leptin.

Topics: Animals; Bony Callus; Disease Models, Animal; Female; Femoral Fractures; Fracture Healing; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Obesity; Recombinant Proteins; RNA, Messenger; Time Factors; Tomography, X-Ray Computed; Treatment Outcome

Obesity is associated with a high circulating leptin level and severe 2009 pandemic influenza A virus subtype H1N1 (A[H1N1]pdm09) infection. The mechanism for severe lung injury in obese patients and the specific treatment strategy remain elusive.. We studied the pathogenesis of A(H1N1)pdm09 infection in a mouse model of diet-induced obesity.. Obese mice had significantly higher initial pulmonary viral titer and mortality after challenge with A(H1N1)pdm09, compared with age-matched lean mice. Compared with lean mice, obese mice had heightened proinflammatory cytokine and chemokine levels and more severe pulmonary inflammatory damage. Furthermore, obese mice had a higher preexisting serum leptin level but a lower preexisting adiponectin level. Recombinant mouse leptin increased the interleukin 6 (IL-6) messenger RNA expression in mouse single-lung-cell preparations, mouse macrophages, and mouse lung epithelial cell lines infected with A(H1N1)pdm09. Administration of anti-leptin antibody improved the survival of infected obese mice, with associated reductions in pulmonary levels of the proinflammatory cytokines IL-6 and interleukin 1β but not the pulmonary viral titer.. Our findings suggest that preexisting high levels of circulating leptin contribute to the development of severe lung injury by A(H1N1)pdm09 in mice with diet-induced obesity. The therapeutic strategy of leptin neutralization for the reduction of proinflammatory responses and pulmonary damage in obese patients warrants further investigations.

Topics: Animals; Antibodies; Diet, High-Fat; Disease Models, Animal; Epithelium; Female; Influenza A Virus, H1N1 Subtype; Interleukin-1beta; Interleukin-6; Kaplan-Meier Estimate; Leptin; Lung; Macrophages; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Orthomyxoviridae Infections; Pandemics; Pneumonia; Recombinant Proteins; RNA, Messenger; Viral Load

To determine how astrocytic leptin signaling regulates the physiological response of mice to diet-induced obesity (DIO), we performed metabolic analyses and hypothalamic leptin signaling assays on astrocytic leptin-receptor knockout (ALKO) mice in which astrocytes lack functional leptin receptor (ObR) signaling. ALKO mice and wild-type (WT) littermate controls were studied at different stages of DIO with measurement of body wt, percent fat, metabolic activity, and biochemical parameters. When fed regular chow, the ALKO mice had similar body wt, percent fat, food intake, heat dissipation, respiratory exchange ratio, and activity as their WT littermates. There was no change in blood concentrations of triglyceride, soluble leptin receptor (sObR), mRNA for leptin and uncoupling protein 1 (UCP1) in adipose tissue, and insulin sensitivity. Unexpectedly, in response to a high-fat diet the ALKO mice had attenuated hyperleptinemia and sObR, a lower level of leptin mRNA in subcutaneous fat, and a paradoxical increase in UCP1 mRNA. Thus, ALKO mice did not show the worsening of obesity that occurs with normal WT mice and the neuronal ObR mutation that results in morbid obesity. The findings are consistent with a competing, counterregulatory model between neuronal and astrocytic leptin signaling.

Topics: Adiposity; Animals; Astrocytes; Biomarkers; Blood Glucose; Body Weight; Diet, High-Fat; Disease Models, Animal; Energy Metabolism; Genotype; Hypothalamus; Insulin; Ion Channels; Leptin; Mice; Mice, Knockout; Mitochondrial Proteins; Motor Activity; Obesity; Phenotype; Receptors, Leptin; RNA, Messenger; Signal Transduction; Subcutaneous Fat; Time Factors; Triglycerides; Uncoupling Protein 1

Liver fibrosis is commonly associated with obesity and most obese patients develop hyperleptinaemia. The adipocytokine leptin has a unique role in the development of liver fibrosis. Activation of hepatic stellate cells (HSCs) is a key step in hepatic fibrogenesis and sterol regulatory element-binding protein-1c (SREBP-1c) can inhibit HSC activation. We have shown that leptin strongly inhibits SREBP-1c expression in rat HSCs. Hence, we aimed to clarify whether the β-catenin pathway, the crucial negative regulator of adipocyte differentiation, mediates the effects of leptin on SREBP-1c expression in HSCs and in mouse liver fibrosis.. HSCs were prepared from rats and mice. Gene expressions were analysed by real-time PCR, Western blot analysis, immunostaining and transient transfection assays.. Leptin increased β-catenin protein but not mRNA levels in cultured HSCs. Leptin induced phosphorylation of glycogen synthase kinase-3β at Ser(9) and subsequent stabilization of β-catenin protein was mediated, at least in part, by ERK and p38 MAPK pathways. The leptin-induced β-catenin pathway reduced SREBP-1c expression and activity but did not affect protein levels of key regulators controlling SREBP-1c activity, and was not involved in leptin inhibition of liver X receptor α. In a mouse model of liver injury, the β-catenin pathway was shown to be involved in leptin-induced liver fibrosis.. The β-catenin pathway contributes to leptin regulation of SREBP-1c expression in HSCs and leptin-induced liver fibrosis in mice. These results have potential implications for clarifying the mechanisms of liver fibrogenesis associated with elevated leptin levels.

Topics: Animals; beta Catenin; Blotting, Western; Disease Models, Animal; Gene Expression Regulation; Hepatic Stellate Cells; Leptin; Liver Cirrhosis; Liver X Receptors; Male; Mice; Mice, Inbred C57BL; Orphan Nuclear Receptors; p38 Mitogen-Activated Protein Kinases; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; RNA, Messenger; Sterol Regulatory Element Binding Protein 1

The 72 kDa inositol polyphosphate 5-phosphatase E (72k-5ptase) controls signal transduction through the catalytic dephosphorylation of the 5-position of membrane-bound phosphoinositides. The reduction of 72k-5ptase expression in the hypothalamus results in improved hypothalamic insulin signal transduction and reduction of food intake and body mass. Here, we evaluated the tissue distribution and the impact of obesity on the expression of 72k-5ptase in peripheral tissues of experimental animals. In addition, insulin signal transduction and action were determined in an animal model of obesity and insulin resistance treated with an antisense (AS) oligonucleotide that reduces 72k-5ptase expression. In lean Wistar rats, 72k-5ptase mRNA and protein are found in highest levels in heart, skeletal muscle, and white adipose tissue. In three distinct models of obesity, Wistar rats, Swiss mice fed on high-fat diet, and leptin-deficient ob/ob mice, the expression of 72k-5ptase is increased in skeletal muscle and adipose tissue. The treatment of obese Wistar rats with an anti-72k-5ptase AS oligonucleotide results in significant reduction of 72k-5ptase catalytic activity, which is accompanied by reduced food intake and body mass and improved insulin signal transduction and action as determined by immunoblotting and clamp studies respectively. 72k-5ptase expression is increased in obesity and its AS inhibition resulted in a significant improvement in insulin signal transduction and restoration of glucose homeostasis.

Topics: Adipose Tissue, White; Animals; Diet, High-Fat; Disease Models, Animal; Inositol Polyphosphate 5-Phosphatases; Insulin; Insulin Resistance; Leptin; Male; Mice; Mice, Obese; Muscle, Skeletal; Myocardium; Obesity; Oligoribonucleotides, Antisense; Phosphoric Monoester Hydrolases; Rats; Rats, Wistar; Signal Transduction

Previously, we reported that Lactobacillus gasseri BNR17 (BNR17), a probiotic strain isolated from human breast milk, inhibited increases in body weight and adipocyte tissue weight in high-sucrose diet-fed Sprague-Dawley (SD) rats and reduced glucose levels in type 2 diabetes mice. In the current study, we conducted further experiments to extend these observations and elucidate the mechanism involved. C57BL/6J mice received a normal diet, high-sucrose diet or high-sucrose diet containing L. gasseri BNR17 (10(9) or 10(10) CFU) for 10 weeks. The administration of L. gasseri BNR17 significantly reduced the body weight and white adipose tissue weight regardless of the dose administered. In BNR17-fed groups, mRNA levels of fatty acid oxidation-related genes (ACO, CPT1, PPARα, PPARδ) were significantly higher and those of fatty acid synthesis-related genes (SREBP-1c, ACC) were lower compared to the high-sucrose-diet group. The expression of GLUT4, main glucose transporter-4, was elevated in BNR17-fed groups. L. gasseri BNR17 also reduced the levels of leptin and insulin in serum. These results suggest that the anti-obesity actions of L. gasseri BNR17 can be attributed to elevated expression of fatty acid oxidation-related genes and reduced levels of leptin. Additionally, data suggested the anti-diabetes activity of L. gasseri BNR17 may be to due elevated GLUT4 and reduced insulin levels.

Topics: Adipose Tissue; Animals; Body Weight; Dietary Sucrose; Disease Models, Animal; Gene Expression Regulation; Humans; Insulin; Lactobacillus; Leptin; Liver; Male; Mice; Mice, Obese; Obesity; Probiotics; RNA, Messenger

To select the optimal combination of five active component of Banxia Xiexin Decoction on gastric ulcer rat, and observe its effect on Leptin and ET-1.. Eighty-seven SD rats were randomly divided into normal group, sham-operated group and acetic acid-induced gastric ulcer group, omeprazole group as a positive control, five active components (glycyrrhetic acid, beta-sitosterol, berberine, baicalin and ginsenoside) of Banxia Xiexin Decoction were divided into groups by L16 orthogonal design. The ulcer area, and the content of Leptin and ET-1, and the mRNA expression level of both were detected.. Among the sixteen orthogonal design groups, the ulcer area of these groups using both beta-sitosterol and berberine was the smallest (P < 0.05), the content of Leptin of these groups using both glycyrrhetic acid and ginsenoside was the highest in blood serum (P < 0.05), the group using glycyrrhetic acid had the minimum concentration of ET-1 in blood plasma. Compared with model group, berberine could raise the mRNA expression level of Leptin (P < 0.01), and beta-sitosterol could lower the mRNA expression level of ET-1 (P < 0.01).. The pathogenesis of gastric ulcer may be related with the down-regulation of concentration and mRNA expression level of Leptin, and upregulation of concentration and mRNA expression level of ET-1, the active components in Banxia Xiexin Decoction may upregulated Leptin and inhibit ET-1 to accelerate the healing of gastric ulcer.

Topics: Acetates; Animals; Berberine; Disease Models, Animal; Drugs, Chinese Herbal; Endothelin-1; Flavonoids; Gastric Mucosa; Leptin; Male; Plants, Medicinal; Random Allocation; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sitosterols; Stomach Ulcer

Chronic low-grade infection has been suggested to be associated with metabolic disorder such as diabetes. However, the molecular mechanism underlying this important association is largely unknown. The only clue established so far is that many subjects exhibit elevated levels of C-reactive protein as measured by highly sensitive assay. Here, we hypothesized that adipocyte-macrophage interaction plays a key role in amplifying such low grade infection to the level of influencing metabolic disorders. The presence of macrophages in abdominal adipose tissues was investigated by immunohistochemistry. To see whether molecules associated with acute phase protein, LPS signaling, and persistent recruitment of monocytes, are produced at higher amounts in adipocytes co-cultured with macrophages stimulated with low concentration of LPS (1 ng/ml), we measured serum amyloid A (SAA), LPS binding protein (LBP), soluble CD14 (sCD14), and RANTES levels in culture supernatant of co-cultures. Lastly, we investigated in vivo effect of low-grade LPS infusion on the production of these molecules using obese model mice. The macrophages were certainly identified in abdominal adipose tissues. Investigated molecules, especially LBP, SAA, and RANTES were produced at higher amounts in co-cultures stimulated with LPS compared with the cells without LPS. The ob/ob, and high-fat diet-induced obesity mice produced higher amounts of LBP, SAA, and RANTES one day after LPS infusion (1 ng/ml/g body weight) compared with ob/- and normal-fat fed control mice. Thus, adipocytes and infiltrated macrophages, and their interaction with low endotoxin stimulation appear to play an important role in amplifying and maintaining LPS-induced low-grade inflammation.

Topics: Abdominal Fat; Acute-Phase Proteins; Adipocytes; Animals; Carrier Proteins; Cell Communication; Cells, Cultured; Chemokine CCL5; Coculture Techniques; Diet, High-Fat; Disease Models, Animal; Gene Expression Regulation; Humans; Inflammation; Leptin; Lipid Metabolism Disorders; Lipopolysaccharide Receptors; Lipopolysaccharides; Macrophages; Membrane Glycoproteins; Mice; Mice, Knockout; Mice, Obese; Serum Amyloid A Protein

Owing to their distinct biochemical properties, chitosan and its derivatives have a great potential in a range of bioapplications. One such application is as a dietary antilipidemic supplement to be used in reducing obesity and to improve insulin resistance. The lipid-binding efficiency of chitosan and its derivatives, however, remains debatable. Accordingly, in this study we investigated the interaction of chitosan and its two derivatives, O-carboxymethyl chitosan (O-CMCs) and N-[(2-hydroxy-3-N,N-dimethylhexadecyl ammonium)propyl]chitosan chloride (N-CQCs), with plasma leptin, glucose, insulin and total cholesterol in a diet-induced insulin-resistant rat model, and further interaction with mRNA expression of adipocytokines and its related molecule PPAR-γ. The experiments were performed using the RT-PCR technique in cultured 3T3-L1 adipocytes, in which the mRNA expression of leptin, adiponectin, resistin and PPAR-γ was recorded in the absence and presence of chitosan, O-CMCs and N-CQCs. The experimental results proved that chitosan, O-CMCs and N-CQCs not only lowered the level of plasma leptin, glucose, insulin and total cholesterol in vivo, but down-regulated mRNA expression of leptin and resistin, and up-regulated mRNA expression of adiponectin and PPAR-γ in vitro, to achieve the desired insulin resistance therapy.

Topics: 3T3 Cells; Adipocytes; Adiponectin; Animals; Anti-Obesity Agents; Chitosan; Diet, High-Fat; Disease Models, Animal; Insulin Resistance; Leptin; Male; Mice; Obesity; PPAR gamma; Random Allocation; Rats, Wistar; Resistin; RNA, Messenger

To investigate the effect of a new soluble fiber, namely cationic hydroxyethyl cellulose (cHEC), on weight loss and metabolic disorders associated with obesity using a high-fat diet-induced obese mouse model.. Obese male C57BL/6J (B6) mice were fed high-fat (60% kcal) diets supplemented with cHEC for 5 weeks. Body weight, energy intake, mesenteric adipose and liver weights, plasma cholesterol, plasma insulin, glucose, adiponectin, and leptin were assessed to determine the effects of cHEC. Hepatic and fecal lipids were also analyzed to investigate the effect of cHEC on lipid absorption and metabolism.. Supplementation of the high-fat diet with cHEC resulted in significant weight loss in obese mice. In addition, significant decreases were seen in mesenteric adipose and liver weights, as well as concentrations of plasma cholesterol and hepatic lipids. A significant improvement in glucose homeostasis, insulin sensitivity, and leptin concentrations were observed at 4% cHEC. Moreover, increases in fecal excretion of total bile acids, sterols, and fats indicated altered fat absorption when cHEC was supplemented in the diet.. We have shown in the present study that cHEC reduces body weight, improves insulin sensitivity, and prevents the development of metabolic syndrome. Furthermore, the effects of cHEC on glucose and lipid homeostasis in B6 mice are mediated by improvements in leptin sensitivity resulting from reduced fat absorption.

Topics: Adiponectin; Animals; Cellulose; Disease Models, Animal; Glucose; Insulin; Leptin; Lipids; Male; Mice; Mice, Inbred C57BL; Obesity; Weight Gain

Adiponutrin/PNPLA3 is a protein highly produced in adipose tissue whose expression is under tight nutritional regulation. It possesses lipogenic/lipolytic capacity and, although adiponutrin polymorphisms are related to obesity, its physiological role is not clear. To help clarify its role, we studied the effect of acute cold exposure on adiponutrin mRNA expression in different adipose tissues of lean/obese Zucker rats subjected to feeding/fasting/refeeding. The effect of cold on the expression of key lipogenic enzymes and on uncoupling protein-1 (UCP1) was evaluated in selected adipose depots. Adiponutrin mRNA levels were also determined in the adipose tissue of isoprenaline-treated rats and in cultured adipocytes treated with noradrenaline, isoprenaline and a selective β3-adrenoceptor (AR) agonist. Adiponutrin expression was strongly down-regulated by cold in the different adipose depots in lean animals, while this down-regulation was impaired in obese rats. Adiponutrin pattern of expression in response to cold correlated positively with that of the lipogenic enzymes and negatively with UCP1 expression. Acute intraperitoneal administration of isoprenaline also produced a decrease in adiponutrin expression in adipose tissue. In vitro data suggest that adiponutrin's inhibitory effect could be mediated, at least in part, by the sympathetic system via β1/β2-AR. In addition, improvement in metabolic parameters related to obesity in cold-exposed animals was related to an improvement in adiponutrin nutritional regulation. Thus, cold inhibition of adiponutrin expression in adipose tissue (which correlates with the response of lipogenic enzymes) supports a physiological role for this protein in lipogenesis. Moreover, alterations in adiponutrin expression and regulation in adipose tissue are related to obesity.

Topics: Adipocytes; Adipose Tissue; Animal Nutrition Sciences; Animals; Blood Glucose; Body Weight; Cells, Cultured; Cold Temperature; Disease Models, Animal; Gene Expression Regulation; Insulin; Insulin Resistance; Ion Channels; Isoproterenol; Leptin; Male; Membrane Proteins; Mice; Mitochondrial Proteins; Norepinephrine; Obesity; Rats; Rats, Zucker; Receptors, Adrenergic, beta-3; RNA, Messenger; Time Factors; Uncoupling Protein 1

The morphology of sciatic nerves from leptin-deficient ob/ob mice and leptin receptor-deficient db/db mice, both models for obesity, peripheral diabetic neuropathy, and the metabolic syndrome, has yet to be examined for changes in nerve fibers and in endoneural microvessels. Sciatic nerves from three groups of 4-month-old mice (WT C57BL6, ob/ob, and db/db) were investigated. In ultrathin sections, the thickness of myelin sheaths was significantly reduced in small, medium-sized, and large axons of db/db mice compared with WT mice. In ob/ob mice, only large fibers showed a decrease in myelin sheath thickness. The number of nonmyelinated nerve fibers was lower in ob/ob mice than in the db/db group. A thickened basal lamina of Schwann cells occurred in the ob/ob group only. In contrast, the basement membrane of endoneural microvessels was thickened in both obese groups. For this reason, laminin expression in Western blot analysis was lower in the db/db group than in the ob/ob one. Endoneural microvessels, which had been injected with fluorescein isothiocyanate, depicted signs of vasodilatation in the ob/ob and vasoconstriction in db/db mice. Endoneural vessels displayed two receptors of oxLDL. LOX-1 was strongly expressed in db/db mice, whereas TLR4 was at its maximum in the ob/ob group. We conclude that changes in nerve fibers and in endoneural microvessels are present in sciatic nerve of both mouse models of type 2 diabetes. Upregulation of oxLDL-dependent receptors in endoneural microvessels might be connected to different degrees of oxidative stress in severe diabetic db/db mice and in the mild diabetic ob/ob group.

Topics: Analysis of Variance; Animals; Basement Membrane; Body Weight; CD36 Antigens; Diabetic Neuropathies; Disease Models, Animal; Laminin; Leptin; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Obese; Microscopy, Electron, Transmission; Microvessels; Myelin Sheath; Obesity; Oxidative Stress; Receptors, Leptin; Scavenger Receptors, Class E; Schwann Cells; Sciatic Nerve; Thiobarbituric Acid Reactive Substances; Toll-Like Receptor 4; von Willebrand Factor

The aim of the present study is to evaluate whether circadian locomotor activity, and the daily profile of plasma parameters related to metabolic syndrome (nutrients: glucose and triacylglycerides, and hormones: insulin and leptin), differ between male and female Neotomodon alstoni mice, both lean and obese. Young adult animals were captured in the field and kept at the laboratory animal facility. After 6 to 7 months feeding the animals ad libitum with a regular diet for laboratory rodents, 50-60% of mice became obese. Comparisons between sexes indicated that lean females were more active than males; however obese females reduced their nocturnal activity either in LD or DD, and advanced the phase of their activity-onset with respect to lights off. No differences in food intake between lean and obese mice, either during the day or night, were observed. Daily profiles of metabolic syndrome-related plasma parameters showed differences between sexes, and obesity was associated with increased values, especially leptin (500% in females and 273% in males) and insulin (150% in both females and males), as compared with lean mice. Our results indicate that lean mice display behavioral and endocrine differences between sexes, and obesity affects the parameters tested in a sex-dependent manner. The aforementioned leads us to propose N. alstoni, studied in captivity, could be an interesting model for the study of sex differences in the effects of obesity.

Topics: Analysis of Variance; Animals; Blood Glucose; Body Weight; Circadian Rhythm; Disease Models, Animal; Eating; Female; Insulin; Leptin; Male; Mice; Motor Activity; Obesity; Sex Characteristics; Triglycerides

It is known that Ca therapy may have anti-obesity effects. Since early weaning leads to obesity, hyperleptinaemia and insulin resistance, we studied the effect of dietary Ca supplementation in a rat model. Lactating rats were separated into two groups: early weaning (EW) - dams were wrapped with a bandage to interrupt lactation in the last 3 d of lactation and control (C) - dams whose pups had free access to milk during the entire lactation period (21 d). At 120 d, EW and C offspring were subdivided into four groups: (1) C, received standard diet; (2) CCa, received Ca supplementation (10 g of calcium carbonate/kg of rat chow); (3) EW, received standard diet; (4) EWCa, received Ca supplementation similar to CCa. The rats were killed at 180 d. The significance level was at P < 0·05. Adult EW offspring displayed hyperphagia (28 %), higher body weight (9 %) and adiposity (77 %), hyperleptinaemia (twofold increase), hypertriacylglycerolaemia (64 %), hyperglycaemia (16 %), higher insulin resistance index (38 %) and higher serum 25-hydroxyvitamin D₃ (fourfold increase), but lower adiponectinaemia:adipose tissue ratio (44 %). In addition, they showed Janus tyrosine kinase 2 and phosphorylated signal transducer and activator of transcription 3 underexpression in hypothalamus (36 and 34 %, respectively), suggesting leptin resistance. Supplementation of Ca for 2 months normalised these disorders. The EW group had no change in serum insulin, thyroxine or triiodothyronine, and Ca treatment did not alter these hormones. In conclusion, we reinforced that early weaning leads to late development of some components of the metabolic syndrome and leptin resistance. Dietary Ca supplementation seems to protect against the development of endocrine and metabolic disorders in EW offspring, maybe through vitamin D inhibition.

Topics: Adiposity; Animals; Blood Glucose; Calcitriol; Calcium Carbonate; Calcium, Dietary; Disease Models, Animal; Female; Hyperglycemia; Hyperphagia; Insulin Resistance; Leptin; Metabolic Syndrome; Obesity; Pregnancy; Rats; Weaning

X-linked adrenoleukodystrophy (X-ALD) is an inherited disorder characterized by axonopathy and demyelination in the central nervous system and adrenal insufficiency. Main X-ALD phenotypes are: (i) an adult adrenomyeloneuropathy (AMN) with axonopathy in spinal cords, (ii) cerebral AMN with brain demyelination (cAMN) and (iii) a childhood variant, cALD, characterized by severe cerebral demyelination. Loss of function of the ABCD1 peroxisomal fatty acid transporter and subsequent accumulation of very-long-chain fatty acids (VLCFAs) are the common culprits to all forms of X-ALD, an aberrant microglial activation accounts for the cerebral forms, whereas inflammation allegedly plays no role in AMN. How VLCFA accumulation leads to neurodegeneration and what factors account for the dissimilar clinical outcomes and prognosis of X-ALD variants remain elusive. To gain insights into these questions, we undertook a transcriptomic approach followed by a functional-enrichment analysis in spinal cords of the animal model of AMN, the Abcd1(-) null mice, and in normal-appearing white matter of cAMN and cALD patients. We report that the mouse model shares with cAMN and cALD a common signature comprising dysregulation of oxidative phosphorylation, adipocytokine and insulin signaling pathways, and protein synthesis. Functional validation by quantitative polymerase chain reaction, western blots and assays in spinal cord organotypic cultures confirmed the interplay of these pathways through IkB kinase, being VLCFA in excess a causal, upstream trigger promoting the altered signature. We conclude that X-ALD is, in all its variants, a metabolic/inflammatory syndrome, which may offer new targets in X-ALD therapeutics.

Topics: Adipokines; Adiponectin; Adrenoleukodystrophy; Adult; Animals; ATP Binding Cassette Transporter, Subfamily D, Member 1; ATP-Binding Cassette Transporters; Biosynthetic Pathways; Brain; Child; Disease Models, Animal; Disease Progression; Fatty Acids; Gene Expression; Gene Expression Profiling; Genetic Association Studies; Humans; I-kappa B Kinase; Insulin; Insulin Resistance; Leptin; Metabolic Networks and Pathways; Mice; NF-kappa B; Oxidative Phosphorylation; Oxidative Stress; Signal Transduction; Spinal Cord; Toll-Like Receptors; Transcriptome

Both starvation and critical illness are hallmarked by changes in circulating thyroid hormone parameters with typically low T(3) concentrations in the absence of elevated TSH. This constellation is labeled nonthyroidal illness (NTI). Because critical illness is often accompanied by anorexia and a failing gastrointestinal tract, the NTI of critical illness may be confounded by nutrient deficiency. In an experimental study performed in a rabbit model, we investigated the impact of nutritional deficit on the NTI of sustained critical illness. Critically ill rabbits were randomly allocated to parenteral nutrition (moderate dose 270 kcal/d) initiated on the day after injury and continued until d 7 of illness or to infusing a similar volume of dextrose 1.4% (14 kcal/d). With early parenteral nutrition during illness, the decrease in serum T(3) observed with fasting was reversed, whereas the fall in T(4) was not significantly affected. The rise in T(3) with parenteral nutrition paralleled an increase of liver and kidney type-1 and a decrease of liver and kidney type-3 deiodinase activity and an increase in circulating and central leptin. Nuclear staining of constitutive androstane receptor and its downstream expression of sulfotransferases were reduced in fasting ill animals. TRH expression in the hypothalamus was not different in fasted and fed ill rabbits, although circulating TSH levels were higher with feeding. In conclusion, in this rabbit model of sustained critical illness, reduced circulating T(3), but not T(4), levels could be prevented by parenteral nutrition, which may be mediated by leptin and its actions on tissue deiodinase activity.

Topics: Animals; Constitutive Androstane Receptor; Critical Illness; Disease Models, Animal; Dithiothreitol; Euthyroid Sick Syndromes; Gene Expression Regulation; Hypothalamo-Hypophyseal System; Iodide Peroxidase; Leptin; Male; Nutrition Disorders; Parenteral Nutrition Solutions; Rabbits; Random Allocation; Receptors, Cytoplasmic and Nuclear; Thyroid Gland; Thyrotropin-Releasing Hormone; Thyroxine; Triiodothyronine

Stress and glucocorticoid stress hormones inhibit neurogenesis, whereas antidepressants increase neurogenesis and block stress-induced decrease in neurogenesis. Our previous studies have shown that leptin, an adipocyte-derived hormone with antidepressant-like properties, promotes baseline neurogenesis in the adult hippocampus. This study aimed to determine whether leptin is able to restore suppression of neurogenesis in a rat chronic unpredictable stress (CUS) model of depression. Chronic treatment with leptin reversed the CUS-induced reduction of hippocampal neurogenesis and depression-like behaviors. Leptin treatment elicited a delayed long-lasting antidepressant-like effect in the forced swim behavioral despair test, and this effect was blocked by ablation of neurogenesis with X-irradiation. The functional isoform of the leptin receptor, LepRb, and the glucocorticoid receptor (GR) were colocalized in hippocampal neural stem/progenitor cells in vivo and in vitro. Leptin treatment reversed the GR agonist dexamethasone (DEX)-induced reduction of proliferation of cultured neural stem/progenitor cells from adult hippocampus. Further mechanistic analysis revealed that leptin and DEX converged on glycogen synthase kinase-3β (GSK-3β) and β-catenin. While DEX decreased Ser9 phosphorylation and increased Tyr216 phosphorylation of GSK-3β, leptin increased Ser9 phosphorylation and attenuated the effects of DEX at both Ser9 and Tyr216 phosphorylation sites of GSK-3β. Moreover, leptin increased total level and nuclear translocation of β-catenin, a primary substrate of GSK-3β and a key regulator in controlling hippocampal neural progenitor cell proliferation, and reversed the inhibitory effects of DEX on β-catenin. Taken together, our results suggest that adult neurogenesis is involved in the delayed long-lasting antidepressant-like behavioral effects of leptin, and leptin treatment counteracts chronic stress and glucocorticoid-induced suppression of hippocampal neurogenesis via activating the GSK-3β/β-catenin signaling pathway.

Topics: Animals; beta Catenin; Cell Proliferation; Cells, Cultured; Cranial Irradiation; Depression; Dexamethasone; Disease Models, Animal; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hippocampus; Leptin; Male; Neurogenesis; Phosphorylation; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Signal Transduction; Stress, Psychological

Leptin, the ob gene product, is a protein released from adipocytes and has been detected in fibrotic and cirrhotic livers. Leptin in brain has an inhibitory effect on food intake. Nonalcoholic steatohepatitis (NASH) is characterized by hyperleptinemia. This study explores the possible mechanisms of hyperleptinemia in relation to increased intrahepatic resistance (IHR) and portal hypertension in NASH cirrhotic rats. NASH cirrhotic rats with hyperleptinemia were induced in Zucker (fa/fa) and lean rats by feeding the animals a high fat/methionine-choline-deficient (HF/MCD) diet with and without exogenous administration of recombinant leptin. Portal venous pressure (PVP), IHR, plasma and hepatic levels of various substances, histopathology of the liver, the hepatic hydroxyproline content, and the expression of various hepatic protein and messenger RNA (mRNA) were measured. Hepatic microcirculatory dysfunction and the vasoconstrictive response to endothelin-1 were also observed using a liver perfusion system and intravital microscopy. Finally, the effect of leptin on hepatic stellate cells (HSCs) was evaluated. Both in HF/MCD-Zucker and HF/MCD+leptin lean rats, significant hepatic fibrogenesis and cirrhosis, marked portal hypertension, microcirculatory dysfunction, an enhanced vasoconstrictive response to endothelin-1, and an increased IHR were found to be associated with higher levels of hepatic endothelin-1 and endocannabinoids, expression levels of the cannabinoid type 1 receptor, endothelin-1 type A receptor (ET(A) R), activator protein-1, transforming growth factor beta (TGF-β)(1), osteopontin, tumor necrosis factor alpha (TNF-α), leptin, and the leptin receptor (OBRb). Interestingly, acute incubation of leptin directly increases the expression of ET(A) R, OBRb and activator protein-1 in HSCs.. An HF/MCD diet and hyperleptinemia increase hepatic endocannabinoids production, promote hepatic fibrogenesis, enhance the hepatic vasoconstrictive response to endothelin-1, and aggravate hepatic microcirculatory dysfunction; these events subsequently increase IHR and portal hypertension in NASH cirrhotic rats.

Topics: Animals; Biopsy, Needle; Body Weight; Cannabinoid Receptor Modulators; Diet, High-Fat; Disease Models, Animal; Disease Progression; Endocannabinoids; Endothelin-1; Fatty Liver; Hepatic Stellate Cells; Hypertension, Portal; Immunohistochemistry; Insulin Resistance; Kupffer Cells; Leptin; Liver; Microcirculation; Non-alcoholic Fatty Liver Disease; Random Allocation; Rats; Rats, Zucker; RNA, Messenger; Statistics, Nonparametric

Glucocorticoids (GCs) are potent pharmacological agents used to treat a number of immune conditions. GCs are also naturally occurring steroid hormones (e.g. cortisol, corticosterone) produced in response to stressful conditions that are thought to increase the preference for calorie dense 'comfort' foods. If chronically elevated, GCs can contribute to the development of type 2 diabetes mellitus (T2DM), although the mechanisms for the diabetogenic effects are not entirely clear. The present study proposes a new rodent model to investigate the combined metabolic effects of elevated GCs and high-fat feeding on ectopic fat deposition and diabetes development. Male Sprague-Dawley rats (aged 7-8 weeks) received exogenous corticosterone or wax (placebo) pellets, implanted subcutaneously, and were fed either a standard chow diet (SD) or a 60% high-fat diet (HFD) for 16 days. Animals given corticosterone and a HFD (cort-HFD) had lower body weight and smaller relative glycolytic muscle mass, but increased relative epididymal mass, compared with controls (placebo-SD). Cort-HFD rats exhibited severe hepatic steatosis and increased muscle lipid deposition compared with placebo-SD animals. Moreover, cort-HFD animals were found to exhibit severe fasting hyperglycemia (60% increase), hyperinsulinemia (80% increase), insulin resistance (60% increase) and impaired β-cell response to oral glucose load (20% decrease) compared with placebo-SD animals. Thus, a metabolic syndrome or T2DM phenotype can be rapidly induced in young Sprague-Dawley rats by using exogenous GCs if a HFD is consumed. This finding might be valuable in examining the physiological and molecular mechanisms of GC-induced metabolic disease.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Adipose Tissue; Adiposity; Animals; Body Composition; Circadian Rhythm; Corticosterone; Diabetes Mellitus, Experimental; Diet, High-Fat; Disease Models, Animal; Energy Intake; Fasting; Feeding Behavior; Glucocorticoids; Hyperglycemia; Hyperinsulinism; Hyperphagia; Insulin; Insulin Resistance; Leptin; Male; Muscular Atrophy; Rats; Receptors, Glucocorticoid; Triglycerides; Weight Gain

Our earlier studies described a disruption of heart rate and blood pressure diurnal rhythms in mice with experimental autoimmune encephalomyelitis (EAE). The present study investigates whether these observations could be extended to additional clock-regulated rhythms in mice with EAE. Analysis of clock gene expression in the liver of EAE mice demonstrated significant variability associated with Per2 rhythmic expression. Corticosterone and leptin hormone rhythms were also altered in EAE mice. The results presented here indicate that disturbances in clock-regulated rhythms are associated with EAE and present a suitable model for investigating the relationship between circadian disruption and autoimmune inflammatory disease.

Topics: Animals; Chronobiology Disorders; Circadian Rhythm; CLOCK Proteins; Corticosterone; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Gene Expression Regulation; Glycoproteins; Hypoxanthine Phosphoribosyltransferase; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Period Circadian Proteins; Pertussis Toxin; T-Lymphocytes; Time Factors

Serotonin and insulin are key regulators of homeostatic mechanisms in the hypothalamus. However, in type 2 diabetes, the hypothalamic responsiveness to serotonin is not clearly established. We used a diabetic model, the Goto Kakizaki (GK) rats, to explore insulin receptor expression, insulin and serotonin efficiency in the hypothalamus and liver by means of Akt phosphorylation. Insulin or dexfenfluramine (stimulator of serotonin) treatment induced Akt phosphorylation in Wistar rats but not in GK rats that exhibit down-regulated insulin receptor. Studies in a neuroblastoma cell line showed that serotonin-induced Akt phosphorylation is PI3-kinase dependent. Finally, in response to food intake, hypothalamic serotonin release was reduced in GK rats, indicating impaired responsiveness of this neurotransmitter. In conclusion, hypothalamic serotonin as insulin efficiency is impaired in diabetic GK rats. The insulin-serotonin cross-talk and impairment observed is one potential key modification in the brain during the onset of diabetes.

Topics: Animals; Blood Glucose; Cell Line, Tumor; Dexfenfluramine; Diabetes Mellitus, Type 2; Disease Models, Animal; Eating; Humans; Hypothalamus; Insulin; Leptin; Liver; Male; Phosphatidylinositol 3-Kinases; Phosphorylation; Postprandial Period; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Receptor Cross-Talk; Receptor, Insulin; Serotonin; Serotonin Receptor Agonists

Ileal interposition (IT), in which the distal ileum is transposed isoperistaltically into the proximal jejunum, is considered as a procedure for metabolic or antidiabetes surgery. Our aim was to study the effects of IT on glycemic control, fat metabolism, and hormonal changes in obese rats with spontaneous diabetes.. Animals were divided into either an IT or a sham (SH) group. They underwent an oral glucose tolerance test (OGTT) before and 4 and 8 weeks after the operation. All animals were killed 10 weeks after operation for analyses of tissue weight (liver, pancreas, epididymal fat, brown fat), immunoblotting of uncoupling protein-1 (UCP1) protein in brown adipose tissue (BAT), and fasting plasma levels of glucose, insulin, glucagon-like peptide (GLP)-1, peptide YY (PYY), glucose-dependent insulinotropic polypeptide (GIP), and leptin.. Body weight increased postoperatively in both groups compared with preoperative weight, but it did not differ between the 2 groups. Eight weeks postoperatively, integrated blood glucose levels during the OGTT were decreased in IT compared with SH (P < .05). Fasting plasma levels of insulin, GLP-1, and GIP did not differ between the 2 groups, but PYY levels were higher in the IT animals (P < .01). The weight of epididymal and BATs, homeostasis model assessment insulin resistance, and fasting plasma leptin levels were decreased in the IT group (P < .05). Expression of UCP1 was higher in IT than SH animals (P < .05).. These results suggest that IT improves glucose and lipid metabolism by decreasing insulin resistance and epididymal fat, and increased expression of UCP1 in BAT might be among the mechanisms responsible.

Topics: Adipose Tissue, Brown; Animals; Body Weight; Comorbidity; Diabetes Mellitus; Disease Models, Animal; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Ileum; Insulin Resistance; Ion Channels; Jejunum; Leptin; Lipid Metabolism; Male; Mitochondrial Proteins; Obesity; Peptide YY; Rats, Inbred OLETF; Uncoupling Protein 1

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

Polycystic ovary syndrome (PCOS), the most common endocrine disorder in women in their reproductive age, is characterized by both reproductive and metabolic features. Recent studies in human, nonhuman primates, and sheep suggest that hyperandrogenism plays an important role in the development of PCOS. We investigated whether chronic dihydrotestosterone (DHT) exposure in mice reproduces both features of PCOS. Such a model would allow us to study the mechanism of association between the reproductive and metabolic features in transgenic mice. In this study, prepubertal female mice received a 90 d continuous release pellet containing the nonaromatizable androgen DHT or vehicle. At the end of the treatment period, DHT-treated mice were in continuous anestrous, their ovaries contained an increased number of atretic follicles, with the majority of atretic antral follicles having a cyst-like structure. Chronic DHT-exposed mice had significantly higher body weights (21%) than vehicle-treated mice. In addition, fat depots of DHT-treated mice displayed an increased number of enlarged adipocytes (P < 0.003). Leptin levels were elevated (P < 0.013), adiponectin levels were diminished (P < 0.001), and DHT-treated mice were glucose intolerant (P < 0.001). In conclusion, a mouse model of PCOS has been developed showing reproductive and metabolic characteristics associated with PCOS in women.

Topics: Adiponectin; Animals; Body Weight; Dihydrotestosterone; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression; Humans; Immunohistochemistry; Insulin; Leptin; Lipid Metabolism; Luteinizing Hormone; Mice; Mice, Inbred C57BL; Ovarian Follicle; Ovary; Phenotype; Polycystic Ovary Syndrome; Reproduction; Reverse Transcriptase Polymerase Chain Reaction

Autophagy is a catabolic cellular process involving the degradation of the cell's own components. Although the role of autophagy of diverse tissues in body metabolism has been investigated, the importance of autophagy in hypothalamic proopiomelanocortin (POMC) neurons, key regulators of energy balance, has not been addressed. The role of autophagy in leptin sensitivity that is critical for the control of body weight and appetite has also not been investigated. We produced mice with specific deletion of autophagy-related 7 (Atg7), an essential autophagy gene, in hypothalamic POMC neurons (Atg7(ΔPOMC) mice). Atg7 expression was deficient in the arcuate nucleus of the hypothalamus of Atg7(ΔPOMC) mice. p62, a specific substrate of autophagy, accumulated in the hypothalamus of Atg7(ΔPOMC) mice, which colocalized with ubiquitin. Atg7(ΔPOMC) mice had increased body weight due to increased food intake and decreased energy expenditure. Atg7(ΔPOMC) mice were not more prone to diet-induced obesity compared with control mice but more susceptible to hyperglycemia after high-fat diet. The ability of leptin to suppress fasting-elicited hyperphagia and weight gain during refeeding was attenuated in Atg7(ΔPOMC) mice. Deficient autophagy did not significantly affect POMC neuron number but impaired leptin-induced signal transducer and activation of transcription 3 activation. Our findings indicate a critical role for autophagy of POMC neurons in the control of energy homeostasis and leptin signaling.

Topics: Animals; Appetite Regulation; Autophagy; Autophagy-Related Protein 7; Body Weight; Disease Models, Animal; Eating; Energy Metabolism; Gene Deletion; Hypothalamus; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Microtubule-Associated Proteins; Neurons; Obesity; Pro-Opiomelanocortin; Signal Transduction

To demonstrate whether leptin modulates reproduction by a direct effect within the ovary.. Animal model.. National Key Laboratory of Infertility.. Adult female db/db mice.. Adult littermate wild-type (WT) and diabetic (db) leptin receptor (LR) mutant female mice were matched for the allograft of the ovary to construct new genotypic models, respectively. WT mouse received only one ovary from a WT or a db/db mouse (WT Ov-WT, WT Ov-db), and db/db mouse received one ovary from a WT or a db/db mouse (db Ov-WT, db Ov-db). WT and db/db mice received one ovary from a WT mouse and another ovary from a db/db mouse (WT Ov-WT/db, db Ov-WT/db) or received two ovaries all from a WT mouse (db Ov-WT/WT).. Hormones, lipids, and reverse transcription polymerase chain reaction.. Both WT Ov-WT and WT Ov-db mice presented normal cycles, comparable serum E(2) and FSH levels, and ovarian expressions of the Star, Cyp17, and Cyp19 mRNA, even with different ovary genotypes. In WT Ov-WT/db with hMG stimulation, db ovaries with LR mutation expressed higher Star, Cyp17, Cyp19, Jak2, Stat3, and Pias3 mRNA than in the basal state, whereas WT ovaries with intact LR expressed higher Star, Cyp17, and Cyp19 but divergently lower Jak2, Stat3, and Pias3 levels.. We confirmed that impairment of reproduction in intact db/db mice is not mediated by intraovary intact/defective leptin signaling even in face of a divergent modulation by gonadotropins.

Topics: Animals; Aromatase; Diabetes Mellitus; Disease Models, Animal; Estradiol; Female; Follicle Stimulating Hormone; Genotype; Janus Kinase 2; Leptin; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Mutant Strains; Mutation; Ovary; Phenotype; Phosphoproteins; Protein Inhibitors of Activated STAT; Receptors, Leptin; Reproduction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Steroid 17-alpha-Hydroxylase; Time Factors; Transplantation, Homologous

Obesity is associated with alterations in upper airway collapsibility during sleep. Obese, leptin-deficient mice demonstrate blunted ventilatory control, leading us to hypothesize that (1) obesity and leptin deficiency would predispose to worsening neuromechanical upper airway function and that (2) leptin replacement would acutely reverse neuromuscular defects in the absence of weight loss. In age-matched, anesthetized, spontaneously breathing C57BL/6J (BL6) and ob(-)/ob(-) mice, we characterized upper airway pressure-flow dynamics during ramp decreases in nasal pressure (P(N)) to determine the passive expiratory critical pressure (P(CRIT)) and active responses to reductions in P(N), including the percentage of ramps showing inspiratory flow limitation (IFL; frequency), the P(N) threshold at which IFL developed, maximum inspiratory airflow (Vi(max)), and genioglossus electromyographic (EMG(GG)) activity. Elevations in body weight were associated with progressive elevations in P(CRIT) (0.1 ± 0.02 cmH(2)O/g), independent of mouse strain. P(CRIT) was also elevated in ob(-)/ob(-) compared with BL6 mice (1.6 ± 0.1 cmH(2)O), independent of weight. Both obesity and leptin deficiency were associated with significantly higher IFL frequency and P(N) threshold and lower VI(max). Very obese ob(-)/ob(-) mice treated with leptin compared with nontreated mice showed a decrease in IFL frequency (from 63.5 ± 2.9 to 30.0 ± 8.6%) and P(N) threshold (from -0.8 ± 1.1 to -5.6 ± 0.8 cmH(2)O) and increase in VI(max) (from 354.1 ± 25.3 to 659.0 ± 71.8 μl/s). Nevertheless, passive P(CRIT) in leptin-treated mice did not differ significantly from that seen in nontreated ob(-)/ob(-) mice. The findings suggest that weight and leptin deficiency produced defects in upper airway neuromechanical control and that leptin reversed defects in active neuromuscular responses acutely without reducing mechanical loads.

Topics: Animals; Disease Models, Animal; Electromyography; Infusions, Subcutaneous; Leptin; Lung; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Pressure; Pulmonary Ventilation; Recombinant Proteins; Respiratory Mechanics; Sleep Apnea, Obstructive; Tidal Volume; Weight Gain

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

Glomus cells within the carotid body are known to respond to hypoxic stimuli. Recently, these cells have been shown to express the long form of the leptin receptor (Ob-Rb). However, whether these glomus cells expressing the Ob-Rb are activated by hypoxic stimuli is not known. Therefore, in this study we investigated whether intermittent hypoxia (IH) or changes in circulating levels of leptin induced phosphorylated signal transducer and activator of transcription 3 (pSTAT3), the immediate early gene c-fos protein, or fos-related antigen-1 protein (Fra-1) within carotid body glomus cells that expressed the Ob-Rb, and within neurons of the petrosal (PG) and nodose (NG) ganglia. Rats were subjected to IH (120 s normoxia, 80s hypoxia for 8h) or normoxia (8h), or intravenous injections of leptin (50 or 200 ng/0.1 mL) or the vehicle saline. Plasma leptin levels were measured in animals exposed to IH and normoxia. Exposure to 8h of IH increased plasma leptin levels greater than 2-fold compared to normoxic controls. Animals were then perfused with Zamboni's fixative, and the region of the carotid bifurcation containing the carotid body and PG/NG complex was removed, paraffin embedded and sectioned at 6 μm for immunohistochemical processing. Carotid body glomus cells were identified by their expression of tyrosine hydroxylase immunoreactivity. These glomus cells also expressed the OB-Rb and were found to express pSTAT3-, fos-, and Fra-1-like immunoreactivity in response to both IH and systemic leptin injections. IH and leptin injections also increased fos and Fra-1 like expression in the PG, NG and jugular ganglion. Taken together, these data suggest IH alters circulating leptin which in turn activates directly carotid body glomus cells to exert a modulatory effect on the peripheral chemoreceptor reflex.

Topics: Animals; Carotid Body; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Hypoxia; Leptin; Male; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, Leptin; STAT3 Transcription Factor

Obesity is associated with an increased risk of colon cancer. High-fat diets that lead to obesity may be a contributing factor, but the mechanisms are unknown.. This study examines susceptibility to azoxymethane (AOM)-induced precancerous lesions in mice in response to consumption of either a low or a high-fat diet and associated molecular changes in the liver and colon.. Gene markers of xenobiotic metabolism, leptin-regulated inflammatory cytokines and proliferation were assessed in liver and colon in response to high-fat feeding to determine links with increased sensitivity to AOM.. High-fat feeding increased development of AOM-induced precancerous lesions and was associated with increased CYP2E1 gene expression in the liver, but not the colon. Leptin receptors and the colon stem cell marker (Lgr5) were down-regulated in the proximal colon, with a corresponding up-regulation of the inflammatory cytokine (IL6) in response to high-fat feeding. Notably in the distal colon, where aberrant crypt foci develop in response to AOM, the proliferative stem cell marker, Lgr5, was significantly up-regulated with high-fat feeding.. The current study provides evidence that high-fat diets can alter regulation of molecular markers of xenobiotic metabolism that may expose the colon to carcinogens, in parallel with activation of β-catenin-regulated targets regulating colon epithelial cells. High-fat diets associated with obesity may alter multiple molecular factors that act synergistically to increase the risk of colon cancer associated with obesity.

Topics: Aberrant Crypt Foci; Animals; Body Composition; Colon; Colorectal Neoplasms; Cytochrome P-450 CYP2E1; Cytokines; Diet, High-Fat; Dietary Fats; Disease Models, Animal; Gene Expression Regulation; Incidence; Leptin; Liver; Mice; Mice, Inbred C57BL; Receptors, G-Protein-Coupled; Receptors, Leptin

Diabetes increases the risk of Alzheimer's disease (AD). The pathological hallmarks for AD brains are extracellular amyloid plaques formed by β-amyloid peptide (Aβ) and intracellular neurofibrillary tangles consisting of hyperphosphorylated tau protein. This study was designed to determine AD-like brain changes in mice modeling for type 2 diabetes. The effects of metformin on these changes also were studied. Seven-week old male db/db mice received intraperitoneal injection of 200 mg kg⁻¹ d⁻¹ metformin for 18 weeks. They were subjected to Barnes maze at an age of 21 weeks and fear conditioning at an age of 24 weeks to assess their cognitive functions. Hippocampus was harvested after these tests for biochemical evaluation. The db/db mice had more tau phosphorylated at S396 and total tau in their hippocampi than their non-diabetic control db+mice. Activated/phosphorylated c-jun N-terminal kinase (JNK), a tau kinase, was increased in the db/db mouse hippocampus. Metformin attenuated the increase of total tau, phospho-tau and activated JNK. The db/db mice had increased Aβ levels. Metformin attenuated the reduction of synaptophysin, a synaptic protein, in the db/db mouse hippocampus. Metformin did not attenuate the impairments of spatial learning and memory as well as long-term hyperglycemia in the db/db mice. Our results suggest that the db/db mice have multiple AD-like brain changes including impaired cognitive functions, increased phospho-tau and Aβ as well as decreased synaptic proteins. Activation of JNK may contribute to the increased phospho-tau in the db/db mice. Metformin attenuates AD-like biochemical changes in the brain of these mice.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Conditioning, Psychological; Diabetes Mellitus, Type 2; Disease Models, Animal; Drug Resistance; Fear; Hippocampus; Hypoglycemic Agents; JNK Mitogen-Activated Protein Kinases; Leptin; Male; Maze Learning; Memory; Metformin; Mice; Mice, Obese; Neurofibrillary Tangles; Phosphorylation; Plaque, Amyloid; Protein Phosphatase 2; Synaptophysin; tau Proteins; Vesicular Transport Proteins

Mutations in the Bdnf gene, which produces transcripts with either short or long 3' untranslated regions (3' UTRs), cause human obesity; however, the precise role of brain-derived neurotrophic factor (BDNF) in the regulation of energy balance is unknown. Here we show the relationship between Bdnf mRNA with a long 3' UTR (long 3' UTR Bdnf mRNA), leptin, neuronal activation and body weight. We found that long 3' UTR Bdnf mRNA was enriched in the dendrites of hypothalamic neurons and that insulin and leptin could stimulate its translation in dendrites. Furthermore, mice harboring a truncated long Bdnf 3' UTR developed severe hyperphagic obesity, which was completely reversed by viral expression of long 3' UTR Bdnf mRNA in the hypothalamus. In these mice, the ability of leptin to activate hypothalamic neurons and inhibit food intake was compromised despite normal activation of leptin receptors. These results reveal a novel mechanism linking leptin action to BDNF expression during hypothalamic-mediated regulation of body weight, while also implicating dendritic protein synthesis in this process.

Topics: 3' Untranslated Regions; Age Factors; Analysis of Variance; Animals; Body Weight; Brain-Derived Neurotrophic Factor; Cells, Cultured; Dendrites; Disease Models, Animal; Energy Metabolism; Female; Gene Expression Regulation; Green Fluorescent Proteins; Humans; Hypothalamus; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Microtubule-Associated Proteins; Neurons; Obesity; Proto-Oncogene Proteins c-fos; Receptor, Insulin; Receptor, trkB; RNA, Messenger; Signal Transduction; Transduction, Genetic

Maternal obesity results in a number of obstetrical and fetal complications with both immediate and long-term consequences. The increased prevalence of obesity has resulted in increasing numbers of women of reproductive age in this high-risk group. Since many of these obese women have been subjected to hypercaloric diets from early childhood we have developed a rodent model of life-long maternal obesity to more clearly understand the mechanisms that contribute to adverse pregnancy outcomes in obese women. Female Sprague Dawley rats were fed a control diet (CON--16% of calories from fat) or high fat diet (HF--45% of calories from fat) from 3 to 19 weeks of age. Prior to pregnancy HF-fed dams exhibited significant increases in body fat, serum leptin and triglycerides. A subset of dams was sacrificed at gestational day 15 to evaluate fetal and placental development. The remaining animals were allowed to deliver normally. HF-fed dams exhibited a more than 3-fold increase in fetal death and decreased neonatal survival. These outcomes were associated with altered vascular development in the placenta, as well as increased hypoxia in the labyrinth. We propose that the altered placental vasculature may result in reduced oxygenation of the fetal tissues contributing to premature demise and poor neonatal survival.

Topics: Adipose Tissue; Animals; Dietary Fats; Disease Models, Animal; Female; Fetal Death; Fetus; Humans; Hypoxia; Leptin; Obesity; Placenta; Pregnancy; Rats; Rats, Sprague-Dawley; Triglycerides

Nutritional approaches are sought to overcome the limits of pioglitazone in metabolic syndrome and non-alcoholic fatty liver disease. Spirulina, a filamentous unicellular alga, reduces serum lipids and blood pressure while exerting antioxidant effects.. To determine whether Spirulina may impact macrophages infiltrating the visceral fat in obesity characterizing our metabolic syndrome mouse model induced by the subcutaneous injection treatment of monosodium glutamate.. Mice were randomized to receive standard food added with 5% Spirulina, 0.02% pioglitazone, or neither. We tested multiple biochemistry and histology (both liver and visceral fat) readouts at 24 weeks of age.. Data demonstrate that both the Spirulina and the pioglitazone groups had significantly lower serum cholesterol and triglyceride levels and liver non-esterified fatty acid compared to untreated mice. Spirulina and pioglitazone were associated with significantly lower leptin and higher levels, respectively, compared to the control group. At liver histology, non-alcoholic fatty liver disease activity score and lipid peroxide were significantly lower in mice treated with Spirulina.. Spirulina reduces dyslipidaemia in our metabolic syndrome model while ameliorating visceral adipose tissue macrophages. Human studies are needed to determine whether this safe supplement could prove beneficial in patients with metabolic syndrome.

Topics: Animals; Cell Aggregation; Cholesterol; Disease Models, Animal; Fatty Acids, Nonesterified; Fatty Liver; Food, Formulated; Hypoglycemic Agents; Insulin; Interleukin-6; Leptin; Lipid Peroxides; Liver; Macrophages; Male; Metabolic Syndrome; Mice; Pioglitazone; Random Allocation; Sodium Glutamate; Spirulina; Thiazolidinediones; Triglycerides; Tumor Necrosis Factor-alpha

The central serotonergic signalling system has been shown to play an important role in appetite control and the regulation of food intake. Serotonin exerts its anorectic effects mainly through the 5-HT(1B), 5-HT(2C) and 5-HT(6) receptors and these are therefore receiving increasing attention as principal pharmacotherapeutic targets for the treatment of obesity. The 5-HT(2C) receptor has the distinctive ability to be modified by posttranscriptional RNA editing on 5 nucleotide positions (A, B, C, D, E), having an overall decreased receptor function. Recently, it has been shown that feeding behaviour and fat mass are altered when the 5-HT(2C) receptor RNA is fully edited, suggesting a potential role for 5-HT(2C) editing in obesity. The present studies investigate the expression of serotonin receptors involved in central regulation of food intake, appetite and energy expenditure, with particular focus on the level of 5-HT(2C) receptor editing. Using a leptin-deficient mouse model of obesity (ob/ob), we show increased hypothalamic 5-HT(1A) receptor expression as well as increased hippocampal 5-HT(1A), 5-HT(1B), and 5-HT(6) receptor mRNA expression in obese mice compared to lean control mice. An increase in full-length 5-HT(2C) expression, depending on time of day, as well as differences in 5-HT(2C) receptor editing were found, independent of changes in total 5-HT(2C) receptor mRNA expression. This suggests that a dynamic regulation exists of the appetite-suppressing effects of the 5-HT(2C) receptor in both the hypothalamus and the hippocampus in the ob/ob mice model of obesity. The differential 5-HT(1A), 5-HT(1B) and 5-HT(6) receptor expression and altered 5-HT(2C) receptor editing profile reported here is poised to have important consequences for the development of novel anti-obesity therapies.

Topics: Adenosine Deaminase; Animals; Appetite; Appetite Regulation; Disease Models, Animal; Eating; Energy Metabolism; Feeding Behavior; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Real-Time Polymerase Chain Reaction; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin; RNA Editing; RNA, Messenger; Serotonin; Thinness

Variable responses of gut hormones have been observed after bariatric procedures. The aim of the present study was to evaluate the ghrelin, glucagon-like peptide 1 (GLP-1), and leptin levels in nonobese canine and obese rat models after weight loss owing to a reversible gastric restriction (RGR) device.. Mongrel dogs and obese Zucker rats were submitted to either surgical implantation or a sham operation and were followed up for 6 wk. The serum fasting ghrelin, GLP-1, and leptin levels in dogs were measured using enzyme-linked immunosorbent assay before and after surgical implantation and after implant removal. The protein expression of mucosa ghrelin, GLP-1, and leptin in the dog and rat stomach were measured using Western blotting.. The RGR implant in dogs and rats resulted in a significant decrease in food intake and body weight. In the nonobese dog, the serum ghrelin level and mucosa ghrelin expression were significantly increased after surgical implantation (P < 0.05) and tended to recover after implant removal. In the obese rat, mucosa ghrelin expression decreased by about 27% (P = 0.06) 6 wk after implantation. A lower serum leptin level in dogs and lower mucosa leptin expression in dogs and rats was observed after surgical implantation compared with the sham procedure (P < 0.05). The RGR implant had no influence on the serum GLP-1 level in dogs or mucosa GLP-1 expression in either animal model.. Our results showed that ghrelin levels are downregulated with short-term RGR implantation in obese rats but upregulated in nonobese dogs, implying that the energy balance could be an important determinant of ghrelin level. The marked suppression of leptin in both animal models might contribute to the weight-reducing effect of the RGR implant.

Topics: Animals; Body Weight; Disease Models, Animal; Dogs; Energy Metabolism; Gastric Mucosa; Gastroplasty; Ghrelin; Glucagon-Like Peptide 1; Leptin; Obesity; Rats; Rats, Zucker; Weight Loss

To investigate a possible direct, growth hormone-releasing, hormone-independent action of a growth hormone secretagogue, GHRP-2, in pituitary somatotroph cells in the presence of inactive growth hormone-releasing hormone receptors.. The responses of serum growth hormone to acutely injected growth hormone-releasing P-2 in lit/lit mice, which represent a model of GH deficiency arising from mutated growth hormone-releasing hormone-receptors, were compared to those observed in the heterozygous (lit/+) littermates and wild-type (+/+) C57BL/6J mice.. After the administration of 10 mcg of growth hormone-releasing P-2 to lit/lit mice, a growth hormone release of 9.3±1.5 ng/ml was observed compared with 1.04±1.15 ng/ml in controls (p<0.001). In comparison, an intermediate growth hormone release of 34.5±9.7 ng/ml and a higher growth hormone release of 163±46 ng/ml were induced in the lit/+ mice and wild-type mice, respectively. Thus, GHRP-2 stimulated growth hormone in the lit/lit mice, and the release of growth hormone in vivo may be only partially dependent on growth hormone-releasing hormone. Additionally, the plasma leptin and ghrelin levels were evaluated in the lit/lit mice under basal and stimulated conditions.. Here, we have demonstrated that lit/lit mice, which harbor a germline mutation in the Growth hormone-releasing hormone gene, maintain a limited but statistically significant growth hormone elevation after exogenous stimulation with GHRP-2. The present data probably reflect a direct, growth hormone-independent effect on Growth hormone S (ghrelin) stimulation in the remaining pituitary somatotrophs of little mice that is mediated by growth hormone S-R 1a.

Topics: Analysis of Variance; Animals; Disease Models, Animal; Female; Ghrelin; Growth Hormone; Heterozygote; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Oligopeptides; Random Allocation; Receptors, Neuropeptide; Receptors, Pituitary Hormone-Regulating Hormone

Osteoporosis is a chronic disease characterized by bone loss and increased skeletal fragility. Large animal models are required for preclinical testing of new therapeutic approaches. We have recently demonstrated that continuous intracerebroventricular (ICV) application of leptin into the lateral ventricle (LV) induces bone loss in ewe. On the basis of these findings, we reasoned that the third ventricle (TV) is an even better target because of its closer location to the hypothalamus that mediates leptin effects on bone.. Corriedale sheep were randomly mixed to four groups of four ewe each: control entire (control), ovarectomy plus ICV application of cerebrospinal fluid (OVX), OVX plus ICV application of leptin into the LV (leptin-LV); and ICV application of leptin into the TV (leptin-TV). After 3 months, histomorphometric characterization and bone turnover parameters were analyzed.. Highly significant loss of trabecular bone was observed only in leptin-LV group. Increased osteoclast indices and urinary cross-lap excretion were observed in OVX and leptin-TV group. In contrast, serum parameters of osteoblast activity were only significantly decreased in leptin-LV group. Autopsy of ewe brain showed fibrosis around the stainless steel cannula in leptin-TV group.. ICV application of leptin into the LV strongly reduces bone formation and leads to a highly significant trabecular bone loss in ewe. In contrast, ICV application of leptin into the TV is technically more demanding and results are unpredictable, because the required use of stainless steel cannula induces peri-implant fibrosis that might prevent leptin to enter the cerebrospinal fluid.

Topics: Animals; Brain Diseases; Disease Models, Animal; Female; Injections, Intraventricular; Lateral Ventricles; Leptin; Osteoblasts; Osteoporosis; Prognosis; Sheep; Third Ventricle

Recent research has indicates that leptin plays a protective role in traumatic brain injury. We studied the protective effect of leptin on cerebral ischemia/reperfusion injury by using mice transient focal cerebral ischemia/reperfusion injury model.. The distribution of 125I-leptin in the mouse brain was assessed by radioimmunoassay method. Mouse models of transient focal cerebral ischemia were established by occlusion of the right middle cerebral artery for two hours followed by 24 hours reperfusion. The neurologic deficits and infarct volume were determined using the Longa's score and 2,3,5-triphenyltetrazolium chloride staining, respectively. Regional cerebral blood flow was monitored by a laser-Doppler blood flowmeter. The levels of malondialdehyde, nitric oxide, nitric oxide synthase, and superoxide dismutase were detected according to respective assay kit. The histologic changes and neuronal apoptosis were observed with hematoxylin and eosin and transferase-mediated dUTP-biotin nick end labeling staining, respectively. The expression of B-cell lymphoma/leukemia-2 (Bcl-2) and cysteineasparateprotease-3 (caspase-3) were investigated by Western blot and real-time polymerase chain reaction assay.. Leptin decreased infarct volume and neurologic defects and improved regional cerebral blood flow and microvascular branch blood flow after injury. The malondialdehyde and nitric oxide levels were reduced, and superoxide dismutase level was increased after leptin treatment, which also minimized histologic changes and neuronal apoptosis, led to the upregulation of Bcl-2 and downregulation of caspase-3 expression after injury.. Peripherally administered leptin crossed the blood-brain barrier and was distributed into multiple regions of the brain; in the brain, leptin directly alleviated the injury-evoked damages by reducing oxidative stress and neuronal apoptosis.

Topics: Animals; Apoptosis; Brain Chemistry; Brain Ischemia; Cerebral Infarction; Cerebrovascular Circulation; Disease Models, Animal; Leptin; Male; Malondialdehyde; Mice; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Superoxide Dismutase

Asthma and obesity are growing epidemics in the world. It is well established that obesity worsens the asthma outcomes. High-fat diet-induced obesity in mice exacerbates the pulmonary eosinophilic inflammation. We have used wild-type (WT) and ob/ob mice to further explore the mechanisms by which obesity aggravates the pulmonary eosinophilic inflammation. The eosinophil (EO) number in bronchoalveolar lavage (BAL) fluid, lung tissue, blood, and bone marrow were evaluated at 24, 48, and 72 h after ovalbumin (OVA) challenge in sensitized mice. The basal EO number (phosphate-buffered saline (PBS)-instilled mice) in lung tissue was about 3.5-fold greater in ob/ob compared with WT mice. OVA challenge in ob/ob mice promoted an EO accumulation into the lung that was accompanied by a lower emigration to airways lumen (BAL fluid) in comparison with WT mice. OVA challenge also markedly elevated the number of mature and immature EO in bone marrow of ob/ob mice at 24 h compared with WT group. Blood EO at 48 h was markedly greater in ob/ob mice. Tumor necrosis factor (TNF)-α and interleukin (IL)-10 levels in BAL fluid were significantly higher in ob/ob mice, whereas no changes for IL-5 and eotaxin were found. The IL-6 levels were significantly lower in ob/ob mice. In conclusion, OVA challenge in ob/ob obese mice potentiates eosinophilopoiesis and promotes an accumulation of EO into the lung tissue, delaying their transit to airways lumen. The longer EO remain into the lung tissue is likely to contribute, at least in part, to the asthma worsened by obesity.

Topics: Allergens; Animals; Bone Marrow; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Eosinophils; Female; Inflammation; Interleukin-6; Leptin; Leukocyte Count; Lung; Male; Mice; Mice, Obese; Obesity; Ovalbumin; Respiratory Hypersensitivity

Transgenic mice expressing dominant-negative retinoic acid receptor (RAR) α specifically in the liver exhibit steatohepatitis, which leads to the development of liver tumors. Although the cause of steatohepatitis in these mice is unknown, diminished hepatic expression of insulin-like growth factor-1 suggests that insulin resistance may be involved. In the present study, we examined the effects of retinoids on insulin resistance in mice to gain further insight into the mechanisms responsible for this condition. Dietary administration of all-trans-retinoic acid (ATRA) significantly improved insulin sensitivity in C57BL/6J mice, which served as a model for high-fat, high-fructose diet-induced nonalcoholic fatty liver disease (NAFLD). The same effect was observed in genetically insulin-resistant KK-A(y) mice, occurring in concert with activation of leptin-signaling pathway proteins, including signal transducer and activator of transcription 3 (STAT3) and Janus kinase 2. However, such an effect was not observed in leptin-deficient ob/ob mice. ATRA treatment significantly up-regulated leptin receptor (LEPR) expression in the livers of NAFLD mice. In agreement with these observations, in vitro experiments showed that in the presence of leptin, ATRA directly induced LEPR gene expression through RARα, resulting in enhancement of STAT3 and insulin-induced insulin receptor substrate 1 phosphorylation. A selective RARα/β agonist, Am80, also enhanced hepatic LEPR expression and STAT3 phosphorylation and ameliorated insulin resistance in KK-A(y) mice.. We discovered an unrecognized mechanism of retinoid action for the activation of hepatic leptin signaling, which resulted in enhanced insulin sensitivity in two mouse models of insulin resistance. Our data suggest that retinoids might have potential for treating NAFLD associated with insulin resistance.

Topics: Animals; Cells, Cultured; Disease Models, Animal; Fatty Liver; Hepatocytes; Immunohistochemistry; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Non-alcoholic Fatty Liver Disease; Random Allocation; Receptors, Leptin; Reference Values; Sensitivity and Specificity; Signal Transduction; Tretinoin; Up-Regulation

The objective of the present study was to determine the suitability of a swine breed with leptin resistance and predisposition to obesity (the Iberian pig) as model for studies on metabolic syndrome and type 2 diabetes. Thus, six Iberian sows had ad libitum access to food enriched with saturated fat (SFAD group; food consumption was estimated to be 4.5 kg/animal/day) whilst four females acted as controls and were fed with 2 kg/animal/day of a commercial maintenance diet. After three months of differential feeding, SFAD animals developed central obesity, dyslipidemia, insulin resistance and impaired glucose tolerance, and elevated blood pressure; the five parameters associated with the metabolic syndrome. Thus, the current study characterizes the Iberian pig as a robust, amenable, and reliable translational model for studies on nutrition-associated diseases.

Topics: Animals; Diabetes Mellitus, Type 2; Dietary Fats; Disease Models, Animal; Female; Humans; Leptin; Metabolic Syndrome; Obesity; Species Specificity; Swine

To analyze the influence of hyperthyroidism on the gene expression and serum concentration of leptin, resistin, and adiponectin in obese animals.. Male Wistar rats were randomly divided into two groups: control (C)-fed with commercial chow ad libitum-and obese (OB)-fed with a hypercaloric diet. After group characterization, the OB rats continued receiving a hypercaloric diet and were randomized into two groups: obese animals (OB) and obese with 25 μg triiodothyronine (T(3))/100 BW (OT). The T(3) dose was administered every day for the last 2 weeks of the study. After 30 weeks the animals were euthanized. Samples of blood and adipose tissue were collected for biochemical and hormonal analyses as well as gene expression of leptin, resistin, and adiponectin.. T(3) treatment was effective, increasing fT(3) levels and decreasing fT(4) and TSH serum concentration. Administration of T(3) promotes weight loss, decreases all fat deposits, and diminishes serum levels of leptin, resistin, and adiponectin by reducing their gene expression.. Our results suggest that T(3) modulate serum and gene expression levels of leptin, resistin, and adiponectin in experimental model of obesity, providing new insights regarding the relationship between T(3) and adipokines in obesity.

Topics: Adiponectin; Adipose Tissue; Animals; Body Weight; Disease Models, Animal; Gene Expression Regulation; Homeostasis; Hyperthyroidism; Leptin; Male; Obesity; Random Allocation; Rats; Rats, Wistar; Resistin; Thyrotropin; Thyroxine; Triiodothyronine

This study evaluated the influence of diet-induced obesity on bone tissue quantity and quality in the proximal tibiae of growing mice and also examined the relationships between the serum total cholesterol, leptin, and adiponectin levels and trabecular and cortical bone mineral parameters.. Six-week-old male C57BL/6J mice were divided into two groups; one received a control diet, and the other received a high-fat-diet. After treatment for 4, 8, or 12 weeks, the bone quantity and quality were analyzed using peripheral quantitative computed tomography (pQCT), micro-computed tomography and histomorphometry.. In the early stages, trabecular bone density decreased with an increase in the number of adipocytes and the deterioration of trabeculae. In contrast, although cortical bone formation was slower in obese mice compared with control mice, bone formation on the periosteal surface increased with age. Serum leptin levels were correlated with trabecular, but not cortical bone density, whereas neither the adiponectin nor total cholesterol level was correlated with bone mass in mice with diet-induced obesity.. We conclude that bone loss at these two sites is differentially regulated in mice. Furthermore, we demonstrate that serum leptin may be a useful indicator of risk for osteoporosis associated with diet-induced obesity.

Topics: Adiponectin; Animals; Bone and Bones; Bone Density; Cholesterol; Diet, High-Fat; Disease Models, Animal; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Osteoporosis; Radiography

The study's purpose was to investigate if physical activity initiated with the start of high-fat feeding would oppose development of endothelial dysfunction, and if it does, then to determine some potential mechanisms. C57BL/6 female mice were randomly divided into three groups: (1) control low-fat diet (LF-SED; 15% of calories from fat), (2) high-fat diet (HF-SED; 45% of calories from fat), and (3) HF diet given access to a voluntary running wheel (HF-RUN). Our hypothesis was that HF-RUN would differ in multiple markers of endothelial dysfunction from HF-SED after 10 weeks of 45%-fat diet, but would not differ from LF-SED. HF-RUN differed from HF-SED in nine determinations in which HF-SED either had decreases in (1) acetylcholine (ACh)-induced and flow-induced vasodilatations in isolated, pressurized coronary arterioles, (2) heart phosphorylated endothelial nitric oxide synthase (p-eNOS/eNOS) protein, (3) coronary arteriole leptin (ob) receptor protein, (4) phosphorylated signal transducer and activator of transcription 3 (p-STAT3/STAT3) protein, and (5) coronary arteriole superoxide dismutase 1 protein; or had increases in (6) percentage body fat, (7) serum leptin, (8) coronary arteriole suppressor of cytokine signalling 3 (SOCS3) protein, and (9) coronary arteriole gp91(phox) protein. Higher endothelium-dependent vasodilatation by ACh or leptin was abolished with incubation of NOS inhibitor N(G)-nitro-l-arginine-methyl ester (l-NAME) in LF-SED and HF-RUN groups. Further, impaired ACh-induced vasodilatation in HF-SED was normalized by apocynin or TEMPOL to LF-SED and HF-RUN. These findings demonstrate multiple mechanisms (eNOS, leptin and redox balance) by which voluntary running opposes the development of impaired coronary arteriolar vasodilatation during simultaneous high-fat feeding.

Topics: Animals; Arterioles; Coronary Artery Disease; Coronary Vessels; Diet, High-Fat; Disease Models, Animal; Endothelium, Vascular; Female; Leptin; Mice; Mice, Inbred C57BL; Motor Activity; Nitric Oxide; Nitric Oxide Synthase Type III; Oxidative Stress; Phosphorylation; Running

Significantly lower circulating leptin level has been reported in adolescent idiopathic scoliosis (AIS) compared to healthy adolescents. It was hypothesized that leptin dysfunction might be involved in the etiopathogenesis of AIS. In this study, a scoliosis model of bipedal amputated mice with high central leptin activity was established to validate this hypothesis. Three days after bipedal amputation, the mice were randomly divided into two groups: then 8 mice were injected in the hypothalamus with lentivirus vectors which expressed leptin, whereas the remaining 8 were injected with lentivirus vectors expressing GFP (control vector). X-rays were obtained at 20th week to determine the development of spinal deformity. After that all mice were sacrificed, and blood samples were collected. Then peripheral leptin levels were measured by an ELISA kit. Comparisons for the incidence of scoliosis and the severity of the curves were performed between groups. The body weight was found to be slightly lower in the leptin-vector-treated C3H/HeJ mice when compared with control mice. Significantly higher peripheral serum leptin level was found in leptin-vector-treated mice than control mice. Scoliosis was observed in all leptin-vector-treated mice with an average Cobb angle of 28.2°, and in 4/8 of control with an average Cobb angle of 23.5°. The incidence of scoliosis was significantly higher in leptin-vector-treated mice than in control group, although no significant difference was found in terms of curve severity. The results of this study indicated that the high central leptin activity might not only increase the risk of developing a scoliosis in bipedal mice but also contribute to the progression of scoliosis. The high central leptin activity might play an important role in the etiopathogenesis of scoliosis.

Topics: Amputation, Surgical; Animals; Brain; Disease Models, Animal; Forelimb; Humans; Leptin; Mice; Mice, Inbred C3H; Scoliosis

Fibroblast growth factor 21 (FGF21) is a potent metabolic regulator, and pharmacological administration elicits glucose and lipid lowering responses in mammals. To delineate if adipose tissue is the predominant organ responsible for anti-diabetic effects of FGF21, we treated mice with reduced body fat (lipodystrophy mice with adipose specific expression of active sterol regulatory element binding protein 1c; Tg) with recombinant murine FGF21 (rmuFGF21). Unlike wildtype (WT) mice, Tg mice were refractory to the beneficial effects of rmuFGF21 on body weight, adipose mass, plasma insulin and glucose tolerance. To determine if adipose mass was critical for these effects, we transplanted WT white adipose tissue (WAT) into Tg mice and treated the mice with rmuFGF21. After transplantation, FGF21 responsiveness was completely restored in WAT transplanted Tg mice compared to sham Tg mice. Further, leptin treatment alone was sufficient to restore the anti-diabetic effects of rmuFGF21 in Tg mice. Molecular analyses of Tg mice revealed normal adipose expression of Fgfr1, Klb and an 8-fold over-expression of Fgf21. Impaired FGF21-induced signaling indicated that residual adipose tissue of Tg mice was resistant to FGF21, whilst normal FGF21 signaling was observed in Tg livers. Together these data suggest that adipose tissue is required for the triglyceride and glucose, but not the cholesterol lowering efficacy of FGF21, and that leptin and FGF21 exert additive anti-diabetic effects in Tg mice.

Topics: Adipose Tissue, White; Animals; Disease Models, Animal; Female; Fibroblast Growth Factors; Gene Expression Regulation; Glucose; Homeostasis; Humans; Leptin; Lipodystrophy; Male; Mice; Mice, Transgenic; PPAR gamma; Receptor, Fibroblast Growth Factor, Type 1; Recombinant Proteins; Signal Transduction

To determine the role of leptin in modulating Th17 cell response and joint inflammation in mice with collagen-induced arthritis (CIA).. Leptin receptor expression on T cells was examined by polymerase chain reaction (PCR) analysis, immunofluorescence microscopy, and flow cytometry. Effects of leptin on Th17 cell differentiation and proliferation were evaluated by quantitative PCR, carboxyfluorescein diacetate succinimidyl ester proliferation assay, and flow cytometry. Dynamic changes in leptin concentrations in the joint tissue and synovial fluid of mice with CIA were determined by immunohistochemistry analysis and enzyme-linked immunosorbent assay (ELISA). Arthritis symptoms and joint pathology in mice with CIA were assessed after injection of leptin into the knee joint. Th1 and Th17 cell populations in the spleen, draining lymph nodes, and joint tissue were analyzed by flow cytometry and enzyme-linked immunospot assay. Interleukin-17 messenger RNA and protein levels in the joint tissue were measured by PCR analysis and ELISA.. In culture, leptin treatment significantly increased Th17 cell generation from naive CD4+ T cells. During CIA development, markedly elevated levels of leptin were detected in the joint tissue and synovial fluid. Moreover, injection of leptin into the knee joint of collagen-immunized mice resulted in an early onset of arthritis and substantially increased the severity of clinical symptoms, accompanied by more pronounced synovial hyperplasia and joint damage. Further examination by immunofluorescence microscopy confirmed the presence of significantly increased numbers of Th17 cells in the joint tissue and draining lymph nodes of leptin-treated mice with CIA.. The results of this study identify a previously undescribed function of leptin in enhancing Th17 cell response and exacerbating joint inflammation in mice with CIA.

Topics: Animals; Arthritis, Experimental; Cell Differentiation; Disease Models, Animal; Female; Injections, Intra-Articular; Interleukin-17; Knee Joint; Leptin; Lymph Nodes; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Mutant Strains; Nuclear Receptor Subfamily 1, Group F, Member 3; Receptors, Leptin; RNA, Messenger; Synovial Fluid; Th17 Cells

The number of patients with diabetes or the metabolic syndrome reaches epidemic proportions. On top of their diabetic cardiomyopathy, these patients experience frequent and severe cardiac ischemia-reperfusion (IR) insults, which further aggravate their degree of heart failure. Food restriction and angiotensin-converting enzyme inhibition (ACE-I) are standard therapies in these patients but the effects on cardiac IR injury have never been investigated. In this study, we tested the hypothesis that 1° food restriction and 2° ACE-I reduce infarct size and preserve cardiac contractility after IR injury in mouse models of diabetes and the metabolic syndrome.. C57Bl6/J wild type (WT) mice, leptin deficient ob/ob (model for type II diabetes) and double knock-out (LDLR-/-;ob/ob, further called DKO) mice with combined leptin and LDL-receptor deficiency (model for metabolic syndrome) were used. The effects of 12 weeks food restriction or ACE-I on infarct size and load-independent left ventricular contractility after 30 min regional cardiac ischemia were investigated. Differences between groups were analyzed for statistical significance by Student's t-test or factorial ANOVA followed by a Fisher's LSD post hoc test.. Infarct size was larger in ob/ob and DKO versus WT. Twelve weeks of ACE-I improved pre-ischemic left ventricular contractility in ob/ob and DKO. Twelve weeks of food restriction, with a weight reduction of 35-40%, or ACE-I did not reduce the effect of IR.. ACE-I and food restriction do not correct the increased sensitivity for cardiac IR-injury in mouse models of type II diabetes and the metabolic syndrome.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Biomarkers; Caloric Restriction; Diabetes Mellitus, Type 2; Disease Models, Animal; Leptin; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Myocardial Contraction; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Receptors, LDL; Time Factors; Ventricular Function, Left; Ventricular Pressure

The kallikrein-kinin system (KKS) has been previously linked to glucose homeostasis. In isolated muscle or fat cells, acute bradykinin (BK) stimulation was shown to improve insulin action and increase glucose uptake by promoting glucose transporter 4 translocation to plasma membrane. However, the role for BK in the pathophysiology of obesity and type 2 diabetes remains largely unknown. To address this, we generated genetically obese mice (ob/ob) lacking the BK B2 receptor (obB2KO). Despite similar body weight or fat accumulation, obB2KO mice showed increased fasting glycemia (162.3 ± 28.2 mg/dl vs 85.3 ± 13.3 mg/dl), hyperinsulinemia (7.71 ± 1.75 ng/ml vs 4.09 ± 0.51 ng/ml) and impaired glucose tolerance when compared with ob/ob control mice (obWT), indicating insulin resistance and impaired glucose homeostasis. This was corroborated by increased glucose production in response to a pyruvate challenge. Increased gluconeogenesis was accompanied by increased hepatic mRNA expression of forkhead box protein O1 (FoxO1, four-fold), peroxisome proliferator-activated receptor gamma co-activator 1-alpha (seven-fold), phosphoenolpyruvate carboxykinase (PEPCK, three-fold) and glucose-6-phosphatase (eight-fold). FoxO1 nuclear exclusion was also impaired, as the obB2KO mice showed increased levels of this transcription factor in the nucleus fraction of liver homogenates during random feeding. Intraportal injection of BK in lean mice was able to decrease the hepatic mRNA expression of FoxO1 and PEPCK. In conclusion, BK modulates glucose homeostasis by affecting hepatic glucose production in obWT. These results point to a protective role of the KKS in the pathophysiology of type 2 diabetes mellitus.

Topics: Analysis of Variance; Animals; Bradykinin; Cell Line, Tumor; Diabetes Mellitus, Type 2; Disease Models, Animal; Female; Forkhead Box Protein O1; Forkhead Transcription Factors; Gluconeogenesis; Glucose; Glucose-6-Phosphatase; Humans; Insulin; Insulin Resistance; Kallikrein-Kinin System; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Obesity; Phosphoenolpyruvate Carboxykinase (GTP); PPAR gamma; Rats; Receptors, Bradykinin

The TALLYHO/Jng (TH) mouse is an inbred polygenic model for type 2 diabetes (T2D) with moderate obesity. Both male and female TH mice are characterized by increased body and fat pad weights, hyperleptinemia, hyperinsulinemia, and hyperlipidemia. Glucose intolerance and hyperglycemia are exhibited only in males. Reduced 2-deoxy-glucose uptake occurs in adipose tissue and skeletal muscle of male TH mice. While both sexes of TH mice exhibit enlarged pancreatic islets, only males have degranulation and abnormal architecture in islets. Endothelial dysfunction and considerably decreased bone density are also observed in male TH mice. The blood pressure of male TH mice is normal. Genetic outcross experiments with non-diabetic strains revealed multiple susceptibility loci (quantitative trait loci) for obesity, hypertriglyceridemia, hypercholesterolemia, and hyperglycemia. In conclusion, TH mice encompass many aspects of polygenic human diabetes and are a very useful model for T2D.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Female; Humans; Hyperglycemia; Hyperinsulinism; Hyperlipidemias; Insulin Resistance; Leptin; Male; Mice; Obesity; Phenotype; Quantitative Trait Loci

We previously demonstrated that animals fed a high-fat (HF) diet for 10 weeks developed insulin resistance and behavioural inflexibility. We hypothesised that intervention with metformin would diminish the HF-feeding-evoked cognitive deficit by improving insulin sensitivity.. Rats were trained in an operant-based matching and non-matching to position task (MTP/NMTP). Animals received an HF (45% of kJ as lard; n = 24), standard chow (SC; n = 16), HF + metformin (144 mg/kg in diet; n = 20) or SC + metformin (144 mg/kg in diet; n = 16) diet for 10 weeks before retesting. Body weight and plasma glucose, insulin and leptin were measured. Protein lysates from various brain areas were analysed for alterations in intracellular signalling or production of synaptic proteins.. HF-fed animals developed insulin resistance and an impairment in switching task contingency from matching to non-matching paradigm. Metformin attenuated the insulin resistance and weight gain associated with HF feeding, but had no effect on performance in either MTP or NMTP tasks. No major alteration in proteins associated with insulin signalling or synaptic function was detected in response to HF diet in the hypothalamus, hippocampus, striatum or cortex.. Metformin prevented the metabolic but not cognitive alterations associated with HF feeding. The HF diet protocol did not change basal insulin signalling in the brain, suggesting that the brain did not develop insulin resistance. These findings indicate that HF diet has deleterious effects on neuronal function over and above those related to insulin resistance and suggest that weight loss may not be sufficient to reverse some damaging effects of poor diet.

Topics: Alzheimer Disease; Animals; Behavior, Animal; Body Weight; Brain; Cognition Disorders; Conditioning, Operant; Dietary Fats; Disease Models, Animal; Hormones; Hypoglycemic Agents; Insulin Resistance; Leptin; Male; Metformin; Nerve Tissue Proteins; Rats; Rats, Wistar; Signal Transduction; Treatment Failure

Circulating levels of leptin are elevated in individuals suffering from chronic intermittent hypoxia (CIH). Systemic and central administration of leptin elicits increases in sympathetic nervous activity (SNA), arterial pressure (AP), and heart rate (HR), and it attenuates the baroreceptor reflex, cardiovascular responses that are similar to those observed during CIH as a result of activation of chemoreceptors by the systemic hypoxia. Therefore, experiments were done in anesthetized Wistar rats to investigate the effects of leptin in nucleus of the solitary tract (NTS) on AP and HR responses, and renal SNA (RSNA) responses during activation of NTS neurons and the chemoreceptor reflex. Microinjection of leptin (5-100 ng; 20 nl) into caudal NTS pressor sites (l-glutamate; l-Glu; 0.25 M; 10 nl) elicited dose-related increases in AP, HR, and RSNA. Leptin microinjections (5 ng; 20 nl) into these sites potentiated the increase in AP and HR elicited by l-Glu. Additionally, bilateral injections of leptin (5 ng; 100 nl) into NTS potentiated the increase in AP and attenuated the bradycardia to systemic activation of the chemoreflex. In the Zucker obese rat, leptin injections into NTS neither elicited cardiovascular responses nor altered the cardiovascular responses to activation of the chemoreflex. Taken together, these data indicate that leptin exerts a modulatory effect on neuronal circuits within NTS that control cardiovascular responses elicited during the reflex activation of arterial chemoreceptors and suggest that increased AP and SNA observed in individuals with CIH may be due, in part, by leptin's effects on the chemoreflex at the level of NTS.

Topics: Animals; Baroreflex; Blood Pressure; Chemoreceptor Cells; Disease Models, Animal; Glutamic Acid; Heart Rate; Leptin; Male; Microinjections; Obesity; Rats; Rats, Wistar; Rats, Zucker; Receptors, Leptin; Signal Transduction; Solitary Nucleus

Obesity is a disease that has become a serious public health issue worldwide, and chronic stressors, which are a problem for modern society, cause neuroendocrine changes with alterations in food intake. Obesity and chronic stress are associated with the development of cardiovascular diseases and metabolic disorders. In this study, a rat model was used to evaluate the effects of a hypercaloric diet plus chronic restraint stress on the serum leptin and lipids levels and on the weight of specific adipose tissue (mesenteric, MAT; subcutaneous, SAT and visceral, VAT). Wistar rats were divided into the following 4 groups: standard chow (C), hypercaloric diet (HD), stress plus standard chow (S), and stress plus hypercaloric diet (SHD). The animals in the stress groups were subjected to chronic stress (placed inside a 25 cm × 7 cm plastic tube for 1h per day, 5 days per week for 6 weeks). The following parameters were evaluated: the weight of the liver, adrenal glands and specific adipose tissue; the delta weight; the Lee index; and the serum levels of leptin, corticosterone, glucose, total cholesterol, and triglycerides. The hypercaloric diet induced obesity in rats, increasing the Lee index, weight, leptin, triglycerides, and cholesterol levels. The stress decreased weight gain even in animals fed a hypercaloric diet but did not prevent a significant increase in the Lee index. However, an interaction between the independent factors (hypercaloric diet and stress) was observed, which is demonstrated by the increased serum leptin levels in the animals exposed to both protocols.

Topics: Adipose Tissue; Animals; Body Weight; Corticosterone; Diet; Disease Models, Animal; Energy Intake; Leptin; Lipids; Lipoproteins, HDL; Lipoproteins, LDL; Liver; Obesity; Organ Size; Rats; Rats, Wistar; Restraint, Physical; Stress, Physiological

In this study, we investigated the anti-obesity effects of kimchi (Korean traditional fermented vegetable) fermented either without starter culture or with a specific starter culture, Weissella koreensis OK1-6.. C57BL/6J mice were divided into four groups (n = 7); normal diet, HF (high-fat diet), HF-KC (high-fat diet containing 3% kimchi manufactured without starter) and HF-KCO (high-fat diet containing 3% kimchi manufactured with the starter culture W. koreensis OK1-6). After 12 weeks of dietary intervention, the mice were killed, and serum and tissue samples were examined. Serum and hepatic lipid profile, insulin, leptin concentration and expression level of lipid anabolic genes like peroxisome proliferator-activated receptor γ, stearoyl-CoA desaturase-1, liver X receptor α and SREBP2 were significantly decreased (<0.05) along with body and epididymal fat pad weight in the HF-KCO group compared with the HF-KC and HF group.. These results suggested that kimchi fermented with the starter W. koreensis OK1-6 has anti-obesity effects in HF-induced obese mice.. These results may contribute to nutraceutical and food industries in developing functional food and probiotics based therapies for the treatment and prevention of obesity.

Topics: Adipose Tissue; Animals; Body Weight; Brassica; Diet, High-Fat; Dietary Fats; Disease Models, Animal; Fermentation; Food Microbiology; Insulin; Leptin; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; PPAR gamma; Weissella

Nonalcoholic fatty liver disease (NAFLD), one of chronic liver diseases, seems to be rising as the obesity epidemic continues. In this study, 54 novel (thio)barbituric acid derivatives have been synthesized and evaluated for pharmacological activity. 7h exhibited potent glucose-lowering effects on insulin-resistant HepG2 cells and regulated adiponectin and leptin expression in 3T3-L1 adipocytes. Oral administration of 7h at 25 mg kg(-1) day(-1) for 4 weeks improved the progression of high fat diet-induced NAFLD by reducing the weight of body, liver, and fat, as well as modulating serum levels of fasting glucose, insulin, triglycerides, LDL-c, ALT, adiponectin and hepatic contents of triglycerides, total cholesterol. H&E stainings revealed that 7h blocked fat deposition in liver and the increase of adipocyte number and size in adipose tissues from NAFLD. Furthermore, treatment with 7h alleviated the obese clinical symptoms, recovered serum biomarkers to appropriate ranges, and improved glucose tolerance by OGTT and IGTT in DIO mice.

Topics: 3T3-L1 Cells; Adipocytes; Adiponectin; Alanine Transaminase; Animals; Barbiturates; Body Weight; Cholesterol; Diet, High-Fat; Disease Models, Animal; Fatty Liver; Female; Glucose; Glucose Tolerance Test; Hep G2 Cells; Humans; Insulin; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity; Piperidines; Pyrimidines; Rats; Rats, Sprague-Dawley; Rats, Wistar; Tissue Distribution; Triglycerides

The homozygous mutant fatty Zucker rat (fa/fa) is the prominent model for the research of obesity, one of the most well-known risk factor of postmenopausal mammary cancer. But the usage as a mammary gland carcinogenesis model is considered to be restricted due to the hypoplasia of mammary gland. In the present study, to find the validity of heterozygous mutant (+/fa) lean Zucker rats as a new leptin-related mammary carcinogenesis model, we examined whether the number of terminal end buds of mammary gland, the serum biochemistry, leptin concentration in serum and adipose tissue are changed in 7-week-old female +/+, +/fa and fa/fa rats, and whether these changes and leptin, TNF-α and VEGF mRNA expression in adipose tissue of +/+ and +/fa rats are influenced by 10% corn oil diet for 5 weeks. We confirmed that mild hyperleptinemia was more pronounced in 7-week-old +/fa as compared with wild type (+/+) and hypoplasia of mammary glands characterized by fewer numbers of terminal end buds in fa/fa was not observed in +/fa. With 10% corn oil diet, leptin mRNA expression in adipose tissue showed increasing tendency both in +/fa and +/+. Comparing with +/+, adipose tissue in +/fa treated with 10% corn oil diet was found to be significantly increased in the concentration of leptin protein and tended to be elevated expression of TNF-α mRNA. These results suggest that +/fa with 10% corn oil diet may be a useful model for investigation of the participation of leptin and TNF-α in mammary gland carcinogenesis.

Topics: Adipose Tissue; Animals; Body Weight; Corn Oil; Diet; Disease Models, Animal; Female; Leptin; Liver; Mammary Neoplasms, Animal; Obesity; Organ Size; Rats; Rats, Zucker; RNA, Messenger; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

Inherent mechanisms leading to vascular smooth muscle cells (VSMC) alterations in obesitylinked type 2 diabetes (T2D) situation remain to be clarified. This study evaluates the impact of supernatant of adipocytes extracted from mice fed high-fat-diets (HFD) on the proliferation and apoptosis of VSMC.. Adipocytes were extracted from visceral white fat pads of male and female C57Bl6 mice showing different stages of metabolic alterations after 20 weeks of vegetal or animal HFD feeding. These cells were stimulated or not with insulin or glucose to condition VSMC media. After 24h of stimulation with adipocyte supernatants (AdS), VSMC proliferation and sustainability were assessed in the absence and presence of AdS. CD36 and insulin receptor mRNA levels were also evaluated.. Proliferation and viability of VSMC were significantly modulated by the nature of the AdS used and the gender of mice from which adipocytes have been extracted. The most extensive effects on VSMC were triggered by adipocytes from males fed animal HFD and females fed vegetal HFD. These effects were concurrent with increased leptin concentration and decreased adiponectin levels in AdS. In addition, adipocytes of HFD-fed mice increased caspase-3 activity and apoptosis in VSMC. Significant up-regulation of CD36 mRNA was also found in these cells.. Adipocytes of HFD-fed mice induce VSMC alterations. These changes involved mouse gender, most probably correlated to the diet-induced adipocyte secretion profile. Greater sensitivity to AdS effects in VSMC raises concerns about the more frequent cardiovascular events associated with obesity in the presence of T2D, which impairs adipocyte activity.

Topics: Adipocytes; Adipokines; Animal Feed; Animals; Apoptosis; Atherosclerosis; Caspase 3; CD36 Antigens; Cell Proliferation; Cells, Cultured; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Female; Glucose; Leptin; Lipids; Male; Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular; RNA, Messenger

We evaluated the effect of the intake of a grapevine-shoot phenolic extract (Vineatrol 30) on early atherosclerosis in hamsters fed a hyperlipidic diet. Golden Syrian hamsters received for 13 weeks either a standard diet, a high-fat (HF) diet, or the HF diet plus Vineatrol 30 at 0.04, 0.2, or 1.0 mg/(kg body weight/d). We measured plasma lipids and glucose, insulin, leptin and adiponectin, as well as liver TNF-α and IL-6 levels. Oxidative stress was assessed by measuring plasma paraoxonase activity (PON) and liver superoxide anion production (O(2)(•-)). The aortic fatty streak area (AFSA) was also determined. In comparison with HF group, we demonstrated that the highest dose of Vineatrol 30 was capable of decreasing AFSA (67%), insulinemia (40%), and leptinemia (8.7%), which were increased by the HF diet. We also showed increased O(2)(•-) production (35%) and a rise in levels of the liver proinflammatory cytokines TNF-α (22%) and IL-6 (21%), accompanied by a fall in PON activity (56%) due to the HF diet versus the standard diet. In contrast, except plasma adiponectin levels that are not changed, Vineatrol 30 treatment lowered AFSA (67%), O(2)(•-) production (36%), insulin resistance (42%), leptinemia (9%), liver TNF-α (18%) and IL-6 (15%), while it rose PON activity (29%). These findings demonstrate the preventive effects of polyphenols present in Vineatrol 30 in managing cardiovascular, metabolic, and inflammatory risk factors.

Topics: Adiponectin; Animals; Aryldialkylphosphatase; Atherosclerosis; Blood Glucose; Cricetinae; Disease Models, Animal; Dose-Response Relationship, Drug; Insulin; Interleukin-6; Leptin; Lipids; Male; Mesocricetus; Oxidative Stress; Phenols; Tumor Necrosis Factor-alpha

Huntington's disease (HD) is a neurodegenerative disorder, which is characterized by progressive motor impairment and cognitive alterations. Changes in energy metabolism, neuroendocrine function, body weight, euglycemia, appetite function, and circadian rhythm can also occur. It is likely that the locus of these alterations is the hypothalamus. We used the HD transgenic (tg) rat model bearing 51 CAG repeats, which exhibits similar HD symptomology as HD patients to investigate hypothalamic function. We conducted detailed hypothalamic proteome analyses and also measured circulating levels of various metabolic hormones and lipids in pre-symptomatic and symptomatic animals. Our results demonstrate that there are significant alterations in HD rat hypothalamic protein expression such as glial fibrillary acidic protein (GFAP), heat shock protein-70, the oxidative damage protein glutathione peroxidase (Gpx4), glycogen synthase1 (Gys1) and the lipid synthesis enzyme acylglycerol-3-phosphate O-acyltransferase 1 (Agpat1). In addition, there are significant alterations in various circulating metabolic hormones and lipids in pre-symptomatic animals including, insulin, leptin, triglycerides and HDL, before any motor or cognitive alterations are apparent. These early metabolic and lipid alterations are likely prodromal signs of hypothalamic dysfunction. Gaining a greater understanding of the hypothalamic and metabolic alterations that occur in HD, could lead to the development of novel therapeutics for early interventional treatment of HD.

Topics: 1-Acylglycerol-3-Phosphate O-Acyltransferase; Animals; Biomarkers; Disease Models, Animal; Disease Progression; Gene Expression; Glial Fibrillary Acidic Protein; Glutathione Peroxidase; Glycogen Synthase; HSP70 Heat-Shock Proteins; Humans; Huntingtin Protein; Huntington Disease; Hypothalamus; Insulin; Leptin; Lipoproteins, HDL; Male; Nerve Tissue Proteins; Nuclear Proteins; Phospholipid Hydroperoxide Glutathione Peroxidase; Rats; Rats, Transgenic; Triglycerides

Obesity is an established risk factor for colorectal cancer. Pioglitazone is a peroxisome proliferator- activated receptor γ(PPARγ) agonist that induces differentiation in adipocytes and induces growth arrest and/or apoptosis in vitro in several cancer cell lines. In the present study, we investigated the effect of pioglitazone on the development of azoxymethane-induced colon aberrant crypt foci (ACF) in KK-Ay obesity and diabetes model mice, and tried to clarify mechanisms by which the PPARγ ligand inhibits ACF development. Administration of 800 ppm pioglitazone reduced the number of colon ACF / mouse to 30% of those in untreated mice and improved hypertrophic changes of adipocytes in KK-Ay mice with significant reduction of serum triglyceride and insulin levels. Moreover, mRNA levels of adipocytokines, such as leptin, monocyte chemoattractant protein-1 and plasminogen activator inhibitor-1, in the visceral fat were decreased. PCNA immunohistochemistry revealed that pioglitazone treatment suppressed cell proliferation in the colorectal epithelium with elevation of p27 and p53 gene expression. These results suggest that pioglitazone prevented obesity-associated colon carcinogenesis through improvement of dysregulated adipocytokine levels and high serum levels of triglyceride and insulin, and increase of p27 and p53 mRNA levels in the colorectal mucosa. These data indicate that pioglitazone warrants attention as a potential chemopreventive agent against obesity-associated colorectal cancer.

Topics: Aberrant Crypt Foci; Adipokines; Animals; Azoxymethane; Biomarkers; Carcinogens; Colorectal Neoplasms; Diabetes Mellitus, Experimental; Disease Models, Animal; Female; Hypoglycemic Agents; Immunoenzyme Techniques; Insulin; Intra-Abdominal Fat; Leptin; Lipids; Mice; Mice, Inbred C57BL; Obesity; Pioglitazone; PPAR gamma; Thiazolidinediones

The impact of leptin deficiency and its replacement in T1D remain unclear in the context of dyslipidemia and atherosclerosis. The current study has investigated the physiologic role of leptin in lipid metabolism and atherosclerosis in T1D.. The present study has employed Ins2(+/Akita):apoE(-/-) mouse model that spontaneously develops T1D, hypercholesterolemia, and atherosclerosis. At age 13 weeks, diabetic Ins2(+/Akita):apoE(-/-) mice showed leptin deficiency by ~92% compared with nondiabetic Ins2(+/+):apoE(-/-) mice. From 13 weeks to 25 weeks of age, diabetic Ins2(+/Akita):apoE(-/-) mice were treated with low-dose leptin (at 0.4 μg/g body weight daily). Leptin treatment diminished food intake by 22-27% in diabetic mice without affecting body weight and lean mass throughout the experiment. Importantly, leptin therapy substantially reduced plasma cholesterol concentrations by ~41%, especially in LDL fractions, in diabetic Ins2(+/Akita):apoE(-/-) mice. Moreover, leptin therapy decreased atherosclerotic lesion in diabetic mice by ~62% comparable to that seen in nondiabetic mice. In addition, leptin restored repressed expression of hepatic sortilin-1, a receptor for LDL clearance, and reversed altered expression of several hepatic genes involved in lipogenesis and cholesterol synthesis characteristic of diabetic mice. These findings were accompanied by normalization of reduced hepatic expression of Irs1 and Irs2 mRNA as well as their protein levels, and improved hepatic insulin-receptor signaling.. The present findings suggest that leptin administration may be useful to improve dyslipidemia and reduce atherosclerosis-related cardiovascular disease in human subjects with T1D.

Topics: Adaptor Proteins, Vesicular Transport; Animals; Apolipoproteins E; Atherosclerosis; Cholesterol; Diabetes Mellitus, Type 1; Disease Models, Animal; Disease Progression; Eating; Gene Expression Regulation; Hypercholesterolemia; Injections, Intraperitoneal; Insulin; Insulin Receptor Substrate Proteins; Leptin; Liver; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Recombinant Proteins; RNA, Messenger; Time Factors

Although metabolic syndrome (MS) and systemic lupus erythematosus (SLE) are often associated, a common link has not been identified. Using the BWF1 mouse, which develops MS and SLE, we sought a molecular connection to explain the prevalence of these two diseases in the same individuals. We determined SLE- markers (plasma anti-ds-DNA antibodies, splenic regulatory T cells (Tregs) and cytokines, proteinuria and renal histology) and MS-markers (plasma glucose, non-esterified fatty acids, triglycerides, insulin and leptin, liver triglycerides, visceral adipose tissue, liver and adipose tissue expression of 86 insulin signaling-related genes) in 8-, 16-, 24-, and 36-week old BWF1 and control New-Zealand-White female mice. Up to week 16, BWF1 mice showed MS-markers (hyperleptinemia, hyperinsulinemia, fatty liver and visceral adipose tissue) that disappeared at week 36, when plasma anti-dsDNA antibodies, lupus nephritis and a pro-autoimmune cytokine profile were detected. BWF1 mice had hyperleptinemia and high splenic Tregs till week 16, thereby pointing to leptin resistance, as confirmed by the lack of increased liver P-Tyr-STAT-3. Hyperinsulinemia was associated with a down-regulation of insulin related-genes only in adipose tissue, whereas expression of liver mammalian target of rapamicyn (mTOR) was increased. Although leptin resistance presented early in BWF1 mice can slow-down the progression of autoimmunity, our results suggest that sustained insulin stimulation of organs, such as liver and probably kidneys, facilitates the over-expression and activity of mTOR and the development of SLE.

Topics: Animals; Antibodies, Antinuclear; Biomarkers; Body Weight; Cytokines; Disease Models, Animal; Feeding Behavior; Female; Gene Expression Regulation; Humans; Insulin; Intra-Abdominal Fat; Leptin; Liver; Lupus Erythematosus, Systemic; Metabolic Syndrome; Mice; Proteinuria; TOR Serine-Threonine Kinases; Triglycerides

To investigate the influence of catgut implantation at acupoints on leptin resistance (LR) and insulin resistance (IR) in the simple obesity rat.. Rats were made obese with high-fat diets, after which surgical catgut was implanted at Zusanli (ST 36) and Neiting (ST 44) acupoints once a week for 4 weeks (implantation group). Rats from the implantation group were compared with normal rats and unoperated obese rats (control group). Gene expression of the leptin receptor (OB-R) was evaluated using RT-PCR and northern blot. Serum and hypothalamus leptin and insulin (INS) levels were determined by radioimmunoassay. Body weight, Lee's index, body fat, serum and hypothalamus leptin and INS levels, and hypothalamic OB-R gene expression were determined before and after treatment.. Body weights, Lee's index, body fat, and serum leptin and INS levels were significantly higher in obese than in normal rats. Hypothalamic leptin and INS levels and OB-R gene expression were significantly lower in obese rats. Catgut implantation at acupoint promoted weight loss and decreased serum leptin and INS levels. Hypothalamic leptin and INS levels and OB-R gene expression increased significantly.. Catgut implantation at acupoint adjusts central and peripheral leptin and promotes hypothalamic OB-R gene expression. This may be an important method for regulation of LR, IR and abnormal endocrinology and metabolism.

Topics: Acupuncture Points; Acupuncture Therapy; Adipose Tissue; Animals; Catgut; Disease Models, Animal; Humans; Insulin; Insulin Resistance; Leptin; Male; Obesity; Prostheses and Implants; Rats; Rats, Sprague-Dawley; Receptors, Leptin

Obesity is reaching epidemic proportions all over the world yet it lacks adequate treatment. Most of the drugs have failed either due to ineffectiveness or adverse effects. Complementary and alternative system of medicine is being used since ancient times. However, many of them have not been tested for efficacy and safety using modern scientific methods. Therefore, the antiobesity effect of Safoof Mohazzil, a polyherbal formulation, was evaluated in cafeteria diet induced obesity in female Sprague Dawley rats. Animals weighing 100-150 g were divided into four groups (n = 8) i.e. standard pellet diet, cafeteria diet control, cafeteria diet + Safoof Mohazzil and standard pellet diet plus Safoof Mohazzil. The formulation was administered orally at a dose of 1 g/kg/day for 14 weeks. At the end of study, cafeteria diet significantly increased body weight, Lee's index, lipid profile (cholesterol and triglycerides), insulin and leptin levels as compared to standard pellet diet control group. Fourteen week treatment with Safoof Mohazzil significantly prevented the increase in body weight, Lee's index, lipid profile, insulin and leptin levels as compared to cafeteria diet control group without affecting food and water intake. Safoof Mohazzil had no adverse effect on hepatic transaminases, locomotor activity and motor coordination. The study provides evidence for antiobesity effect of Safoof Mohazzil.

Topics: Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Disease Models, Animal; Drinking; Eating; Female; Leptin; Motor Activity; Obesity; Plant Preparations; Rats; Rats, Sprague-Dawley

In order to assess the effect of obesity on epididymal and germinal epithelia in control rats and obese rats induced by a high fat diet, we evaluated the epididymal and testicular morphologies, lipid peroxidation in the epididymis, leptin serum levels, steroid hormones, insulin, cholesterol, triglycerides, glycemia and some spermatobioscopic parameters. No significant difference was observed in the levels of insulin, glucose, cholesterol and triglycerides between the two groups. Nonetheless, in the obese rats, circulating leptin and estradiol levels showed a significant increase and there was a decline in the testosterone levels. The same group showed an increase in the lipid peroxidation of the epididymis and reduced spermatobioscopic parameters. The heads of the epididymis showed morphological differences in obese rats. No significant difference was observed between the testes of both groups. There is a clear evidence of an effect on sperm in obese rats and this seems to occur in the epididymis.

Topics: Animals; Dietary Fats; Disease Models, Animal; Epididymis; Epithelial Cells; Estradiol; Leptin; Lipid Peroxidation; Male; Obesity; Rats; Rats, Sprague-Dawley; Spermatozoa; Testis; Testosterone

Topics: Animals; Autistic Disorder; Diet, Ketogenic; Disease Models, Animal; Epilepsy; Humans; Leptin; Receptors, Leptin; Rett Syndrome

To test the hypothesis that exercise increases central leptin signaling, and thus reduces dietary weight gain in an aged obese model, we assessed the effects of voluntary wheel running (WR) in 23-month-old F344×BN rats fed a 60% high-fat (HF) diet for 3 months. After 2 months on the HF diet, half of the rats were provided access to running wheels for 2 weeks while the other half remained sedentary. Following the removal of the wheels, physical performance was evaluated, and 4 weeks later leptin signaling was assessed in hypothalamus and VTA after an acute bout of WR. Introduction of a HF diet led to prolonged hyperphagia (63.9 ± 7.8 kcal/day on chow diet vs. 88.1 ± 8.2 kcal/day on high-fat diet (when food intake stabilized), p < 0.001). As little as 9 (ranging to 135) wheel revolutions per day significantly reduced caloric consumption of HF food (46.8 ± 11.2 kcal/day) to a level below that on chow diet (63.9 ± 7.8 kcal/day, p < 0.001). After 2 weeks of WR, body weight was significantly reduced (7.9 ± 2.1% compared with prerunning weight, p < 0.001), and physical performance (latency to fall from an incline plane) was significantly improved (p = 0.04). WR significantly increased both basal (p = 0.04) and leptin-stimulated (p = 0.001) STAT3 phosphorylation in the ventral tegmental area (VTA), but not in the hypothalamus. Thus, in aged dietary obese rats, the act but not the extent of voluntary WR is highly effective in reversing HF consumption, decreasing body weight, and improving physical performance. It appears to trigger a response that substitutes for the reward of highly palatable food that may be mediated by increased leptin signaling in the VTA.

Topics: Age Factors; Aging; Animals; Body Weight; Dietary Fats; Disease Models, Animal; Feeding Behavior; Hyperphagia; Leptin; Male; Obesity; Physical Conditioning, Animal; Random Allocation; Rats; Rats, Inbred F344; Sensitivity and Specificity; Signal Transduction; Ventral Tegmental Area

Epidemiological studies estimate that greater than 60% of the adult US population may be categorized as either overweight or obese and there is a growing appreciation that obesity affects the functional integrity of the central nervous system (CNS). We recently developed a lentivirus (LV) vector that produces an insulin receptor (IR) antisense RNA sequence (IRAS) that when injected into the hypothalamus selectively decreases IR signaling in hypothalamus, resulting in increased body weight, peripheral adiposity and plasma leptin levels. To test the hypothesis that this obesity/hyperleptinemic phenotype would impair hippocampal synaptic transmission, we examined short term potentiation (STP) and long term potentiation (LTP) in the hippocampus of rats that received the LV-IRAS construct or the LV-Control construct in the hypothalamus (hypo-IRAS and hypo-Con, respectively). Stimulation of the Schaffer collaterals elicits STP that develops into LTP in the CA1 region of hypo-Con rats; conversely, hypo-IRAS rats exhibit STP that fails to develop into LTP. To more closely examine the potential role of hyperleptinemia in these electrophysiological deficits, hypo-IRAS were subjected to mild food restriction paradigms that would either: 1) prevent the development of the obesity phenotype; or 2) reverse an established obesity phenotype in hypo-IRAS rats. Both of these paradigms restored LTP in the CA1 region and reversed the decreases in the phosphorylated/total ratio of GluA1 Ser845 AMPA receptor subunit expression observed in the hippocampus of hypo-IRAS rats. Collectively, these data support the hypothesis that obesity impairs hippocampal synaptic transmission and support the hypothesis that these deficits are mediated through the impairment of hippocampal leptin activity.

Topics: Adiposity; Animals; Area Under Curve; Autoradiography; Body Weight; Corticosterone; Disease Models, Animal; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Food Deprivation; Hippocampus; Hypothalamus; In Vitro Techniques; Insulin; Leptin; Long-Term Potentiation; Male; Obesity; Phosphorylation; Rats; Rats, Sprague-Dawley; Receptor, Insulin; Receptors, AMPA; RNA, Antisense; Serine

A recent population-based genome-wide association study has revealed that the Niemann-Pick C1 (NPC1) gene is associated with early-onset and morbid adult obesity. Concurrently, our candidate gene-based mouse growth study performed using the BALB/cJ NPC1 mouse model (Npc1) with decreased Npc1 gene dosage independently supported these results by suggesting an Npc1 gene-diet interaction in relation to early-onset weight gain. To further investigate the Npc1 gene in relation to weight gain and metabolic features associated with insulin resistance, we interbred BALB/cJ Npc1(+/-) mice with wild-type C57BL/6J mice, the latter mouse strain commonly used to study aspects of diet-induced obesity and insulin resistance. This breeding produced a hybrid (BALB/cJ-C57BL/6J) Npc1(+/-) mouse model with increased susceptibility to weight gain and insulin resistance. The results from our study indicated that these Npc1(+/-) mice were susceptible to increased weight gain characterized by increased whole body and abdominal adiposity, adipocyte hypertrophy and hepatic steatosis in the absence of hyperphagia. Moreover, these Npc1(+/-) mice developed abnormal metabolic features characterized by impaired fasting glucose, glucose intolerance, hyperinsulinemia, hyperleptinemia and dyslipidemia marked by an increased concentration of cholesterol and triacylglycerol associated with low-density lipoprotein and high-density lipoprotein. The overall results are consistent with a unique Npc1 gene-diet interaction that promotes both weight gain and metabolic features associated with insulin resistance. Therefore, the NPC1 gene now represents a previously unrecognized gene involved in maintaining energy and metabolic homeostasis that will contribute to our understanding concerning the current global epidemic of obesity and type 2 diabetes mellitus.

Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Cholesterol; Diet; Disease Models, Animal; Fatty Liver; Haploinsufficiency; Humans; Insulin; Insulin Resistance; Intracellular Signaling Peptides and Proteins; Leptin; Magnetic Resonance Imaging; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Niemann-Pick C1 Protein; Proteins; Triglycerides; Weight Gain

This study investigates the molecular mechanisms and the center-periphery cross talk underlying the anti-obesity effect of the cannabinoid receptor 1 (CB(1)) antagonist/inverse agonist rimonabant in diet-induced obese (DIO) mice exposed to a 31 days chronic treatment with the drug. Present data showed a significant and stable weight loss both in animals treated with rimonabant 10mg/kg by oral gavage exposed to a high fat diet (SRFD) and in vehicle treated mice switched to a regular chow (VEND) with respect to vehicle fat diet fed mice (VEFD). Caloric intake was significantly lowered in SRFD and VEND during the first two and four days, respectively, then reaching the VEFD consume throughout the treatment. The drop of body weight was accompanied by leptin mRNA decrease in visceral fat tissue both in VEND and SRFD, as revealed by Real time PCR analysis. No difference in CB(1) mRNA receptor expression in hypothalamus and in visceral fat tissue among groups was observed. Leptin receptors were decreased in the hypothalamus of SRFD but not of VEND mice. Moreover, in SRFD and VEND mice the expression of orexigenic genes Neuropeptide Y and Agouti Related Protein (AGRP) was increased, while anorexigenic ones, Pro-OpioMelanoCortin (POMC) and Cocaine-and-Amphetamine-Regulated Transcript (CART) displayed no alteration in any group. This data contribute to clarify the molecular basis of the anti-obesity properties of rimonabant, underlying the role of the peripheral modulators which affect central circuits involved in the regulation of food intake and energy homeostasis.

Topics: Analysis of Variance; Animals; Body Weight; Diet; Disease Models, Animal; Gene Expression Regulation; Hypothalamus; Leptin; Mice; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; RNA, Messenger; Signal Transduction

The consumption of a high-fat diet (HFD) is considered a risk factor for obesity development. Nonetheless, a causal role of dietary fat has never been documented, because of inadequate animal models. In our study, one group of rats was fed with standard rat diet, while other group of rats fed with high-fat diet for 4 weeks. After 4 weeks of feeding, the hemodynamic parameters in the rats fed with HFD were significantly increased as compared with control rats. Rats fed with HFD had elevated levels of serum lipids, insulin, leptin, glucose and apolipoprotein B. Lipid peroxides and caspase-3 levels were increased while serum apolipoprotein A1 and antioxidant enzymes levels in heart tissues were decreased in HFD-induced obesity in rats as compared to normal healthy control rats fed on standard rat pellet diet. This model of diet-induced obesity will be a useful tool for studying the mechanisms by which dietary fat induces the obesity in humans.

Topics: Animals; Apolipoprotein A-I; Apolipoproteins B; Blood Glucose; Cardiovascular Physiological Phenomena; Caspase 3; Dietary Fats; Disease Models, Animal; Hemodynamics; Insulin; Leptin; Lipid Peroxidation; Lipids; Male; Myocardium; Obesity; Rats; Rats, Wistar

The adipokine adiponectin is decreased in severe obesity and is inversely associated with adipose mass. Adiponectin is associated with insulin sensitivity and cardioprotection. Obesity frequently results in the development of a "cardiometabolic syndrome" characterized by increased circulating insulin and leptin, and cardiac hypertrophy and dysfunction. This study examined if adiponectin-deficiency affects the development of metabolic and cardiac abnormalities in response to modest obesity. Mice were studied under normal conditions and with mild cardiac pressure-overload induced by abdominal aortic banding. After surgery, wild type and adiponectin-deficient mice were fed a high-fat diet for 8 weeks (45% energy from fat vs. 10%). In wild type mice the high-fat diet increased fat and whole body mass, which corresponded with elevated circulating insulin and leptin and a decrease the glucose/insulin ratio. On the other hand, in adiponectin-deficient mice the high-fat diet had less impact on body mass and no effect on fat mass, insulin, leptin, or glucose/insulin. There was modest cardiac hypertrophy with aortic banding, but no cardiac dysfunction or effects of adiponectin deficiency or diet. The results suggest that the increase in adipose mass, leptin and insulin induced by a high fat diet is dependent on adiponectin. The lack of accelerated cardiac hypertrophy and dysfunction in the adiponectin-deficient mice subjected to aortic banding and the high-fat diet suggest that adiponectin may not play a major role in protecting the heart during the early stages of diet-induced obesity.

Topics: Adiponectin; Adipose Tissue; Animals; Blood Pressure; Body Weight; Cardiovascular Diseases; Dietary Fats; Disease Models, Animal; Female; Humans; Insulin; Leptin; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity

Hyperactivity in anorexia nervosa (AN) is associated with low plasma leptin levels and negatively impacts on disease outcome. Using an animal model that mimics features of AN including food-restriction induced hyperlocomotion, we demonstrate that central leptin injections in the lateral ventricle and local injections of leptin into the ventral tegmental area (VTA) suppress running wheel activity. The results support that falling levels of leptin, that accompany caloric restriction, result in increased activity levels because of decreased leptin signaling in the VTA, part of the mesolimbic reward system.

Topics: Animals; Anorexia Nervosa; Body Weight; Disease Models, Animal; Eating; Female; Hyperkinesis; Infusions, Intraventricular; Insulin; Leptin; Motor Activity; Rats; Rats, Wistar; Ventral Tegmental Area

Obesity results from a complex interaction of genes with environmental factors. Our experimental design compared obesity in three rat strains with the corpulent (cp) mutation. The three strains included Lister and Albany NIH (LAN) rats, Spontaneously Hypertensive Rats (SHR) and Dahl Salt Sensitive (DSS) rats that were congenically bred. The strains were selected because of different reported metabolic complications generally clustered with obesity, and defined as the metabolic syndrome. Body weight, food intake, carcass composition, plasma hormones and hypothalamic expression of Y5 receptors were assessed in obese (cp) and lean (wt) rats after adrenalectomy (ADX) or sham surgeries. Plasma corticosterone in sham-operated wtDSS and cpDSS were significantly higher (approx. 165ng/ml) than that in cpLAN and cpSHR (~77 and 68ng/ml respectively). All cp groups had a higher % carcass fat than wt groups. The % carcass fat was greater in cpDSS>cpLAN>cpSHR but plasma leptin was greatest in cpLAN>cpSHR>cpDSS. Hypothalamic expression of the Y5R after ADX resulted in a phenotype×surgery interaction since Y5R expression was slightly increased in cp rats and slightly decreased in wt rats. The strain with greatest number of metabolic syndrome traits, SHR, was not the fattest of the strains and had little response to ADX. The strains with fewer metabolic syndrome traits LAN and DSS had more extreme obesities which were attenuated after ADX. The results of the current experiment provide evidence that the corpulent mutation is not fully characterized in one strain.

Topics: Adipose Tissue; Adrenalectomy; Analysis of Variance; Animals; Behavior, Animal; Body Composition; Body Weight; Corticosterone; Disease Models, Animal; Eating; Hypothalamus; Leptin; Male; Metabolic Diseases; Obesity; Rats; Rats, Inbred Dahl; Rats, Inbred SHR; Receptors, Neuropeptide Y; RNA, Messenger; Time Factors

The hypothalamic arcuate nucleus (ARC) is considered a major site for leptin signaling that regulates several physiological processes.. To test the hypothesis that leptin receptor in the ARC is required to mediate leptin-induced sympathetic activation.. First, we used the ROSA Cre-reporter mice to establish the feasibility of driving Cre expression in the ARC in a controlled manner with bilateral microinjection of adenovirus-expressing Cre-recombinase (Ad-Cre). Ad-Cre microinjection into the ARC of ObR(flox/flox) mice robustly reduced ObR expression and leptin-induced Stat3 activation in the ARC but not in the adjacent nuclei, confirming the efficacy and selectivity of the ARC deletion of ObR. Critically, deletion of ObR in the ARC attenuated brown adipose tissue and renal sympathetic nerve responses to leptin. We also examined whether ObR in the ARC is required for the preserved leptin-induced increase in renal sympathetic activity in dietary obesity. We found that deletion of ARC ObR abrogated leptin-induced increases in renal sympathetic discharge and resolved arterial pressure elevation in diet-induced obese ObR(flox/flox) mice.. These data demonstrate a critical role for ObR in the ARC in mediating the sympathetic nerve responses to leptin and in the adverse sympathoexcitatory effects of leptin in obesity.

Topics: Adenoviridae; Animals; Arcuate Nucleus of Hypothalamus; Disease Models, Animal; Gene Deletion; Green Fluorescent Proteins; Homozygote; Integrases; Leptin; Mice; Mice, Inbred C57BL; Obesity; Receptors, Leptin; Sympathetic Nervous System

Diabetic patients have a lower incidence of acute respiratory distress syndrome (ARDS), and those who develop ARDS are less likely to die. The mechanisms that underlie this protection are unknown.. To determine whether leptin resistance, a feature of diabetes, prevents fibroproliferation after lung injury.. We examined lung injury and fibroproliferation after the intratracheal instillation of bleomycin in wild-type and leptin-resistant (db/db) diabetic mice. We examined the effect of leptin on transforming growth factor (TGF)-β(1)-mediated transcription in primary normal human lung fibroblasts. Bronchoalveolar lavage fluid (BAL) samples from patients with ARDS and ventilated control subjects were obtained for measurement of leptin and active TGF-β(1) levels.. Diabetic mice (db/db) were resistant to lung fibrosis. The db/db mice had higher levels of peroxisome proliferator-activated receptor-γ (PPARγ), an inhibitor of the transcriptional response to TGF-β(1), a cytokine critical in the pathogenesis of fibroproliferative ARDS. In normal human lung fibroblasts, leptin augmented the transcription of profibrotic genes in response to TGF-β(1) through a mechanism that required PPARγ. In patients with ARDS, BAL leptin levels were elevated and correlated with TGF-β(1) levels. Overall, there was no significant relationship between BAL leptin levels and clinical outcomes; however, in nonobese patients, higher BAL leptin levels were associated with fewer intensive care unit- and ventilator-free days and higher mortality.. Leptin signaling is required for bleomycin-induced lung fibrosis. Leptin augments TGF-β(1) signaling in lung fibroblasts by inhibiting PPARγ. These findings provide a mechanism for the observed protection against ARDS observed in diabetic patients.

Topics: Animals; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Female; Humans; Leptin; Lung; Male; Mice; Middle Aged; PPAR gamma; Respiratory Distress Syndrome; Transforming Growth Factor beta

Ketogenic diets (KTD) are reported to have beneficial effects on the regulation of energy and glucose homeostasis, but remain controversial. We investigated the effects of KTD and ketones on insulin resistance and secretion in non-obese type 2 diabetic rats and their mechanism. KTD (82% energy as fat), intraperitoneal injection of β-hydroxybutyrate (IHB; 150 mg/kg bw/12 h) with a control diet (COD; 20% energy as fat) or saline injection with COD was given to 90% pancreatectomized (Px) diabetic rats for five weeks. KTD increased epididymal fat pads and serum leptin levels without increasing energy intake, but IHB decreased them. KTD, but not IHB, attenuated hypothalamic signal transducer and activator of transcription 3 and 5'-adenosine monophosphate-activated protein kinase (AMPK) phosphorylation in KTD. Serum glucagon levels were markedly higher in the KTD group than in other groups. During an oral glucose tolerance test, serum glucose levels slowly increased until 80 min in the KTD group and then decreased very slowly. Insulin secretion capacity during a hyperglycemic clamp was significantly lower in the IHB group than in other groups. However, a euglycemic hyperinsulinemic clamp revealed that KTD decreased glucose infusion rates and increased hepatic glucose output in hyperinsulinemic states while IHB had opposite effects to KTD. The increased hepatic glucose output in KTD was associated with increased hepatic phosphoenolpyruvate carboxykinase expression through attenuated tyrosine phosphorylation of IRS2 and phosphorylation of Akt(Ser473). Hepatic AMPK(Thr172) phosphorylation was reduced in KTD. In conclusion, KTD impairs energy and glucose homeostasis by exacerbating insulin resistance and attenuating hypothalamic leptin signaling in non-obese type 2 diabetic rats. These changes are not associated with increased serum ketone levels.

Topics: Animals; Diabetes Mellitus, Type 2; Diet, Ketogenic; Disease Models, Animal; Energy Metabolism; Glucose; Homeostasis; Insulin; Leptin; Rats; Signal Transduction

We have found that ventromedial hypothalamic (VMH) lesions produced by electrocoagulation induce cell proliferation in visceral organs through vagal hyperactivity, and also stimulate regeneration of partially resected liver in rats. To facilitate identification of proliferative and/or regenerative factors at the gene level, we developed electrical production of VMH lesions in mice, for which more genetic information is available compared to rats, and examined the pathophysiological profiles in these mice. Using ddy mice, we produced VMH lesions with reference to the previously reported method in rats. We then examined the pathophysiological profiles of the VMH-lesioned mice. Electrical VMH lesions in mice were produced using the following coordinates: 1.6 mm posterior to the bregma, anteriorly; 0.5 mm lateral to the midsagittal line, transversely; and 0.2 mm above the base of the skull, vertically, with 1 mA of current intensity and 10 s duration. The VMH-lesioned mice showed similar metabolic characteristics to those of VMH-lesioned rats, including body weight gain, increased food intake, increased percentage body fat, and elevated serum insulin and leptin. However, there were some differences in short period of hyperphagia, and in normal serum lipids compared to those of VMH-lesioned rats. The mice showed a similar cell proliferation in visceral organs, including stomach, small intestine, liver, and, exocrine and endocrine pancreas. In conclusion, procedures for development of VMH lesions in mice by electrocoagulation were developed and the VMH-lesioned mice showed pathophysiological profiles similar to those of VMH-lesioned rats, particularly in cell proliferation in visceral organs. These findings have not been observed previously in gold thioglucose-induced VMH-lesioned mice. This model may be a new tool for identifying factors involved in cell proliferation or regeneration in visceral organs.

Topics: Animals; Cell Proliferation; Disease Models, Animal; Eating; Electrocoagulation; Female; Insulin; Intestine, Small; Leptin; Lipids; Liver; Mice; Obesity; Pancreas; Rats; Regeneration; Stomach; Ventromedial Hypothalamic Nucleus

Lack of compensatory or even reduced food intake is frequently observed in weight-losing cancer patients and contributes to increased morbidity and mortality. Our previous work has shown increased transcription factor expression in the hypothalamus and ventral striatum of anorectic rats bearing small tumors. mRNA expression of molecules known to be involved in pathways regulating appetite in these structures was therefore assessed in this study. Given that pain, pro-inflammatory cytokines and metabolic hormones can modify food intake, spinal cord cellular activation patterns and plasma concentrations of cytokines and hormones were also studied. Morris hepatoma 7777 cells injected subcutaneously in Buffalo rats provoked a 10% lower body weight and 15% reduction in food intake compared to free-feeding tumor-free animals 4 weeks later when the tumor represented 1-2% of body mass. No differences in spinal cord activation patterns or plasma concentration of pro-inflammatory cytokines were observed between groups. However, the changes in plasma ghrelin and leptin concentrations found in food-restricted weight-matched rats in comparison to ad libitum-fed animals did not occur in anorectic tumor-bearing animals. Real-time PCR showed that tumor-bearing rats did not display the increase in hypothalamic agouti-related peptide mRNA observed in food-restricted weight-matched animals. In addition, microarray analysis and real-time PCR revealed increased ventral striatal prostaglandin D synthase expression in food-restricted animals compared to anorectic tumor-bearing rats. These findings indicate that blunted hypothalamic AgRP mRNA expression, probably as a consequence of relatively high leptin and low ghrelin concentrations, and reduced ventral striatal prostaglandin D synthesis play a role in maintaining cancer-associated anorexia.

Topics: Adaptation, Physiological; Agouti-Related Protein; Analysis of Variance; Animals; Appetite Regulation; Basal Ganglia; Body Weight; Cachexia; Carcinoma, Hepatocellular; Cytokines; Disease Models, Animal; Eating; Gene Expression Regulation; Ghrelin; Hypothalamus; Immunohistochemistry; Intramolecular Oxidoreductases; Leptin; Lipocalins; Liver Neoplasms; Male; Matched-Pair Analysis; Neoplasms, Experimental; Pain Perception; Rats; Rats, Inbred BUF; RNA, Messenger; Spinal Cord; Weight Loss

Few studies have investigated if exercise by itself has anti-atherosclerotic effects, without combining interventions with a low-fat diet. We studied the effects of exercise as a stand-alone intervention on preexisting atheromata by measuring not only plaque size but also the levels of plaque-destabilizing matrix-metalloproteinase (MMP) activity in vivo.. We used near-infrared fluorescent (NIRF) molecular imaging with an MMP-2/9 activatable NIRF probe to visualize the inflammatory protease activity within preexisting atheromata of 17-week-old ApoE(-/-) mice on: (a) normal chow diet (NCD), (b) Western diet (WD), and (c) WD with treadmill exercise for 10 weeks. We also measured tissue levels of aortic lipid peroxidation (LPO) and plasma levels of glucose/lipid/cytokine profiles. Exercise did not attenuate growth of preexisting atheromatous plaques. However, exercise strongly decreased proteolytic activity in plaques for animals on WD, with levels decreasing almost to NCD levels. Exercise was associated with decreased aortic LPO levels and increased blood adiponectin/leptin levels; however, exercise did not affect WD-consumption/weight-gain or improve blood glucose/lipid profiles.. Exercise training reduced aortic MMP activity in mice with preexisting atheromata, even though they remained on a high fat diet and plaque-growth was not attenuated.

Topics: Adiponectin; Analysis of Variance; Animals; Aorta; Aortic Diseases; Apolipoproteins E; Atherosclerosis; Blood Glucose; Body Weight; Cytokines; Disease Models, Animal; Down-Regulation; Exercise Therapy; Immunohistochemistry; Infrared Rays; Leptin; Lipid Peroxidation; Lipids; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Knockout; Microscopy; Molecular Imaging; Plaque, Atherosclerotic

Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with senile amyloid-β (Aβ) plaques, neuronal death, and cognitive decline. Neurogenesis in the adult hippocampus, which is notably affected by progressive neurodegeneration and Aβ pathology, is implicated in learning and memory regulation. Human postmortem brains of AD patients and AβPP/PS1 double transgenic mice show increased neurodegeneration. Leptin, an adipose-derived hormone, promotes neurogenesis in the adult hippocampus, but the way in which this process occurs in the AD brain is still unknown. Thus, we sought to determine if leptin stimulated the proliferation of neuronal precursors in AβPP/PS1 mice. We estimated the number proliferating hippocampal cells after intracerebroventricular administration of a lentiviral vector encoding leptin. After 3 months of treatment with leptin we observed an increase in the number of BrdU-positive cells in the subgranular zone of the dentate gyrus, as shown by morphometric analysis. This increase resulted mainly from an increased proliferation of neuronal precursors. Additionally, leptin led to an attenuation of Aβ-induced neurodegeneration, as revealed by Fluoro-Jade staining. Our results suggest that in AβPP/PS1 mice, leptin exerts changes resembling acute neurotrophic and neuroprotective effects. These effects could serve as the basis for the design of future treatment strategies in AD.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Cell Proliferation; Cells, Cultured; Cerebral Cortex; Disease Models, Animal; Doublecortin Domain Proteins; Fluoresceins; Gene Expression Regulation; Green Fluorescent Proteins; Humans; Indoles; Leptin; Male; Mice; Mice, Transgenic; Microtubule-Associated Proteins; Neural Stem Cells; Neuropeptides; Neuroprotective Agents; Organic Chemicals; Presenilin-1; Rats; Rats, Wistar

Skeletal abnormalities are one of the hallmarks of growth delay during gestation. The aim of this study was to determine changes induced by leptin in skeletal growth and development in a rat model of intrauterine growth retardation (IUGR) and to elucidate the possible underlying mechanisms.. Intrauterine growth retardation was induced prepartum and the effects of leptin to mothers prenatally or to offspring postnatally were studied. Radii were harvested and tested mechanically and structurally. Tibias were evaluated for growth-plate morphometry.. On day 40 postpartum, total bone length and mineral density and tibial growth-plate width and numbers of cells within its zones of offspring treated with leptin were significantly greater than in the control group.. Postnatal leptin administration in an IUGR model improves the structural properties and elongation rate of bone. These findings could pave the way to preventing some phenotypic presentations of IUGR.

Topics: Animals; Bone and Bones; Bone Density; Disease Models, Animal; Female; Fetal Development; Fetal Growth Retardation; Growth Plate; Leptin; Pregnancy; Radius; Rats; Rats, Wistar; Skeleton; Tibia

Diabetes increases the chances of stroke and the stroke itself is thought to induce hyperglycemia and diabetes. However, this latter contention remains uncorroborated. We investigated whether ischemic hippocampal neuronal cell death induces glucose dysregulation by modulating insulin resistance, glucose-stimulated insulin secretion, and β-cell mass in Mongolian gerbils fed either a high fat or low fat diet.. Gerbils were subjected to either an occlusion of the bilateral common carotid arteries for 8 mins to render them ischemic, or a sham operation. Ischemic gerbils were fed either an 11% fat diet (LFD) or a 40% fat diet (HFD) for 7, 14 or 28 days.. Artery occlusion resulted in a 70% or greater initial reduction in hippocampal CA1 neurons and only HFD decreased the percentage of CA1 neurons as the ischemic periods became longer. Oral glucose tolerance test (OGTT) results revealed that ischemia induced glucose intolerance, and longer ischemic periods and HFD exacerbated this glucose intolerance in ischemic gerbils. Insulin secretion during the OGTT was lower in ischemic gerbils than sham gerbils and the decrease was greatest in the 28 day-HFD among all the groups. Insulin resistance was elevated the most in 28 day-HFD ischemic gerbils. There was a progressive loss of pancreatic β-cell mass as the post-ischemic time period increased as consequence of HFD; the decrease being caused by increased apoptosis. This increase in apoptosis was partly associated with increased serum levels of IL-1β, TNF-α and non-esterified fatty acids.. Hippocampal neuronal cell death deteriorates glucose homeostasis initially through the modulation of insulin secretion and also causes a decrease in β-cell mass while HFD negatively impacts glucose regulation.

Topics: Animals; Apoptosis; Brain Ischemia; Cell Death; Diet, Fat-Restricted; Dietary Fats; Disease Models, Animal; Fatty Acids, Nonesterified; Gerbillinae; Glucose; Glucose Tolerance Test; Hippocampus; Insulin; Insulin Secretion; Insulin-Secreting Cells; Interleukin-1beta; Leptin; Male; Neurons; Tumor Necrosis Factor-alpha

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

Several fine-tuned and interconnected hypothalamic peptidergic systems orchestrate the regulation of energy homeostasis in the body. The orexigenic peptide ghrelin and the anorexigenic peptide leptin are among the most important, and both have been implicated in the development of eating disorders from obesity to anorexia nervosa.. The goal of these studies was to examine the response of leptin-deficient ob/ob mice in ghrelin-receptor ligands in a food intake task.. Changes in cumulative food intake were measured after peripheral administration of ghrelin (1 and 2 nmol/10 g) and the ghrelin-receptor antagonist (D-Lys(3))-GHRP-6 (66.6 and 133.3 nmol/10 g) in obese and lean control mice during the light and dark cycle as well as in a state of food restriction. Hypothalamic ghrelin and ghrelin-receptor expression was measured in ob/ob and lean mice at two different timepoints.. Ghrelin increased food intake in lean and obese mice in the light and dark cycle, whereas the ghrelin-receptor antagonist caused significantly stronger reduction in food intake in obese mice only in the dark cycle. After fasting, ob/ob mice displayed decreased light cycle sensitivity to the anorexigenic effects of the ghrelin-receptor antagonist. Hypothalamic expression levels of ghrelin were unaltered during the light cycle but decreased during the dark cycle in ob/ob mice; whereas, although unchanged in the light cycle, ghrelin-receptor expression was increased in the dark cycle in obese mice.. The functionality and sensitivity of the ghrelinergic system is dependent on the time of day and the satiety state in leptin-deficient ob/ob mice.

Topics: Animals; Disease Models, Animal; Eating; Ghrelin; Hypothalamus; Leptin; Ligands; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Obesity; Oligopeptides; Photoperiod; Real-Time Polymerase Chain Reaction; Receptors, Ghrelin; Satiation

Chronic stress is associated with dysregulation of energy homeostasis, but the link between the two is largely unknown. For most rodents, periods of chronic stress reduce weight gain. We hypothesized that these reductions in weight are an additional homeostatic challenge, contributing to the chronic stress syndrome. Experiment #1 examined cardiovascular responsivity following exposure to prolonged intermittent stress. We used radio-telemetry to monitor mean arterial pressure and heart rate in freely moving, conscious rats. Three groups of animals were tested: chronic variable stress (CVS), weight-matched (WM), and controls. Using this design, we can distinguish between effects due to stress and effects due to the changing body weight. WM, but not CVS, markedly reduced basal heart rate. Although an acute stress challenge elicited similar peak heart rate, WM expedited the recovery to baseline heart rate. The data suggest that CVS prevents the weight-induced attenuation of cardiovascular stress reactivity. Experiment #2 investigated hypothalamic-pituitary-adrenal axis and metabolic hormone reactivity to novel psychogenic stress. WM increased corticosterone area under the curve. CVS blunted plasma glucose, leptin, and insulin levels in response to restraint. Experiment #3 tested the effects of WM and CVS on PVN oxytocin and corticotrophin-releasing hormone mRNA expression. CVS increased, while WM reduced PVN CRH mRNA expression, whereas both CVS and WM reduced dorsal parvocellular PVN oxytocin mRNA. Overall, the data suggest that weight loss is unlikely to account for the deleterious effects of chronic stress on the organism, but in fact produces beneficial effects that are effectively absent or indeed, reversed in the face of chronic stress exposure.

Topics: Animals; Blood Glucose; Body Weight; Cardiovascular Physiological Phenomena; Corticosterone; Disease Models, Animal; Gene Expression Regulation; Hypothalamo-Hypophyseal System; Insulin; Leptin; Male; Neurosecretory Systems; Pituitary-Adrenal System; Rats; Rats, Sprague-Dawley; Statistics, Nonparametric; Stress, Psychological; Telemetry

Forty-four barbituric acid or thiobarbituric acid derivatives were synthesized and evaluated for their effects on adipogenesis of 3T3-L1 adipocytes by measuring the expression of adiponectin in vitro. Four compounds (3a, 3o, 3s, 4t) were found to increase the expression of adiponectin and lower the leptin level in 3T3-L1 adipocytes at respective concentration of 10 μM. Among them, 3s showed the most efficacious. Oral administration of 3s effectively reduced body weight, liver weight, and visceral fat and regulated serum levels of biochemical markers in the high-fat/diet-induced Wistar rats. Histopathological evaluation of liver sections by Oil Red O and H&E staining confirmed 3s as a potent, orally active molecule for reducing fat deposition against non-alcoholic fatty liver disease.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Adiponectin; Animals; Barbiturates; Cell Differentiation; Disease Models, Animal; Fatty Liver; Leptin; Male; Mice; Molecular Structure; Non-alcoholic Fatty Liver Disease; Rats; Rats, Wistar; Stereoisomerism; Structure-Activity Relationship; Thiobarbiturates

Leptin resistance has been associated with cardiac lipotoxicity; however, whether leptin resistance is a risk factor associated with cardiac lipotoxicity at different time points in diet-induced obesity is unclear. The objective of this study was to evaluate this relationship.. Male Wistar rats were fed a normal chow diet (12% from fat) or a high-fat diet (49% from fat) for 15 and 45 weeks, respectively. The adiposity index, body weight and co-morbidities were evaluated. Heart lipotoxicity was assessed by analyzing cardiac function and morphological changes as well as cardiac triglyceride, ceramide and lipid hydroperoxide accumulations. Cardiac apoptosis was examined using the TUNEL method. Leptin function was determined by examining plasma leptin levels, cardiac leptin receptors (OB-R) and related phosphorylations of AMP-activated kinase protein (AMPK) and Acetyl CoA carboxylase (ACC).. The diet-induced obesity was characterized by an elevated adiposity index, body weight and leptin levels at both 15 and 45 weeks. There was no difference between groups in the cardiac triglyceride or lipid hydroperoxide levels. Interestingly, ceramide levels decreased in obese animals in both experimental periods. The cardiac morphological and functional parameters were not altered. Although down-regulation of OB-R has occurred in chronic obesity, it did not adversely affect AMPK or ACC phosphorylation.. The development of obesity via long-term feeding of a high-fat diet to rats does not result in cardiac lipotoxicity but promotes the down-regulation of OB-R. However, this does not result in altered levels of AMPK or ACC phosphorylations in this animal model.

Topics: Acetyl-CoA Carboxylase; Adiposity; AMP-Activated Protein Kinases; Animals; Apoptosis; Ceramides; Dietary Fats; Disease Models, Animal; Down-Regulation; In Situ Nick-End Labeling; Leptin; Lipid Peroxides; Male; Myocardium; Obesity; Phosphorylation; Rats; Rats, Wistar; Receptors, Leptin; Risk Factors; Time Factors; Triglycerides

Ongoing epidemiological studies estimate that greater than 60% of the adult US population may be categorized as either overweight or obese. There is a growing appreciation that the complications of obesity extend to the central nervous system (CNS) and may result in increased risk for neurological co-morbidities like depressive illness. One potential mechanistic mediator linking obesity and depressive illness is the adipocyte derived hormone leptin. We previously demonstrated that lentivirus-mediated downregulation of hypothalamic insulin receptors increases body weight, adiposity and plasma leptin levels, which is consistent with features of the metabolic syndrome. Using this novel model of obesity, we examined performance in the forced swim test (FST), the sucrose preference test and the elevated plus maze (EPM), approaches that are often used as measures of depressive-like and anxiety-like behaviors, in rats that received third ventricular injections of either an insulin receptor antisense lentivirus (hypo-IRAS) or a control lentivirus (hypo-Con). Hypo-IRAS rats exhibited significant increases in immobility time and corresponding decreases in active behaviors in the FST and exhibited anhedonia as measured by decreased sucrose intake compared to hypo-Con rats. Hypo-IRAS rats also exhibited increases in anxiety-like behaviors in the EPM. Plasma, hippocampal and amygdalar brain-derived neurotrophic factor (BDNF) levels were reduced in hypo-IRAS rats, suggesting that the obesity/hyperleptinemic phenotype may elicit this behavioral phenotype through modulation of neurotrophic factor expression. Collectively, these data support the hypothesis for an increased risk for mood disorders in obesity, which may be related to decreased expression of hippocampal and amygdalar BDNF.

Topics: Adiposity; Analysis of Variance; Animals; Body Weight; Depression; Disease Models, Animal; Down-Regulation; Food Preferences; Genetic Vectors; Hypothalamus; Leptin; Male; Maze Learning; Oligodeoxyribonucleotides, Antisense; Rats; Rats, Sprague-Dawley; Receptor, Insulin; Swimming; Triglycerides

It has been suggested that access to high caloric food attenuates stress response. The present paper investigates whether access to commercial chow enriched with glucose and fat, here referred to as comfort food alters behavioral, metabolic, and hormonal parameters of rats submitted to three daily sessions of foot-shock stress. Food intake, anxiety-like behaviors, and serum levels of insulin, leptin, corticosterone, glucose and triglycerides were determined. The rats submitted to stress decreased the intake of commercial chow, but kept unaltered the intake of comfort food. During the elevated plus maze (EPM) test, stressed rats increased the number of head dipping, entries into the open arms, as well as the time spent there, and decreased the number of stretched-attend posture and risk assessment. These effects of stress were independent of the type of food consumed. Non-stressed rats ingesting comfort food decreased risk assessment as well. Stress and comfort food increased time spent in the center of the open field and delayed the first crossing to a new quadrant. Stress increased the plasma level of glucose and insulin, and reduced triglycerides, although consumption of comfort food increases glucose, triglyceride and leptin levels; no effect on leptin level was associated to stress. The stress induced increase in serum corticosterone was attenuated when rats had access to comfort food. It was concluded that foot-shock stress has an anorexigenic effect that is independent of leptin and prevented upon access to comfort food. Foot-shock stress also has an anxiolytic effect that is potentiated by the ingestion of comfort food and that is evidenced by both EPM and open field tests.

Topics: Animals; Anxiety; Blood Glucose; Corticosterone; Dietary Carbohydrates; Dietary Fats; Disease Models, Animal; Eating; Insulin; Leptin; Male; Maze Learning; Motor Activity; Rats; Rats, Wistar; Stress, Physiological; Stress, Psychological; Triglycerides

Calorie restriction (CR) has been demonstrated to alter cytokine levels; however, its potential to modify sickness behavior (fever, anorexia, cachexia) has not. The effect of CR on sickness behavior was examined in male C57BL/6J mice fed ad libitum or restricted 25% (CR25%) or restricted 50% (CR50%) in food intake for 28 days and injected with 50 μg/kg of LPS on day 29. Changes in body temperature, locomotor activity, body weight, and food intake were determined. A separate cohort of mice were fed ad libitum or CR50% for 28 days, and hypothalamic mRNA expression of inhibitory factor κB-α (IκB-α), cyclooxygenase-2 (COX-2), prostaglandin E(2) (PGE(2)), suppressor of cytokine signaling 3 (SOCS3), IL-10, neuropeptide Y (NPY), leptin, proopiomelanocortin (POMC), and corticotrophin-releasing hormone (CRH) were determined at 0, 2, and 4 h post-LPS. CR50% mice did not develop fevers, whereas the CR25% mice displayed a fever shorter in duration but with the same peak as the controls. Both CR25% and CR50% mice showed no sign of anorexia and reduced cachexia after LPS administration. Hypothalamic mRNA expression of NPY and CRH were both increased by severalfold in CR50% animals preinjection compared with controls. The CR50% mice did not demonstrate the expected rise in hypothalamic mRNA expression of COX-2, microsomal prostaglandin E synthase-1, POMC, or CRH 2 h post-LPS, and leptin expression was decreased at this time point. Increases in SOCS3, IL-10, and IκB-α expression in CR50% animals were enhanced compared with ad libitum-fed controls at 4 h post-LPS. CR results in a suppression of sickness behavior in a dose-dependent manner, which may be due to CR attenuating proinflammatory pathways and enhancing anti-inflammatory pathways.

Topics: Animals; Body Temperature; Body Weight; Caloric Restriction; Cyclooxygenase 2; Disease Models, Animal; Eating; Hypothalamus; Illness Behavior; Inflammation; Intramolecular Oxidoreductases; Leptin; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Motor Activity; Pro-Opiomelanocortin; Prostaglandin-E Synthases; Signal Transduction; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins

Leptin is an adipokine that increases fatty acid (FA) oxidation, decreases intramuscular lipid stores, and improves insulin response in skeletal muscle. In an attempt to elucidate the underlying mechanisms by which these metabolic changes occur, we administered leptin (Lep) or saline (Sal) by miniosmotic pumps to rats during the final 2 wk of a 6-wk low-fat (LF) or high-fat (HF) diet. Insulin-stimulated glucose transport was impaired by the HF diet (HF-Sal) but was restored with leptin administration (HF-Lep). This improvement was associated with restored phosphorylation of Akt and AS160 and decreased in reactive lipid species (ceramide, diacylglycerol), known inhibitors of the insulin-signaling cascade. Total muscle citrate synthase (CS) activity was increased by both leptin and HF diet, but was not additive. Leptin increased subsarcolemmal (SS) and intramyofibrillar (IMF) mitochondria CS activity. Total muscle, sarcolemmal, and mitochondrial (SS and IMF) FA transporter (FAT/CD36) protein content was significantly increased with the HF diet, but not altered by leptin. Therefore, the decrease in reactive lipid stores and subsequent improvement in insulin response, secondary to leptin administration in rats fed a HF diet was not due to a decrease in FA transport protein content or altered cellular distribution.

Topics: AMP-Activated Protein Kinase Kinases; Animals; Body Composition; Citrate (si)-Synthase; Dietary Fats; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Glucose Transporter Type 4; GTPase-Activating Proteins; Insulin; Leptin; Lipid Metabolism; Mitochondria, Muscle; Muscle, Skeletal; Obesity; Protein Kinases; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Time Factors

Polycystic ovary syndrome (PCOS) is the most common reproductive dysfunction in premenopausal women. PCOS is also associated with increased risk of cardiovascular disease when PCOS first occurs and later in life. Hypertension, a common finding in women with PCOS, is a leading risk factor for cardiovascular disease. The mechanisms responsible for hypertension in women with PCOS have not been elucidated.. This study characterized the cardiovascular-renal consequences of hyperandrogenemia in a female rat model.. Female Sprague-Dawley rats (aged 4-6 weeks) were implanted with dihydrotestosterone or placebo pellets lasting 90 days. After 10 to 12 weeks, blood pressure (by radiotelemetry), renal function (glomerular filtration rate, morphology, protein, and albumin excretion), metabolic parameters (plasma insulin, glucose, leptin, cholesterol, and oral glucose tolerance test), inflammation (plasma tumor necrosis factor-α), oxidative stress (mRNA expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits, p22(phox), p47(phox), gp91(phox), and NOX4), nitrate/nitrite excretion and mRNA expression of components of the renin-angiotensin system (angiotensinogen, angiotensin-I-converting enzyme [ACE], and AT1 receptor) were determined.. Plasma dihydrotestosterone increased 3-fold in hyperandrogenemic female (HAF) rats, whereas plasma estradiol levels did not differ compared with control females. HAF rats exhibited estrus cycle dysfunction. They also had increased food intake and body weight, increased visceral fat, glomerular filtration rate, renal injury, insulin resistance and metabolic dysfunction, oxidative stress, and increased expression of angiotensinogen and ACE and reduced AT1 receptor expression.. The HAF rat is a unique model that exhibits many of the characteristics of PCOS in women and is a useful model to study the mechanisms responsible for PCOS-mediated hypertension.

Topics: Angiotensinogen; Animals; Blood Glucose; Blood Pressure; Cardiovascular Diseases; Dihydrotestosterone; Disease Models, Animal; Estradiol; Female; Glomerular Filtration Rate; Glucose Tolerance Test; Kidney Diseases; Leptin; Metabolic Syndrome; Oxidative Stress; Polycystic Ovary Syndrome; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System

The present study investigated the role of IGF1 in lactating lean and non-lactating obese dairy cows by injecting 1 μg IGF1 into the ovaries prior to superovulation. This amount of IGF1 has been linked with pregnancy loss in women with the polycystic ovary syndrome (PCOS) and was associated with impaired bovine oocyte competence in vitro. Transcript abundance and protein expression of selected genes involved in apoptosis, glucose metabolism, and the IGF system were analyzed. Plasma concentrations of IGF1 and leptin, and IGF1 in uterine luminal fluid (ULF), were also measured. IGF1 treatment decreased embryo viability in lean cows to the levels observed in obese cows. Obese cows were not affected by IGF1 treatment and showed elevated levels of IGF1 (in both plasma and ULF) and leptin. Blastocysts from lean cows treated with IGF1 showed a higher abundance of SLC2A1 and IGFBP3 transcripts. IGF1 treatment reduced protein expression of tumor protein 53 in blastocysts of lean cows, whereas the opposite was observed in obese cows. IGF1 in plasma and ULF was correlated only in the control groups. Blastocyst transcript abundance of IGF1 receptor and IGFBP3 correlated positively with IGF1 concentrations in both plasma and ULF in lean cows. The detrimental microenvironment created by IGF1 injection in lean cows and the lack of effect in obese cows resemble to a certain extent the situation observed in PCOS patients, where IGF1 bioavailability is increased in normal-weight women but reduced in obese women, suggesting that this bovine model could be useful for studying IGF1 involvement in PCOS.

Topics: Animals; Blastocyst; Cattle; Disease Models, Animal; Embryo Loss; Female; Gene Expression Regulation, Developmental; Glucose Transporter Type 1; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Lactation; Leptin; Obesity; Oogenesis; Polycystic Ovary Syndrome; Pregnancy; Receptor, IGF Type 1; RNA, Messenger; Superovulation; Thinness; Tumor Suppressor Protein p53; Uterus

The lack of safe and effective treatments for obesity has increased interest in natural products that may serve as alternative therapies. From this perspective, we have analysed the effects of daidzein, one of the main soy isoflavones, on diet-induced obesity in rats.. Rats made obese after exposure to a very (60%) high fat-content diet were treated with daidzein (50 mg·kg(-1)) for 14 days. The dose was selected on the basis of the acute effects of this isoflavone on a feeding test. After 14 days, animals were killed and plasma, white and brown adipose tissue, muscle and liver studied for the levels and expression of metabolites, proteins and genes relevant to lipid metabolism.. A single treatment (acute) with daidzein dose-dependently reduced food intake. Chronic treatment (daily for 14 days) reduced weight gain and fat content in liver, accompanied by high leptin and low adiponectin levels in plasma. While skeletal muscle was weakly affected by treatment, both adipose tissue and liver displayed marked changes after treatment with daidzein, affecting transcription factors and lipogenic enzymes, particularly stearoyl coenzyme A desaturase 1, a pivotal enzyme in obesity. Expression of uncoupling protein 1, an important enzyme for thermogenesis, was increased in brown adipose tissue after daidzein treatment.. These results support the use of isoflavones in diet-induced obesity, especially when hepatic steatosis is present and open a new field of use for these natural products.

Topics: Acetyl-CoA Carboxylase; Acyl-CoA Oxidase; Adiponectin; Adipose Tissue; Adipose Tissue, White; Animals; Anti-Obesity Agents; Body Weight; Diet, High-Fat; Disease Models, Animal; Eating; Fatty Acid Synthases; Fatty Liver; Insulin; Isoflavones; Leptin; Liver; Male; Muscle, Skeletal; Obesity; PPAR alpha; PPAR gamma; Rats; Rats, Wistar; Stearoyl-CoA Desaturase

Hypothalamic obesity (HO) is a major and unsolved problem in patients with medial hypothalamic lesions and is associated with hyperinsulinemia and hyperleptinemia. The purpose of this study was to create a rodent model that mimics metabolic changes in HO for use in therapeutic testing. Female Sprague-Dawley rats were used to test the individual and combined effects of two types of medial hypothalamic lesions: arcuate nucleus (ARC) lesions by injection of monosodium glutamate at neonatal age, and ventromedial nucleus (VMN) lesions by passing an anodal current through an electrode placed in the VMN at age 80 days. Adiposity in ARC-lesioned animals was associated with decreased food intake and stunted growth, while VMN lesions were associated with hyperphagia but not reduced growth. The greatest weight gain (weight at age 200 days 712 +/- 65 vs. 451 +/- 19 g in controls), hyperphagia (food intake 10 days following surgery 33 +/- 0.8 vs. 18.5 +/- 0.7 g/day in sham-treated rats), hyperinsulinemia and hyperleptinemia occurred in rats that received both ARC and VMN lesions. Thus, the combined medial hypothalamic lesions result in an obesity phenotype similar to that of patients that suffer from HO and are consequently more suitable for testing potential therapeutics for this disorder than lesions of single hypothalamic nuclei.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Brain; Disease Models, Animal; Female; Hyperinsulinism; Hyperphagia; Hypothalamic Diseases; Insulin; Leptin; Obesity; Rats; Rats, Sprague-Dawley; Sodium Glutamate; Ventromedial Hypothalamic Nucleus; Weight Gain

Topics: Animals; Disease Models, Animal; Fatty Liver; Humans; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Non-alcoholic Fatty Liver Disease; Obesity; Rats; Rats, Sprague-Dawley; Receptors, Leptin

A potential link between obesity, circulating leptin levels and autoimmune disease symptoms suggests that targeting the leptin receptor (ObR) might be a viable novel strategy to combat rheumatoid arthritis (RA). However, studies in animal models and evaluation of clinical cases did not provide clear view on leptin's involvement in RA. To validate ObR as RA target, we used our peptide-based ObR agonists and antagonist in different in vitro and in vivo models of the disease. In human peripheral blood mononuclear cells, leptin and its agonist fragment, desI(2)-E1/Aca, moderately induced constitutive activation of a major proinflammatory transcription factor, NF-κB, while the ObR antagonist peptide Allo-aca inhibited the process. Leptin administration itself did not induce arthritis in rats, but worsened the clinical condition of mice given K/BxN serum transfer arthritis. Simultaneous administration of Allo-aca reduced leptin-dependent increase in disease severity by more than 50%, but the antagonist was ineffective when injected with a 3-day delay. In rats inflicted with mild adjuvant-induced arthritis, both leptin and Allo-aca reduced the extent of joint swelling and the number of arthritic joints. In a more aggressive disease stage, Allo-aca decreased the number of arthritic joints in a dose-dependent manner but did not affect other arthritis markers. In summary, leptin exerts diverse effects on RA depending on the experimental model. This might reflect the heterogeneous character of RA, which is differently impacted by leptin and is unmasked by ObR antagonism. Nevertheless, the results suggest that ObR antagonists might become useful therapeutics in leptin-sensitive early stages of RA.

Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Disease Models, Animal; Female; Humans; Leptin; Leukocytes, Mononuclear; Mice; Mice, Transgenic; Oligopeptides; Rats; Receptors, Leptin

Obstructive sleep apnea (OSA) causes intermittent hypoxia (IH) during sleep. Both obesity and OSA are associated with insulin resistance and systemic inflammation, which may be attributable to tissue hypoxia. We hypothesized that a pattern of hypoxic exposure determines both oxygen profiles in peripheral tissues and systemic metabolic outcomes, and that obesity has a modifying effect. Lean and obese C57BL6 mice were exposed to 12 h of intermittent hypoxia 60 times/h (IH60) [inspired O₂ fraction (Fi(O₂)) 21-5%, 60/h], IH 12 times/h (Fi(O₂) 5% for 15 s, 12/h), sustained hypoxia (SH; Fi(O₂) 10%), or normoxia while fasting. Tissue oxygen partial pressure (Pti(O₂)) in liver, skeletal muscle and epididymal fat, plasma leptin, adiponectin, insulin, blood glucose, and adipose tumor necrosis factor-α (TNF-α) were measured. In lean mice, IH60 caused oxygen swings in the liver, whereas fluctuations of Pti(O₂) were attenuated in muscle and abolished in fat. In obese mice, baseline liver Pti(O₂) was lower than in lean mice, whereas muscle and fat Pti(O₂) did not differ. During IH, Pti(O₂) was similar in obese and lean mice. All hypoxic regimens caused insulin resistance. In lean mice, hypoxia significantly increased leptin, especially during SH (44-fold); IH60, but not SH, induced a 2.5- to 3-fold increase in TNF-α secretion by fat. Obesity was associated with striking increases in leptin and TNF-α, which overwhelmed effects of hypoxia. In conclusion, IH60 led to oxygen fluctuations in liver and muscle and steady hypoxia in fat. IH and SH induced insulin resistance, but inflammation was increased only by IH60 in lean mice. Obesity caused severe inflammation, which was not augmented by acute hypoxic regimens.

Topics: Acute Disease; Adiponectin; Adipose Tissue; Animals; Blood Glucose; Disease Models, Animal; Hypoxia; Inflammation; Inflammation Mediators; Insulin; Insulin Resistance; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Obesity; Oxygen; Time Factors; Tumor Necrosis Factor-alpha

Leptin acts in the brain to prevent obesity. The underlying neurocircuitry responsible for this is poorly understood, in part because of incomplete knowledge regarding first-order, leptin-responsive neurons. To address this, we and others have been removing leptin receptors from candidate first-order neurons. While functionally relevant neurons have been identified, the observed effects have been small, suggesting that most first-order neurons remain unidentified. Here we take an alternative approach and test whether first-order neurons are inhibitory (GABAergic, VGAT⁺) or excitatory (glutamatergic, VGLUT2⁺). Remarkably, the vast majority of leptin's antiobesity effects are mediated by GABAergic neurons; glutamatergic neurons play only a minor role. Leptin, working directly on presynaptic GABAergic neurons, many of which appear not to express AgRP, reduces inhibitory tone to postsynaptic POMC neurons. As POMC neurons prevent obesity, their disinhibition by leptin action on presynaptic GABAergic neurons probably mediates, at least in part, leptin's antiobesity effects.

Topics: Agouti-Related Protein; Animals; Brain; Disease Models, Animal; Excitatory Postsynaptic Potentials; gamma-Aminobutyric Acid; Glutamic Acid; Inhibitory Postsynaptic Potentials; Leptin; Mice; Mice, Transgenic; Neurons; Obesity; Pro-Opiomelanocortin; Receptors, Leptin

Insulin signaling depends on tyrosine phosphorylation of insulin receptor substrates (IRSs) to mediate downstream effects; however, elevated serine phosphorylation of IRS impairs insulin signaling. Here, we investigated IRS protein expression patterns in dorsal root ganglia (DRG) of mice and whether their signaling was affected by diabetes. Both IRS1 and IRS2 are expressed in DRG; however, IRS2 appears to be the prevalent isoform and is expressed by many DRG neuronal subtypes. Phosphorylation of Ser(731)IRS2 was significantly elevated in DRG neurons from type 1 and type 2 diabetic mice. Additionally, Akt activation and neurite outgrowth in response to insulin were significantly decreased in DRG cultures from diabetic ob/ob mice. These results suggest that DRG neurons express IRS proteins that are altered by diabetes similar to other peripheral tissues, and insulin signaling downstream of the insulin receptor may be impaired in sensory neurons and contribute to the pathogenesis of diabetic neuropathy.

Topics: Animals; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Disease Models, Animal; Ganglia, Spinal; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurites; Neurons; Obesity; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; Streptozocin

Leptin is produced by white adipose tissue and other cell types and is involved in both short- and long-term appetite control. Here we studied effects of starvation on serum, pituitary and hypothalamic levels of leptin during 72 h period. Each of the starved groups was sacrificed simultaneously with the group of ad libitum fed animals. The progression of the discrete starvation response phases was monitored by testing the blood glucose, free fatty acid, urea and corticosterone levels. Starvation caused biphasic increase in corticosterone and free fatty acid levels, and significant but transient decrease in urea and glucose levels. Starvation also abolished diurnal rhythm of changes in leptin concentrations in serum and hypothalamic and pituitary tissues. Only 6 h starving period was sufficient to lock serum leptin at low levels, whereas 12 h were needed to silence leptin production/secretion in hypothalamus for the whole examined period. In contrast, leptin production by pituitary tissues of starved animals required 24 h to reach minimum, followed by full recovery by the end of starvation period. These results indicate the tissue specific pattern of leptin release and suggest that the locally produced leptin could activate its receptor in pituitary cells independently of serum levels of this hormone.

Topics: Animals; Biomarkers; Blood Glucose; Circadian Rhythm; Corticosterone; Disease Models, Animal; Energy Metabolism; Fatty Acids, Nonesterified; Food Deprivation; Hypothalamus; Leptin; Male; Pituitary Gland; Rats; Rats, Wistar; Starvation; Time Factors; Urea

In obesity and type 2 diabetes, efficient skeletal muscle repair following injury may be required, not only for restoring muscle structure and function, but also for maintaining exercise capacity and insulin sensitivity. The hypothesis of this study was that muscle regeneration would be impaired in ob/ob and db/db mice, which are common mouse models of obesity and type 2 diabetes. Muscle injury was produced by cardiotoxin injection, and regeneration was assessed by morphological and immunostaining techniques. Muscle regeneration was delayed in ob/ob and db/db mice, but not in a less severe model of insulin resistance - feeding a high-fat diet to wild-type mice. Angiogenesis, cell proliferation, and myoblast accumulation were also impaired in ob/ob and db/db mice, but not the high-fat diet mice. The impairments in muscle regeneration were associated with impaired macrophage accumulation; macrophages have been shown previously to be required for efficient muscle regeneration. Impaired regeneration in ob/ob and db/db mice could be due partly to the lack of leptin signaling, since leptin is expressed both in damaged muscle and in cultured muscle cells. In summary, impaired muscle regeneration in ob/ob and db/db mice was associated with reduced macrophage accumulation, angiogenesis, and myoblast activity, and could have implications for insulin sensitivity in the skeletal muscle of obese and type 2 diabetic patients.

Topics: Animals; Diet, High-Fat; Disease Models, Animal; Insulin; Insulin Resistance; Leptin; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Obese; Muscle, Skeletal; Myoblasts, Skeletal; Neovascularization, Physiologic; Regeneration; Signal Transduction

The objective of this research was to determine body composition, total fat content, fat distribution, and serum leptin concentration in hyperlipidemic (high responder, HR) and normolipidemic (low responder, LR) California mice (Peromyscus californicus). In our initial experiments, we sought to determine whether differences in regional fat storage were associated with hyperlipidemia in this species. To further characterize the hepatic steatosis in the mice, we performed 2 additional experiments by using a diet containing 45% of energy as fat. The body fat content of mice fed a low fat-diet (12.3% energy as fat) was higher than that of mice fed a moderate-fat diet (25.8% energy as fat). Total body fat did not differ between HR and LR mice. There was no significant difference between intraabdominal, gonadal, or inguinal fat pad weights. Liver weights of HR mice fed the moderate-fat diet were higher than those of LR mice fed the same diet, and the moderate-fat diet was associated with nonalcoholic fatty liver (NAFL). Mice fed the 45% diet had higher histologic score for steatosis but very little inflammatory response. Chemical analysis indicated increased lipid in the livers of mice fed the high-fat diet compared with those fed the low-fat diet. HR and LR mice had similar serum leptin concentrations. California mice develop NAFL without excess fat accumulation elsewhere. NAFL was influenced by genetic and dietary factors. These mice may be a naturally occuring model of partial lipodystrophy.

Topics: Animals; Body Composition; Body Fat Distribution; Diet; Disease Models, Animal; Energy Metabolism; Fatty Liver; Hyperlipidemias; Leptin; Liver; Organ Size; Peromyscus

The causes of anxiety and depression in women with polycystic ovary syndrome (PCOS) remain elusive. To identify steps linking androgen signaling to the regulation of affective symptoms in vivo, we compared behavioral responses in female rats continuously exposed to DHT from puberty (a model of DHT-induced PCOS) and in rats exposed to DHT for 1week. Continuous and 1week of DHT exposure resulted in a general decrease in locomotor activity and time spent on the open arms in the elevated plus maze, indicating anxiety-like behavior. Rats with DHT-induced PCOS have increases in adiposity and circulating leptin levels accompanied by leptin resistance. One week of DHT exposure decreased androgen receptor (AR) expression in the hypothalamus and leptin synthesis and function in adipocytes; it also inhibited signal transducer and activator of transcription 3 (STAT3) and attenuated leptin activity by increasing levels of soluble leptin receptor, a leptin-binding protein, in the hypothalamus. This may affect the androgen-induced anxiety-related behavior in female rats. In conclusion, our results highlight the central role of androgens in behavioral function in female rats and suggest that androgens directly regulate the AR by decreasing its hypothalamic expression. Androgens also increase leptin synthesis in adipocytes, which drives central leptin signaling, and may regulate anxiety-related behaviors. Elucidating mechanisms by which androgens modulate female anxiety-like behavior may uncover useful approaches for treating women with PCOS who have symptoms of anxiety.

Topics: Androgens; Animals; Behavior, Animal; Body Weight; Brain; Cell Physiological Phenomena; Dihydrotestosterone; Disease Models, Animal; Female; Humans; Leptin; Maze Learning; Organ Size; Polycystic Ovary Syndrome; Rats; Rats, Wistar; Receptors, Androgen

Cross-sectional studies in both humans and animals have demonstrated associations between obesity and altered reward functions at the behavioral and neural level, but it is unclear whether these alterations are cause or consequence of the obese state. Reward behaviors were quantified in male, outbred Sprague-Dawley (SD) and selected line obesity-prone (OP) and obesity-resistant (OR) rats after induction of obesity by high-fat diet feeding and after subsequent loss of excess body weight by chronic calorie restriction. As measured by the brief access lick and taste-reactivity paradigms, both obese SD and OP rats "liked" low concentrations of sucrose and corn oil less, but "liked" the highest concentrations more, compared with lean rats, and this effect was fully reversed by weight loss in SD rats. Acute food deprivation was unable to change decreased responsiveness to low concentrations but eliminated increased responsiveness to high concentrations in obese SD rats, and leptin administration in weight-reduced SD rats shifted concentration-response curves toward that seen in the obese state in the brief access lick test. "Wanting" and reinforcement learning as assessed in the incentive runway and progressive ratio lever-pressing paradigms was paradoxically decreased in both obese (compared with lean SD rats) and OP (compared with OR rats). Thus, reversible, obesity-associated, reduced "liking" and "wanting" of low-calorie foods in SD rats suggest a role for secondary effects of the obese state on reward functions, while similar differences between select lines of OP and OR rats before induction of obesity indicate a genetic component.

Topics: Adiposity; Animals; Caloric Restriction; Corn Oil; Dietary Fats; Disease Models, Animal; Feeding Behavior; Food Preferences; Genetic Predisposition to Disease; Leptin; Male; Motivation; Obesity; Phenotype; Rats; Rats, Sprague-Dawley; Reinforcement, Psychology; Reward; Sucrose; Taste; Weight Loss

An acute injection of brain-derived neurotrophic factor (BDNF) in the hypothalamic ventromedial nucleus (VMN) decreases body weight by reducing feeding and increasing energy expenditure (EE) in animals on standard laboratory chow. Animals have divergent responses to high-fat diet (HFD) exposure, with some developing obesity and others remaining lean. In the current study, we tested the hypothesis that BDNF in the VMN reduces HFD-induced obesity. Seventy-two 10-week old rats were allowed HFD ad libitum for 8 weeks and then prepared with bilateral VMN cannulae. Animals were then divided into tertiles based on their fat mass rank: high, intermediate, and low (H, I, and L). Each group was further divided into two subgroups: BDNF (1 μg) or control (artificial cerebrospinal fluid, aCSF); they were then injected every other day for 20 days according to subgroup. Energy intake, body weight, and body composition were measured. Other metabolic indexes were measured before and after treatment. In parallel, another 12 rats were fed control diet (CD), VMN-cannulated, and injected with aCSF. HFD exposure induced obesity in the H group, with a significant increase in energy intake, body weight, fat mass, liver size, and serum glucose, insulin, and leptin. BDNF significantly reduced body weight and fat mass in all phenotypes, while it reduced energy intake only in the I group. However, BDNF increased EE, spontaneous physical activity, and fat oxidation in the H group, suggesting that BDNF-induced EE elevation contributed to reduction of body weight and fat mass. Chronic VMN BDNF reduced insulin elevation and/or reversed hyperleptinemia. These data suggest that the VMN is an important site of action for BDNF reduction of HFD-induced obesity.

Topics: Adipose Tissue; Animals; Brain-Derived Neurotrophic Factor; Contraindications; Diet, High-Fat; Disease Models, Animal; Energy Intake; Hyperinsulinism; Leptin; Male; Obesity; Rats; Rats, Sprague-Dawley; Ventromedial Hypothalamic Nucleus

Leptin regulates body weight in mice by decreasing appetite and increasing sympathetic nerve activity (SNA), which increases energy expenditure in interscapular brown adipose tissue (iBAT). Diet-induced obese mice (DIO) are resistant to the anorectic actions of leptin. We evaluated whether leptin still stimulated sympathetic outflow in DIO mice. We measured iBAT temperature as a marker of SNA. We found that obese hyperleptinemic mice have higher iBAT temperature than mice on regular diet. Conversely, obese leptin-deficient ob/ob mice have lower iBAT temperature. Additionally, leptin increased SNA in obese (DIO and ob/ob) and control mice, despite DIO mice being resistant to anorectic action of leptin. We demonstrated that neurons in the dorsomedial hypothalamus (DMH) of DIO mice mediate the thermogenic responses to hyperleptinemia in obese mammals because blockade of leptin receptors in the DMH prevented the thermogenic effects of leptin. Peripheral Melotan II (MTII) injection increased iBAT temperature, but it was blunted by blockade of DMH melanocortin receptors (MC4Rs) by injecting agouti-related peptide (AgRP) directly into the DMH, suggesting a physiological role of the DMH on temperature regulation in animals with normal body weight. Nevertheless, obese mice without a functional melanocortin system (MC4R KO mice) have an increased sympathetic outflow to iBAT compared with their littermates, suggesting that higher leptin levels drive sympathoexcitation to iBAT by a melanocortin-independent pathway. Because the sympathetic nervous system contributes in regulating blood pressure, heart rate, and hepatic glucose production, selective leptin resistance may be a crucial mechanism linking adiposity and metabolic syndrome.

Topics: Adipose Tissue, Brown; Animals; Body Temperature; Disease Models, Animal; Dorsomedial Hypothalamic Nucleus; Drug Resistance; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Obesity; Receptors, Leptin; Sympathetic Nervous System; Thermogenesis

Behavioral satiety sequence (BSS) is a useful paradigm to assess the effects of orexigenic and anorexigenic profiles of novel pharmacological and genetic manipulations in rodents. To date, no studies have described the satiety profile of leptin-deficient ob/ob mice, an important animal model of obesity in this task. Furthermore, no studies have described changes in the BSS after treatment with ghrelin receptor ligands, which have become an attractive therapeutic target in obesity drug discovery efforts. BSS testing was carried out in ob/ob mice and their lean controls. After baseline analysis, effects of ghrelin (2 nmol/10 g) and of the ghrelin receptor antagonist (D-Lys)-GHRP-6 (66.6 and 133.3 nmol/10 g) were studied in BSS in mice of both genotypes. The baseline BSS profile of ob/ob mice showed an increased eating and a decreased resting activity. Ob/ob mice presented with a decreased sensitivity to the stimulation with ghrelin and with the ghrelin receptor antagonist, which caused strong anorexic and adverse side effects in lean mice, thereby disrupting the BSS profile. BSS is an indispensable tool for parsing the role of the ghrelinergic system in satiety, to characterize transgenic mice and to elicit behavioral feeding profiles of novel anorectic agents.

Topics: Animals; Appetite Depressants; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Eating; Fasting; Ghrelin; Leptin; Ligands; Male; Mice; Mice, Knockout; Mice, Obese; Obesity; Oligopeptides; Receptors, Ghrelin; Satiation; Time Factors

The Berlin Fat Mouse BFMI860 is a polygenic obesity mouse model which harbors a natural major gene defect resulting in early onset of obesity. To elucidate adult bodily responses in BFMI860 mice that develop juvenile obesity, we studied features of the metabolic syndrome at 20 weeks.. We examined fat deposition patterns, adipokines, lipid profiles in serum, glucose homeostasis, and insulin sensitivity in mice that were fed either a standard maintenance (SMD) or a high-fat diet (HFD).. Like many obese humans, BFMI860 mice showed hyperleptinemia accompanied by hypoadiponectinemia already at SMD that was further unbalanced as a result of HFD. Furthermore, BFMI860 mice had high triglyceride concentrations. However, triglyceride clearance after an oral oil gavage was impaired on SMD but improved on HFD. The oral and intraperitoneal glucose as well as the insulin tolerance tests provided evidence for reduced insulin sensitivity under SMD and insulin resistance on HFD. BFMI860 mice can maintain normal glucose clearance over a wide range of feeding conditions according to an adaptation via increasing the insulin concentrations.. BFMI860 mice show obesity, dyslipidemia, and insulin resistance as three major components of the metabolic syndrome. As these mice develop the described phenotype as a result of a major gene defect, they are a unique model for the investigation of genetic and pathophysiological mechanisms underlying the observed features of the metabolic syndrome and to search for potential strategies to revert the adverse effects under controlled conditions.

Topics: Adipokines; Adiponectin; Animals; Blood Glucose; Diet, High-Fat; Dietary Fats; Disease Models, Animal; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Mice; Mice, Obese; Obesity; Triglycerides

The present study aimed to investigate time-dependent changes in leptin concentrations in brain tissue following experimental traumatic brain injury and to examine the relationship with cytokines.. After circular craniectomy, 33 male Wistar-albino rats were positioned on a stereotaxic frame and subjected to cortical contusion injury and then divided into 3 groups based on the depth of deformation as: 0 mm (sham controls, n=3), 1.5 mm (moderate injury, n=15) and 2.7 mm (severe injury, n=15). Animals were sacrificed on the 1st, 3rd and 5th days post-injury.. One day after moderate injury, interleukin-1 beta (IL-1ß), IL-6, tumor necrosis factor-alpha (TNF-?), and leptin levels were found to be markedly increased in the brain tissue. On the 3rd and 5th days, the levels returned to the shamcontrol levels. Following severe injury, IL-1ß, IL-6 and TNF-? levels increased in correlation after the 1st day and reached the sham-control levels on the same days. However, leptin tissue levels decreased on the 1st and 3rd days and normalized to the sham-control levels on the 5th day.. Our results showed that the release of leptin is decreased in the early stage of severe injury. Thus, leptin replacement may play an important role in therapy in cases with severe traumatic brain injury.

Topics: Animals; Brain Injuries; Cytokines; Disease Models, Animal; Injury Severity Score; Interleukin-1beta; Interleukin-6; Leptin; Male; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Interleukin 1 beta (IL-1β) is a proinflammatory cytokine with potent cardiosuppressive effects. Previous studies have shown that leptin blunts the negative inotropic effects of IL-1β in isolated adult rat cardiac myocytes. However, the interactions between leptin and IL-1β in the heart have not been examined on a background of chronic hyperleptinemia. To study this interaction, we have chosen the SHHF rat, a model of spontaneous hypertension that ultimately develops congestive heart failure. SHHF that are heterozygous for a null mutation of the leptin receptor (+/fa(cp), HET) are phenotypically lean but chronically hyperleptinemic and develop heart failure earlier than their normoleptinemic true lean (+/+, LN) littermates. Simultaneous cell shortening and calcium transients were measured in isolated ventricular cardiac myocytes from LN and HET SHHF in response to leptin, IL-1β or IL-1β following one hour pretreatment with leptin. Despite evidence of metabolic leptin resistance, HET myocytes were sensitive to the negative inotropic effect of leptin, similar to LN. Contractility returned to control levels in myocytes from HET that were pretreated with leptin prior to IL-1β, while contractility remained depressed compared with control and similar to leptin alone in LN. Chronic hyperleptinemia resulted in altered JAK/STAT signaling in response to leptin and IL-1β in isolated perfused hearts from HET compared with LN SHHF. Phosphorylated STAT3 (pSTAT3) and STAT5 (pSTAT5) decreased when HET hearts were treated with leptin followed by IL-1β. While decreases in pSTAT3 and pSTAT5 may be associated with abrogation of the acute negative inotropic effects of IL-1β in the presence of leptin in HET, long-term consequences remain to be explored. This study demonstrates that the heart remains sensitive to leptin in a hyperleptinemic state. Crosstalk between leptin and IL-1β can influence cardiac function and cytokine signaling and these interactions are moderated by the presence of long-term hyperleptinemia.

Topics: Animals; Disease Models, Animal; Hypertension; Interleukin-1beta; Leptin; Male; Myocytes, Cardiac; Rats; Rats, Inbred Strains; Receptors, Leptin; Signal Transduction

We previously mapped a type 2 diabetes (T2D) locus on chromosome 16 (Chr 16) in an F2 intercross from the BTBR T (+) tf (BTBR) Lep(ob/ob) and C57BL/6 (B6) Lep(ob/ob) mouse strains. Introgression of BTBR Chr 16 into B6 mice resulted in a consomic mouse with reduced fasting plasma insulin and elevated glucose levels. We derived a panel of sub-congenic mice and narrowed the diabetes susceptibility locus to a 1.6 Mb region. Introgression of this 1.6 Mb fragment of the BTBR Chr 16 into lean B6 mice (B6.16(BT36-38)) replicated the phenotypes of the consomic mice. Pancreatic islets from the B6.16(BT36-38) mice were defective in the second phase of the insulin secretion, suggesting that the 1.6 Mb region encodes a regulator of insulin secretion. Within this region, syntaxin-binding protein 5-like (Stxbp5l) or tomosyn-2 was the only gene with an expression difference and a non-synonymous coding single nucleotide polymorphism (SNP) between the B6 and BTBR alleles. Overexpression of the b-tomosyn-2 isoform in the pancreatic β-cell line, INS1 (832/13), resulted in an inhibition of insulin secretion in response to 3 mM 8-bromo cAMP at 7 mM glucose. In vitro binding experiments showed that tomosyn-2 binds recombinant syntaxin-1A and syntaxin-4, key proteins that are involved in insulin secretion via formation of the SNARE complex. The B6 form of tomosyn-2 is more susceptible to proteasomal degradation than the BTBR form, establishing a functional role for the coding SNP in tomosyn-2. We conclude that tomosyn-2 is the major gene responsible for the T2D Chr 16 quantitative trait locus (QTL) we mapped in our mouse cross. Our findings suggest that tomosyn-2 is a key negative regulator of insulin secretion.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Adaptor Proteins, Vesicular Transport; Animals; Chromosome Mapping; Cloning, Molecular; Diabetes Mellitus, Type 2; Disease Models, Animal; Genetic Predisposition to Disease; Glucose; HEK293 Cells; Humans; Hypoglycemia; Insulin; Insulin Secretion; Islets of Langerhans; Leptin; Mice; Mice, Inbred C57BL; Polymorphism, Single Nucleotide; Qa-SNARE Proteins; Quantitative Trait Loci; R-SNARE Proteins; Rats; SNARE Proteins; Syntaxin 1

Leptin is a potent AMP kinase (AMPK) inhibitor that is central to cell survival. Hence, we explored the effects of leptin on neurogenesis and angiogenesis after stroke. Neural stem cells (NSC) were grown as neurospheres in culture and treated with vehicle or leptin and neurosphere size and terminal differentiation were then determined. We then explored the effects of leptin on endogenous repair mechanisms in vivo. Sabra mice underwent photothrombotic stroke, were given vehicle or leptin and newborn cells were labeled with Bromo-deoxy-Uridine. Functional outcome was studied with the neurological severity score for 90 days post stroke and the brains were then evaluated with immunohistochemistry. In a subset of animals the brains were also evaluated for changes in the expression of leptin receptor and AMPK. In vitro, leptin led to a 2-fold increase in neurosphere size but did not change the differentiation of newborn cells. Following stroke, exogenous leptin led to a 4-fold increase in the number of NSC in the cortex abutting the lesion. There was a 1.5-fold increase in the number of newborn neurons and glia in leptin treated animals. Leptin also significantly increased the number of blood vessels in the peri-lesioned cortex. Leptin treated mice had increased expression of leptin receptor and increased phosphorylated AMPK concentration. Animals treated with leptin also had significantly better functional states. In conclusion, leptin induces neurogenesis and angiogenesis after stroke and leads to increased leptin receptor and pAMPK concentrations. This may explain at least in part the better functional outcome observed in leptin treated animals after stroke.

Topics: AMP-Activated Protein Kinase Kinases; Animals; Blood Vessels; Brain Infarction; Bromodeoxyuridine; CD3 Complex; Cell Count; Cell Differentiation; Cells, Cultured; Disability Evaluation; Disease Models, Animal; Dose-Response Relationship, Drug; Embryo, Mammalian; Fibroblast Growth Factors; Glial Fibrillary Acidic Protein; Leptin; Mice; Neovascularization, Pathologic; Neural Stem Cells; Neurogenesis; Neuroprotective Agents; Protein Kinases; Receptors, Leptin; Stroke; Time Factors; TRPV Cation Channels; Tubulin

To investigate the diagnosis of nonalcoholic steatohepatitis (NASH) using contrast ultrasonography in the NASH rat model.. The liver in methionine choline-deficient diet (MCDD) rats, a NASH model constructed by feeding an MCDD, was examined by contrast ultrasonography at weeks 2, 4, 8, 12 and 16, with late phase images of contrast ultrasonography (Kupffer imaging) in which contrast enhancement was achieved by incorporation of a contrast agent by Kupffer cells (KCs), and images were compared to those in rats taking a regular chow.. Decrease in contrast enhancement was observed first in MCDD rats at week 2. KCs were counted based on immunohistochemistry, but their numbers were not reduced and it was assumed that attenuation of contrast enhancement was attributable to reduced phagocytic activity of the KCs.. It is suggested that clinical application of contrast ultrasonography may be valuable for non-invasive diagnosis of NASH.

Topics: Animals; Body Weight; Choline Deficiency; Contrast Media; Diet; Disease Models, Animal; Fatty Liver; Kupffer Cells; Leptin; Liver; Male; Methionine; Non-alcoholic Fatty Liver Disease; Rats; Rats, Wistar; Ultrasonography

Prediabetes (PreDM) in asymptomatic adults is associated with abnormal circadian blood pressure variability (abnormal CBPV).. Systemic inflammation and glycemia influence circadian blood pressure variability.. Dahl salt-sensitive (S) rats (n = 19) after weaning were fed either an American (AD) or a standard (SD) diet. The AD (high-glycemic-index, high-fat) simulated customary human diet, provided daily overabundant calories which over time lead to body weight gain. The SD (low-glycemic-index, low-fat) mirrored desirable balanced human diet for maintaining body weight. Body weight and serum concentrations for fasting glucose (FG), adipokines (leptin and adiponectin), and proinflammatory cytokines [monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α)] were measured. Rats were surgically implanted with C40 transmitters and blood pressure (BP-both systolic; SBP and diastolic; DBP) and heart rate (HR) were recorded by telemetry every 5 minutes during both sleep (day) and active (night) periods. Pulse pressure (PP) was calculated (PP = SBP-DBP).. [mean(SEM)]: The AD fed group displayed significant increase in body weight (after 90 days; p < 0.01). Fasting glucose, adipokine (leptin and adiponectin) concentrations significantly increased (at 90 and 172 days; all p < 0.05), along with a trend for increased concentrations of systemic pro-inflammatory cytokines (MCP-1 and TNF-α) on day 90. The AD fed group, with significantly higher FG, also exhibited significantly elevated circadian (24-hour) overall mean SBP, DBP, PP and HR (all p < 0.05).. These data validate our stated hypothesis that systemic inflammation and glycemia influence circadian blood pressure variability. This study, for the first time, demonstrates a cause and effect relationship between caloric excess, enhanced systemic inflammation, dysglycemia, loss of blood pressure control and abnormal CBPV. Our results provide the fundamental basis for examining the relationship between dysglycemia and perturbation of the underlying mechanisms (adipose tissue dysfunction induced local and systemic inflammation, insulin resistance and alteration of adipose tissue precursors for the renin-aldosterone-angiotensin system) which generate abnormal CBPV.

Topics: Adiponectin; Animals; Biomarkers; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Chemokine CCL2; Circadian Rhythm; Diet, High-Fat; Disease Models, Animal; Heart Rate; Inflammation; Inflammation Mediators; Leptin; Prediabetic State; Rats; Rats, Inbred Dahl; Telemetry; Time Factors; Tumor Necrosis Factor-alpha; Weight Gain

Few studies have reported a relationship between leptin induced by spinal cord injury (SCI) and healing bone tissue.. To observe serum and callus leptin expression within the setting of fracture and traumatic SCI.. Seventy-two male Sprague Dawley rats were randomized equally into four groups: control, SCI group, fracture group, and fracture/SCI group. Rats were sacrificed at 7, 14, 21, and 28 days post-fracture/SCI. Serum leptin was detected using radioimmunoassay at 1, 7, 14, 21, and 28 days, and callus formation was measured radiologically at 14, 21, and 28 days. Callus leptin was analyzed by means of immunohistochemistry.. Serum leptin in the fracture group, SCI group, and combined fracture/SCI group were all significantly increased compared to control group at the 1, 7, 14, and 2-day time points (P < 0.05). Serum leptin in the combined fracture/SCI group was significantly higher than in the fracture group at 7, 14, and 21 days (P < 0.05), and higher than in SCI groups at 14 and 21days after operation (P < 0.05). The percentage of leptin-positive cells in the fracture/SCI callus, and callus volume was significantly higher than in the fracture-only group (P < 0.001).. Overall, elevated leptin expression was demonstrated within healing bone especially in the 21 days of a rat model combining fracture and SCI. A close association exists between leptin levels and the degree of callus formation in fractures.

Topics: Animals; Disease Models, Animal; Femoral Fractures; Leptin; Male; Microscopy, Electron, Transmission; Muscle, Skeletal; Radioimmunoassay; Random Allocation; Rats; Rats, Sprague-Dawley; Spinal Cord; Spinal Cord Injuries; Statistics as Topic; Time Factors

We previously investigated the effects of an aqueous extract of maté (mate) tea, made from the leaves of Ilex paraguariensis, on the diabesity and metabolic syndrome features in a mouse model. Mate induced significant decreases in body weight (BW), body mass index, and food intake (FI). In this study, to verify the mode of action of mate on FI and consequently on BW, we examined the anorexic effects of mate on the appetite and satiety markers glucagon-like peptide 1 (GLP-1) and leptin in high-fat diet-fed ddY mice. GLP-1 is a peptide signal generated by the gastrointestinal tract, which regulates appetite and influences BW, whereas leptin is an afferent signal from the periphery to the brain in a homeostatic feedback loop that regulates adipose tissue mass, thus leading to decreased appetite and FI and increased energy expenditure. Chronic administration of mate (50, 100 mg/kg) for 3 weeks significantly reduced FI, BW, and ameliorated blood fats, liver fats, and adipose tissue. Mate induced significant increases in GLP-1 levels and leptin levels compared with the control. Acute administration of major constituents of mate showed significant increases in GLP-1 levels by dicaffeoyl quinic acids and matesaponins, and significant induction of satiety by caffeoyl quinic acids and caffeine in ddY mice. These findings suggest that mate may induce anorexic effects by direct induction of satiety and by stimulation of GLP-1 secretion and modulation of serum leptin levels.

Topics: Animals; Anti-Obesity Agents; Beverages; Diet, High-Fat; Dipeptidyl Peptidase 4; Disease Models, Animal; Eating; Fatty Acids; Glucagon-Like Peptide 1; Ilex paraguariensis; Leptin; Liver; Male; Mice; Obesity; Phytotherapy; Plant Extracts; Plant Leaves; Satiation; Triglycerides; Weight Gain

In addition to its effects in the hypothalamus to control body weight, leptin is involved in the regulation of neuronal function, development and survival. Recent findings have highlighted the neuroprotective effects of leptin against ischemic brain injury; however, to date, little is known about the role performed by the signal transducer and activator of transcription (STAT)-3, a major mediator of leptin receptor transduction pathway in the brain, in the beneficial effects of the hormone. Our data demonstrate that systemic acute administration of leptin produces neuroprotection in rats subjected to permanent middle cerebral artery occlusion (MCAo), as revealed by a significant reduction of the brain infarct volume and neurological deficit up to 7 days after the induction of ischemia. By combining a subcellular fractionation approach with immunohistofluorescence, we observe that neuroprotection is associated with a cell type-specific modulation of STAT3 phosphorylation in the ischemic cortex. The early enhancement of nuclear phospho-STAT3 induced by leptin in the astrocytes of the ischemic penumbra may contribute to a beneficial effect of these cells on the evolution of tissue damage. In addition, the elevation of phospho-STAT3 induced by leptin in the neurons after 24 h MCAo is associated with an increased expression of tissue inhibitor of matrix metalloproteinases-1 in the cortex, suggesting its possible involvement to the neuroprotection produced by the adipokine.

Topics: Adipokines; Animals; Brain; Brain Ischemia; Disease Models, Animal; Immunohistochemistry; Leptin; Male; Neurons; Phosphorylation; Rats; Rats, Wistar; STAT3 Transcription Factor; Tissue Inhibitor of Metalloproteinase-1

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is upregulated in a variety of tissues in obesity. It is still unclear as to whether NADPH oxidase upregulation in a specific tissue is part of a systemic response. Here we analyzed the expression pattern of NADPH oxidase in vascular, adipose, and kidney tissues in a rat model of diet-induced obesity. After weaning, rats were fed either a normal or high-fat diet for 12 weeks. The high-fat diet resulted in 20% increased body weight. In the aorta, Nox4 expression was increased by three-fold in obese rats. Upregulations of p22phox and p47phox in adipose, and Nox4, p22phox, and p47phox in kidney were observed in obesity. Marked increases in plasma leptin and insulin were observed, with more modest changes in adiponectin in obese rats. The average systolic blood pressure in the obese group was 11 mmHg higher than that of lean rats (P < 0.005). There was a significant correlation between blood pressure and aortic Nox4 expression (P < 0.01). In cultured vascular smooth muscle cells, adiponectin reduced the expression of Nox4 in a protein kinase A-dependent manner. Our results suggest that upregulation of NADPH oxidase in multiple tissues during obesity appears to be a systemic response. At least in vitro, adiponectin may have a protective antioxidant role by suppressing vascular NADPH oxidase expression. The association between NADPH oxidase Nox4 expression in the vasculature and the elevated blood pressure in obesity requires further investigation.

Topics: Adiponectin; Adipose Tissue, White; Animals; Antioxidants; Aorta, Thoracic; Blood Pressure; Cells, Cultured; Diet, High-Fat; Disease Models, Animal; Enzyme Activation; Insulin; Kidney; Leptin; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; NADPH Oxidase 4; NADPH Oxidases; Obesity; Rats; Rats, Sprague-Dawley; Up-Regulation; Weight Gain

The objective of this study is to explore whether diabetes play roles on histopathological change of Achilles tendon in leptin-deficient mice. Ob mice (specific-pathogen free SPF) were identified at 10 days after birth and killed via dislocation of cervical spine at 12 weeks. Achilles tendon was isolated as quickly as possible and histopathological changes were investigated. Degeneration of tendinocytes, vascular proliferation, chondrocyte-like tendon cell and ruptures at insertion areas were observed. We conclude that diabetes is associated with histopathologic change in Achilles tendon of ob mice.

Topics: Achilles Tendon; Animals; Diabetic Neuropathies; Disease Models, Animal; Gene Silencing; Genotype; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Specific Pathogen-Free Organisms; Tendinopathy

Hyperandrogenemia predisposes an organism toward developing impaired insulin sensitivity. The aim of our study was to evaluate endocrine and metabolic effects during early allostasis induced by a fructose-rich diet (FRD) in normal (control; CT) and neonatal-androgenized (testosterone propionate; TP) female adult rats. CT and TP rats were fed either a normal diet (ND) or an FRD for 3 weeks immediately before the day of study, which was at age 100 days. Energy intake, body weight (BW), parametrial (PM) fat characteristics, and endocrine/metabolic biomarkers were then evaluated. Daily energy intake was similar in CT and TP rats regardless of the differences in diet. When compared with CT-ND rats, the TP-ND rats were heavier, had larger PM fat, and were characterized by basal hypoadiponectinemia and enhanced plasma levels of non-esterified fatty acid (NEFA), plasminogen activator inhibitor-1 (PAI-1), and leptin. FRD-fed CT rats, when compared with CT-ND rats, had high plasma levels of NEFA, triglyceride (TG), PAI-1, leptin, and adiponectin. The TP-FRD rats, when compared with TP-ND rats, displayed enhanced leptinemia and triglyceridemia, and were hyperinsulinemic, with glucose intolerance. The PM fat taken from TP rats displayed increase in the size of adipocytes, decrease in adiponectin (protein/gene), and a greater abundance of the leptin gene. PM adipocyte response to insulin was impaired in CT-FRD, TP-ND, and TP-FRD rats. A very short duration of isocaloric FRD intake in TP rats induced severe metabolic dysfunction at the reproductive age. Our study supports the hypothesis that the early-androgenized female rat phenotype is highly susceptible to developing endocrine/metabolic dysfunction. In turn, these abnormalities enhance the risk of metabolic syndrome, obesity, type 2 diabetes, and cardiovascular disease.

Topics: Adipocytes; Adipokines; Adiponectin; Adipose Tissue; Adiposity; Androgens; Animals; Body Weight; Dietary Sucrose; Disease Models, Animal; Energy Intake; Fatty Acids, Nonesterified; Female; Fructose; Genitalia, Female; Glucose Metabolism Disorders; Hyperandrogenism; Insulin; Leptin; Obesity; Plasminogen Activator Inhibitor 1; Rats; Rats, Sprague-Dawley; Risk Factors; Testosterone Propionate; Triglycerides

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

Our previous studies in rats have shown that the adipocyte-derived hormone leptin induces antidepressant-like effects with a behavioral profile similar to selective serotonin reuptake inhibitor (SSRI) antidepressants. Acute SSRI treatment causes paradoxical anxiogenic responses, although chronic treatment has therapeutic effects on anxiety. However, the role of leptin in anxiety remains to be established.. The scope of this study was to investigate the acute effects of leptin on anxiety-related behaviors in comparison with the SSRI antidepressant fluoxetine.. Adult male C57BL/6J mice received intraperitoneal injection of leptin or fluoxetine. Thirty minutes after injection, mice were subjected to the tail suspension test (TST) and forced swim test (FST) for evaluating antidepressant activity. Anxiety-like behavior was assessed in the elevated plus maze (EPM), social interaction, and open field tests 30 min following drug treatment.. While leptin and fluoxetine showed similar antidepressant-like behavioral effects in the TST and FST, they differed in the behavioral assays for anxiety. Open arm exploration in the EPM was increased by leptin but decreased by fluoxetine. Analysis of social interaction revealed that distinct social behavioral components were modulated by leptin and fluoxetine. The total time of active social behaviors was increased by leptin but reduced by fluoxetine. In addition, self-grooming, a non-social behavior, was suppressed by leptin treatment. Neither leptin nor fluoxetine produced significant effects in the open field test.. In contrast to anxiogenic-like effects induced by acute fluoxetine, leptin elicits anxiolytic-like effects after acute administration. These results suggest that leptin has both antidepressant-like and anxiolytic-like properties.

Topics: Animals; Antidepressive Agents, Second-Generation; Anxiety; Disease Models, Animal; Exploratory Behavior; Fluoxetine; Leptin; Male; Maze Learning; Mice; Mice, Inbred C57BL; Social Behavior; Time Factors

We demonstrated previously that chronic maternal micronutrient restriction altered the body composition in rat offspring and may predispose offspring to adult-onset diseases. Chromium (Cr) regulates glucose and fat metabolism. The objective of this study is to determine the long-term effects of maternal Cr restriction on adipose tissue development and function in a rat model.. Female weanling WNIN rats received, ad libitum, a control diet or the same with 65% restriction of Cr (CrR) for 3 months and mated with control males. Some pregnant CrR mothers were rehabilitated from conception or parturition and their pups weaned to control diet. Whereas some CrR offspring were weaned to control diet, others continued on CrR diet. Various parameters were monitored in the offspring at three monthly intervals up to 15-18 months of age.. Maternal Cr restriction significantly increased body weight and fat percentage, especially the central adiposity in both male and female offspring. Further, the expression of leptin and 11 beta-hydroxysteroid dehydrogenase 1 genes were significantly increased in CrR offspring of both the sexes. Adipocytokine levels were altered in plasma and adipose tissue; circulating triglyceride and FFA levels were increased, albeit in female offspring only. Rehabilitation regimes did not correct body adiposity but restored the circulating levels of lipids and adipocytokines.. Chronic maternal Cr restriction increased body adiposity probably due to increased stress and altered lipid metabolism in WNIN rat offspring, which may predispose them to obesity and associated diseases in later life.

Topics: Adiponectin; Adipose Tissue; Animals; Body Weight; Chromium; Disease Models, Animal; Female; Leptin; Lipids; Male; Maternal Deprivation; PPAR gamma; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Inbred Strains; Reverse Transcriptase Polymerase Chain Reaction; RNA, Ribosomal, 18S

Overweight and obesity are rapidly expanding health problems in children and adolescents. Obesity is associated with greater bone mineral content that might be expected to protect against fracture, which has been observed in adults. Paradoxically, however, the incidence of bone fractures has been found to increase in overweight and obese children and adolescents. Prior studies have shown some reduced mechanical properties as a result of high-fat diet (HFD) but do not fully address size-independent measures of mechanical properties, which are important to understand material behavior. To clarify the effects of HFD on the mechanical properties and microstructure of bone, femora from C57BL/6 mice fed either a HFD or standard laboratory chow (Chow) were evaluated for structural changes and tested for bending strength, bending stiffness and fracture toughness. Here, we find that in young, obese, high-fat fed mice, all geometric parameters of the femoral bone, except length, are increased, but strength, bending stiffness, and fracture toughness are all reduced. This increased bone size and reduced size-independent mechanical properties suggests that obesity leads to a general reduction in bone quality despite an increase in bone quantity; yield and maximum loads, however, remained unchanged, suggesting compensatory mechanisms. We conclude that diet-induced obesity increases bone size and reduces size-independent mechanical properties of cortical bone in mice. This study indicates that bone quantity and bone quality play important compensatory roles in determining fracture risk.

Topics: Animals; Biomechanical Phenomena; Body Composition; Bone and Bones; Bone Density; Diet; Dietary Fats; Disease Models, Animal; Glucose Tolerance Test; Insulin-Like Growth Factor I; Leptin; Male; Mice; Microscopy, Electron, Scanning; Microscopy, Electron, Transmission; Obesity; Tomography, X-Ray Computed

Obesity is widely recognized as cause of metabolic syndrome and cardiovascular disease. It is provoked by imbalance between the spending and consumption of energy associated with a chronic inflammatory condition due to excessive storage of fat tissue. Obese patients have an impaired inflammatory profile that contributes to the development of vascular complications, with fat tissue being partially responsible for controlling both processes: energy balance (through PPAR) and inflammatory condition (through inflammatory markers). White adipose tissue produces cytokines (IL-6, TNF-α, resistin, adiponectin, etc.) and participates in a broad spectrum of processes. Recently, glycine has been reported to have anti-inflammatory properties which reduce TNF-α and IL-6 levels and increase adiponectin in 3T3-L1 adipocytes and in fat tissue of obese mice. In this study, the possible regulatory role of glycine on some factors involved in storage and energy burning (PPAR-γ, PPAR-α, PPAR-δ and UCP-2) was analyzed in lean and monosodium glutamate-induced obese mice (MSG/Ob mice). Glycine clearly increased fat tissue PPAR-γ expression in lean but not in MSG/Ob mice. The PPAR-γ and PPAR-α liver expression was repressed in both groups of mice, while the expression of PPAR-δ decreased only in lean mice. Interestingly, glycine treatment also suppressed the expression of UCP-2, TNF-α and IL-6 in lean mice, and increased adiponectin and insulin serum levels. In conclusion, glycine regulates the production of inflammatory cytokines through PPAR-γ. These results provide clues on glycine signaling mechanisms as an anti-inflammatory agent that might be useful for treatment of metabolic and vascular complications associated to inflammation in obesity.

Topics: Adipose Tissue; Animals; Anti-Inflammatory Agents; Cytokines; Disease Models, Animal; Energy Metabolism; Glycine; Insulin; Interleukin-6; Ion Channels; Leptin; Mice; Mitochondrial Proteins; Obesity; Peroxisome Proliferator-Activated Receptors; Reverse Transcriptase Polymerase Chain Reaction; Sodium Glutamate; Tumor Necrosis Factor-alpha; Uncoupling Protein 2

To investigate the capacity of the adipokine leptin to promote angiogenesis by modulating the function of circulating angiogenic cells (CACs).. In vitro, leptin specifically promoted CAC adhesion to tubular endothelial structures and migration along outgrowing sprouts of endothelial cells. In vivo, stimulation of CACs with leptin increased their capacity to promote new vessel formation in the chorioallantoic membrane of chicken embryos and to improve neovascularization of ischemic murine hind limbs. These effects required the phosphorylation of alphavbeta5 integrins, which depended on the interaction of leptin with its receptor ObR, and on Janus kinase (JAK) 2- and phospholipase C (PLC) gamma-mediated activation of Src kinase. Protein tyrosine phosphatase 1B, a negative regulator of leptin signaling, was overexpressed in CACs from obese, hyperleptinemic individuals, and this was associated with insensitivity of CACs to the angiogenic effects of leptin. Weight loss (by 30+/-15 kg) normalized protein tyrosine phosphatase 1B expression in CACs and restored their responsiveness to leptin. A similar dose-dependent response was found after incubation of CACs from obese subjects with a protein tyrosine phosphatase 1B inhibitor ex vivo.. Our results point to the ObR-Src kinase-alphavbeta5 cross talk as a distinct novel component of the network of specific interactions between integrins and cytokine receptors in angiogenesis.

Topics: Animals; Antigens, CD34; Case-Control Studies; Cell Adhesion; Cell Movement; Chick Embryo; Chorioallantoic Membrane; Disease Models, Animal; Endothelial Cells; Enzyme Activation; Hindlimb; Humans; Ischemia; Janus Kinase 2; Leptin; Leukocyte Common Antigens; Leukocytes, Mononuclear; Male; Mice; Mice, Nude; Muscle, Skeletal; Neovascularization, Physiologic; Obesity; Phospholipase C gamma; Phosphorylation; Platelet Endothelial Cell Adhesion Molecule-1; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Receptors, Leptin; Receptors, Vitronectin; Recombinant Proteins; Signal Transduction; Spheroids, Cellular; src-Family Kinases; Transfection; Up-Regulation; Weight Loss

Adipose tissue is an important target for thyroid hormones (TH). However, the metabolism of TH in white adipose tissue is poorly characterized. Our objective was to describe possible changes in activities of TH-metabolizing enzymes in white adipose tissue, and the role of TH metabolism in the tissue during obesogenic treatment, caloric restriction and in response to leptin in mice. Activity of type I iodothyronine 5'-deiodinase (D1) in white fat was stimulated by a high-fat diet, which also increased plasma leptin levels, while brown adipose tissue D1 activity did not change. Caloric restriction decreased the activity of D1 in white fat (but not in the liver), reduced leptin levels, and increased the expression of stearoyl CoA desaturase 1 (SCD-1), a marker and mediator of the effect of leptin on tissue metabolism. Leptin injections increased D1 activity and down-regulated SCD-1 in white fat. Our results demonstrate changes in D1 activity in white adipose tissue under the conditions of changing adiposity, and a stimulatory effect of leptin on D1 activity in the tissue. These results suggest a functional role for D1 in white adipose tissue, with D1 possibly being involved in the control of adipose tissue metabolism and/or accumulation of the tissue.

Topics: Adipose Tissue, Brown; Adipose Tissue, White; Animal Nutritional Physiological Phenomena; Animals; Caloric Restriction; Disease Models, Animal; Gene Expression Regulation, Enzymologic; Injections, Subcutaneous; Iodide Peroxidase; Leptin; Mice; Mice, Inbred C57BL; Obesity; Recombinant Proteins; RNA, Messenger; Stearoyl-CoA Desaturase; Thyroid Hormones

Leptin, a pleiotropic hormone regulating food intake and metabolism, plays an important role in the regulation of inflammation and immunity. We previously demonstrated that serum leptin levels are profoundly increased in mice which received azoxymethane (AOM) and dextran sulfate sodium (DSS) as tumor-initiator and -promoter, respectively, in a colon carcinogenesis model. In this study, we attempted to address underlying mechanism whereby leptin is up-regulated in this rodent model. Five-week-old male ICR mice were given a single intraperitoneal injection of AOM (week 0), followed by 1% DSS in drinking water for 7 days. Thereafter, the weights of visceral fats and the serum concentration of leptin were determined at week 20. Of interest, the relative epididymal fat pad and mesenteric fat weights, together with serum leptin levels in the AOM and/or DSS-treated mice were markedly increased compared to that in untreated mice. In addition, leptin protein production in epididymal fat pad with AOM/DSS-treated mice was 4.7-fold higher than that of control. Further, insulin signaling molecules, such as protein kinase B (Akt), S6, mitogen-activate protein kinase/extracellular signaling-regulated kinase 1/2, and extracellular signaling-regulated kinase 1/2, were concomitantly activated in epididymal fat of AOM/DSS-treated mice. This treatment also increased the serum insulin and IGF-1 levels. Taken together, our results suggest that higher levels of serum insulin and IGF-1 promote the insulin signaling in epididymal fat and thereby increasing serum leptin, which may play an crucial role in, not only obesity-related, but also -independent colon carcinogenesis.

Topics: Animals; Azoxymethane; Carcinogens; Colitis; Colonic Neoplasms; Dextran Sulfate; Disease Models, Animal; Insulin; Insulin-Like Growth Factor I; Intra-Abdominal Fat; Leptin; Male; Mice; Mice, Inbred ICR; Signal Transduction

Early trauma contributes to psychosocial disorders later in life. An adverse early environment induced by maternal separation (MS) is known to alter behavioural and stress responses in rats. Palatable food dampens stress responses. We investigated the influence of palatable cafeteria high-fat diet (HFD) on behavioural responses following MS or non-handling (NH), versus 15min brief separation. After littering, Sprague-Dawley rats were exposed to short separation, S15 (15min), prolonged separation, S180 (180min) daily from postnatal days 2 to 14 or were non-handled. Pups were assigned to HFD or chow at weaning. We assessed depression and anxiety-like behaviour with sucrose preference test (SPT) and elevated plus maze (EPM) respectively, and measured hypothalamic CRH and hippocampal glucocorticoid receptor (GR) expression. S180 rats showed increased anxiety-and depression-like behaviours, with increased plasma corticosterone, hypothalamic CRH, and reduced hippocampal GR expression versus S15 rats. Similar effects were observed across gender. These were normalized by provision of HFD, with greater beneficial effects in males. S15 showed no benefit of HFD. NH female rats had less adverse impacts; HFD had beneficial impact on behaviour in NH males. Thus behavioural deficits and gene expression changes induced by early life stress were ameliorated by HFD. These results highlight the important place of palatable food in reducing central stress responses supporting the therapeutic value of 'comfort food'.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Animals; Anxiety; Corticosterone; Corticotropin-Releasing Hormone; Depression; Dietary Fats; Disease Models, Animal; Eating; Female; Handling, Psychological; Hippocampus; Hypothalamus; Insulin; Leptin; Male; Maternal Behavior; Maternal Deprivation; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Receptors, Glucocorticoid; Sex Characteristics; Time Factors

Obesity causes complex metabolic and endocrine changes that may lead to adverse outcomes, including hypogonadism. We herein studied the reproductive axis function in male rats under a high-fat diet and analyzed the impact of changes in glycosylation of pituitary LH on the bioactivity of this gonadotropin. Rats were fed with a diet enriched in saturated fat (20% of total calories) and euthanized on days 90 or 180 of diet. Long-term (180 days), high-fat feeding rats exhibited a metabolic profile compatible with insulin resistance and metabolic syndrome; they concomitantly showed decreased intrapituitary and serum LH concentrations, low serum testosterone levels, and elevated serum 17beta-estradiol concentrations. A fall in biological to immunological ratio of intrapituitary LH was detected in 180 days control diet-treated rats but not in high-fat-fed animals, as assessed by a homologous in vitro bioassay. Chromatofocusing of pituitary extracts yielded multiple LH charge isoforms; a trend towards decreased abundance of more basic isoforms (pH 9.99-9.0) was apparent in rats fed with the control diet for 180 days but not in those that were fed the diet enriched in saturated fat. It is concluded that long-term high-fat feeding alters the function of the pituitary-testicular axis, resulting in hypogonadotropic hypogonadism. The alterations in LH function found in these animals might be subserved by changes in hypothalamic GnRH output and/or sustained gonadotrope exposure to an altered sex steroid hormone milieu, representing a distinctly different regulatory mechanism whereby the pituitary attempts to counterbalance the effects of long-term obesity on reproductive function.

Topics: Animals; Blood Glucose; Dietary Fats; Disease Models, Animal; Estradiol; Glycosylation; Hydrogen-Ion Concentration; Insulin Resistance; Leptin; Luteinizing Hormone; Male; Metabolic Syndrome; Obesity; Pituitary Gland, Anterior; Protein Isoforms; Rats; Rats, Wistar; Reproduction; Testosterone; Triglycerides

The leptin-deficient ob/ob mice are insulin resistant and obese. However, the control of blood pressure in this model is not well defined. The goal of this study was to evaluate the role of leptin and of the renin-angiotensin system in the cardiovascular abnormalities observed in obesity using a model lacking leptin. To this purpose, we measured blood pressure in ob/ob and control animals by radiotelemetry combined with fast Fourier transformation before and after both leptin and enalapril treatment. Autonomic function was assessed pharmacologically. Blood pressure during daytime was slightly higher in the ob/ob compared to control mice, while no difference in heart rate was observed. Blood pressure response to trimetaphane and heart rate response to metoprolol were greater in ob/ob mice than in control littermates indicating an activated sympathetic nervous system. Heart rate response to atropine was attenuated. Baroreflex sensitivity and heart rate variability were blunted in ob/ob mice, while low frequency of systolic blood pressure variability was found increased. Chronic leptin replacement reduced blood pressure and reversed the impaired autonomic function observed in ob/ob mice. Inhibition of angiotensin-converting enzyme by enalapril treatment had similar effects, prior to the loss of weight. These findings suggest that the renin-angiotensin system is involved in the autonomic dysfunction caused by the lack of leptin in ob/ob mice and support a role of this interplay in the pathogenesis of obesity, hypertension, and metabolic syndrome.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Baroreflex; Disease Models, Animal; Fourier Analysis; Hypertension; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Peptidyl-Dipeptidase A; Renin-Angiotensin System

Acute leptin increase as well as endogenous hyperleptinemia evoked by high-fat diets (HF) activate fatty acid metabolism in nonadipose tissues. This supports the notion that hyperleptinemia is pivotal to prevent/delay steatosis during periods of positive energy balance. We have previously shown that long-term HF spares ectopic accumulation of lipids specifically in the miocardium. Because carnitine palmitoyltransferase I (CPT-I) allows mitochondrial uptake/oxidation of fatty acids, we have hypothesized that leptin drives cardiac CPT-I activity. In the current study, hyperleptinemia was induced in C57BL/6J mice either by exogenous leptin administration or by means of HF, and the ability of malonyl-coenzyme A (malonyl-CoA) (the main endogenous inhibitor of CPT-I) to inhibit cardiac CPT was analyzed. IC(50) values of malonyl-CoA were 8.1 +/- 1.5 micromol/liter in controls vs. 69.3 +/- 5.2 micromol/liter (P < 0.01) in leptin-treated mice. This effect was also observed in cardiac explants incubated with leptin and was blocked by triciribine, a compound shown to inhibit protein kinase B (Akt) phosphorylation (pAkt). In accordance, acute leptin evoked an increase of cardiac pAkt levels, which correlated with CPT sensitivity to malonyl-CoA. Otherwise, the inhibitory effect of malonyl-CoA was hindered in HF hyperleptinemic mice, and in this case, pAkt levels also correlated with CPT sensitivity to malonyl-CoA. Our data show that leptin reduces the sensitivity of cardiac CPT-I to malonyl-CoA and suggest the involvement of an Akt-related signaling pathway in this effect. This mechanism appears to be sensitive to both acute and chronic hyperleptinemia. We conclude that this action of leptin is pivotal to drive cardiac metabolism under situations associated to hyperleptinemia.

Topics: Animals; Carnitine O-Palmitoyltransferase; Dietary Fats; Disease Models, Animal; Heart Diseases; Leptin; Lipid Metabolism; Male; Malonyl Coenzyme A; Mice; Mice, Inbred C57BL; Myocardium; Phosphorylation; Proto-Oncogene Proteins c-akt; Ribonucleosides; STAT3 Transcription Factor; Triglycerides

Leptin, a key hormone in regulation of food intake and energy expenditure, exerts pleiotropic cytokine-like biological effects. Its role in gastric ulcer healing is unclear. In this study, we investigated the role of leptin in gastric ulcer healing.. Experimental gastric ulcer was induced by focal serosal application of acetic acid in leptin-deficient ob/ob mice and wild-type mice. Healing of gastric ulcer and angiogenesis in the ulcer tissue was evaluated.. Gastric ulcer healing was delayed in ob/ob mice compared with that in wild-type mice. The impairment of ulcer healing observed in ob/ob mice was characterized by reduced expression of vascular endothelial growth factor (VEGF) and impairment of angiogenesis. Systemic administration of leptin to ob/ob mice reversed the impairment of gastric ulcer healing; this reversal was accompanied by an increase in VEGF expression and angiogenesis. Although mRNA for leptin was not expressed in normal gastric mucosa and not induced in ulcerous tissue, leptin receptor expression was markedly upregulated in gastric epithelial cells at ulcer margins, and was colocalized with VEGF.. These findings suggest that leptin promotes gastric ulcer healing by induction of angiogenesis in the granular tissue of ulcers via upregulation of VEGF expression.

Topics: Animals; Blotting, Western; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Neovascularization, Physiologic; Reverse Transcriptase Polymerase Chain Reaction; Statistics, Nonparametric; Stomach Ulcer; Up-Regulation; Vascular Endothelial Growth Factor A; Wound Healing

Inflammatory bowel disease that begins prior to puberty frequently causes a delay in puberty resulting in losses of growth, bone mineralization, and self esteem. A major cause of this pubertal delay is likely due in part to the effect of decreased levels of leptin on the function of the hypothalamic-pituitary-gonadal axis, though systemic inflammation is also thought to play a role.. To investigate further whether low leptin levels alone were responsible for delayed puberty in colitis, we induced colitis in 23-day-old female mice using 3% dextran sodium sulfate (DSS), resulting in 10 days of worsening colitis. These mice were compared to controls that were free-feeding and food-restricted (FR) mice that were given only enough food to keep them the same weight as the DSS group. All groups were followed for the timing of vaginal opening until 33 days old, when they were euthanized and their serum collected.. DSS-treated mice exhibited later timing of vaginal opening relative to both of the other groups, as well as increased colonic inflammation by cytology and increased serum levels of interleukin (IL)-6 and tumor necrosis factor(TNF)-alpha. The difference in the timing of vaginal opening between the DSS and FR groups occurred despite equivalent serum levels of leptin between the groups and despite an increase in corticosterone in the FR group relative to both of the other groups.. We conclude that DSS colitis causes delay in puberty in sexually immature mice beyond what would be expected from decreases in weight and leptin levels.

Topics: Animals; Colitis; Corticosterone; Dextran Sulfate; Disease Models, Animal; Female; Hypothalamo-Hypophyseal System; Interleukin-6; Leptin; Mice; Mice, Inbred C57BL; Pituitary-Adrenal System; Puberty, Delayed; Tumor Necrosis Factor-alpha

Trodusquemine (MSI-1436) causes rapid and reversible weight loss in genetic models of obesity. To better predict the potential effects of trodusquemine in the clinic, we investigated the effects of trodusquemine treatment in a murine model of diet-induced obesity (DIO). Trodusquemine suppressed appetite, reduced body weight (BW) in a fat-specific manner, and improved plasma insulin and leptin levels in mice. Screening assays revealed that trodusquemine selectively inhibited protein-tyrosine phosphatase 1B (PTP1B), a key enzyme regulating insulin and leptin signaling. Trodusquemine significantly enhanced insulin-stimulated tyrosine phosphorylation of insulin receptor (IR) beta and STAT3, direct targets of PTP1B, in HepG2 cells in vitro and/or hypothalamic tissue in vivo. These data establish trodusquemine as an effective central and peripheral PTP1B inhibitor with the potential to elicit noncachectic fat-specific weight loss and improve insulin and leptin levels.

Topics: Animals; Appetite; Body Composition; Cholestanes; Diet; Disease Models, Animal; Hep G2 Cells; Humans; Hypolipidemic Agents; Hypothalamus; Insulin; Leptin; Male; Mice; Mice, Inbred AKR; Mice, Obese; Obesity; Phosphorylation; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Receptor, Insulin; Spermine; STAT3 Transcription Factor; Weight Loss

Topics: Androstadienes; Animals; Cell Division; Disease Models, Animal; Enzyme Inhibitors; Humans; Leptin; Mice; Obesity; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Wortmannin

Pro-inflammatory cytokines, such as tumour necrosis factor (TNF)-alpha, are known to be involved in the establishment of insulin resistance. Insulin resistance plays a key role in the development of obesity-related pathologies, such as type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). The state of chronic inflammation associated with obesity led us to hypothesize that TNF-alpha blockade may have an effect on experimentally obese animals.. We studied the effects of thalidomide, an immunosuppressant and anti-TNF-alpha drug, on hepatic alterations that were induced by a high-fat diet (HFD) in mice.. Obesity was induced in Swiss mice using a HFD for 12 weeks. Thalidomide-treated animals received thalidomide i.p. (100 mg/kg/day, 10 days). Glucose, aspartate aminotransferases and alanine aminotransferases levels were assessed in the blood. Insulin and glucose tolerance tests were performed. The liver was excised for histological, triglyceride, gene and protein expression analyses.. We found improvements in both the basal glucose blood levels and the response to insulin administration in the treated animals. The molecular analysis of insulin signalling revealed a restoration of the hepatic insulin receptor substrate (IRS)-1 and AKT phosphorylation. The hepatic expression of TNF-alpha was inhibited and the levels correlated with a significant reduction in the steatosis area. Other hepatic inflammatory markers, such as iNOS and suppressor of cytokine signalling (SOCS-3), were also reduced.. We suggest that immunosuppressant drugs that target TNF-alpha and that may also contribute to reductions in the inflammatory markers that are associated with obesity could be a therapeutic option in NAFLD and type 2 diabetes.

Topics: Animals; Biopsy, Needle; Blood Glucose; Diet; Dietary Fats; Disease Models, Animal; Fatty Liver; Immunohistochemistry; Immunosuppressive Agents; Inflammation Mediators; Insulin Resistance; Interleukin-6; Leptin; Liver; Liver Function Tests; Male; Mice; Nitric Oxide Synthase; Obesity; Probability; Random Allocation; Reference Values; Reverse Transcriptase Polymerase Chain Reaction; RNA; Thalidomide; Treatment Outcome; Tumor Necrosis Factor-alpha

Cholecystokinin (CCK) is a satiation peptide released during meals in response to lipid intake; it regulates pancreatic digestive enzymes that are required for absorption of nutrients. We proposed that mice with a disruption in the CCK gene (CCK knockout [CCK-KO] mice) that were fed a diet of 20% butter fat would have altered fat metabolism.. We used quantitative magnetic resonance imaging to determine body composition and monitored food intake of CCK-KO mice using an automated measurement system. Intestinal fat absorption and energy expenditure were determined using a noninvasive assessment of intestinal fat absorption and an open circuit calorimeter, respectively.. After consuming a high-fat diet for 10 weeks, CCK-KO mice had reduced body weight gain and body fat mass and enlarged adipocytes, despite the same level of food intake as wild-type mice. CCK-KO mice also had defects in fat absorption, especially of long-chain saturated fatty acids, but pancreatic triglyceride lipase did not appear to have a role in the fat malabsorption. Energy expenditure was higher in CCK-KO than wild-type mice, and CCK-KO mice had greater oxidation of carbohydrates while on the high-fat diet. Plasma leptin levels in the CCK-KO mice fed the high-fat diet were markedly lower than in wild-type mice, although levels of insulin, gastric-inhibitory polypeptide, and glucagon-like peptide-1 were normal.. CCK is involved in regulating the metabolic rate and is important for lipid absorption and control of body weight in mice placed on a high-fat diet.

Topics: Adiposity; Animals; Biomarkers; Butter; Calorimetry; Cholecystokinin; Dietary Fats; Disease Models, Animal; Eating; Energy Metabolism; Fatty Acids; Intestinal Absorption; Leptin; Lipase; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Obesity; Time Factors; Weight Gain

To establish nonalcoholic fatty liver disease (NAFLD) in young rats, and to investigate the metabolic characteristics of these rats.. Fifteen male and fifteen female SD rats of 3 weeks old were randomly divided into three groups, normal group (N), 20% high fat group (HF1) and 30% high fat group (HF2). All the rats were fed under Specific pathogen Free (SPF) condition for 6 weeks and executed at the end of the 6th week. Body length and weight of each rat as well as their liver weight were measured for calculating Liver Index (LI). ALT, AST, TG, TC, INS, Glu and HOMA-IR in the blood were measured. Liver tissue homogenate was prepared for detecting TG level. The liver section was stained with HE and oil red. The expression of SPEBP-1 and leptin in liver was detected by immunostaining.. The typical pathological change of NAFLD was found in the rats of HF groups. In HF2 group, no rats died during the experiment and the degree of fat degeneration is homogeneous. Comparing with those in N group, TC (mmol/L), liver TG (mmol/L) and ALT levels in HF2 group were significantly elevated (2.50+/-0.39 vs 1.82+/-0.43, P less than 0.01; 25.38+/-13.29 vs 12.09+/-9.59, P less than 0.01 and 69.80+/-18.22 vs 48.00+/-10.45, P less than 0.01, respectively). Comparing with those in N group, TG level in HF1 group was significantly decreased (0.17+/-0.10 vs 0.32+/-0.12, P less than 0.05), Glu level in HF1 group was significantly elevated (12.33+/-3.48 vs 8.13+/-2.53, P less than 0.05). There were no significant difference between the results of AST, INS and HOMA-IR among the groups. The expression level of SREBP-1 and leptin increased in HF groups.. NAFLD can be induced by 30% high-fat feeding for 6 weeks in young rats, high-fat feeding induces the expression of SREBP-1 and leptin expression and fat synthesis.

Topics: Animals; Blood Glucose; Body Mass Index; Cholesterol; Dietary Fats; Disease Models, Animal; Fatty Liver; Female; Immunohistochemistry; Insulin; Insulin Resistance; Leptin; Liver; Male; Non-alcoholic Fatty Liver Disease; Random Allocation; Rats; Rats, Sprague-Dawley; Sterol Regulatory Element Binding Protein 1; Triglycerides

The metabolic syndrome (MS) has become an epidemiological problem in Western countries. We developed a diet-induced obese rat model that mimics all the symptoms of MS in humans, but whose insulin resistance, hyperphagia and hyperleptinemia are caused by nutrition rather than genetic modifications.. Spontaneously hypertensive rats (SHR) were allowed for 12 weeks to choose between a cafeteria diet (CD, 20.3 kJ/g) and standard rat chow (11.7 kJ/g). Controls received rat chow.. Body weight (BW) exceeded control levels when SHR were fed with CD. The increase in BW was attributed to enhanced energy intake. The abundance of abdominal fat as well as the plasma levels of leptin and triglycerides increased concomitant with glucose, insulin and C-peptide. This prediabetic condition was further confirmed by a markedly increased insulin response following glucose challenge and by impaired glucose utilization after insulin tolerance tests.. Increases in food intake and BW despite hyperleptinemia indicate leptin resistance following CD feeding. CD-fed SHR feature leptin and insulin resistance, hypertension and obesity, thus mimicking the situation of MS patients. As such, our model is more suitable than the genetically modified rat models used to study human MS.

Topics: Abdominal Fat; Animals; Biomarkers; Blood Glucose; Blood Pressure; Body Weight; C-Peptide; Diet; Disease Models, Animal; Energy Intake; Heart Rate; Hyperphagia; Insulin; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Obesity; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Triglycerides

Male C57BL/6J mice (25 days of age) were fed either a low-fat diet (10% kcal from fat) (LF) or a high-fat diet (45% kcal from fat) (HF45) for a period of 72 days. Blueberry juice or purified blueberry anthocyanins (0.2 or 1.0 mg/mL) in the drinking water were included in LF or HF45 treatments. Sucrose was added to the drinking water of one treatment to test if the sugars in blueberry juice would affect development of obesity. Total body weights (g) and body fat (%) were higher and body lean tissue (%) was lower in the HF45 fed mice compared to the LF fed mice after 72 days, but in mice fed HF45 diet plus blueberry juice or blueberry anthocyanins (0.2 mg/mL), body fat (%) was not different from those mice fed the LF diet. Anthocyanins (ACNs) decreased retroperitoneal and epididymal adipose tissue weights. Fasting serum glucose concentrations were higher in mice fed the HF45 diet. However, it was reduced to LF levels in mice fed the HF45 diet plus 0.2 mg of ACNs/mL in the drinking water, but not with blueberry juice. beta cell function (HOMA-BCF) score was lowered with HF45 feeding but returned to normal levels in mice fed the HF45 diet plus purified ACNs (0.2 mg/mL). Serum leptin was elevated in mice fed HF45 diet, and feeding either blueberry juice or purified ACNs (0.2 mg/mL) decreased serum leptin levels relative to HF45 control. Sucrose in drinking water, when consumption was restricted to the volume of juice consumed, produced lower serum leptin and insulin levels, leptin/fat, and retroperitoneal and total fat (% BW). Blueberry juice was not as effective as the low dose of anthocyanins in the drinking water in preventing obesity. Additional studies are needed to determine factors responsible for the differing responses of blueberry juice and whole blueberry in preventing the development of obesity.

Topics: Adipose Tissue; Animals; Anthocyanins; Beverages; Blood Glucose; Blueberry Plants; Dietary Fats; Disease Models, Animal; Humans; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Plant Extracts

To study the effects and role of leptin pretreatment and ischemic preconditioning (IPC) on the reduction of myocardial ischemia/reperfusion injury (MIRI) in mouse.. Thirty-six male C57BL/6 mice were randomized into five groups: (1)sham operation group (n=12); (2) brief ischemia/reperfusion (I/R) treatment group (n=6), in which the mice were subjected to three cycles of a 3-minute regional ischemia followed by a 5-minute reperfusion (I/R cycle); (3) MIRI group (n=6), in which MIRI was established in the mice by blocking anterior descending branch of left coronary artery for 30 minutes, followed by 120 minutes reperfusion; (4) IPC group (n=6), in which three I/R cycles were performed on the mice followed by the MIRI protocol; (5) leptin pretreatment group (leptin group, n=6), in which 50 microg/kg of leptin was injected intraperitoneally to the mice 30 minutes before myocardial ischemia. From 6 mice of the sham operation group and from the mice of brief I/R group, serum samples were collected at different time points (0, 5, 30 and 120 minutes) after reperfusion to measure changes in serum leptin level. From the rest of the mice, blood and heart samples were harvested at 120 minutes after reperfusion to analyze the myocardial function and infarct size, leptin, myeloperoxidase (MPO), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) levels.. IPC procedure resulted in an increase in serum leptin level shortly after reperfusion. The leptin level increased significantly than that of sham operation group [(6.24+/-2.34) microg/L vs. (1.35+/-0.45) microg/L] at 5 minutes after I/R, and reached the peak value of (12.36+/-1.33) microg/L at 30 minutes after I/R. Then it gradually decreased to its original (0 minute after reperfusion) value [(1.96+/-1.33) microg/L] at 120 minutes after I/R. There was no difference compared with sham operation group [(1.16+/-0.25) microg/L, P>0.05]. Administration of leptin or IPC before MIRI significantly reduced infarct size [(11.50+/-2.26)%, (9.00+/-1.90)% vs. (37.00+/-2.53)%], the myocardial leptin levels [(8.36+/-3.42) microg/g, (6.71+/-2.03) microg/g vs. (15.51+/-3.92) microg/g], MPO [(17.10+/-3.95) microg/g, (13.33+/-2.88) microg/g vs. (30.83+/-4.06) microg/g], serum leptin levels [(15.03+/-1.87) microg/L, (11.85+/-0.72) microg/L vs. (29.55+/-2.31) microg/L], serum TNF-alpha [(35.10+/-10.12) ng/L, (27.04+/-5.18) ng/L vs. (81.34+/-14.20) ng/L], and IL-6 levels [(167.39+/-72.83) ng/L, (149.13+/-37.69) ng/L vs. (477.30+/-29.09) ng/L, all P<0.01].. Pretreatment using leptin results in preconditioning-like tolerance against infarction dysfunction. This cardiac protection effect is mediated, in part, via suppression of inflammation in preconditioned myocardium.

Topics: Animals; Disease Models, Animal; Interleukin-6; Ischemic Preconditioning, Myocardial; Leptin; Male; Mice; Mice, Inbred C57BL; Myocardial Reperfusion Injury; Myocardium; Tumor Necrosis Factor-alpha

The goal of the current was to elucidate if treatment with gonadotrophins and leptin can circumvent infertility in obese mice and to establish whether reproductive effects of leptin are influenced at the hypothalamus-hypophysis or ovarian level by using a leptin deficient mouse model of obesity/type 2 diabetes (ob/ob) treated with leptin. The ovulatory response and the fertilization success were compared with the results obtained in ob/ob dams pretreated with a gonadotrophin-replacement therapy or in two groups (ob/ob and wild-type) of control non-pretreated females. The number of corpora lutea was significantly lower in control ob/ob mice than in wild-type dams. Treatment with gonadotrophin-replacement therapy did not increase significantly the ovulation rate in ob/ob, but the administration of leptin-replacement treatment allowed the authors to obtain a number of corpora lutea and oocytes/zygotes similar to those obtained in wild-type females. Furthermore, the leptin supply succeeded in producing fertilized zygotes, although in a lower number than found in the wild-type control. Thus, the hypogonadotrophic state in obese mice may be circumvented by the administration of a gonadotrophin-replacement therapy combined with a protocol for controlled ovarian stimulation, but fertile ovulations are only obtained after applying leptin-replacement therapy. Current results strongly support the existence of direct local effects of leptin on the ovary.

Topics: Animals; Diabetes Mellitus, Experimental; Disease Models, Animal; Estrus Synchronization; Female; Injections, Subcutaneous; Leptin; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Obese; Obesity; Ovary; Ovulation Induction; Pregnancy

Recent studies suggest that hyperinsulinemia and insulin resistance are linked to Alzheimer's disease (AD). In this study, we used Tg2576 transgenic (Tg) mice, a widely used transgenic mouse model for AD, to explore the relationship between increased amyloid beta-peptide (Abeta) and insulin resistance. When fed a high-fat diet (HFD), Tg mice developed obesity and insulin resistance at 16 wk of age. Furthermore, HFD-fed Tg mice displayed abnormal feeding behavior and increased caloric intake with time. Although caloric intake of HFD-fed Tg mice was similar to that of normal diet-fed Tg or wild-type mice during 4 to 8 wk of age, it increased sharply at 12 wk, and went up further at 16 wk, which paralleled changes in the level of Abeta40 and Abeta42 in the brain of these mice. Limiting food intake in HFD-fed Tg mice by pair-feeding a caloric intake identical with that of normal diet-fed mice completely prevented the obesity and insulin intolerance of HFD-fed Tg mice. The hypothalamus of HFD-fed Tg mice had a significant decrease in the expression of the anorexigenic neuropeptide, brain-derived neurotrophic factor, at both the mRNA and protein levels. These findings suggest that the increased Abeta in the brain of HFD-fed Tg2576 mice is associated with reduced brain-derived neurotrophic factor expression, which led to abnormal feeding behavior and increased food intake, resulting in obesity and insulin resistance in these animals.

Topics: Adipose Tissue; Alzheimer Disease; Amyloid beta-Peptides; Analysis of Variance; Animals; Blotting, Western; Brain-Derived Neurotrophic Factor; Dietary Fats; Disease Models, Animal; Eating; Energy Intake; Fluorescent Antibody Technique; Ghrelin; Glucose Tolerance Test; Hypothalamus; Insulin Resistance; Leptin; Mice; Motor Activity; Obesity; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Satiety Response; Time Factors

Cholecystokinin (CCK) acutely synergizes with amylin to suppress food intake in lean mice. To extend on these findings, the present studies sought to identify neural correlates for the interaction of amylin and CCK, as well as further understand the therapeutic potential of CCK-based combinations in obesity. First, c-Fos activation was assessed in various brain nuclei after a single intraperitoneal injection of amylin (5microg/kg) and/or CCK (5microg/kg). Amylin and CCK additively increased c-Fos within the area postrema (AP), predominantly in noradrenergic (e.g., dopamine-beta-hydroxylase-containing) cells. Next, amylin (100 or 300microg/kg/d) and/or CCK (100 or 300microg/kg/d) were subcutaneously infused for 7days in diet-induced obese (DIO) rats. Amylin treatment of DIO rats for 7days induced significant body weight loss. CCK, while ineffective alone, significantly enhanced body weight loss when co-administered with the higher dose of amylin. Finally, the addition of CCK (300microg/kg/d) to leptin (125microg/kg/d), and to the combination of amylin (50microg/kg/d) and leptin (125microg/kg/d), was also explored in DIO rats via sustained subcutaneous infusion for 14days. Infusion of amylin/leptin/CCK for 14days exerted significantly greater body weight loss, inhibition of food intake, and reduction in adiposity compared to amylin/leptin treatment alone in DIO rats. However, co-infusion of CCK and leptin was an ineffective weight loss regimen in this model. Whereas CCK agonism alone is ineffective at eliciting or maintaining weight loss, it durably augmented the food intake and body weight-lowering effects of amylin and amylin/leptin in a relevant disease model, and when combined with amylin, cooperatively activated neurons within the caudal brainstem.

Topics: Amyloid; Analysis of Variance; Animals; Appetite Depressants; Area Postrema; Body Weight; Cholecystokinin; Disease Models, Animal; Dopamine beta-Hydroxylase; Dose-Response Relationship, Drug; Drug Therapy, Combination; Eating; Islet Amyloid Polypeptide; Leptin; Male; Neurons; Obesity; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Weight Loss

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

Low birth weight and catch-up growth predict increased adiposity in children and adults. This may be due in part to leptin resistance, as adults who were born small exhibit increased plasma leptin concentration relative to adiposity. Placental restriction (PR), a major cause of intrauterine growth restriction, reduces size at birth and increases feeding activity and adiposity by 6 wk in sheep. We hypothesized that PR would increase plasma leptin concentration and alter its relationship with feeding activity and adiposity in young lambs. Body size, plasma leptin, feeding activity, adiposity, leptin, and leptin receptor gene expression in adipose tissue were measured (12 control, 12 PR). PR reduced size at birth and increased adiposity. Plasma leptin concentration decreased with age, but to a lesser extent after PR and correlated positively with adiposity similarly in control and PR. PR increased plasma leptin concentration and perirenal adipose tissue leptin expression. Feeding activity correlated negatively with plasma leptin concentration in controls, but positively after PR. PR increases adipose tissue leptin expression and plasma leptin concentration, however, this increased abundance of peripheral leptin does not inhibit feeding activity (suckling event frequency), suggesting PR programs resistance to appetite and energy balance regulation by leptin, leading to early onset obesity.

Topics: Adipose Tissue; Adiposity; Age Factors; Animals; Animals, Newborn; Animals, Suckling; Birth Weight; Blood Glucose; Disease Models, Animal; Fatty Acids, Nonesterified; Feeding Behavior; Female; Fetal Growth Retardation; Hyperphagia; Insulin; Lactation; Leptin; Male; Placental Insufficiency; Pregnancy; Receptors, Leptin; Sheep; Up-Regulation

Hepatic stellate cell (HSC) activation is a key cellular event in the development of liver fibrosis. Peroxisome proliferator-activated receptor-gamma (PPARgamma) has been shown to function as a key transcription regulator linked to suppressing HSC activation. Compelling evidence indicates that leptin plays a unique role in the development of liver fibrosis. The aim of this study is to investigate the in vivo impact of leptin on PPARgamma expression in HSCs in the model of TAA-induced liver damage. The results of the present study provide the first in vivo evidence that leptin might exert an inhibitory effect on PPARgamma protein expression in HSCs, which is mediated at least through leptin-induced ERK1/2 activation. Long-form leptin receptor is involved in leptin-induced ERK1/2 activation and the subsequent decline in PPARgamma expression in HSCs in the model. Furthermore, the inhibitory effect of leptin on PPARgamma protein expression enhances HSC activation and proliferation in this model. The in vivo findings from this report might provide additional insights into the mechanisms underlying the profibrogenic action of leptin in liver.

Topics: Animals; Cell Proliferation; Disease Models, Animal; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation; Hepatic Stellate Cells; Leptin; Liver Diseases; Male; Mice; Mice, Inbred C57BL; Mice, Obese; PPAR gamma; Random Allocation; Rats; Receptors, Leptin

We have previously reported anti-amyloidogenic effects of leptin using in vitro and in vivo models and, more recently, demonstrated the ability of leptin to reduce tau phosphorylation in neuronal cells. The present study examined the efficacy of leptin in ameliorating the Alzheimer's disease (AD)-like pathology in 6-month old CRND8 transgenic mice (TgCRND8) following 8 weeks of treatment. Leptin-treated transgenic mice showed significantly reduced levels of amyloid-beta (Abeta){1-40} in both brain extracts (52% reduction, p= 0.047) and serum (55% reduction, p= 0.049), as detected by ELISA, and significant reduction in amyloid burden (47% reduction, p=0.041) in the hippocampus, as detected by immunocytochemistry. The decrease in the levels of Abeta in the brain correlated with a decrease in the levels of C99 C-terminal fragments of the amyloid-beta protein precursor, consistent with a role for beta -secretase in mediating the effect of leptin. In addition, leptin-treated TgCRND8 mice had significantly lower levels of phosphorylated tau, as detected by AT8 and anti-tau-Ser{396} antibodies. Importantly, after 4 or 8 weeks of treatment, there was no significant increase in the levels of C-reactive protein, tumor necrosis factor-alpha, and cortisol in the plasma of leptin-treated TgCRND8 animals compared to saline-treated controls, indicating no inflammatory reaction. These biochemical and pathological changes were correlated with behavioral improvements, as early as after 4 weeks of treatment, as recorded by a novel object recognition test and particularly the contextual and cued fear conditioning test after 8 weeks of treatment. Leptin-treated TgCRND8 animals significantly outperformed saline-treated littermates in these behavioral tests. These findings solidly demonstrate the potential for leptin as a disease modifying therapeutic in transgenic animals of AD, driving optimism for its safety and efficacy in humans.

Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Animals; C-Reactive Protein; Conditioning, Psychological; Disease Models, Animal; Fear; Hippocampus; Immunohistochemistry; Infusion Pumps, Implantable; Leptin; Memory Disorders; Mice; Mice, Transgenic; Neurons; Phosphorylation; Recognition, Psychology; tau Proteins

sleep deeply affects cardiac autonomic control, the impairment of which is associated with cardiovascular mortality. Obesity entails increased cardiovascular risk and derangements in sleep and cardiac autonomic control. We investigated whether cardiac autonomic control is impaired during sleep in ob/ob mice with morbid obesity caused by congenital leptin deficiency.. indexes of cardiac autonomic control based on spontaneous cardiovascular fluctuations were compared between ob/ob and lean wild-type (+/+) mice during wakefulness, non-rapid eye movement sleep (NREMS), and rapid eye movement sleep (REMS).. N/A PATIENTS OR PARTICIPANTS: 7 ob/ob and 11 +/+ male mice.. instrumentation with electrodes for sleep recordings and a telemetric transducer for measuring blood pressure and heart period.. In ob/ob mice, the variability of heart period and cardiac baroreflex sensitivity (sequence technique) were significantly lower than in +/+ mice during each wake-sleep state. The vagal modulation of heart period was significantly weaker in ob/ob than in +/+ mice during NREMS and REMS. In ob/ob mice, the cross-correlation function between heart period and blood pressure suggested that the baroreflex contribution to cardiac control was lower than in +/+ mice during wakefulness and NREMS, whereas the contribution of central autonomic commands was lower than in +/+ mice during NREMS and REMS.. These data indicate a dysregulation of cardiac autonomic control during sleep in ob/ob mice. Ob/ob mice may represent a useful tool to understand the molecular pathways that lead to cardiac autonomic dysregulation during sleep in obesity.

Topics: Animals; Autonomic Nervous System; Baroreflex; Blood Pressure; Disease Models, Animal; Electrocardiography; Heart; Heart Rate; Leptin; Male; Mice; Obesity; Signal Processing, Computer-Assisted; Sleep Stages; Sleep, REM; Vagus Nerve; Wakefulness

Epidemiological and experimental studies have associated development of metabolic syndrome with stressful events (nutritional, hormonal, or environmental) in early life. This phenomenon is known as programing and changes in adipokines levels in early life, especially leptin, seem to be involved with its development. We have shown that neonatal hyperleptinemia on lactation programs for leptin resistance, hyperthyroidism, and higher corticosterone and catecholamines levels with cardiovascular consequences. In the present study, we evaluated the effect of hyperleptinemia during lactation on the glucose and lipid metabolism and liver morphology of adult rats, which were saline or leptin-treated (8 microg/100 g of body weight) daily, for the first 10 days of life. Leptin group had lower body mass during treatment, but higher body mass and hyperleptinemia at adulthood, without difference in fat mass. We showed that the probable source of hyperleptinemia is the higher leptin content in the subcutaneous adipose tissue. The programed rats showed hyperinsulinemia and hypoadiponectinemia with higher expression of the hypothalamic Suppressor of Cytokine Signaling 3 (SOCS3), suggesting insulin resistance. Besides, they presented higher liver glycogen and hypertriglyceridemia. We also observed liver microsteatosis in the leptin-programed adult rats. Our data show that neonatal hyperleptinemia alters glucose metabolism, which seems to be partially compensated by the hyperinsulinemia. However, changes in the lipid metabolism are not compensated. It is probable that these changes induced by neonatal hyperleptinemia result from a selective tissue specific resistance both to insulin and leptin at adulthood, and the increase of SOCS3 may play an important role in this process.

Topics: Adipose Tissue; Animals; Disease Models, Animal; Fatty Liver; Female; Glucose; Humans; Lactation; Leptin; Lipid Metabolism; Liver; Male; Muscles; Rats; Rats, Wistar

Brain ischemia is associated with detrimental changes in energy production and utilization. Therefore, we hypothesized that leptin, an adipokynin hormone protecting against severe energy depletion, would reduce infarct volume and improve functional outcome after stroke. Male Sabra mice underwent permanent middle cerebral artery occlusion (PMCAO) by photothrombosis. Following initial dose-response and time-window experiments animals were treated with vehicle or leptin, were examined daily by a neurological severity score (NSS) and were sacrificed 72 hours after stroke. Infarct volume was determined and the expression of key genes involved in neuroprotection and survival including the cannabinoid receptors CB1, CB2 and TRPV1, SIRT-1, leptin receptor and Bcl-2 was quantified in the cortex. A separate group of mice were examined with the neurological severity scale 1, 24 and 48 hours and 1, 2 and 3 weeks after stroke, and were killed 3 weeks post stroke to examine metabolic status in the peri-infarct area. Leptin given at a dose of 1mg/kg intra-peritoneally 30 minutes after PMCAO significantly improved neurological disability and reduced infarct volume. Leptin treatment led to increased expression of CB2 receptor, TRPV1, SIRT-1 and leptin receptor and reduced expression of CB1 receptor. There was also a non-significant increase in Bcl-2 gene expression following leptin administration. These results suggest that leptin may be used for attenuating ischemic injury after stroke via induction of an anti-apoptotic state.

Topics: Analysis of Variance; Animals; Brain Infarction; Disability Evaluation; Disease Models, Animal; Dose-Response Relationship, Drug; Infarction, Middle Cerebral Artery; Leptin; Male; Mice; Receptor, Cannabinoid, CB2; Receptors, Leptin; Sirtuin 1; Time Factors; TRPV Cation Channels; Up-Regulation

Topics: Animals; Diabetes Mellitus, Type 1; Disease Models, Animal; Humans; Leptin; Mice

We investigated whether hypothalamic leptin alters beta-cell function and mass directly via the sympathetic nervous system (SNS) or indirectly as the result of altered insulin resistant states.. The 90% pancreatectomized male Sprague Dawley rats had sympathectomy into the pancreas by applying phenol into the descending aorta (SNSX) or its sham operation (Sham). Each group was divided into two sections, receiving either leptin at 300ng/kgbw/h or artificial cerebrospinal fluid (aCSF) via intracerebroventricular (ICV) infusion for 3h as a short-term study. After finishing the infusion study, ICV leptin (3mug/kg bw/day) or ICV aCSF (control) was infused in rats fed 30 energy % fat diets by osmotic pump for 4weeks. At the end of the long-term study, glucose-stimulated insulin secretion and islet morphometry were analyzed.. Acute ICV leptin administration in Sham rats, but not in SNSX rats, suppressed the first- and second-phase insulin secretion at hyperglycemic clamp by about 48% compared to the control. Regardless of SNSX, the 4-week administration of ICV leptin improved glucose tolerance during oral glucose tolerance tests and insulin sensitivity at hyperglycemic clamp, compared to the control, while it suppressed second-phase insulin secretion in Sham rats but not in SNSX rats. However, the pancreatic beta-cell area and mass were not affected by leptin and SNSX, though ICV leptin decreased individual beta-cell size and concomitantly increased beta-cell apoptosis in Sham rats.. Leptin directly decreases insulin secretion capacity mainly through the activation of SNS without modulating pancreatic beta-cell mass.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Disease Models, Animal; Glucose Clamp Technique; Glucose Tolerance Test; Injections, Intraventricular; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Leptin; Male; Rats; Rats, Sprague-Dawley; Sympathectomy, Chemical; Sympathetic Nervous System

The aim of this study was to determine the effect of the antioxidant vitamin E (VE) on adiponectin and leptin expression in obese rats. Thirty weaning male Sprague-Dawley rats were divided into three groups as follows: (1) a control group, fed with normal chow; (2) a diet-induced obesity group (DIO), fed with a high-fat diet and (3) an intervention group, fed with a high-fat diet supplemented with VE (350 mg/kg). After 10 weeks of being fed according to these group assignments, rats were weighed and euthanized. Blood and adipose tissues were then immediately collected; mRNA and protein levels of leptin and adiponectin were measured by realtime reverse transcription-polymerase chain reaction and Western blotting. Biomarkers of oxidative stress, including serum levels of 8-epi-prostaglandin-F(2)alpha (8-epi-PGF(2)alpha) and glutathione peroxidase activity, were also examined. Adiponectin and leptin levels were lower in the DIO group than in the control group. VE intervention increased the expression of both leptin and adiponectin (P values < 0.05). Association analysis showed that serum leptin levels correlated positively with body fat mass (r = 0.601, P < 0.05). Both serum leptin and adiponectin levels were associated with the presence of serum 8-epi-PGF2 alpha (leptin, r = 0.513, P < 0.05; adiponectin, r = -0.422, P < 0.05). Administration of VE decreases leptin and adiponectin expression in obese rats. This finding is consistent with the view that antioxidants can play an important role in the treatment of obesity-related diseases.

Topics: Adiponectin; Adipose Tissue; Animals; Antioxidants; Base Sequence; Biomarkers; Dietary Fats; Dinoprost; Disease Models, Animal; DNA Primers; Gene Expression; Glutathione Peroxidase; Leptin; Male; Obesity; Oxidative Stress; Rats; Rats, Sprague-Dawley; RNA, Messenger; Vitamin E; Weight Gain

Atherosclerosis is accelerated in people with systemic lupus erythematosus, and the presence of dysfunctional, pro-inflammatory high-density lipoproteins is a marker of increased risk. We developed a mouse model of multigenic lupus exposed to environmental factors known to accelerate atherosclerosis in humans - high-fat diet with or without injections of the adipokine leptin. BWF1 mice were the lupus-prone model; BALB/c were non-autoimmune controls. High-fat diet increased total serum cholesterol in both strains. In BALB/c mice, non-high-density lipoprotein cholesterol levels increased; they did not develop atherosclerosis. In contrast, BWF1 mice on high-fat diets developed increased quantities of high-density lipoproteins as well as elevated high-density lipoprotein scores, indicating pro-inflammatory high-density lipoproteins; they also developed atherosclerosis. In the lupus-prone strain, addition of leptin increased pro-inflammatory high-density lipoprotein scores and atherosclerosis, and accelerated proteinuria. These data suggest that environmental factors associated with obesity and metabolic syndrome can accelerate atherosclerosis and disease in a lupus-prone background.

Topics: Animals; Atherosclerosis; Diet; Dietary Fats; Disease Models, Animal; Female; Humans; Leptin; Lipoproteins, HDL; Lupus Erythematosus, Systemic; Metabolic Syndrome; Mice; Mice, Inbred BALB C; Mice, Inbred NZB; Obesity; Risk Factors

To design, manufacture and test a second generation leptin receptor (ObR) agonist glycopeptide derivative. The major drawback to current experimental therapies involving leptin protein is the appearance of treatment resistance. Our novel peptidomimetic was tested for efficacy and lack of resistance induction in rodent models of obesity and appetite reduction.. The glycopeptide containing two additional non-proteinogenic amino acids was synthesized by standard solid-phase methods. Normal mice were fed with peanuts until their blood laboratory data and liver histology showed typical signs of obesity but not diabetes. The mice were treated with the peptidomimetic at 0.02, 0.1 or 0.5 mg/kg/day intraperitoneally side-by-side with 0.1 mg/kg/day leptin for 11 days. After termination of the assay, the blood cholesterol and glucose amounts were measured, the liver fat content was visualized and quantified and the remaining mice returned to normal diet and were allowed to mate. In parallel experiments normal rats were treated intranasally with the glycopeptide at 0.1 mg/kg/day for 10 days.. The 12-residue glycosylated leptin-based peptidomimetic E1/6-amino-hexanoic acid (Aca) was designed to target a principal leptin/ObR-binding interface. E1/Aca induced leptin effects in ObR-positive cell lines at picomolar concentrations and readily crossed the blood-brain barrier (BBB) following intraperitoneal administration. The peptide initiated typical leptin-dependent signal transduction pathways both in the presence and absence of leptin protein. The peptide also reduced weight gain in mice fed with high-fat peanut diet in a dose-dependent manner. Obese mice receiving peptide E1/Aca at a 0.5 mg/kg/day dose lost weight, corresponding to a net 6.5% total body weight loss, while similar mice treated with leptin protein did not. Upon cessation of the weight loss treatment, several obesity-related pathologies (i.e. abnormal metabolic profile and liver histology as well as infertility) normalized in peptide-, but not leptin-treated, mice. Peptide E1/Aca added intranasally to growing normal rats decelerated normal weight gain corresponding to a net 6.8% net total body weight loss with statistical significance.. No resistance induction to peptide E1/Aca or toxicity in either obese or healthy rodents was observed, indicating the potential for widespread utility of the peptidomimetic in the treatment of leptin-deficiency disorders. We provide additional proof for the hypothesis that difficulties in current leptin therapies reside at the BBB penetration stage, and we document that by either glycosylation or intranasal peptide administration we can overcome this limitation.

Topics: Animals; Blood-Brain Barrier; Cell Proliferation; Disease Models, Animal; Fertility; Glycopeptides; Leptin; Mice; Mice, Obese; Obesity; Rats; Receptors, Leptin; Weight Loss

The individual's emotional state influences food intake in both humans and rodents. Moreover, specific cognitive processes regulating the salient aspects of food reward are also critical for ingestive behaviour. However, the molecular mechanisms underlying such influence remain unclear. Genetic mouse models thus are important tools in dissecting the molecular and pathophysiological processes which cause complex human diseases. Leptin, encoded by the ob gene, plays an important part in the energy homeostasis and is critical for the development of obesity.. In these studies, we assess the impact of leptin on behaviours relevant to anxiety and appetitive learning.. Anxiety-related behaviour was assessed in the light dark box and two tests of hyponeophagia. Spatial learning and behavioural flexibility by re-learning was assessed in an appetitive Y-maze task.. Leptin-deficient (ob/ob) mice displayed higher levels of anxiety-related behaviour in both anxiety tests. In the appetitive Y-maze task, leptin deficiency caused no deficit in learning or re-learning and acute restrained stress had no influence on the learning process.. These results emphasise that whilst leptin has previously been shown to modulate aversively motivated learning we found no difference between leptin-deficient mice and their controls in an appetitive learning task. Moreover, both groups showed behavioural flexibility under stressful conditions. On the other hand, leptin deficiency resulted in marked alterations in behaviours relevant to anxiety.

Topics: Animals; Anxiety; Appetitive Behavior; Body Weight; Choice Behavior; Disease Models, Animal; Feeding Behavior; Leptin; Male; Maze Learning; Mice; Mice, Obese; Obesity

Sepsis describes a complex clinical syndrome that results from an infection, setting off a cascade of systemic inflammatory responses that can lead to multiple organ failure and death. Leptin is a 16 kDa adipokine that, among its multiple known effects, is involved in regulating immune function. Here we demonstrate that leptin deficiency in ob/ob mice leads to higher mortality and more severe organ damage in a standard model of sepsis in mice [cecal ligation and puncture (CLP)]. Moreover, systemic leptin replacement improved the immune response to CLP. Based on the molecular mechanisms of leptin regulation of energy metabolism and reproductive function, we hypothesized that leptin acts in the CNS to efficiently coordinate peripheral immune defense in sepsis. We now report that leptin signaling in the brain increases survival during sepsis in leptin-deficient as well as in wild-type mice and that endogenous CNS leptin action is required for an adequate systemic immune response. These findings reveal the existence of a relevant neuroendocrine control of systemic immune defense and suggest a possible therapeutic potential for leptin analogs in infectious disease.

Topics: Animals; Bacteremia; Brain; Disease Models, Animal; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuroimmunomodulation; Neutrophils; Random Allocation; Receptors, Leptin; Sepsis

Panax notoginseng (Burk) F.H. Chen (Araliaceae) is a well-known and commonly used traditional Chinese herb for treatment of various diseases, such as hemostasis, edema and odynolysis.. Our aim was to investigate the mechanisms of anti-hyperglycemic and anti-obese effects of Panax notoginseng saponins (PNS) in KK-Ay mice, and explore the components in PNS for such effects.. KK-Ay mice received daily intraperitoneal injections of PNS 200mg/kg or vehicle for 30 days while ginsenoside Re 14 mg/kg, Rd 15 mg/kg, Rg1 40 mg/kg, Rb1 60 mg/kg and notoginsenoside R1 6 mg/kg for 12 days. Fasting blood glucose levels (FBGL), glucose tolerance (GT), serum insulin, leptin levels, body weight changes, food intake, adipose tissues and blood fat levels were measured at different time points.. The PNS group had significantly lower FBGL, improved GT and smaller body weight incremental percentage after the 30-day treatment. Additionally, Rb1 exhibited significant reduction of FBGL on day 12, and Re also exhibited a decreasing trend after the 12-day treatment.. PNS possess anti-hyperglycemic and anti-obese activities by improving insulin- and leptin sensitivity, and Rb1 is responsible for the anti-hyperglycemic effect among the five saponins in KK-Ay mice.

Topics: Adiposity; Animals; Anti-Obesity Agents; Biomarkers; Blood Glucose; Body Weight; Diabetes Mellitus; Disease Models, Animal; Eating; Glucose Tolerance Test; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Lipids; Male; Mice; Mice, Inbred C57BL; Panax notoginseng; Plant Roots; Saponins; Time Factors

The availability of useful animal models reflecting the human obesity syndrome is crucial in the search for novel compounds for the pharmacological treatment of obesity. In the current study, we have performed an extensive characterization of the obesity syndrome in a polygenetic animal model, namely the selectively bred diet-induced obese (DIO) and diet-resistant (DR) rat strains. We show that they constitute useful models of the human obesity syndrome. DIO and DR rats were fed either a high-energy (HE) or a standard chow (Chow) diet from weaning to 9 months of age. Metabolic characterization including blood biochemistry and glucose homeostasis was examined at 2, 3, 6, and 9 months of age. Furthermore, in 6-month-old HE-fed DIO rats, the anti-obesity effects of liraglutide and sibutramine were examined in a 28-day study. Only HE-fed DIO rats developed visceral obesity, hyperleptinemia, hyperinsulinemia, and dyslipidemia, and showed a worsening of glucose tolerance over time. In line with the hyperlipidemic profile, a severe hepatic fat infiltration was observed in DIO rats at 6 months of age. The effects of liraglutide and sibutramine were tested in 6-month-old DIO rats. Both compounds effectively reduced food intake and body weight in DIO rats. Liraglutide furthermore improved glucose tolerance when compared with sibutramine. Our data highlights the usefulness of a polygenetic animal model for screening of compounds affecting food intake, body weight, and glucose homeostasis. Furthermore, the results underscore the effectiveness of GLP-1 mimetics both as anti-diabetes and anti-obesity agents.

Topics: Analysis of Variance; Animals; Appetite Depressants; Blood Glucose; Cyclobutanes; Diet; Disease Models, Animal; Eating; Enzyme-Linked Immunosorbent Assay; Feeding Behavior; Glucagon-Like Peptide 1; Insulin; Insulin Resistance; Leptin; Liraglutide; Metabolic Syndrome; Obesity; Rats; Rats, Sprague-Dawley

Topics: Animals; Blood Pressure; Cardiovascular Physiological Phenomena; Disease Models, Animal; Hypertension; Leptin; Melanocortins; Mice; Obesity; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Rats; Thyrotropin-Releasing Hormone

To investigate the effect of nutritional recovery with rice bran on energy balance, leptin and insulin levels.. Weaned Wistar rats were fed on a 17% (Control - C) or 0.5% (Aproteic - A) protein diet for 12d. After this, rats were kept on a C diet (C) or recovered with control (Recovered Control - RC) or control plus recovered rice bran diet (Recovered Rice Bran - RRB).. Despite the increased food intake, group A exhibited lower carcass fat associated to low serum leptin. RRB and RC groups showed lower carcass weight and energy intake and expenditure. Energy expenditure was positively associated with food intake and carcass weight. Negative correlations between HOMA-IR and energy expenditure and energy intake were observed.. Nutritional recovery with rice bran did not modify energy balance, leptin and insulin levels.

Topics: Animals; Animals, Newborn; Body Weight; Dietary Fiber; Disease Models, Animal; Eating; Energy Intake; Insulin; Leptin; Male; Oryza; Protein-Energy Malnutrition; Random Allocation; Rats; Rats, Wistar

Fasting increases c-Fos expression in neuropeptide Y (NPY) neurons of the hypothalamic arcuate nucleus (ARC) in lean, but not in hyperleptinemic mice with late-onset obesity (LOO). Although obesity is associated with leptin resistance, we hypothesized that under fasting conditions, leptin sensitivity might be restored and that hyperleptinemia may counteract the neuronal response to fasting. We investigated whether the reduced fasting response of ARC neurons in LOO is paralleled by an increase in leptin sensitivity, as measured by leptin-induced STAT-3 phosphorylation. To assess leptin's role in the modulation of the fasting-induced ARC activation, we investigated c-Fos responses and hormone and metabolite levels in hyperleptinemic diet-induced obese (DIO) and in leptin-deficient ob/ob mice. Leptin induced a stronger STAT-3 phosphorylation in fasted LOO and lean mice than in ad libitum-fed animals. Similar to LOO, hyperleptinemic DIO mice showed no c-Fos response after fasting, while ob/ob mice showed a stronger response than lean control mice. Mimicking hyperleptinemia by repeated leptin injections in lean mice during fasting attenuated the fasting-induced c-Fos expression. Our findings indicate that high leptin levels prevent the fasting-induced activation of ARC neurons in mice. Moreover, leptin sensitivity is dynamic in obese subjects and depends on the feeding status. During short-term increases in leptin sensitivity, e.g., during fasting, leptin signaling appears to be effective, even in hyperleptinemic obesity. As reflected by the blockade of the fasting-induced ARC activation, fasting seems to interfere with the responsiveness of the ARC to signals related to the status of energy intake.

Topics: 3-Hydroxybutyric Acid; Animals; Arcuate Nucleus of Hypothalamus; Blood Glucose; Dietary Fats; Disease Models, Animal; Fasting; Fatty Acids, Nonesterified; Ghrelin; Injections, Subcutaneous; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Neurons; Obesity; Phosphorylation; Proto-Oncogene Proteins c-fos; STAT3 Transcription Factor; Time Factors

There is no animal model that displays the features of non-alcoholic steatohepatitis (NASH) characterized by insulin resistance (IR) and fibrosing steatohepatitis. This study aimed to develop a novel IR-associated rat model of NASH.. Male Sprague-Dawley rats were fed with the high-fat diet (HFD) supplemented with 0.25% propylthiouracil for 2, 4, 6, 8 and 12 weeks. The IR-associated metabolic parameters, histological assessment and the expression of key insulin signaling molecules were determined. The circulating and tissue pro-inflammatory factors and adipocytokines were examined.. In the HFD-fed rats, the systemic and multiple-organ IR was developed after 4 weeks, whereas the histological changes characterized by steatohepatitis, inflammatory response in the visceral adipose tissue and proliferative pancreatic islet β-cells appeared after 6 weeks, concomitant with altered expression of key insulin signaling molecules. In addition, the elevated levels of serum tumor necrosis factor α (TNF-α), soluble TNF receptor2, interleukin (IL)-6, CC-chemokine ligand (CCL)2 and resistin were parallel with the severity of hepatic inflammation, while the levels of serum adiponectin, leptin and TNF-α, but not resistin, were correlated with IR.. We have developed a systemic IR-associated NASH model of rats, with impaired insulin signaling, systemic inflammation and appropriate pathology characterized by human NASH, and provided a realistic experimental model for elucidating the association between IR and the pathogenesis of NASH.

Topics: Adiponectin; Animals; Chemokines; Disease Models, Animal; Disease Progression; Fatty Liver; Gene Expression Regulation; Hepatitis; Insulin Resistance; Leptin; Liver Cirrhosis; Male; Polymerase Chain Reaction; Rats; Rats, Sprague-Dawley; Resistin; RNA; Severity of Illness Index

Plasma insulin concentration is increased in prostate cancer patients during androgen deprivation therapy (ADT) and hyperinsulinemia has been associated with aggressive prostate cancer behavior. To investigate the possible role of castration-induced hyperinsulinemia as a mechanism that may attenuate the beneficial effects of ADT in patients with prostate cancer, a murine model would be useful. We therefore investigated long-term metabolic effects of castration in several mouse models.. We studied the long-term influence of castration on energy intake, body weight, glucose tolerance, plasma-insulin, plasma insulin-like growth factor-1 (IGF-1), plasma adiponectin, and plasma leptin in C57BL/6, Swiss nu/nu, and CB17 scid mice receiving various diets. In each case, mice were randomized to have either bilateral orchiectomy or a sham operation.. Energy intake, body weight, blood glucose levels in glucose tolerance test, plasma insulin, plasma IGF-1, and plasma leptin level in all had a trend to be decreased in castrated as compared to sham operated mice. Plasma adiponectin level was increased in the castrated mice.. The effects of castration on glucose, insulin, and related markers in several mouse models studied does not coincide with clinical observations; further studies in this area will require clinical research and/or the use of alternate models such as the dog.

Topics: Adiponectin; Androgens; Animals; Blood Glucose; Body Weight; Disease Models, Animal; Energy Intake; Glucose Tolerance Test; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Nude; Mice, SCID; Neoplasms, Hormone-Dependent; Orchiectomy; Prostatic Neoplasms; Random Allocation

Factors released by perivascular adipose tissue (PVAT) disrupt coronary endothelial function via phosphorylation of endothelial NO synthase by protein kinase C (PKC)-beta. However, our understanding of how PVAT potentially contributes to coronary disease as a complication of obesity/metabolic syndrome (MetS) remains limited. The current study investigated whether PVAT-derived leptin impairs coronary vascular function via PKC-beta in MetS.. Coronary arteries with and without PVAT were collected from lean or MetS Ossabaw miniature swine for isometric tension studies. Endothelial-dependent vasodilation to bradykinin was significantly reduced in MetS. PVAT did not affect bradykinin-mediated dilation in arteries from lean swine but significantly exacerbated endothelial dysfunction in arteries from MetS swine. PVAT-induced impairment was reversed by inhibition of either PKC-beta with ruboxistaurin (Eli Lilly and Company, Indianapolis, Ind) or leptin receptor signaling with a recombinant, pegylated leptin antagonist. Western blot and immunohistochemical analyses demonstrated increased PVAT-derived leptin and coronary leptin receptor density with MetS. Coronary PKC-beta activity was increased in both MetS arteries exposed to PVAT and lean arteries exposed to leptin. Finally, leptin-induced endothelial dysfunction was reversed by ruboxistaurin.. Increases in epicardial PVAT leptin exacerbate coronary endothelial dysfunction in MetS via a PKC-beta-dependent pathway. These findings implicate PVAT-derived leptin as a potential contributor to coronary atherogenesis in MetS.

Topics: Adipose Tissue; Animals; Coronary Vessels; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelium, Vascular; Female; Leptin; Male; Metabolic Syndrome; Pericardium; Phenotype; Protein Kinase C; Protein Kinase C beta; Protein Kinase Inhibitors; Receptors, Leptin; Signal Transduction; Swine; Swine, Miniature; Up-Regulation; Vasodilation; Vasodilator Agents

Most people with diabetes develop severe complications of the autonomic nervous system; yet, the underlying causes of many diabetic-induced dysautonomias are poorly understood. Here we explore the idea that these dysautonomias results, in part, from a defect in synaptic transmission. To test this idea, we investigated cultured sympathetic neurons and show that hyperglycemia inactivates nAChRs through a mechanism involving an elevation in reactive oxygen species and an interaction with highly conserved cysteine residues located near the intracellular mouth of the nAChR channel. Consistent with this, we show that diabetic mice have depressed ganglionic transmission and reduced sympathetic reflexes, whereas diabetic mice expressing mutant postsynaptic nAChRs that lack the conserved cysteine residues on the alpha3 subunit have normal synaptic transmission in sympathetic ganglia and normal sympathetic reflexes. Our work suggests a new model for diabetic-induced dysautonomias and identifies ganglionic nAChRs as targets of hyperglycemia-induced downstream signals.

Topics: Acetylcholine; Adenoviridae; Age Factors; Aldehydes; Animals; Animals, Newborn; Body Temperature; Cells, Cultured; Cysteine; Diabetes Mellitus, Experimental; Disease Models, Animal; Enzyme Inhibitors; Excitatory Postsynaptic Potentials; Glucose; Guanidines; Heart Rate; Hypoglycemic Agents; Insulin; Leptin; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Oxidative Stress; Patch-Clamp Techniques; Reactive Oxygen Species; Receptors, Leptin; Receptors, Nicotinic; Sensory Receptor Cells; Superior Cervical Ganglion; Synaptic Transmission

The Ca(2+)/calmodulin stimulated adenylyl cylcase 8 (AC8) is a pure Ca(2+) sensor, catalyzing the conversion of ATP to cAMP, with a critical role in neuronal plasticity. A role for AC8 in modulating complex behavioral outcomes has been demonstrated in AC8 knock out (KO) mouse models in which anxiety-like responses were differentially modulated following repeated stress experiences, suggesting an involvement of AC8 in stress adaptation and mood disorders. To further investigate the role of this enzyme in phenotypes relevant for psychiatric conditions, AC8 KO mice were assessed for baseline behavioral and hormonal parameters, responses to repeated restraint stress experience, and long-term effects of chronic social defeat stress. The lack of AC8 conferred a hyperactive-phenotype both in home-cage behaviors and the forced swim test response as well as lower leptin plasma levels and adrenal hypertrophy. AC8 KO mice showed baseline "anxiety" levels similar to wild type littermates in a variety of procedures, but displayed decreased anxiety-like responses following repeated restraint stress. This increased stress resilience was not seen during the chronic social defeat procedure. AC8 KO did not differ from wild type mice in response to social stress; similar alterations in body weight, food intake and increased social avoidance were found in all defeated subjects. Altogether these results support a complex role of cAMP signaling pathways confirming the involvement of AC8 in the modulation of stress responses. Furthermore, the hyperactivity and the increased risk taking behavior observed in AC8 KO mice could be related to a manic-like behavioral phenotype that warrants further investigation.

Topics: Adenylyl Cyclases; Adrenal Glands; Animals; Behavior, Animal; Biomarkers; Disease Models, Animal; Hypertrophy; Leptin; Male; Mice; Mice, Knockout; Mood Disorders; Stress, Psychological

Obesity is an epidemic problem affecting millions of people in the Western hemisphere and costs the United States economy more than $200 billion annually. Currently, there are no effective treatments to combat obesity. Recent studies have implicated the constitutive activity of estrogen receptor (ER) β as an important regulator of metabolic diseases. However, the potential of ER-β-selective ligands to offset obesity is not clear. We evaluated the pharmacological effect of ER-β-selective ligands (β-LGNDs) in animal models of high-fat diet- and ovariectomy-induced obesity. Ligand binding, transactivation, and uterotrophic studies with β-LGNDs demonstrated selectivity for ER-β over ER-α. Animals fed a high-fat diet showed a significant increase in body weight, and this weight gain was attenuated by β-LGNDs. High-fat diet-mediated increases in serum cholesterol, leptin, glucose, and fat accumulation in organs were also reduced by β-LGNDs. In addition, MRI scanning indicated that β-LGNDs altered body composition by reducing fat mass and increasing lean body mass. Organ weights and gene expression analyses demonstrated that adipose tissue is the center of action for β-LGNDs, and the reduction in body weight is likely due to increased energy expenditure. In vitro and in vivo mechanistic studies indicated that the anti-obesity effects of β-LGNDs were due to indirect peroxisome proliferator-activated receptor γ antagonistic actions requiring the ligand binding domain of ER-β and through abrogation of the ability of PGC-1 to coactivate peroxisome proliferator-activated receptor γ. In conclusion, these studies indicate that ligand-activated ER-β is a potential therapeutic target to combat obesity and obesity-related metabolic diseases.

Topics: Animals; Blood Glucose; Cholesterol; Dietary Fats; Disease Models, Animal; Estrogen Receptor beta; Female; Isoquinolines; Leptin; Ligands; Male; Mice; Obesity; Organ Size; Ovariectomy; PPAR gamma; Rats; Rats, Sprague-Dawley; Transcription Factors

The Spontaneously Diabetic Torii-Lepr(fa) (SDT-fa/fa) rat, a new model of obese type 2 diabetes, shows obesity, hyperglycemia, and hyperlipidemia from 6 weeks of age. Diabetic complications such as nephropathy and cataract are observed with aging; however, blood pressure change with age has not previously been examined. In this study, blood pressure was periodically measured and the change was investigated. Blood pressure in male SDT-fa/fa rats was elevated at 8, 16, and 24 weeks of age, whereas the heart rate was not changed. In addition to hyperglycemia, hyperlipidemia, and proteinuria, hyperleptinemia and increased urine angiotensinogen were observed in SDT-fa/fa rats. Blood pressure and heart rate in the male original SDT (SDT-+/+) rat did not significantly change. In conclusion, the SDT-fa/fa rat is a promising model, showing significant hypertension with diabetes mellitus.

Topics: Angiotensinogen; Animals; Blood Pressure; Diabetes Mellitus, Type 2; Disease Models, Animal; Heart Rate; Hyperglycemia; Hyperlipidemias; Hypertension; Leptin; Male; Obesity; Proteinuria; Rats; Rats, Sprague-Dawley

Obesity has been associated with increased incidence and aggressiveness of prostate cancer. Although controversial, several studies suggest that leptin could influence tumour cell growth and proliferation. The main goal of this study was to assess cellular growth of prostate adenocarcinoma cells in obese mice with different endogenous hormonal environments in what relates to leptin circulating levels and sensitivity. Four groups of mice (n = 6/group) were used, namely obese mice with congenital non-functioning leptin receptor OBR (db/db), obese mice with congenital leptin deficiency (ob/ob), mice with diet induced obesity (DIO) and normal weight C57BL/6J mice (control). All groups of mice were injected subcutaneously with 3.0 x 10(5) RM1 cells/500 microl PBS (murine prostate carcinoma androgen insensitive cells) and tumour growth and angiogenesis were evaluated 14 days after inoculation. The tumours induced in ob/ob and DIO mice were significantly larger (P < 0.001) while those induced in db/db mice were significantly smaller (P = 0.047), when compared with controls. Morphometric analysis revealed that mitotic index and Ki-67 positive nuclear density, both cell proliferation markers, were also significantly lower in the tumours of db/db mice (P < 0.001) when compared to controls. An inverse correlation was observed between leptin plasma levels and tumour weight (r = -0.642, P < 0.001), mitotic index (r = -0.646, P < 0.01) and Ki-67 positive nuclear density (r = -0.795, P < 0.001). These results suggest that high leptin concentrations are not favourable to RM1 cell growth and proliferation. On the contrary, high plasma leptin levels were associated with less cellular proliferation and angiogenesis in vivo.

Topics: Adenocarcinoma; Animals; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Immunohistochemistry; Insulin; Insulin-Like Growth Factor I; Ki-67 Antigen; Leptin; Male; Mice; Mice, Inbred C57BL; Mitotic Index; Mutation; Neovascularization, Pathologic; Obesity; Prostatic Neoplasms; Receptors, Leptin; Time Factors; Tumor Burden

The objectives of this study were to use magnetic resonance (MR) molecular imaging to 1) characterize the aortic neovascular development in a rat model of atherosclerosis and 2) monitor the effects of an appetite suppressant on vascular angiogenesis progression.. The James C. Russell:LA corpulent rat strain (JCR:LA-cp) is a model of metabolic syndrome characterized by obesity, insulin resistance, hyperlipidemia, and vasculopathy, although plaque neovascularity has not been reported in this strain. MR molecular imaging with alpha(nu)beta(3)-targeted nanoparticles can serially map angiogenesis in the aortic wall and monitor the progression of atherosclerosis.. Six-week old JCR:LA-cp (+/?; lean, n = 5) and JCR:LA-cp (cp/cp; obese, n = 5) rats received standard chow, and 6 obese rats were fed the appetite suppressant benfluorex over 16 weeks. Body weight and food consumption were recorded at baseline and weeks 4, 8, 12, and 16. MR molecular imaging with alpha(nu)beta(3)-targeted paramagnetic nanoparticles was performed at weeks 0, 8, and 16. Fasted plasma triglyceride, cholesterol, and glucose were measured immediately before MR scans. Plasma insulin and leptin levels were assayed at weeks 8 and 16.. Benfluorex reduced food consumption (p < 0.05) to the same rate as lean animals, but had no effect on serum cholesterol or triglyceride levels. MR (3-T) aortic signal enhancement with alpha(nu)beta(3)-targeted nanoparticles was initially equivalent between groups, but increased (p < 0.05) in the untreated obese animals over 16 weeks. No signal change (p > 0.05) was observed in the benfluorex-treated or lean rat groups. MR differences paralleled adventitial microvessel counts, which increased (p < 0.05) among the obese rats and were equivalently low in the lean and benfluorex-treated animals (p > 0.05). Body weight, insulin, and leptin were decreased (p < 0.05) from the untreated obese animals by benfluorex, but not to the lean control levels (p < 0.05).. Neovascular expansion is a prominent feature of the JCR:LA-cp model. MR imaging with alpha(nu)beta(3)-targeted nanoparticles provided a noninvasive assessment of angiogenesis in untreated obese rats, which was suppressed by benfluorex.

Topics: Animals; Aorta; Appetite Depressants; Atherosclerosis; Body Weight; Cholesterol; Disease Models, Animal; Eating; Fenfluramine; Insulin; Integrin alphaVbeta3; Leptin; Magnetic Resonance Angiography; Male; Metabolic Syndrome; Nanoparticles; Neovascularization, Pathologic; Obesity; Rats; Time Factors; Triglycerides

We investigated the potential neuroprotective effects of leptin (LEP) against cellular damage, long-term recurrent spontaneous seizures, and behavioral changes associated with kainate (KA)-induced status epilepticus (SE). Adult Sprague-Dawley rats were sacrificed 24 hours after KA injections, and hippocampi were subjected to histological analysis. In the acute condition, one group received 12 mg/kg KA intraperitoneally (KAac group), and another group received 12 mg/kg KA intraperitoneally, followed by two intraperitoneal LEP injections of 4 mg/kg each, 1 and 13 hours after KA (KALEPac group). For long-term outcomes, one group received KA (KA group), and the other group received three intraperitoneal LEP injections (4 mg/kg at 1 hour, and 2mg/kg at 13 and 24 hours) after KA (KALEP group). Controls were sham manipulated. Behavioral tests started 6 weeks after SE. All rats that received KA underwent behavioral seizures of comparable severity. Compared with the KAac group, the KALEPac group had significantly larger pyramidal cell surface areas and fewer black-stained degenerating neurons with silver stain. The KALEP and KA groups were comparable with respect to recurrent spontaneous seizures, aggression, hyperactivity, and impaired memory. We show that leptin reduces cellular injury associated with KA-induced SE, but does not prevent long-term recurrent spontaneous seizures and behavioral deficits.

Topics: Analysis of Variance; Animals; Cell Count; Disease Models, Animal; Drug Interactions; Hippocampus; Kainic Acid; Leptin; Male; Neuroprotective Agents; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Status Epilepticus

Obesity is associated with an increased incidence of many cancers, including leukemia, although it is unknown whether leukemia incidence is increased directly by obesity or rather by associated genetic, lifestyle, health, or socioeconomic factors. We developed animal models of obesity and leukemia to test whether obesity could directly accelerate acute lymphoblastic leukemia (ALL) using BCR/ABL transgenic and AKR/J mice weaned onto a high-fat diet. Mice were observed until development of progressive ALL. Although obese and control BCR/ABL mice had similar median survival, older obese mice had accelerated ALL onset, implying a time-dependent effect of obesity on ALL. Obese AKR mice developed ALL significantly earlier than controls. The effect of obesity was not explained by WBC count, thymus/spleen weight, or ALL phenotype. However, obese AKR mice had higher leptin, insulin, and interleukin-6 levels than controls, and these obesity-related hormones all have potential roles in leukemia pathogenesis. In conclusion, obesity directly accelerates presentation of ALL, likely by increasing the risk of an early event in leukemogenesis. This is the first study to show that obesity can directly accelerate the progression of ALL. Thus, the observed associations between obesity and leukemia incidence are likely to be directly related to biological effects of obesity.

Topics: Adiponectin; Age of Onset; Animals; Diet; Disease Models, Animal; Disease Progression; Genes, abl; Humans; Insulin; Interleukin-6; Leptin; Mice; Mice, Inbred AKR; Mice, Transgenic; Obesity; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Multiple lines of evidence suggest innate immune response pathways to be involved in the development of obesity-associated diabetes although the molecular mechanism underling the disease is unknown. Recent observations suggest that saturated fatty acids can act as a ligand for toll-like receptor (TLR) 4, which is thought to mediate obesity-associated insulin resistance. Myeloid differentiation factor 88 (MyD88) is an adapter protein for TLR/IL-1 receptor signaling, which is involved in the activation of inflammatory pathways. To evaluate molecular mechanisms linking obesity-associated diabetes down-stream of TLR4, we investigated physiological role of MyD88 in high-fat diet (HFD)-induced obesity.. In the present study, we found MyD88-deficient mice fed a HFD had increased circulating levels of insulin, leptin and cholesterol, as well as liver dysfunction (increased induction of ALT levels, increased activation of JNK and cleavage of PARP), which were linked to the onset of severe diabetes. On the other hand, TNF-alpha would not be involved in HFD-induced diabetes in MyD88-deficient mice, because TNF-alpha level was attenuated in MyD88-deficient mice fed with HFD.. The present finding of an unexpected role for MyD88 in preventing diabetes may provide a potential novel target/strategy for treating metabolic syndrome.

Topics: Animals; Diabetes Mellitus; Disease Models, Animal; Humans; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid Differentiation Factor 88; Obesity; Risk Factors; Tumor Necrosis Factor-alpha

Leptin monotherapy reverses the deadly consequences and improves several of the metabolic imbalances caused by insulin-deficient type 1 diabetes (T1D) in rodents. However, the mechanism(s) underlying these effects is totally unknown. Here, we report that intracerebroventricular (icv) infusion of leptin reverses lethality and greatly improves hyperglycemia, hyperglucagonemia, hyperketonemia, and polyuria caused by insulin deficiency in mice. Notably, icv leptin administration leads to increased body weight while suppressing food intake, thus correcting the catabolic consequences of T1D. Also, icv leptin delivery improves expression of the metabolically relevant hypothalamic neuropeptides proopiomelanocortin, neuropeptide Y, and agouti-related peptide in T1D mice. Furthermore, this treatment normalizes phosphoenolpyruvate carboxykinase 1 contents without affecting glycogen levels in the liver. Pancreatic β-cell regeneration does not underlie these beneficial effects of leptin, because circulating insulin levels were undetectable at basal levels and following a glucose overload. Also, pancreatic preproinsulin mRNA was completely absent in these icv leptin-treated T1D mice. Furthermore, the antidiabetic effects of icv leptin administration rapidly vanished (i.e., within 48 h) after leptin treatment was interrupted. Collectively, these results unveil a key role for the brain in mediating the antidiabetic actions of leptin in the context of T1D.

Topics: Animals; Central Nervous System; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Models, Animal; Humans; Injections, Intraventricular; Insulin; Insulin-Secreting Cells; Leptin; Male; Mice; Muscle, Skeletal; Pancreas; Placebos; Protein Precursors; Receptors, Leptin

Chronic obstructive pulmonary disease (COPD) is characterized by pulmonary and extrapulmonary manifestations including systemic inflammation and weight loss. Increased levels of interleukin-6 (IL-6) have been demonstrated in sputum and serum of COPD patients. Therefore, the authors investigated the in vivo role of IL-6 in a murine model of COPD. Wild-type (WT) and IL-6 knockout (KO) mice were exposed subacutely (4 weeks) and chronically (24 weeks) to air or cigarette smoke (CS). Subacute and chronic CS exposure significantly increased pulmonary IL-6 mRNA expression in lung tissue and IL-6 protein levels in bronchoalveolar lavage fluid of WT mice. However, CS-induced accumulation of inflammatory cells at both time points and lymphoid aggregate formation upon chronic CS exposure were independent of IL-6. Chonic CS exposure was associated with a significant failure to gain weight in both WT mice and IL-6 KO mice. Remarkably, air-exposed IL-6 KO mice have lower body weight, serum leptin levels, and adipose tissue mass compared to air-exposed WT mice. In conclusion, IL-6 is of minor importance in CS-induced pulmonary and systemic manifestations in mice, but this study confirms the role for IL-6 as regulator of body weight and body composition.

Topics: Adipose Tissue, White; Animals; Bronchoalveolar Lavage Fluid; Cell Count; Cytokines; Disease Models, Animal; Gene Expression; Interleukin-6; Leptin; Lung; Lymphocytes; Male; Mice; Mice, Knockout; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; RNA, Messenger; Smoking; Tobacco Smoke Pollution

To determine the effect of obesity on simulated birth trauma in leptin-deficient obese mice as measured by relative monocyte chemotactic protein 3 (MCP-3) expression.. A total of 25 wild-type and 25 obese C57BL/6 virgin female mice underwent 1 hour of vaginal distension (VD), sham VD, or anesthesia without VD. Pelvic organ tissues were then harvested either immediately or 24-hours post VD and subsequent real-time polymerase chain reaction analysis was performed.. Urethral MCP-3 levels in wild-type mice were elevated from baseline at 0 hours with a return to baseline at 24 hours in both VD and sham VD groups. In obese mice, there was a 6-fold elevation in MCP-3 levels at 0 hours after sham VD vs control (P <.05), which then returned to baseline levels at 24 hours. After undergoing VD, MCP-3 levels increased to 6-fold baseline values (P = .002) at 0 hours, with continued elevation in MCP-3 levels to 15 times control levels (P = .0003) at 24 hours.. MCP-3 is significantly over-expressed in the urethral tissues of both wild-type and obese mice immediately after any urethral manipulation. At 24 hours, the MCP-3 expression patterns become divergent between VD and sham VD in obese mice. With a greater degree of trauma, MCP-3 continued to rise at 24 hours, suggesting that the underlying obesity resulted in alterations in response to tissue injury, paralleling the degree of injury. Such associations warrant further investigation into the role of MCP-3 as a chemokine for stem cell migration, with implications for subsequent tissue repair mechanisms after birth trauma.

Topics: Animals; Cell Movement; Chemokine CCL7; Delivery, Obstetric; Disease Models, Animal; Female; Gene Expression Regulation; Humans; Leptin; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Mice, Obese; Models, Biological; Obesity; Obstetric Labor Complications; Pregnancy; Risk Factors; Stress, Mechanical; Time Factors; Urethra; Urinary Incontinence, Stress; Vagina

Lipodystrophy in HIV type-1 (HIV-1)-infected patients is the consequence of effects originating from antiretroviral treatment and HIV-1 infection. We have studied adipose tissues and circulating parameters in mice bearing the HIV-1 transgene as a model to provide insight into the role of HIV-1-infection-related events in fat alterations.. Heterozygous transgenic mice expressing a 7.7 kb HIV-1 construct (Tg26+/-) were used. Cytokine and adipokine levels were quantified using multiplex procedures. Gene expression and mitochondrial DNA abundance in visceral and subcutaneous white adipose tissues and in brown fat were determined using quantitative real-time PCR.. The amount of visceral, but not subcutaneous, adipose depot was lower in Tg26+/- mice. Serum proinflammatory cytokine levels were increased in Tg26+/- mice, whereas adiponectin and leptin levels were reduced. Gene expression of monocyte chemoattractant protein-1 was induced in visceral and subcutaneous fat, whereas tumour necrosis factor-α and interleukin-6 were induced in visceral and subcutaneous white adipose tissues, respectively. Adiponectin and leptin gene expression was repressed in all white fat depots, in concert with reduced expression of peroxisome proliferator-activated receptor γ, a master controller of adipogenesis. In brown fat, a coordinate induction in the expression of thermogenesis marker genes was observed.. HIV-1 transgene expression in mice causes changes in adipose tissue reminiscent of those in patients with HIV-1 lipodystrophy, particularly early pretreatment changes. These data support a role for HIV-1-infection-related events in eliciting adipose tissue dysfunction. The Tg26+/- mouse appears as a promising model to assess the effects of HIV-1 infection on adipose tissue and for determining the effects of antiretroviral drugs on an HIV-1-infected background.

Topics: Adipogenesis; Adipokines; Adiponectin; Adipose Tissue; Animals; Antiretroviral Therapy, Highly Active; Chemokine CCL2; Disease Models, Animal; Gene Expression Profiling; HIV Infections; HIV-1; HIV-Associated Lipodystrophy Syndrome; Interleukin-6; Leptin; Male; Mice; Mice, Transgenic; Subcutaneous Fat; Subcutaneous Tissue

Pre-eclampsia, a pregnancy-specific multisystemic disorder is a leading cause of maternal and perinatal mortality and morbidity. This syndrome has been known to medical science since ancient times. However, despite considerable research, the cause/s of preeclampsia remain unclear, and there is no effective treatment. Development of an animal model that recapitulates this complex pregnancy-related disorder may help to expand our understanding and may hold great potential for the design and implementation of effective treatment.. Here we show that the CBA/J x DBA/2 mouse model of recurrent miscarriage is also a model of immunologically-mediated preeclampsia (PE). DBA/J mated CBA/J females spontaneously develop many features of human PE (primigravidity, albuminuria, endotheliosis, increased sensitivity to angiotensin II and increased plasma leptin levels) that correlates with bad pregnancy outcomes. We previously reported that antagonism of vascular endothelial growth factor (VEGF) signaling by soluble VEGF receptor 1 (sFlt-1) is involved in placental and fetal injury in CBA/J x DBA/2 mice. Using this animal model that recapitulates many of the features of preeclampsia in women, we found that pravastatin restores angiogenic balance, ameliorates glomerular injury, diminishes hypersensitivity to angiotensin II and protects pregnancies.. We described a new mouse model of PE, were the relevant key features of human preeclampsia develop spontaneously. The CBA/J x DBA/2 model, that recapitulates this complex disorder, helped us identify pravastatin as a candidate therapy to prevent preeclampsia and its related complications. We recognize that these studies were conducted in mice and that clinical trials are needed to confirm its application to humans.

Topics: Animals; Blood Pressure; Disease Models, Animal; Female; Leptin; Mice; Mice, Inbred CBA; Mice, Inbred DBA; Pravastatin; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Vascular Endothelial Growth Factor A

To observe the content of leptin in the abdominal subcutaneous tissues of the higher temperature zone along the Gallbladder (GB) Meridian in cholecystitis rabbits so as to explore the correlation between the temperature response and the leptin level.. Twenty-five rabbits were randomized into normal control group (n = 10) and cholecystitis model group (n = 15). Cholecystitis model was established by injection of Escherichia coli solution (0.1 mL) into the gallbladder via common bile duct after surgery. Three, 7 and 11 days following modeling, the abdominal surface thermographic images along the GB Meridian were collected by the AGA-782-type infrared imaging system (AGA's capacity). And then the subcutaneous tissues of the high temperature reaction region and the contralateral corresponding tissues of different groups were collected for assaying the leptin contents in the supernatant by radioimmunoassay after processing (homogenization and centrifugation) and for observing the morphological structure under light microscopy after sectioning and staining (toluidine blue).. Thermographic images showed that about 70% of the animals in the model group, various lengths of high temperature reaction (0.5-1.4 degrees C) zones or bands in the abdominal region along the bilateral GB Meridian were seen, in comparison with the control group. The leptin levels in the ipsilateral (affected side) and contralateral (healthy side) tissues of the abdominal high temperature reaction zones along the GB Meridian were significantly higher in the model group than in the control group (P < 0.01), suggesting a close correlation between the leptin content change and the high temperature reaction. In addition, most fat cells were crowded to distribute closely along the blood vessels in the subcutaneous tissues of the higher temperature reaction zone in the model group, but those of the control group distribute more loosely along the blood vessels.. The leptin content in the abdominal sub- cutaneous tissues of high temperature reaction zone along the GB Meridian is higher in cholecystitis rabbits, suggests a relevance of the endocrine function of fat cells to the high temperature reaction along the GB Meridian.

Topics: Acupuncture Points; Acupuncture Therapy; Animals; Body Temperature; Cholecystitis; Disease Models, Animal; Female; Gallbladder; Humans; Leptin; Male; Meridians; Rabbits; Random Allocation; Subcutaneous Tissue; Thermography

To observe the effects of electroacupuncture (EA) on leptin and leptin receptor(Ob-rb) mRNA expression in the hypothalamus of nonalcoholic fatty liver disease (NAFLD) rats, so as to reveal its underlying mechanism in the treatment of NAFLD inflammation.. Thirty-two male SD rats were randomly divided into control group (n = 10), model group (n = 11) and EA group (n = 11). NAFLD model was established by feeding the animals with high fat diet for 8 weeks. EA (10 Hz, 1.5 V, 30 min) was applied to unilateral "Fenglong" (ST 40) and "Zusanli" (ST 36), once daily for 4 weeks. After the treatment, all the rats were sacrificed for collecting the liver to make pathological observation after HE staining and for taking the hypothalamus tissue out to detect the leptin mRNA and leptin receptor (Ob-rb) mRNA expression by reverse transcription polymerase chain reaction (RT-PCR). Serum total cholesterol (TC) and triglyeride (TG) contents were detected by chromatometry.. Compared with the control group, serum TC and TG levels increased significantly in the model group (P < 0.05). While compared with model group, both TC and TG levels in EA group were reduced considerably (P < 0.05). In comparison with control group, the expression of hypothalamic leptin mRNA and Ob-rb mRNA was down-regulated remarkably (P < 0.05), while 4 weeks after EA treatment, both leptin mRNA expression and Ob-rb mRNA expression were up-regulated obviously (P < 0.05).. EA can lower serum TG and TC contents in NAFLD rats, which is closely related to its effects in up-regulating the expression of hypothalamic leptin mRNA and Ob-rb mRNA.

Topics: Animals; Cholesterol; Disease Models, Animal; Electroacupuncture; Fatty Liver; Gene Expression; Humans; Hypothalamus; Leptin; Male; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Leptin; RNA, Messenger

Although zinc status is an important parameter in insulin sensitivity, data concerning its implication in noxious burn-induced insulin resistance are scarce. The present study was designed to evaluate the impact of zinc status before burn on the recovery of injury with focus on plasma insulin and glucose levels. The experiment was performed in male adult Wistar rats fed from weaning with a zinc normal diet (80 ppm) or a depleted zinc diet (10 ppm) for 8 weeks and burned to third degree on 20% of their total body surface area. Blood and tissue samples were collected 3, 6, and 24 h after injury in order to study biochemical parameters and the glucose/insulin response in relation with the zinc status. After burn, zinc-depleted rats presented an exacerbated decrease in plasma zinc level. In addition, the burn-induced insulin resistance, leading to protein catabolism, was emphasized, with higher plasma insulin, glucose, and leptin levels in zinc-deficient animals versus normal-fed rats. Our experimental results underlined the interest to early control the zinc status in order to limit the deleterious effects of oxidative stress and insulin resistance in burned patients.

Topics: Animals; Antioxidants; Blood Glucose; Burns; Corticosterone; Diet; Disease Models, Animal; Femur; Insulin; Insulin Resistance; Leptin; Liver; Male; Muscles; Random Allocation; Rats; Rats, Wistar; Zinc

While the role of insulin in glucose uptake and its aberration in diabetes are well established, the effect of insulin on lipoprotein clearance in the postprandial phase is not yet fully understood. The dietary lipids are carried in chylomicron remnants (CR) which are taken up into the liver mainly via LDLR-related protein 1 (LRP1). In this study, the effect of insulin on LRP1-mediated hepatic CR uptake was investigated.. The study was based on determining the subcellular localisation of LRP1 by subcellular fractionation and immunofluorescence microscopy and correlating those findings with the hepatic uptake of fluorescently or radioactively labelled LRP1-specific ligands and CR in hepatoma cells, primary hepatocytes and mouse models.. In vitro and in vivo, insulin stimulated the translocation of hepatic LRP1 from intracellular vesicles to the plasma membrane, which correlates with an increased uptake of LRP1-specific ligands. In wild-type mice, a glucose-induced insulin response increased the hepatic uptake of LRP1 ligands while in leptin-deficient obese mice (ob/ob), which are characterised by hepatic insulin resistance, insulin-inducible LRP1 ligand uptake was abolished. Finally, upon hepatic LRP1 knockdown, insulin no longer significantly enhanced CR uptake into the liver. The insulin-induced LRP1-mediated CR uptake, as demonstrated here, suggests that impaired hepatic LRP1 translocation can contribute to the postprandial lipaemia in insulin resistance.

Topics: Animals; Cell Line, Tumor; Chylomicron Remnants; Disease Models, Animal; Hepatocytes; Humans; Hyperlipidemias; Insulin; Insulin Resistance; Leptin; Ligands; Lipoproteins; Low Density Lipoprotein Receptor-Related Protein-1; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Fluorescence; Postprandial Period; Protein Transport; Rats; Receptors, LDL; Recombinant Proteins; Subcellular Fractions; Tumor Suppressor Proteins

Maternal obesity is becoming more prevalent. We used borderline hypertensive rats (BHR) to investigate whether a high-fat diet at different stages of development has adverse programming consequences on metabolic parameters and blood pressure. Wistar dams were fed a high- or low-fat diet for 6 wk before mating with spontaneously hypertensive males and during the ensuing pregnancy. At birth, litters were fostered to a dam from the same diet group as during gestation or to the alternate diet condition. Female offspring were weaned on either control or "junk food" diets until about 6 mo of age. Rats fed the high-fat junk food diet were hyperphagic relative to their chow-fed controls. The junk food-fed rats were significantly heavier and had greater fat pad mass than those rats maintained on chow alone. Importantly, those rats suckled by high-fat dams had heavier fat pads than those suckled by control diet dams. Fasting serum leptin and insulin levels differed as a function of the gestational, lactational, and postweaning diet histories. Rats gestated in, or suckled by high-fat dams, or maintained on the junk food diet were hyperleptinemic compared with their respective controls. Indirect blood pressure did not differ as a function of postweaning diet, but rats gestated in the high-fat dams had lower mean arterial blood pressures than those gestated in the control diet dams. The postweaning dietary history affected food-motivated behavior; junk food-fed rats earned less food pellets on fixed (FR) and progressive (PR) ratio cost schedules than chow-fed controls. In conclusion, the effects of maternal high-fat diet during gestation or lactation were mostly small and transient. The postweaning effects of junk food diet were evident on the majority of the parameters measured, including body weight, fat pad mass, serum leptin and insulin levels, and operant performance.

Topics: Adiposity; Age Factors; Aging; Animal Nutritional Physiological Phenomena; Animals; Behavior, Animal; Blood Pressure; Body Weight; Conditioning, Operant; Dietary Fats; Disease Models, Animal; Feeding Behavior; Female; Hybridization, Genetic; Hyperphagia; Hypertension; Insulin; Lactation; Leptin; Male; Maternal Nutritional Physiological Phenomena; Metabolic Syndrome; Motivation; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Inbred SHR; Rats, Wistar; Reward; Weaning

Influences of genetic and nutritional factors on body weight, fat mass, and leptin production and effects of leptin were assessed in normal [Wistar-Kyoto (WKY)] and diabetic [Goto-Kakizaki (GK)] rats by mechanism-based modeling. The study included 60 WKY and 60 GK rats; half received high-fat diet (HF), and the others received normal rat chow (N). Body weights and food consumption were measured twice weekly. Six rats per group were sacrificed at 4, 8, 12, 16, and 20 weeks. Abdominal fat was weighed, and plasma leptin was measured by enzyme-linked immunosorbent assay. All data were comodeled using NONMEM version VI level 1.1 (first-order conditional estimation with interaction) (Beal SL, Boeckmann AJ, Sheiner LB, and NONMEM Project Group, NONMEM Users Guides, University of California, San Francisco, CA, 2007). Weight gain was modeled as differences between energy intake and metabolic rate based on allometrically scaled lean body mass (LBM). The GK had higher metabolic rates (1.15 kcal/day/g LBM(0.75)) than WKY-N (0.92) and WKY-HF (1.02) rats and higher efficiency in transforming energy into body weight. Leptin effect was modeled as inhibition of food consumption. Total body fat was estimated from abdominal fat. Leptin production from fat was 4.7-fold higher for GK (3.03 ng/ml/day/g) than WKY (0.66 ng/ml/day/g). Leptin production rate from LBM was 0.53 ng/ml/day/g for all groups. The IC(50) for inhibition of food intake by leptin was approximately 3-fold higher in GK versus WKY, indicating leptin resistance for the effect on food consumption in GK. The GK had similar intake of kilocalories but lower body weights and fat mass than WKY, possibly because of higher metabolic rates. Our mechanism-based model explains intrinsic reasons for differences in growth, food intake, and leptin concentrations among these two strains of rats.

Topics: Animals; Biological Phenomena; Body Weight; Diabetes Mellitus; Disease Models, Animal; Eating; Growth; Leptin; Male; Obesity; Rats; Rats, Inbred WKY

Excessive physical activity is commonly described as symptom of Anorexia Nervosa (AN). Activity-based anorexia (ABA) is considered an animal model for AN. The ABA model mimics severe body weight loss and increased physical activity. Suppression of hyperactivity by olanzapine in anorectic patients as well as in ABA rats suggested a role of dopamine and/or serotonin in this trait. Here, we investigated the effect of a non-selective dopamine antagonist in the ABA model. A dose-response curve of chronic treatment with the non-selective dopaminergic antagonist cis-flupenthixol was determined in the ABA model. Treatment reduced activity levels in both ad libitum fed and food-restricted rats. Treated ABA rats reduced body weight loss and increased food intake. These data support a role for dopamine in anorexia associated hyperactivity. Interestingly, in contrast to leptin treatment, food-anticipatory activity still persists in treated ABA rats.

Topics: Adipose Tissue; Analysis of Variance; Animals; Anorexia Nervosa; Behavior, Animal; Body Composition; Body Temperature; Body Weight; Disease Models, Animal; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Delivery Systems; Eating; Female; Flupenthixol; Food Deprivation; Insulin; Leptin; Motor Activity; Radioimmunoassay; Rats; Rats, Wistar

To evaluate the protective effects of total flavonoids of Litsea Coreana leve (TFLC) on rat high fat diet-induced hepatic steatosis model.. Rats were given either a high fat diet alone or the same diet plus TFLC for 4 weeks.. TFLC improved liver histology with reduced serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), as well as decreased the over accumulation lipids in serum and liver. TFLC increased serum levels of leptin and insulin, while decreased serum TNFalpha level in high fat diet fed rat. Furthermore, TFLC was found increased the expression of peroxisome proliferator-activated receptor alpha (PPARalpha) in high fat diet fed rat liver. These benefits were associated with increased superoxide dismutase (SOD) and decreased malondialdehyde (MDA) in high fat diet fed rat liver.. TFLC exerts protective effects against hepatic steatosis in rats fed with high fat diet possibly through its antioxidant actions, improving the adipocytokines release and increasing the expression of PPARalpha.

Topics: Alanine Transaminase; Animals; Antioxidants; Aspartate Aminotransferases; Dietary Fats; Disease Models, Animal; Drugs, Chinese Herbal; Fatty Liver; Flavonoids; Insulin; Leptin; Litsea; Liver; Male; Malondialdehyde; Phytotherapy; Plant Leaves; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Growth hormone (GH)-deficiency is usually associated with elevated adiposity, hyperleptinemia, and increased fracture risk. Since leptin is thought to enhance cortical bone formation, we have investigated the contribution of elevated adiposity and hyperleptinemia on femoral strength in rodent models of GH deficiency. Quantification of the transpubertal development of femoral strength in the moderately GH-deficient/hyperleptinemic Tgr rat and the profoundly GH-deficient/hypoleptinemic dw/dw rat revealed that the mechanical properties of cortical bone in these two models were similarly compromised, a 25-30% reduction in failure load being entirely due to impairment of geometric variables. In contrast, murine models of partial (GH antagonist transgenic) and complete (GH receptor-null) loss of GH signaling and elevated adiposity showed an impairment of femoral cortical strength proportionate to the reduction of GH signaling. To determine whether impaired femoral strength is exacerbated by obesity/hyperleptinemia, femoral strength was assessed in dw/dw rats following two developmental manipulations that elevate abdominal adiposity and circulating leptin, neonatal monosodium glutamate (MSG) treatment, and maintenance on an elevated fat diet. The additional impairment of femoral strength following MSG treatment is likely to have resulted from a reduction in residual activity of the hypothalamo-pituitary-GH-IGF-I axis, but consumption of elevated dietary fat, which did not reduce circulating IGF-I, failed to exacerbate the compromised femoral strength in dw/dw rats. Taken together, our data indicate that the obesity and hyperleptinemia usually associated with GH deficiency do not exert a significant influence over the strength of cortical bone.

Topics: Adiposity; Animals; Animals, Genetically Modified; Bone Density; Disease Models, Animal; Femur; Growth Hormone; Leptin; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Obesity; Rats; Signal Transduction

Immunity and metabolism are closely linked. The liver is an important metabolic organ in the body. However, the interactions between hepatocytes and the immune system are poorly understood. In mice developing concanavalin A (ConA)-induced hepatitis (CIH), we found extensive lipid accumulation in hepatocytes. Critical enzyme involved in fat synthesis such as stearoyl-CoA desaturase 1 (SCD1) was upregulated. When we injected ConA to SCD1-deficient mice, we found these mice to be highly resistant to CIH. The mechanisms of the protective effect of SCD1 deficiency might be attributed to the reduced leptin levels in those mice, which modulated critical cytokines and signaling pathways in CIH pathogenesis. In conclusion, our study suggests that SCD1 deficiency protects mice from liver injury in a leptin-dependent manner.

Topics: Animals; Apoptosis; Chemical and Drug Induced Liver Injury; Concanavalin A; Disease Models, Animal; Fatty Liver; Gene Expression; Hepatocytes; Leptin; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mitogens; NF-kappa B p50 Subunit; RNA, Messenger; STAT1 Transcription Factor; Stearoyl-CoA Desaturase; Up-Regulation

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat model of obesity (a spontaneous CCK1 receptor knockout) has been extensively studied as model of hyperphagia-induced obesity. In previous studies, young OLETF rats presented abnormal eating patterns [compared with Long-Evans Tokushima Otsuka (LETO) controls] in a variety of independent ingestion and nursing tests during the suckling period. The aim of the present study was to characterize the early emergence of abnormal adiposity in the pups. Moreover, because both the dams and the pups present the genetic mutation, a close follow-up of the dams' body weight and intake during pregnancy and lactation was performed to examine the circumstances that contribute to build up the pups' early adiposity. Compared with controls, OLETF pups presented higher fat levels, larger adipocytes, and increased waist circumference as early as postnatal day 7 and this profile persisted to the age of weaning. While LETO dams gained weight throughout pregnancy and lactation, OLETF dams were obese and hyperphagic during pregnancy but lost weight during lactation, probably as a result of rearing hyperphagic pups. Current and previous results suggest a possible influence of the dams' obesity during gestation and a high investment in nursing time during lactation on the pups' obesity levels during childhood. This, combined with the innate hyperphagia repeatedly observed in the pups at these early ages, makes the OLETF strain a useful tool in the research of childhood-onset obesity.

Topics: Adipocytes; Adipose Tissue, Brown; Adiposity; Age Factors; Age of Onset; Aging; Animal Nutritional Physiological Phenomena; Animals; Animals, Newborn; Animals, Suckling; Body Mass Index; Body Weight; Disease Models, Animal; Energy Intake; Feeding Behavior; Female; Hyperphagia; Lactation; Leptin; Male; Maternal Nutritional Physiological Phenomena; Obesity; Pregnancy; Pregnancy, Animal; Prenatal Exposure Delayed Effects; Rats; Rats, Inbred OLETF; Receptor, Cholecystokinin A; Weaning

Low levels of adiponectin, a fat-derived hormone, are found to be correlated with coronary heart disease, type 2 diabetes, obesity, and insulin resistance. Conversely, high adiponectin levels are predictive of reduced coronary risk in long-term epidemiologic studies. However, the precise role of adiponectin in cardiomyocyte function is still not clear. This study was designed to examine the role of adiponectin in cardiac contractile function in the db/db model of diabetic obesity. Mechanical properties and intracellular Ca(2+) transients were evaluated in cardiomyocytes from lean control and db/db mice with or without adiponectin (10 microg/ml) treatment. Expression and phosphorylation of IRS-1, Akt, c-Jun, and c-Jun N terminal kinase (JNK) as well as markers of endoplasmic reticulum (ER) stress were evaluated using western blotting. Cardiomyocytes from db/db mice exhibited greater cross-sectional area, depressed peak shortening (PS), and maximal velocity of shortening/re-lengthening as well as prolonged duration of re-lengthening. Consistently, myocytes from db/db mice displayed a reduced electrically stimulated rise in intracellular Ca(2+) and prolonged intracellular Ca(2+) decay, which were abrogated by adiponectin treatment. Ratios between phosphorylated c-Jun and c-Jun as well as phosphorylated IRS-1 and IRS-1 were increased in db/db mice, the effect of which was attenuated by adiponectin. Levels of the phosphorylated ER stress makers PERK (Thr980), IRE-1, and eIF2alpha were significantly elevated in db/db mice compared with lean controls, although the effect was unaffected by adiponectin. Collectively, our data suggest that adiponectin improves cardiomyocyte dysfunction in db/db diabetic obese mice through a mechanism possibly related to c-Jun and IRS-1.

Topics: Adiponectin; Animals; Cells, Cultured; Diabetes Mellitus, Experimental; Disease Models, Animal; eIF-2 Kinase; Endoplasmic Reticulum; Insulin Receptor Substrate Proteins; Leptin; Male; MAP Kinase Kinase 4; Membrane Proteins; Mice; Mice, Obese; Myocardial Contraction; Myocytes, Cardiac; Obesity; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-jun

Apoptotic myocyte cell death, diastolic dysfunction, and progressive deterioration in left ventricular pump function characterize the clinical course of diabetic cardiomyopathy. A key question concerns the mechanism(s) by which hyperglycemia (HG) transmits danger signals in cardiac muscle cells. The growth factor adapter protein p66ShcA is a genetic determinant of longevity, which controls mitochondrial metabolism and cellular responses to oxidative stress. Here we demonstrate that interventions which attenuate or prevent HG-induced phosphorylation at critical position 36 Ser residue (phospho-Ser36) inhibit the redox function of p66ShcA and promote the survival phenotype. Adult rat ventricular myocytes obtained by enzymatic dissociation were transduced with mutant-36 p66ShcA (mu-36) dominant-negative expression vector and plated in serum-free media containing 5 or 25 mM glucose. At HG, adult rat ventricular myocytes exhibit a marked increase in reactive oxygen species production, upregulation of phospho-Ser36, collapse of mitochondrial transmembrane potential, and increased formation of p66ShcA/cytochrome-c complexes. These indexes of oxidative stress were accompanied by a 40% increase in apoptosis and the upregulation of cleaved caspase-3 and the apoptosis-related proteins p53 and Bax. To test whether p66ShcA functions as a redox-sensitive molecular switch in vivo, we examined the hearts of male Akita diabetic nonobese (C57BL/6J) mice. Western blot analysis detected the upregulation of phospho-Ser36, the translocation of p66ShcA to mitochondria, and the formation of p66ShcA/cytochrome-c complexes. Conversely, the correction of HG by recombinant adeno-associated viral delivery of leptin reversed these alterations. We conclude that p66ShcA is a molecular switch whose redox function is turned on by phospho-Ser36 and turned off by interventions that prevent this modification.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Cardiomyopathies; Caspase 3; Catalase; Cells, Cultured; Cytochromes c; Disease Models, Animal; Genetic Therapy; Hyperglycemia; Leptin; Male; Membrane Potential, Mitochondrial; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mitochondria, Heart; Mutation; Myocytes, Cardiac; Oxidation-Reduction; Oxidative Stress; Phosphorylation; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Shc Signaling Adaptor Proteins; Src Homology 2 Domain-Containing, Transforming Protein 1; Superoxide Dismutase; Transduction, Genetic; Tumor Suppressor Protein p53

The hypothalamic arcuate nucleus was initially regarded as the principal site of leptin action, but there is increasing evidence for functional leptin receptors in extrahypothalamic sites, including the nucleus tractus solitarii (NTS). We demonstrated previously that arcuate injection of leptin increases sympathetic nerve activity (SNA) to brown adipose tissue and kidney. In this study, we tested the hypothesis that leptin signaling in the NTS affects sympathetic neural outflow. Using a stereotaxic device in anesthetized rats, we microinjected leptin (0.25 to 1.00 microg) or saline into the NTS while recording SNA to kidney and brown adipose tissue. Microinjection of leptin into the commissural and medial subnuclei of the caudal NTS at the level of the area postrema in Sprague-Dawley rats produced a dose-related increase in renal SNA (+112+/-15% with leptin 1 microg; n=7; P<0.001) but did not increase SNA to brown adipose tissue (-15+/-12%; P value not significant). This effect depended on intact functional leptin receptors, because it was not observed in Zucker obese rats that have a missense mutation in the leptin receptor. Rostral NTS injection of leptin failed to increase SNA, indicating that leptin signaling in the NTS is probably confined to the caudal NTS at the level of the area postrema. In summary, this study demonstrates that leptin signaling in the caudal NTS increases SNA to the kidney but not to the brown adipose tissue. The study strengthens the concept of a distributed brain network of leptin action and demonstrates that these distributed brain sites can mediate contrasting sympathetic responses to leptin.

Topics: Adipose Tissue, Brown; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Kidney; Leptin; Microinjections; Mutation, Missense; Obesity; Rats; Rats, Sprague-Dawley; Rats, Zucker; Receptors, Leptin; Signal Transduction; Solitary Nucleus; Sympathetic Nervous System

Leptin increases sympathetic activity, possibly contributing to hypertension in obese subjects. Hypertension increases cardiovascular mortality, with nighttime (sleep) blood pressure having a substantial prognostic value. We measured blood pressure in male leptin-deficient obese mice (ob/ob; n=7) and their lean wild-type littermates (+/+; n=11) during wakefulness, non-rapid-eye-movement sleep, and rapid-eye-movement sleep to investigate whether, in the absence of leptin, derangements of blood pressure are still associated with obesity and depend on the wake-sleep state. Mice were implanted with a telemetric pressure transducer and electrodes for discriminating wake-sleep states. Mean blood pressure was significantly higher in ob/ob than in +/+ mice during wakefulness (7.3+/-2.6 mm Hg) and non-rapid-eye-movement sleep (6.7+/-2.8 mm Hg) but not during rapid-eye-movement sleep (2.6+/-2.6 mm Hg). In ob/ob and +/+ mice, mean blood pressure was substantially higher during wakefulness than during non-rapid-eye-movement sleep. On passing from non-rapid-eye-movement sleep to rapid-eye-movement sleep, mean blood pressure decreased significantly in ob/ob but not in +/+ mice. The time spent during wakefulness was lower in ob/ob than in +/+ mice during the dark (active) period, whereas the opposite occurred during the light (rest) period. Consequently, mean blood pressure was significantly higher in ob/ob than in +/+ mice during the light (8.2+/-2.4 mm Hg) but not during the dark (3.0+/-2.9 mm Hg) period. These data suggest that, in the absence of leptin, obesity may entail hypertensive derangements of blood pressure, which are substantially modulated by the cardiovascular effects of the wake-sleep states.

Topics: Animals; Blood Pressure; Codon, Nonsense; Disease Models, Animal; Hypertension; Leptin; Male; Mice; Mice, Mutant Strains; Obesity; Sleep; Sleep, REM; Wakefulness

Leptin is a major determinant of energy homeostasis, acting both centrally and in the gastrointestinal tract. We previously reported that acute leptin treatment enhances the absorption of di- and tripeptides via the proton-dependent PepT1 transporter. In this study, we investigated the long term effect of leptin on PepT1 levels and activity in Caco2 cell monolayers in vitro. We then assessed the significance of the regulation of PepT1 in vivo in a model of diet-induced obesity. We demonstrated that 1) leptin regulated PepT1 at the transcriptional level, via the MAPK pathway, and at the translational level, via ribosomal protein S6 activation, in Caco2 cells and 2) this activation was systematically followed by a time- and concentration-dependent loss of leptin action reflecting desensitization. Deciphering this desensitization, we demonstrated that leptin induced a down-regulation of its own receptor protein and mRNA expression. More importantly, we showed, in mice with diet-induced obesity, that a 4-week hypercaloric diet resulted in a 46% decrease in PepT1-specific transport, because of a 30% decrease in PepT1 protein and a 50% decrease in PepT1 mRNA levels. As shown in Caco2 cells, these changes in PepT1 were supported by a parallel 2-fold decrease in leptin receptor expression in mice. Taken together, these results indicate that during induction of obesity, leptin resistance may also occur peripherally in the gastrointestinal tract, disrupting the absorption of oligopeptides and peptidomimetic drugs.

Topics: Animals; Biological Transport; Caco-2 Cells; Diet; Dipeptides; Disease Models, Animal; Down-Regulation; Gastrointestinal Tract; Humans; Intestinal Absorption; Leptin; Male; MAP Kinase Signaling System; Mice; Obesity; Peptide Transporter 1; Receptors, Leptin; RNA, Messenger; Symporters; Time Factors

Renin initiates angiotensin II formation and has no other known functions. We observed that transgenic rats (TGR) overexpressing the human renin gene (hREN) developed moderate obesity with increased body fat mass and glucose intolerance compared with nontransgenic Sprague-Dawley (SD) rats. The metabolic changes were not reversed by an angiotensin-converting enzyme inhibitor, a direct renin inhibitor, or by (pro)renin receptor blocker treatment. The obese phenotype in TGR(hREN) originated from higher food intake, which was partly compensated by increases in resting energy expenditure, total thermogenesis (postprandial and exercise activity), and lipid oxidation during the first 8 weeks of life. Once established, the difference in body weight between TGR(hREN) and SD rats remained constant over time. When restricted to the caloric intake of SD, TGR(hREN) developed an even lower body weight than nontransgenic controls. We did not observe significant changes in the cocaine and amphetamine-regulated transcript, pro-opiomelanocortin, both anorexigenic, or neuropeptide Y, orexigenic, mRNA levels in TGR(hREN) versus SD controls. However, the mRNA level of the agouti-related peptide, orexigenic, was significantly reduced in TGR(hREN) versus SD controls at the end of the study, which indicates a compensatory mechanism. We suggest that the human renin transgene initiates a process leading to increased and early appetite, obesity, and metabolic changes not related to angiotensin II. The mechanisms are independent of any currently known renin-related effects.

Topics: Adipocytes; Amides; Angiotensin II; Animals; Cells, Cultured; Disease Models, Animal; Energy Metabolism; Fumarates; Humans; Leptin; Lipid Metabolism; Male; Obesity; Phenotype; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Renin; Thermogenesis

Activity-based anorexia (ABA) is considered an animal model for anorexia nervosa (AN). By scheduled feeding and voluntary wheel running, it mimics severe body weight loss and increased physical activity in AN. Pharmacological, genetic and imaging studies implicate dopamine and serotonin in the regulation of feeding behavior, food-anticipatory activity, and food reward. Previous studies propose that the nucleus accumbens (NAc) plays an important role in these food-related processes. Here we determined dopamine and serotonin levels in the NAc upon exposure to the ABA model. Surprisingly, the release of dopamine and serotonin in the NAc were not increased during the initiation of food-anticipatory behavior in ABA rats. Dopamine release in the NAc was increased during feeding behavior in ABA rats. During ABA, levels of serotonin were low and circadian activity is blunted. We conclude that during the early stages of development of food-anticipatory activity, increased dopamine does not trigger hyperactivity.

Topics: 3,4-Dihydroxyphenylacetic Acid; Analysis of Variance; Animals; Body Temperature; Body Weight; Chromatography, High Pressure Liquid; Disease Models, Animal; Dopamine; Eating; Female; Homovanillic Acid; Hydroxyindoleacetic Acid; Hyperkinesis; Insulin; Leptin; Microdialysis; Nucleus Accumbens; Radioimmunoassay; Rats; Rats, Wistar; Serotonin; Starvation

Excess lipid accumulation resulting from an elevated supply of plasma fatty acids is linked to the pathogenesis of the metabolic syndrome and heart disease. The term 'lipotoxicity' was coined to describe how lipid accumulation leads to cellular dysfunction and death in non-adipose tissues including the heart, pancreas and liver. While lipotoxicity has been shown in cultured skeletal muscle cells, the degree of lipotoxicity in vivo and the functional consequences are unresolved. We studied three models of fatty acid overload in male mice: 5 h Intralipid((R)) and heparin infusion, prolonged high fat feeding (HFF) and genetic obesity induced by leptin deficiency (ob/ob mice). Markers of apoptosis, proteolysis and autophagy were assessed as readouts of lipotoxicity. The Intralipid((R)) infusion increased caspase 3 activity in skeletal muscle, demonstrating that enhancing fatty acid flux activates pro-apoptotic pathways. HFF and genetic obesity increased tissue lipid content but did not influence apoptosis. Gene array analysis revealed that HFF reduced the expression of 31 pro-apoptotic genes. Markers of autophagy (LC3beta and beclin-1 expression) were unaffected by HFF and were associated with enhanced Bcl(2) protein expression. Proteolytic activity was similarly unaffected by HFF or in ob/ob mice. Thus, contrary to our previous findings in muscle culture in vitro and in other non-adipose tissues in vivo, lipid overload did not induce apoptosis, autophagy or proteolysis in skeletal muscle. A broad transcriptional suppression of pro-apoptotic proteins may explain this resistance to lipid-induced cell death in skeletal muscle.

Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Autophagy; Caspase 3; Dietary Fats; Disease Models, Animal; Down-Regulation; Fat Emulsions, Intravenous; Fatty Acids, Nonesterified; Gene Expression Profiling; Hypertrophy; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle Fibers, Skeletal; Muscle, Skeletal; Muscular Atrophy; Obesity; Oligonucleotide Array Sequence Analysis; Proteasome Endopeptidase Complex; Time Factors; Transcription, Genetic

In order to investigate the mechanism of the therapeutic effect of puerarin on non-alcoholic fatty liver disease, a non-alcoholic fatty disease male rat model was induced by a high fat diet, all rats were randomly divided into a blank group, model group, simavastatin group and puerarin group. After 4 weeks of drug treatment, the liver was slided to investigate pathological morphology. Elisa was used to measure the total cholesterol (TC), triglyeride (TG) in liver, and leptin content in serum. RT-PCR and Western blotting were employed to detect liver leptin mRNA receptor expression and P-JAK2, P-STAT3 expression levels in the liver respectively. The results showed that puerarin significantly decreased the TG, TC content in liver of the non-alcoholic fatty disease rats, ameliorated steatosis in liver, lowered liver inflammatory reaction, decreased leptin level in serum, and enhanced the expression of leptin receptor mRNA and P-JAK2/P-STAT3 level. All the results demonstrated that puerarin can exhibit therapeutic effect on non-alcoholic fatty liver disease by improving leptin signal transduction through JAK2/STAT3 pathways.

Topics: Animals; Cholesterol; Dietary Fats; Disease Models, Animal; Dose-Response Relationship, Drug; Fatty Liver; Inflammation; Isoflavones; Janus Kinase 2; Leptin; Lipid Metabolism; Liver; Male; Phytotherapy; Plant Extracts; Pueraria; Rats; Rats, Wistar; Receptors, Leptin; RNA, Messenger; Signal Transduction; Simvastatin; STAT3 Transcription Factor; Triglycerides

We have previously shown that activation of leptin signalling in the heart reduces cardiac morbidity and mortality after myocardial infarction (MI). In the present study, we tested the hypothesis that leptin signalling limits cardiac apoptosis after MI through activation of signal transducer and activator of transcription (STAT)-3 responsive anti-apoptotic genes, including B-cell lymphoma (bcl)-2 and survivin, that serve to downregulate the activity of caspase-3.. Hearts from C57BL/6J and three groups of leptin-deficient Ob/Ob mice (food-restricted, ad libitum, and leptin-repleted) were examined 4 weeks after permanent left coronary artery ligation or sham operation. Inflammatory and apoptotic cell number was determined in cardiac sections by immunostaining. Expression of cardiac bcl-2, survivin, and pro and active caspase-3 was determined and correlated with in vitro caspase-3 activity. In the absence of MI, both lean and obese leptin-deficient mice exhibited increased cardiac apoptosis compared with wild-type mice. After MI, the highest rates of apoptosis were seen in the infarcted tissue of lean and obese Ob/Ob mice. Further, leptin-deficient hearts, as well as hearts from wild-type mice treated with the STAT-3 inhibitor WP1066, exhibited blunted anti-apoptotic bcl-2 and survivin gene expression, and increased caspase-3 protein expression and activity. The increased caspase-3 activity and apoptosis in hearts of leptin-deficient mice after MI was significantly attenuated in Ob/Ob mice replete with leptin, reducing apoptosis to levels comparable to that observed in wild-type mice after MI.. These results demonstrate that intact leptin signalling post-MI acts through STAT-3 to increase anti-apoptotic bcl-2 and survivin gene expression and reduces caspase-3 activity, consistent with a cardioprotective role of leptin in the setting of chronic ischaemic injury.

Topics: Animals; Apoptosis; bcl-Associated Death Protein; Caspase 3; Chronic Disease; Coronary Vessels; Disease Models, Animal; Inflammation; Inhibitor of Apoptosis Proteins; Leptin; Ligation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microtubule-Associated Proteins; Myocardial Infarction; Myocardium; Phosphorylation; Proto-Oncogene Proteins c-bcl-2; Pyridines; Repressor Proteins; Signal Transduction; STAT3 Transcription Factor; Survivin; Tyrphostins

Estrogen-deficient states are associated with hepatic steatosis. Based on previous findings obtained at the molecular and enzymatic levels, it has been suggested that estradiol exerts its lipid-lowering effects in liver through partitioning of triacylglycerols into oxidative pathways. However, information on relevant physiological response was lacking. Therefore, the purpose of the present study was to assess fatty acid oxidation rate in the liver of intact and ovariectomized rats. Tritiated water released from liver slices incubated with 9,10-[ (3)H]palmitate was measured as a reflection of in vivo fatty acid metabolism. Fatty acid oxidation rate was lowered by 34% (p<0.05), associated with 114% higher (p<0.01) hepatic triacylgylcerol content in the liver of ovariectomized as compared to intact rats. Estrogen replacement prevented all of these changes. Fatty liver has been linked with hepatic leptin resistance in obese male rats. Since leptin stimulates fatty acid oxidation in liver, we hypothesized that increased liver triacylglycerol content and decreased fatty acid oxidation might be associated with leptin resistance in ovariectomized rats. To this end, acute leptin delivery was performed. The 120-min intravenous leptin infusion increases fatty acid oxidation by 23% in the liver of ovariectomized rats, which was coupled with 24% lower hepatic triacylglycerol content. We conclude that fatty acid oxidation is decreased in the liver of ovariectomized rats, which is likely to contribute to hepatic steatosis development. Furthermore, our results suggest that leptin sensitivity is not completely lost in the liver of rats ovariectomized for 5 weeks.

Topics: Animals; Disease Models, Animal; Fatty Acids; Fatty Liver; Female; Humans; Leptin; Liver; Ovariectomy; Oxidation-Reduction; Random Allocation; Rats; Rats, Sprague-Dawley; Triglycerides

We tested the hypothesis that maternal consumption of dietary fat, independent from obesity, increases serum leptin in neonatal pups and predisposes them to adult obesity. Female rats either were fed a high-fat (HF) diet or a low-fat (LF) diet or were fed the HF diet but pair fed (PF) to the caloric intake of the LF group for 4 wk before breeding and throughout gestation and lactation. Dams consuming the HF diet had increased adiposity and were hyperphagic. At weaning, pups born to obese dams had significantly higher body fat and serum leptin levels and reduced insulin tolerance compared with offspring of LF-fed dams. Pups were weaned onto a chow diet until 8 wk of age, when they were then fed either HF or LF diet. At 18 wk of age, offspring from obese HF dams weighed more than offspring from nonobese LF or PF dams, and offspring eating HF diet weighed significantly more than those eating LF diet. Consequently, HF-fed offspring of obese HF dams weighed the most and LF-fed offspring from obese HF dams were similar in weight to HF-fed offspring from nonobese LF dams. These data suggest that maternal obesity exerts an independent effect on offspring body weight that is of similar magnitude as the effect of the offspring's adult diet. Furthermore, there was no difference in body weight between the nonobese LF and PF offspring on either diet. Together, these data suggest that maternal adiposity, and not dietary fat per se, induces hyperleptinemia and insulin resistance in offspring, as well as an increased body weight that persists into adulthood.

Topics: Adiposity; Animals; Body Composition; Body Weight; Dietary Fats; Disease Models, Animal; Eating; Female; Insulin Resistance; Leptin; Maternal Nutritional Physiological Phenomena; Obesity; Pregnancy; Pregnancy, Animal; Prenatal Exposure Delayed Effects; Rats; Rats, Long-Evans

The aim was to examine the role of cyclooxygenase (COX)-2-mediated inflammation in the development of obese linked insulin resistance and fatty liver. The rats were fed separately regular diet (CONT), high-fat diet (HFD) ad libitum, or energy restrictedly for 12 weeks. Rats fed HFD ad libitum were further divided into three subgroups co-treated with vehicle (HFa), or a selective COX-2 inhibitor celecoxib (HFa-Cel) or mesulid (HFa-Mes). Euglycemic hyperinsulinemic clamp (EHC) experiment was performed at the end of study. Another set of rats with similar grouping was further divided into those with a 4, 8, or 12-week intervention period for hepatic sampling. Body weight was increased significantly and similarly in HFa, HFa-Cel, and HFa-Mes. Time-dependent increases in plasma insulin, glucose, 8-isoprostanes, leptin levels, homeostasis model assessment of insulin resistance (HOMA-IR) and hepatic triglyceride contents shown in HFa were significantly reversed in HFa-Cel and HFa-Mes. During EHC period, the reduction in stimulation of whole body glucose uptake, suppression of hepatic glucose production and metabolic clearance rate of insulin shown in HFa were significantly reversed in HFa-Cel and HFa-Mes. The enhanced COX-2 and tumor necrosis factor-alpha (TNF-alpha) but attenuated PPAR-gamma and C/EBP-alpha mRNA expressions in epididymal fat shown in HFa were significantly reversed in HFa-Cel and HFa-Mes. The increases in average cell size of adipocytes and CD68 positive cells shown in HFa were also significantly reversed in HFa-Cel and HFa-Mes. Our findings suggest that COX-2 activation in fat inflammation is important in the development of insulin resistance and fatty liver in high fat induced obese rats.

Topics: Adipocytes; Adipogenesis; Adipose Tissue; Animals; Blood Glucose; Body Weight; Celecoxib; Cell Size; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dinoprost; Disease Models, Animal; Fatty Liver; Insulin; Insulin Resistance; Leptin; Liver; Macrophages; Male; Membrane Proteins; Obesity; Panniculitis; Pyrazoles; Rats; Rats, Sprague-Dawley; Sulfonamides; Time Factors; Triglycerides; Tumor Necrosis Factor-alpha

Obesity and type 2 diabetes increase the risk of atherosclerosis. It is unknown to what extent this reflects direct effects on the arterial wall or secondary effects of hyperlipidaemia.. The effect of obesity and type 2 diabetes on the development of atherosclerosis and inflammation, in the absence or presence of hyperlipidaemia, was assed in wild-type (n = 36) and human apolipoprotein B (apoB) transgenic mice (n = 27) that were fed normal chow or 60% fat for 12 months.. Fat-feeding caused obesity, glucose intolerance and elevated plasma leptin and soluble vascular cell adhesion molecule-1 (sVCAM-1) in both wild-type and apoB transgenic mice. In wild-type mice, plasma very low-density lipoprotein cholesterol (VLDL-C) and low-density lipoprotein cholesterol (LDL-C) were unaffected by fat-feeding. ApoB transgenic mice had mildly elevated plasma LDL-C (approximately 1 mmol L(-1)), which was slightly increased by fat-feeding. Sixty-four per cent of fat-fed wild-type mice vs. 7% of chow-fed wild-type mice had lipid-staining intimal lesions in the aortic root (P = 0.002). Eighty-six per cent of fat-fed apoB transgenic mice had lipid-staining lesions and the median lesion area was 8.0 times higher than in fat-fed wild-type mice (P = 0.001). Intracellular adhesion molecule-1 staining of the aortic endothelium was most pronounced in the fat-fed apoB transgenic mice.. Our findings suggest that diet-induced type 2 diabetes causes early atherosclerosis in the absence of dyslipidaemia, and that even a moderate level of LDL-C markedly augments this effect.

Topics: Animals; Arteritis; Atherosclerosis; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dietary Fats; Disease Models, Animal; Female; Humans; Hyperlipidemias; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Obesity; Random Allocation; Risk Factors; Statistics as Topic; Time Factors; Vascular Cell Adhesion Molecule-1

Drinking tea is recommended for promoting health due to its bioactive nutrients, such as catechins and caffeine. In Tokushima area, we have a unique traditional tea, named Awa tea, which are fermented with Lactobacillus pentosus and Lactobacillus plantarum. The present study was designed to investigate anti-obesity effects of the Awa tea and compare with those of non-fermented green tea. Obese male Wistar rats (19 weeks of age) were given by low energy diets containing 3% of Awa and green tea extracts, respectively, or without any tea extracts (control), for 4 weeks. Awa tea contained smaller amount of catechins than green tea, although they contained similar amounts of polyphenols. This finding indicates that there are distinct kinds of polyphenols from catechins. The diets containing Awa and green tea extracts further decreased whole body weight, fat tissue mass and plasma leptin level, compared with control diet. In addition, their diets increased the daily amount of lipid excreted to feces and total 24-h-energy consumption, compared with the control group. However, there is no significant difference in these anti-obesity effects between Awa tea and green tea. Our results indicate that Awa lactate-fermented tea as well as green tea similarly enhance the effect of diet restriction on obesity, at least in part, through the increase in fat energy consumption and the decrease in fat absorption in rats.

Topics: Adipose Tissue; Animals; Body Weight; Camellia sinensis; Combined Modality Therapy; Diet, Reducing; Disease Models, Animal; Energy Metabolism; Fermentation; Insulin; Lactobacillus plantarum; Leptin; Lipid Metabolism; Male; Obesity; Plant Extracts; Rats; Rats, Wistar; Tea

Gastrointestinal mucositis occurs as a consequence of cytotoxic treatment. In the present study, we tested whether leptin can protect gut epithelial cells from methotrexate (MTX)-induced intestinal damage. Non-pretreated and pretreated with MTX Caco-2 cells were incubated with increasing concentrations of leptin for 24 h. Cell proliferation and apoptosis were assessed using FACS analysis. Adult rats were divided into three experimental groups: Control rats; MTX-rats were treated with a single dose of MTX, and MTX-LEP rats were also treated with leptin for 3 d. Intestinal mucosal damage (Park score), mucosal structural changes (bowel and mucosal weight, mucosal DNA and protein content, villus height and crypt depth), enterocyte proliferation, and enterocyte apoptosis were measured at sacrifice. RT-PCR was used to determine the level of bax and bcl-2 mRNA expression. In the vitro experiment, treatment with leptin of Caco-2 cells pre-treated with MTX resulted in a significant stimulation of cell proliferation and inhibition of cell apoptosis in a dose-dependent manner. In the vivo experiment, MTX-LEP rats demonstrated a greater jejunal and ileal bowel and mucosal weight, mucosal DNA and protein, villus height and crypt depth, as well as a greater enterocyte proliferation index compared to MTX-animals. MTX-LEP rats also showed a trend toward an increase in enterocyte apoptosis that was accompanied by an increase in bax mRNA and decrease in bcl-2 mRNA expression. In conclusion, leptin enhances proliferation and decreases apoptosis in Caco-2 cells pretreated with MTX. In a rat model of MTX-induced mucositis, treatment with leptin improves intestinal recovery and enhances enterocyte turnover.

Topics: Animals; Annexin A5; Apoptosis; bcl-2-Associated X Protein; Caco-2 Cells; Cell Proliferation; Disease Models, Animal; Dose-Response Relationship, Drug; Enterocytes; Fluorescein-5-isothiocyanate; Fluorescent Dyes; Humans; Ileum; Intestinal Mucosa; Jejunum; Leptin; Male; Methotrexate; Mucositis; Organ Size; Random Allocation; Rats; Rats, Sprague-Dawley; Recovery of Function; RNA, Messenger; Time Factors

Corticosterone and insulin play complex roles in the amount and composition of calories ingested, and the utilization and deposition of this energy. Understanding the interplay of these two hormones is complicated because increasing concentrations of corticosterone dose-dependently increase circulating insulin levels. We addressed individual contributions of each hormone by controlling, at steady-state levels, corticosterone (by adrenalectomy and exogenous replacement) and insulin (by streptozotocin-induced destruction of pancreatic beta-cells and exogenous replacement) across a spectrum of concentrations in rats, creating 8 hormonal combinations. For 5 days after surgery, all rats received chow. At day 5, they were subdivided into those that continued to receive chow and those that had a choice between chow, lard, and 32% sucrose for a further 5 days. During the choice/chow period, total calories ingested were stimulated by corticosterone and choice diet, and subject to a corticosterone-insulin interaction. Sucrose, but not lard, intake was stimulated by insulin. Body weight was increased by insulin, decreased by high corticosterone, and unaffected by diet. White adipose tissue depot weights were stimulated by insulin, corticosterone, and diet. Plasma triglycerides, free fatty acids, total ketone bodies, glucose, and glycerol were all significantly increased by corticosterone and the choice diet but inhibited by insulin. In contrast, plasma leptin was only increased by insulin and diet, plasma glucagon and liver glycogen was only affected by insulin and liver triglycerides, and arcuate nucleus proopiomelanocortin mRNA was only influenced by diet. Collectively, these data show that corticosterone and insulin determine the intake, form, and compartmentalization of energy both independently and interactively.

Topics: Adrenalectomy; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Corticosterone; Diabetes Mellitus, Experimental; Disease Models, Animal; Energy Intake; Energy Metabolism; Glycogen; Insulin; Leptin; Liver; Male; Neuropeptide Y; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Streptozocin; Triglycerides

Maternal obesity due to long-term high-fat diet (HFD) consumption leads to faster growth in offspring during suckling, and increased adiposity at 20 days of age. Decreased expression of the orexigenic neuropeptide Y (NPY) and increased anorexigenic proopiomelanocortin (POMC) mRNA expression were observed in the fed state. However, hunger is the major drive to eat and hypothalamic appetite regulators change in response to meals. Therefore, it is important to compare both satiated and fasting states. Female Sprague-Dawley rats (8 weeks old) were fed a cafeteria-style HFD (15.33 kJ/g) or chow for 5 weeks before mating, with the same diet continuing throughout gestation and lactation. At postnatal day 20, male pups were killed either after overnight fasting or in the fed state. Pups from obese dams were hyperphagic during both pre- and postweaning periods. Pups from obese dams had higher hypothalamic mRNA expression of POMC and NPY Y1 receptor, but lower hypothalamic melanocortin-4 receptor (MC4R) and its downstream target single-minded gene 1 (Sim1), in the fed state. Overnight fasting reduced circulating glucose, insulin, and leptin and increased hypothalamic NPY Y1 receptor mRNA in pups from both lean and obese dams. Hypothalamic NPY and agouti-related protein (AgRP) were only increased by fasting in pups from obese dams; reductions in MC4R and Sim1 were only seen in pups from lean dams. At weaning, the suppressed orexigenic signals in offspring from obese dams were normalized after overnight fasting, although anorexigenic signaling appeared impaired in these animals. This may contribute to their hyperphagia and faster growth.

Topics: Agouti-Related Protein; Animals; Animals, Newborn; Appetite Regulation; Basic Helix-Loop-Helix Transcription Factors; Blood Glucose; Disease Models, Animal; Fasting; Female; Hyperphagia; Hypothalamus; Insulin; Leptin; Male; Maternal Nutritional Physiological Phenomena; Neuropeptide Y; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Receptor, Melanocortin, Type 4; Repressor Proteins; RNA, Messenger

The aim of the study was develop to an animal model that links coping style to insulin resistance. We hypothesized that the psychogenetically selected Roman Low Avoidance (RLA) rats may serve as such a model. To test this hypothesis, we submitted both RLA and Roman High avoidance (RHA) rats to a series of intravenous glucose tolerance tests (IVGTT). These IVGTT were followed by post mortem metabolic characterization of the selection lines. It was found that plasma insulin levels are markedly elevated in the passively coping RLA rat, both in baseline conditions and during the intravenous glucose tolerance tests. The elevation in plasma insulin was accompanied with increased levels of plasma corticosterone, FFA, leptin and triglycerides but not by changes in body weight. We conclude that the passive, highly emotional RLA rat is metabolically different from both the RHA rat and the standard control Wistar rat and may serve as a non-obese animal model for insulin resistance.

Topics: Analysis of Variance; Animals; Avoidance Learning; Behavior, Animal; Blood Glucose; Body Weight; Disease Models, Animal; Drinking; Eating; Exploratory Behavior; Glucose Tolerance Test; Insulin; Insulin Resistance; Leptin; Male; Rats; Rats, Inbred Strains

Conjugated linoleic acid (CLA) isomers have been reported to reduce body weight and beneficially affect glucose metabolism in animals, but the results are inconsistent and seem to depend on animal model and type of CLA isomer. In the present study, feeding male Zucker fa/fa rats diets supplemented with 1% trans-10, cis-12-CLA for 10 d reduced the liver TAG content without improving the overall adiposity, and enhanced hepatic mitochondrial and peroxisomal beta-oxidation. The increased carnitine palmitoyltransferase (CPT)-I activity and mRNA level as well as the increased n-3:n-6 PUFA ratio in liver suggest that trans-10, cis-12-CLA increased the hepatic beta-oxidation by stimulation of PPARalpha. The reduced hepatic TAG content may be partly due to lower activity of stearoyl-CoA desaturase, as the ratios of 18 : 1n-9:18 : 0 and 16 : 1n-7:16 : 0 were reduced in liver. Trans-10, cis-12-CLA increased the CPT-I mRNA in retroperitoneal white adipose tissue (WAT), and increased uncoupling protein-2 mRNA in epididymal and inguinal WAT depots. Leptin mRNA level was decreased in all examined WAT depots, implying reduced insulin sensitivity. The resistin mRNA level was increased in all WAT depots, whereas adiponectin mRNA was reduced in inguinal and retroperitoneal WAT. The present results suggest that dietary supplementation with trans-10, cis-12-CLA may increase the catabolism of lipids in liver and adipose tissue. Moreover, we provide new data suggesting that trans-10, cis-12-CLA modulates the expression of resistin and adiponectin inversely in adipose tissue. Hence, the present results suggest that trans-10, cis-12-CLA may have some beneficial effects on lipid metabolism and adiposity but possibly reduces insulin sensitivity.

Topics: Adipokines; Adipose Tissue; Animals; Carnitine O-Palmitoyltransferase; Dietary Supplements; Disease Models, Animal; Fatty Acids; Growth; Ion Channels; Leptin; Linoleic Acids, Conjugated; Lipid Metabolism; Liver; Male; Mitochondrial Proteins; Obesity; Organ Size; Rats; Rats, Zucker; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Triglycerides; Uncoupling Protein 2

Treatment of diabetes type 2 using chronic pharmacological inhibition of dipeptidyl peptidase 4 (DP4) still requires an in-depth analysis of models for chronic DP4 deficiency, because adverse reactions induced by some DP4 inhibitors have been described.. In the present study, a novel congenic rat model of DP4 deficiency on a "DP4-high" DA rat genetic background was generated (DA.F344-Dpp4(m)/ SvH rats) and comprehensively phenotyped.. Similar to chronic pharmacological inhibition of DP4, DP4 deficient rats exhibited a phenotype involving reduced diet-induced body weight gain and improved glucose tolerance associated with increased levels of glucagon-like peptide-1 (GLP-1) and bound leptin as well as decreased aminotransferases and triglycerides. Additionally, DA.F344-Dpp4(m)/SvH rats showed anxiolytic-like and reduced stress-like responses, a phenomenon presently not targeted by DP4 inhibitors. However, several immune alterations, such as differential leukocyte subset composition at baseline, blunted natural killer cell and T-cell functions, and altered cytokine levels were observed.. While this animal model confirms a critical role of DP4 in GLP-1-dependent glucose regulation, genetically induced chronic DP4 deficiency apparently also affects stress-regulatory and immuneregulatory systems, indicating that the use of chronic DP4 inhibitors might have the potential to interfere with central nervous system and immune functions in vivo.

Topics: Animals; Animals, Congenic; Body Weight; Cytokines; Dipeptidyl Peptidase 4; Disease Models, Animal; Female; Glucagon-Like Peptide 1; Killer Cells, Natural; Leptin; Phenotype; Rats; Rats, Inbred F344; T-Lymphocytes; Transaminases; Triglycerides

Behavioral therapies aimed at reducing excess body fat result in limited fat loss after dieting. To understand the causes for maintenance of adiposity, high-fat (HF) diet-induced obese (DIO) mice were switched to a low-fat chow diet, and the effects of chow on histological and molecular alterations of adipose tissue and metabolic parameters were examined. DIO mice reduced and stabilized their body weights after being switched to chow (HF-chow), but retained a greater amount of adiposity than chow-fed mice. Reduction in adipocyte volume, not number, caused a decrease in fat mass. HF-chow mice showed normalized circulating insulin and leptin levels, improved glucose tolerance, and reduced inflammatory status in white adipose tissue (WAT). Circulating leptin levels corrected for fat mass were lower in HF-chow mice. Leptin administration was used to test whether reduced leptin level of HF-chow mice inhibited further fat loss. Leptin treatment led to an additional reduction in adiposity. Finally, HF-HF mice had lower mRNA levels of beta(3) adrenergic receptor (beta(3)-AR) in epididymal WAT (EWAT) compared to chow-fed mice, and diet change led to an increase in the WAT beta(3)-AR mRNA levels that were similar to the levels of chow-fed mice, suggesting an elevation in sympathetic activation of WAT during diet switch relative to HF-HF mice leading to the reduced leptin level and proinflammatory cytokine content. In summary, HF-chow mice were resistant to further fat loss due to leptin insufficiency. Diet alteration from HF to low fat improved metabolic state of DIO mice, although their adiposity was defended at a higher level.

Topics: Adipose Tissue, Brown; Adipose Tissue, White; Adiposity; Animals; Blood Glucose; Cell Size; Diet, Fat-Restricted; Dietary Fats; Disease Models, Animal; Eating; Fatty Liver; Feeding Behavior; Inflammation; Insulin; Leptin; Macrophages; Male; Mice; Mice, Inbred C57BL; Obesity; Receptors, Adrenergic, beta-3; RNA, Messenger; Time Factors; Weight Loss

Leptin has profibrogenic effects in liver, although the mechanisms of this process are unclear. We sought to elucidate the direct and indirect effects of leptin on hepatic stellate cells (HSCs).. HSCs from Sprague-Dawley rats were exposed to leptin and expression of collagen-I, tissue inhibitor of matrix metalloproteinases-1 (TIMP1), transforming growth factor beta1 (TGF-beta1), and connective tissue growth factor (CTGF/CCN2) was assessed. The effects of medium from Kupffer cells (KCs) and sinusoidal endothelial cells (SECs) following leptin were evaluated in HSCs; alpha-smooth muscle actin (alphaSMA) production and KC signaling were analyzed.. HSCs were not activated by incubation with leptin. However, HSCs cultured with medium taken from KCs that were incubated with leptin had increased expression of collagen I, TIMP1, TGF-beta1, and CTGF/CCN2, as well as alphaSMA protein levels and proliferation. These effects were leptin receptor dependent because conditioned medium from KCs isolated from leptin receptor-deficient Zucker (fa/fa) rats did not activate HSCs. In KCs incubated with leptin, messenger RNA and protein expression of TGF-beta1 and CTGF/CCN2 increased. Leptin potentiated signal transducer and activator of transcription 3, AKT, and extracellular signal-related kinase 1/2 phosphorylation in KCs and increased AP-1 and nuclear factor-kappaB DNA binding. Finally, addition of anti-TGF-beta to KC-conditioned medium inhibited HSC expression of collagen I, TIMP1, and CTGF/CCN2, whereas signal transducer and activator of transcription 3 inhibitor attenuated TGF-beta1 production by KC.. Leptin mediates HSC activation and liver fibrosis through indirect effects on KC; these effects are partly mediated by TGF-beta1.

Topics: Animals; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Hepatic Stellate Cells; Hydrogen Peroxide; Immunoblotting; Immunohistochemistry; Kupffer Cells; Leptin; Liver Cirrhosis; Male; Random Allocation; Rats; Rats, Sprague-Dawley; Reference Values; Reverse Transcriptase Polymerase Chain Reaction; Sensitivity and Specificity; Transforming Growth Factor beta1; Up-Regulation

A growing percentage of the population is resistant to two key hormones - insulin and leptin - as a result of increased obesity, often leading to significant health consequences such as type 2 diabetes. Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of signalling by both of these hormones, so that inhibitors of this enzyme may provide promise for correcting endocrine abnormalities in both diabetes and obesity. As with other tyrosine phosphatases, identification of viable drug candidates targeting PTP1B has been elusive because of the nature of its active site. Beginning with novel phosphotyrosine mimetics, we have designed some of the most potent PTP1B inhibitors. However, their highly acidic structures limit intrinsic permeability and pharmacokinetics. Ester prodrugs of these inhibitors improve their drug-like properties with the goal of delivering these nanomolar inhibitors to the cytoplasm of cells within target tissues. In addition to identifying prodrugs that is able to deliver active drugs into cells to inhibit PTP1B and increase insulin signalling, these compounds were further modified to gain a variety of cleavage properties for targeting activity in vivo. One such prodrug candidate improved insulin sensitivity in ob/ob mice, with lowered fasting blood glucose levels seen in the context of lowered fasting insulin levels following 4 days of intraperitoneal dosing. The results presented in this study highlight the potential for design of orally active drug candidates targeting PTP1B, while also delineating the considerable challenges remaining.

Topics: Administration, Oral; Animals; Biomimetics; Blood Glucose; Diabetes Mellitus; Disease Models, Animal; Drug Design; Fasting; Insulin; Leptin; Male; Mice; Obesity; Prodrugs; Protein Kinase Inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Rats; Rats, Zucker; Signal Transduction

We have previously reported that transgenic mice expressing nuclear sterol regulatory element-binding protein 1c (nSREBP-1c) in adipose tissue under the control of aP2 promoter, an inherited lipodystrophic model with insulin resistance and fatty liver, developed with age liver lesions similar to those of human nonalcoholic steatohepatitis (NASH). Because the spontaneous NASH model mice had marked hypoadiponectinemia, here we assessed the effect of adiponectin transgenically expressed in the liver of nSREBP-1c transgenic mice. The nSREBP-1c/adiponectin double-transgenic mice showed hepatic adiponectin production and restored circulating adiponectin levels. Both subtypes of adiponectin receptors proved to be expressed normally in the liver. Peroxisome proliferator-activated receptor-alpha was up-regulated in the double-transgenic mice. Histologic findings similar to those observed in the liver specimens of patients with NASH were observed in the livers from nSREBP-1c transgenic mice at the age of 30 weeks. In contrast, the NASH-like hepatic lesions were obviously attenuated in age-matched double-transgenic mice. Immunoreactivity of 8-hydroxy-2'-deoxyguanosine and proliferating cell nuclear antigen-positive cells were increased in nSREBP-1c transgenic mice, but not in the double-transgenic mice. Postload plasma glucose levels were significantly lower in the double-transgenic mice compared with nSREBP-1c transgenic mice, whereas serum leptin levels did not differ significantly in the 2 groups. These observations suggest that hypoadiponectinemia plays a key role in the pathogenesis of NASH associated with insulin resistance and may provide a clue to the novel therapy for human NASH.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adiponectin; Alanine Transaminase; Animals; Aspartate Aminotransferases; Blotting, Northern; Blotting, Western; Deoxyguanosine; Disease Models, Animal; Fatty Liver; Female; Glucose Tolerance Test; Histocytochemistry; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; PPAR alpha; Proliferating Cell Nuclear Antigen; Receptors, Adiponectin; RNA; Sterol Regulatory Element Binding Protein 1

Metabolic syndrome (MS) encompasses a clustering of risk factors for cardiovascular disease, including obesity, insulin resistance, and dyslipidemia. We characterized a new mouse model carrying a dominant mutation, C57BL/6J-Nmf15/+ (B6-Nmf15/+), which develops additional complications of MS such as adipose tissue inflammation and cardiomyopathy. A backcross was used to genetically map the Nmf15 locus. Mice were examined in the comprehensive laboratory animal monitoring system, and dual energy X-ray absorptiometry and blood chemistry analyses were performed. Hypothalamic LEPR, SOCS1, and STAT3 phosphorylation were examined. Cardiac function was assessed by echo- and electrocardiography. Adipose tissue inflammation was characterized by in situ hybridization and measurement of Jun kinase activity. The Nmf15 locus mapped to distal mouse chromosome 5 with an LOD (logarithm of odds) score of 13.8. Nmf15 mice developed obesity by 12 weeks of age. Plasma leptin levels were significantly elevated in pre-obese Nmf15 mice at 8 weeks of age and an attenuated STAT3 phosphorylation in the hypothalamus suggests a primary leptin resistance. Adipose tissue from Nmf15 mice showed a remarkable degree of inflammation and macrophage infiltration as indicated by expression of the F4/80 marker and increased phosphorylation of JUN N-terminal kinase 1/2. Lipidosis was observed in tubular epithelial cells and glomeruli of the kidney. Nmf15 mice demonstrate both histological and pathophysiological evidence of cardiomyopathy. The Nmf15 mouse model provides a new entry point into pathways mediating leptin resistance and obesity. It is one of few models that combine many aspects of MS and can be useful for testing new therapeutic approaches for combating obesity complications, particularly cardiomyopathy.

Topics: Adipose Tissue; Animals; Blood Glucose; Cardiomyopathies; Chromosome Mapping; Disease Models, Animal; Female; Hypothalamus; Inflammation; Leptin; Lipidoses; Male; Metabolic Syndrome; Mice; Mice, Inbred AKR; Mice, Inbred C57BL; Mice, Mutant Strains; Obesity; Oxygen Consumption; Quantitative Trait Loci

Major components of energy homeostasis, including feeding behavior and glucose and lipid metabolism, are subject to circadian rhythms. Recent studies have suggested that dysfunctions of molecular clock genes are involved in the development of obesity and diabetes. To examine whether metabolic states per se alter the circadian clock in the central nervous system (CNS), we analyzed the daily mRNA expression profiles of core clock genes in the caudal brainstem nucleus of the solitary tract (NTS). In lean C57BL/6 mice, transcript levels of the core clock genes (Npas2, Bmal1, Per1, Per2 and Rev-erbalpha) clearly showed 24-h rhythmicity. On the other hand, the expression profiles of Bmal1 and Rev-erbalpha were attenuated in mice with high fat diet-induced obesity as well as genetically obese KK-A(y) and ob/ob mice. Clock expression levels were increased in mice with high fat diet-induced obesity and Cry1 expression levels were decreased in KK-A(y) and ob/ob mice. In addition, peroxisome proliferator-activated receptor alpha (PPARalpha), which reportedly increases the BMAL1 transcriptional level, was up-regulated in the NTS of these murine models of obesity and insulin resistance, suggesting involvement of PPARalpha in the attenuation of circadian rhythms in the NTS in obese states. Furthermore, a circadian expression profile of a downstream target of clock genes, the large conductance Ca(2+)-activated K(+)channel, was disturbed in the NTS of these murine obesity models. These perturbations might contribute to neuronal dysfunction in obese states. This is the first report showing that obesity perturbs the circadian expressions of core clock genes in the CNS.

Topics: Animals; ARNTL Transcription Factors; Basic Helix-Loop-Helix Transcription Factors; Cell Cycle Proteins; Circadian Rhythm; CLOCK Proteins; Disease Models, Animal; DNA-Binding Proteins; Gene Expression; Gene Expression Profiling; Intracellular Signaling Peptides and Proteins; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Tissue Proteins; Nuclear Proteins; Nuclear Receptor Subfamily 1, Group D, Member 1; Obesity; Period Circadian Proteins; Potassium Channels, Calcium-Activated; PPAR alpha; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Solitary Nucleus; Trans-Activators; Transcription Factors

Does diet-induced obesity persist after an obesigenic diet is removed? We investigated this question by providing male C57BL/6 mice with free access to two different obesigenic diets followed by a switch to chow to determine if obesity was reversible.. Male C57BL/6 mice were randomly assigned to five weight-matched groups: 1) C group that continuously received a chow diet; 2) HF group on a 60% high fat diet; 3) EN group on the high fat diet plus liquid Ensure; 4) HF-C group switched from high fat to chow after 7 weeks; 5) EN-C group switched from high fat plus Ensure to chow after 7 weeks. All food intake was ad libitum. Body weight was increased after 7 weeks on both obesigenic diets (44.6+/-0.65, 39.8+/-0.63, and 28.6+/-0.63 g for EN, HF, and C groups, respectively) and resulted in elevated concentrations of serum insulin, glucose, and leptin and lower serum triglycerides. Development of obesity in HF and EN mice was caused by increased energy intake and a relative decrease of average energy output along with decreased ambulatory activity. After the switch to chow, the HF-C and EN-C groups lost weight but subsequently maintained a state of persistent obesity in comparison to the C group (34.8+/-1.2, 34.1+/-1.2 vs. 30.8+/-0.8 g respectively; P<0.05) with a 40-50% increase of body fat. All serum hormones and metabolites returned to control levels with the exception of a trend for increased leptin. The HF-C and EN-C groups had an average energy output in line with the C group and the persistent obesity was maintained despite a non-significant increase of energy intake of less than 1 kcal/d at the end of the study.. Our results illustrate the importance of considering the history of energy imbalance in determining body weight and that a persistent elevation of body weight after removal of obesigenic diets can result from very small increases of energy intake.

Topics: Adipose Tissue; Animals; Blood Glucose; Body Fat Distribution; Body Weight; Diet; Disease Models, Animal; Energy Intake; Energy Metabolism; Glycerol; Leptin; Male; Mice; Mice, Inbred C57BL; Motor Activity; Obesity; Time Factors

In 2005, a Japanese epidemiological study showed that increase in plasma glucose levels is a risk factor for gastric cancer. However, no animal model has hitherto shown any association between diabetes mellitus and neoplasia in the stomach. Diabetic (db/db) mice have obese and diabetic phenotypes, including hyperglycemia, because of disruption of the leptin receptor. In the present study, effects of hyperglycemia and/or hyperinsulinemia on the development of proliferative lesions were therefore examined in db/db mice given N-methyl-N-nitrosourea (MNU). A total of 120 mice were assigned to four groups: Group A, 40 db/db mice with MNU; Group B, 40 + /db mice with MNU; Group C, 30 misty (wild-type) mice with MNU; Group D, 10 db/db mice without MNU. MNU was given at 60 ppm in drinking water for 20 weeks. Subgroups of animals were sacrificed at weeks 21 and 30 and blood samples were collected to measure glucose, insulin, leptin, and adiponectin concentrations. The removed stomachs were fixed in formalin, and embedded in paraffin for histological examination and immunohistochemistry. At week 30 in Groups A, B, C and D, hyperplasia was observed in 100, 79, 57, and 0%, and dysplasia in 91, 43, 71, and 0%, respectively. Adenocarcinomas and pepsinogen-altered pyloric glands (PAPG), putative preneoplastic lesions, were observed only in Group A, at an incidence of 45%. The serum levels of insulin and leptin were also elevated in Group A. Gastric carcinogenesis by MNU was enhanced in db/db mice, possibly in association with hyperinsulinemia and hyperleptinemia.

Topics: Adenocarcinoma; Animals; Body Weight; Carcinogens; Diabetes Complications; Disease Models, Animal; Gastric Mucosa; Insulin; Leptin; Male; Methylnitrosourea; Mice; Mice, Inbred Strains; Precancerous Conditions; Stomach Neoplasms

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, oligo-/anovulation, and polycystic ovarian morphology and is a complex endocrine disorder that also presents with features of the metabolic syndrome, including obesity, insulin resistance, and dyslipidemia. These latter symptoms form cardiometabolic risk factors predisposing individuals to the development of type 2 diabetes and cardiovascular disease (CVD). To date, animal models to study PCOS in the context of the metabolic syndrome and CVD risk have been lacking. The aim of this study was to investigate the JCR:LA-cp rodent as an animal model of PCOS associated with the metabolic syndrome. Metabolic indices were measured at 6 and 12 wk, and reproductive parameters including ovarian morphology and estrous cyclicity were assessed at 12 wk or adulthood. At 6 wk of age, the cp/cp genotype of the JCR:LA-cp strain developed visceral obesity, insulin resistance, and dyslipidemia (hypertriglyceridemia and hypercholesterolemia) compared with control animals. Serum testosterone concentrations were not significantly different between groups at 6 wk of age. However, at 12 wk, the cp/cp genotype had higher serum testosterone concentrations, compared with control animals, and presented with oligoovulation, a decreased number of corpora lutea, and an increased number of total follicles, in particular atretic and cystic follicles. The cardiometabolic risk factors in the cp/cp animals were exacerbated at 12 wk including obesity, insulin resistance, and dyslipidemia. The results of this study demonstrate that the JCR:LA-cp rodent may be a useful PCOS-like model to study early mechanisms involved in the etiology of cardiometabolic risk factors in the context of both PCOS and the metabolic syndrome.

Topics: Animals; Blood Glucose; Disease Models, Animal; Estrous Cycle; Fasting; Female; Insulin; Insulin Resistance; Intra-Abdominal Fat; Leptin; Liver; Metabolic Syndrome; Ovary; Polycystic Ovary Syndrome; Rats; Receptors, Leptin; Risk Factors; Triglycerides

We investigated the effect of adiponectin (APN) deficiency in the CD4(+)CD45RB(high) transfer model of colitis. Recombination activating gene (Rag)-1 knockout (KO) and Rag-1 APN KO mice receiving CD4(+)CD45RB(high) cells developed colitis of comparable severity. Colonic mRNA expression of IL-6 and IL-17 was lower in Rag-1 APN KO mice compared to Rag-1 KO mice. Rag-1 APN KO and Rag-1 KO mice released comparable amounts of IL-6 from colon cultures, whereas release of IL-17 was higher in Rag-1 APN KO compared to Rag-1 KO mice. Expression of TNFalpha mRNA was comparable in Rag-1 KO and Rag-1 APN KO mice, but protein release was lower in Rag-1 APN KO mice compared to Rag-1 KO mice. Levels of IFNgamma and IL-10 at mRNA and protein were comparable in Rag-1 KO and Rag-1 APN KO mice. Higher mRNA expression of VCAM-1 was observed in the colon of healthy APN KO compared to WT mice, while induction of colitis resulted in a comparable increase in VCAM-1 expression in Rag-1 KO and Rag-1 APN KO mice. In conclusion, although APN regulates expression of cytokines and adhesion molecules in the colon, this does not result in alteration of overall colitis severity in the CD4(+)CD45RB(high) transfer model.

Topics: Adiponectin; Animals; Cell Adhesion Molecules; Colitis; Colon; Cytokines; Disease Models, Animal; Homeodomain Proteins; Leptin; Leukocyte Common Antigens; Leukocytes; Lymphocyte Transfusion; Mice; Mice, Inbred C57BL; Mice, Knockout

Feeding behavior control and dietetics with consequent weight reduction can be the most efficacious and fundamental methods to normalize fasting blood glucose. However, pioglitazone treatment has been found to incrementally increase body weight. In this study, we investigated whether the combined application of a 5-HT(2A) receptor antagonist, sarpogrelate, with pioglitazone can provide a clinical benefit.. Diabetic male KK-A(y) mice were randomly assigned to four groups: those receiving 10 mg/kg/day pioglitazone treatment for 30 days (pioglitazone group, n = 7), those receiving 30 mg/kg/day sarpogrelate treatment for 30 days (sarpogrelate group, n = 7), those receiving both agents for 30 days (pioglitazone + sarpogrelate group, n = 7) and those receiving no treatment (control group, n = 7).. Feed intake was lower in the pioglitazone + sarpogrelate group than in the pioglitazone group. Water intake was also significantly lower in the pioglitazone, sarpogrelate and pioglitazone + sarpogrelate groups than in the control group. Combined application (pioglitazone + sarpogrelate) resulted in a 176% increase in leptin concentration compared with vehicle control. Body weight was significantly higher in the pioglitazone group, and there was a trend toward a smaller increment in body weight in the pioglitazone + sarpogrelate group. Mean values, calculated by multiplying insulin concentration and nonfasting glucose concentration, were significantly lower in the pioglitazone + sarpogrelate group than in the control group.. These results suggest that the combined application of sarpogrelate with pioglitazone provides therapeutic benefits not only in preventing adverse effects but also in the treatment of diabetes.

Topics: Abdominal Fat; Adipocytes; Animals; Blood Glucose; Cell Count; Diabetes Mellitus, Type 2; Disease Models, Animal; Drinking; Drug Therapy, Combination; Eating; Hypoglycemic Agents; Insulin; Leptin; Lipids; Male; Mice; Pioglitazone; Serotonin 5-HT2 Receptor Antagonists; Succinates; Thiazolidinediones

Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the HD gene. Besides psychiatric, motor and cognitive symptoms, HD patients suffer from sleep disturbances. In order to screen a rat model transgenic for HD (tgHD rats) for sleep-wake cycle dysregulation, we monitored their circadian activity peaks in the present study. TgHD rats of both sexes showed hyperactivity during the dark cycle and more frequent light cycle activity peaks indicative for a disturbed sleep-wake cycle. Focusing on males at the age of 4 and 14 months, analyses of receptor levels in the hypothalamus and the basal forebrain revealed that 5-HT(2A)- and adrenergic alpha(2)-receptor densities in these regions were significantly altered in tgHD rats compared to their wild-type littermates. Adrenergic receptor densities correlated negatively with the light cycle hyperactivity peaks at later stages of the disease in male tgHD rats. Furthermore, reduced leptin levels, a feature associated with circadian misalignment, were present. Our study demonstrates that the male tgHD rat is a suitable model to investigate HD associated sleep alterations. Further studies are warranted to elucidate the role of adrenergic- and 5-HT(2A)-receptors as therapeutic targets for dysregulation of the circadian activity in HD.

Topics: Animals; Brain; Choline O-Acetyltransferase; Disease Models, Animal; Female; Huntington Disease; Hypothalamus; Intracellular Signaling Peptides and Proteins; Leptin; Male; Motor Activity; Neurons; Neuropeptides; Orexins; Parasomnias; Photoperiod; Prosencephalon; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Receptor, Serotonin, 5-HT2A; Receptors, Adrenergic, alpha-2

WOKW (Wistar Ottawa Karlsburg W) rats develop metabolic syndrome closely resembling human disorder. In crossing studies between disease-prone WOKW and disease-resistant DA (Dark Agouti) rats, several quantitative trait loci (QTLs) were mapped. To prove the in vivo relevance of QTLs, congenic DA.WOKW rats, briefly termed DA.3aW, DA.3bW, DA.5W, DA.10W, and DA.16W, were generated by transferring chromosomal regions of WOKW chromosomes 3, 5, 10, and 16 onto DA genetic background. Male (n=12) and female (n=12) rats of each congenic strain and their parental strain DA were characterized for adiposity index (AI), serum leptin, and serum insulin as well as serum cholesterol and serum triglycerides as single facets of metabolic syndrome at the age of 30 weeks. The data showed a significant higher AI for male and female DA.3aW and female DA.16W compared with DA. Serum leptin was significantly elevated in male and female DA.3aW, DA.10W, and DA.16W rats in comparison with DA. Rats of both sexes of DA.10W and female DA.16W showed significantly elevated serum insulin in comparison to DA. Female rats of all congenics had significantly higher serum cholesterol compared with DA, while males did not differ. Finally, triglycerides were only elevated in male DA.16W. The results demonstrate an involvement of WOKW chromosomes 3, 5, 10, and 16 in developing facets of the metabolic syndrome.

Topics: Adiposity; Animals; Animals, Congenic; Cholesterol; Chromosomes, Mammalian; Crosses, Genetic; Disease Models, Animal; Female; Genetic Predisposition to Disease; Insulin; Leptin; Male; Metabolic Syndrome; Phenotype; Quantitative Trait Loci; Rats; Rats, Inbred Strains; Sex Factors; Species Specificity; Time Factors; Triglycerides

The purpose of this study was to determine the long-term impact of obesity and related metabolic abnormalities in the absence and presence of hypertension on renal injury and salt-sensitivity of blood pressure. Markers of renal injury and blood pressure salt sensitivity were assessed in 52- to 55-wk-old normotensive melanocortin-4 receptor-deficient (MC4R-/-) mice and lean C57BL/6J wild-type (WT) mice and in 22-wk-old MC4R-/- and WT mice made hypertensive by N(G)-nitro-L-arginine methyl ester (L-NAME) in the drinking water for 8 wk. Old MC4R-/- mice were 60% heavier, hyperinsulinemic, and hyperleptinemic but had similar mean arterial pressure (MAP) as WT mice (115 +/- 2 and 117 +/- 2 mmHg) on normal salt diet (0.4% NaCl). A high-salt diet (4.0% NaCl) for 12 days did not raise MAP in obese or lean mice [DeltaMAP: MC4R (-/-) 4 +/- 2 mmHg; WT, 2 +/- 1 mmHg]. Obese MC4R-/- mice had 23% greater glomerular tuft area and moderately increased GFR compared with WT mice. Bowman's space, total glomerular area, mesangial matrix, urinary albumin excretion (UAE), renal TGF-beta and collagen expression were not significantly different between old MC4R-/- and WT mice. Renal lipid content was greater but renal macrophage count was markedly lower in MC4R-/- than WT mice. Mild increases in MAP during L-NAME treatment (approximately 16 mmHg) caused small, but greater, elevations in UAE, renal TGF-beta content, and macrophage infiltration in MC4R-/- compared with WT mice without significant changes in glomerular structure. Thus despite long-term obesity and multiple metabolic abnormalities, MC4R-/- mice have no evidence of renal injury or salt-sensitivity of blood pressure. These observations suggest that elevations in blood pressure may be necessary for obesity and related metabolic abnormalities to cause major renal injury or that MC4R-/- mice are protected from renal injury by mechanisms that are still unclear.

Topics: Age Factors; Albuminuria; Animals; Biomarkers; Blood Pressure; Body Weight; Disease Models, Animal; Glomerular Filtration Rate; Heart Rate; Hyperinsulinism; Hypertension; Kidney; Kidney Diseases; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Receptor, Melanocortin, Type 4; Sodium Chloride, Dietary

Food intake is activated by hypothalamic orexigenic neuropeptide Y (NPY), which is mainly under the dual control of leptin and ghrelin. Rat adjuvant arthritis (AA), similarly as human rheumatoid arthritis, is associated with cachexia caused by yet unknown mechanisms. The aim of our study was to evaluate NPY expression in hypothalamic arcuate nuclei (nARC) under the conditions of AA-induced changes in leptin, ghrelin and adiponectin. Since IL-1beta is involved in the central induction of anorexia, we studied its expression in the nARC as well.. AA was induced to Lewis rats using complete Freund's adjuvant. On days 12, 15 and 18 after complete Freund's adjuvant injection, the levels of leptin, adiponectin, ghrelin and IL-1beta were determined by RIA or ELISA. The mRNA expressions for NPY, leptin receptor (OB-R), ghrelin receptor (Ghsr) and IL-1beta were determined by TaqMan RT-PCR from isolated nARC.. In AA rats, decreased appetite, body mass and epididymal fat stores positively correlated with reduced circulating and epididymal fat leptin and adiponectin. Ghrelin plasma levels were increased. In nARC, mRNA for OB-R, Ghsr and NPY were overexpressed in AA rats. AA rats showed overexpression of mRNA for IL-1beta in nARC while circulating, and spleen IL-1beta was unaltered.. During AA, overexpression of orexigenic NPY mRNA in nARC along with enhanced plasma ghrelin and lowered leptin levels occur. Decreased food intake indicates a predominant effect of the anorexigenic pathway. Activated expression of IL-1beta in nARC suggests its role in keeping AA-induced anorexia in progress. The reduction in adiponectin may also contribute to AA-induced anorexia.

Topics: Adiponectin; Animals; Anorexia; Appetite; Appetite Regulation; Arcuate Nucleus of Hypothalamus; Arthritis; Disease Models, Animal; Gene Expression Regulation; Ghrelin; Hypothalamo-Hypophyseal System; Interleukin-1beta; Leptin; Male; Neuropeptide Y; Rats; Rats, Inbred Lew; RNA, Messenger; Signal Transduction; Up-Regulation

Maternal obesity is present in 20-34% of pregnant women and has been associated with both intrauterine growth restriction and large-for-gestational age fetuses. While fetal and placental functions have been extensively studied in the baboon, no data are available on the effect of maternal obesity on placental structure and function in this species. We hypothesize that maternal obesity in the baboon is associated with a maternal inflammatory state and induces structural and functional changes in the placenta. The major findings of this study were: 1) decreased placental syncytiotrophoblast amplification factor, intact syncytiotrophoblast endoplasmic reticulum structure and decreased system A placental amino acid transport in obese animals; 2) fetal serum amino acid composition and mononuclear cells (PBMC) transcriptome were different in fetuses from obese compared with non-obese animals; and 3) maternal obesity in humans and baboons is similar in regard to increased placental and adipose tissue macrophage infiltration, increased CD14 expression in maternal PBMC and maternal hyperleptinemia. In summary, these data demonstrate that in obese baboons in the absence of increased fetal weight, placental and fetal phenotype are consistent with those described for large-for-gestational age human fetuses.

Topics: Adaptation, Physiological; Amino Acid Transport System A; Amino Acids; Animals; Body Weight; Chorionic Villi; Crown-Rump Length; Disease Models, Animal; Female; Fetal Blood; Inflammation; Kidney; Leptin; Leukocytes, Mononuclear; Lipopolysaccharide Receptors; Macrophages; Matched-Pair Analysis; Maternal-Fetal Exchange; Obesity; Organ Size; Papio; Placenta; Pregnancy; Pregnancy Complications; Trophoblasts

The aim of this research was to investigate differential gene expression of cyclin-dependent kinase inhibitors (CKIs) in white adipose tissue (WAT) and liver from high-fat fed male Wistar rats with or without vitamin C (VC) supplementation (750 mg/kg of body weight). After 56 d of experimentation, animals fed on a cafeteria diet increased significantly body weights and total body fat. Reverse transcription-polymerase chain reaction (RT-PCR) studies showed that cafeteria diet decreased p21 and p57 mRNA expression in subcutaneous WAT and increased p21 mRNA in liver. Overall, these data provide new information about the role of high fat intake on mRNA levels of several CKIs with implications in adipogenesis, cell metabolism and weight homeostasis. Interestingly, VC supplementation partially prevented diet-induced adiposity and increased p27 mRNA in liver without any changes in the other tissues and genes analyzed. Thus, hepatic mRNA changes induced by ascorbic acid indicate a possible role of these genes in diet-induced oxidative stress processes.

Topics: Adipogenesis; Adipose Tissue, White; Animals; Antioxidants; Ascorbic Acid; Body Weight; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Cyclin-Dependent Kinase Inhibitor p57; Cyclin-Dependent Kinase Inhibitor Proteins; Dietary Fats; Disease Models, Animal; Energy Intake; Gene Expression Regulation; Leptin; Liver; Male; Malondialdehyde; Obesity; Organ Size; Oxidative Stress; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

We examined mechanisms leading to the impairment of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF)-dependent vasorelaxation in response to acutely administered leptin in rats with the metabolic syndrome.. Effects of leptin on blood pressure and NO and cGMP in the aortic wall were studied in four groups of rats: (1) lean control, (2) obese, fed "cafeteria diet" for 3months (hyperleptinemia and hyperinsulinemia), (3) hyperleptinemia induced by administration of exogenous leptin for 8days, and (4) fructose-fed, receiving 20% fructose in the drinking water for 8weeks (hyperinsulinemia with slightly elevated leptin).. Stimulatory effect of leptin on NO and cGMP production in the aortic wall was impaired in obese and hyperleptinemic groups but not in the fructose group. In contrast, EDHF-mimetic effect of leptin was impaired in obese and fructose-fed but not in the hyperleptinemic group. Leptin increased tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) in the aortic wall, and this effect was impaired in obese and fructose-fed animals. The EDHF-mimetic effect of leptin was abolished by phosphoinositide 3-kinase inhibitor, wortmannin, whereas its effect on NO was not. In addition, IRS-1 phosphorylation at Ser(307) and Ser(612) was enhanced in obese and fructose-fed but not in hyperleptinemic rats.. These results indicate that: (1) long-term hyperleptinemia induces resistance to acute vascular NO-mimetic effect of leptin in obesity/metabolic syndrome, (2) leptin stimulates EDHF in IRS-1 and PI3K-dependent manner, and this effect is impaired in obesity due to excessive serine phosphorylation of IRS-1.

Topics: Animals; Aorta; Biological Factors; Blood Pressure; Cyclic GMP; Disease Models, Animal; Endothelium, Vascular; Insulin; Leptin; Male; Metabolic Syndrome; Nitric Oxide; Obesity; Phosphorylation; Rats; Rats, Wistar; Recombinant Proteins; Vasodilation

Maternal obesity accentuates offspring obesity in dams bred to develop diet-induced obesity (DIO) on a 31% fat, high-sucrose, high-energy (HE) diet but has no effect on offspring of diet-resistant (DR) dams. Also, only DIO dams become obese when they and DR dams are fed HE diet throughout gestation and lactation. We assessed glucose and oleic acid (OA) sensitivity of dissociated ventromedial hypothalamic nucleus (VMN) neurons from 3- to 4-wk old offspring of DIO and DR dams fed chow or HE diet using fura-2 calcium imaging to monitor intracellular calcium fluctuations as an index of neuronal activity. Offspring of DIO dams fed chow had approximately 2-fold more glucose-inhibited (GI) neurons than did DR offspring. This difference was eliminated in offspring of DIO dams fed HE diet. At 2.5 mM glucose, offspring of chow-fed DIO dams had more GI neurons that were either excited or inhibited by OA than did DR offspring. Maternal HE diet intake generally increased the percentage of neurons that were excited and decreased the percentage that were inhibited by OA in both DIO and DR offspring. However, this effect was more pronounced in DIO offspring. These data, as well as concentration-dependent differences in OA sensitivity, suggest that genotype, maternal obesity, and dietary content can all affect the sensitivity of offspring VMN neurons to glucose and long-chain fatty acids. Such altered sensitivities may underlie the propensity of DIO offspring to become obese when fed high-fat, high-sucrose diets.

Topics: Animals; Animals, Newborn; Blood Glucose; Body Weight; Calcium; Dietary Fats; Dietary Sucrose; Disease Models, Animal; Fatty Acids; Female; Genotype; Insulin; Leptin; Male; Neurons; Obesity; Oleic Acid; Pregnancy; Pregnancy, Animal; Prenatal Exposure Delayed Effects; Rats; Rats, Inbred Strains; Ventromedial Hypothalamic Nucleus

Leptin is thought to reduce food intake, in part, by increasing sensitivity to satiation signals, including CCK. Leptin action in both forebrain and hindbrain reduces food intake, and forebrain leptin action augments both the anorexic and neuronal activation responses to CCK. Here, we asked whether leptin signaling in hindbrain also enhances these responses to CCK. We found that food intake was strongly inhibited at 30 min after a combination of 4th-intracerebroventricular (4th-icv) leptin injection and intraperitoneal CCK administration, whereas neither hormone affected intake during this period when given alone. Leptin injections targeted directly at the dorsal vagal complex (DVC) similarly enhanced the anorexic response to intraperitoneal CCK. Intra-DVC leptin injection also robustly increased the number of neurons positive for phospho-STAT3 staining in the area surrounding the site of injection, confirming local leptin receptor activation. Conversely, the anorexic response to 4th-icv leptin was completely blocked by IP devazepide, a CCKA-R antagonist, suggesting that hindbrain leptin reduces intake via a mechanism requiring endogenous CCK signaling. We then asked whether hindbrain leptin treatment enhances the dorsomedial hindbrain, hypothalamus, or amygdala c-Fos responses to IP CCK. We found that, in contrast to the effects of forebrain leptin administration, 4th-icv leptin injection had no effect on CCK-induced c-Fos in any structures examined. We conclude that leptin signaling in either forebrain or hindbrain areas can enhance the response to satiation signals and that multiple distinct neural circuits likely contribute to this interaction.

Topics: Animals; Anorexia; Cholecystokinin; Devazepide; Disease Models, Animal; Eating; Hormone Antagonists; Injections, Intraventricular; Leptin; Male; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Receptors, Leptin; Rhombencephalon; Satiety Response; STAT3 Transcription Factor; Vagus Nerve

The purpose of the current study was to determine the effect of the Artemisia capillaris ethyl acetate (ACE) fraction on diet-induced obesity and to elucidate the underlying mechanism. The ACE fraction treatment decreased the leptin level and fat accumulation in cultured 3T3-L1 adipocytes through the free fatty acids released in the medium. The ACE fraction significantly suppressed the expression of peroxisome proliferator-activated receptor-gamma in cultured 3T3-L1 adipocytes. To determine the effect of the ACE fraction on C57BL/6J male mice, the mice were separated into six groups: normal control (N), N plus 0.1 g/kg body weight ACE (NB), high fat control group (HF), HF plus 0.05 g/kg of body weight ACE (HFA), HF plus 0.1 g/kg of body weight ACE (HFB), and HF plus 0.03 g/kg of body weight rosiglitazone (RG) groups. We speculate that the HFB group exhibits a lipid-lowering effect via increased mitochondrial beta-oxidation, of which the rate-limiting enzyme is carnitine palmitoyl transferase I, the activity of which was significantly increased. Also, the activity of fatty acid synthase, a key enzyme of fatty acid synthesis, was markedly suppressed (19%) in the HFB group, as compared to the HF group, and glycerol-3-phosphate dehydrogenase activity, which is very useful in studying adipogenic differentiation in vitro, was markedly suppressed (30%) in the HFB group compared with the HF group. Furthermore, the HFB group showed lowered hepatic lipid droplet accumulation and adipose tissue weight and size. We suggest that 0.1 g of the ACE fraction/kg of body weight may exert an anti-obesity effect in C57BL/6J mice by enhancing lipid metabolism.

Topics: 3T3-L1 Cells; Adipocytes; Adipose Tissue; Animals; Artemisia; Carnitine O-Palmitoyltransferase; Cell Line; Diet; Dietary Fats; Disease Models, Animal; Fatty Acids, Nonesterified; Flavonoids; Glycerolphosphate Dehydrogenase; Hypolipidemic Agents; Leptin; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Obesity; Phenols; Phytotherapy; Plant Extracts; PPAR gamma; Rosiglitazone; Thiazolidinediones; Triglycerides

Carnitine-deficient juvenile visceral steatosis (JVS) mice, suffering from fatty acid metabolism abnormalities, have reduced locomotor activity after fasting. We examined whether JVS mice exhibit specific defect in the feeding response to fasting, a key process of anti-famine homeostatic mechanism. Carnitine-deficient JVS mice showed grossly defective feeding response to 24 h-fasting, with almost no food intake in the first 4 h, in marked contrast to control animals. JVS mice also showed defective acyl-ghrelin response to fasting, less suppressed leptin, and seemingly normal corticotropin-releasing factor (CRF) expression in the hypothalamus despite markedly increased plasma corticosterone. The anorectic response was ameliorated by intraperitoneal administration of carnitine or acyl-ghrelin, with decreased CRF expression. Intracerebroventricular treatment of CRF type 2 receptor antagonist, anti-sauvagine-30, recovered the defective feeding response of 24 h-fasted JVS mice. The defective feeding response to fasting in carnitine-deficient JVS mice is due to the defective acyl-ghrelin and enhanced CRF signaling in the hypothalamus through fatty acid metabolism abnormalities. In this animal model, carnitine normalizes the feeding response through an inhibition of CRF.

Topics: Animals; Carnitine; Corticotropin-Releasing Hormone; Disease Models, Animal; Fasting; Fatty Acids; Fatty Liver; Feeding Behavior; Ghrelin; Hypothalamus; Leptin; Mice; Mice, Mutant Strains; Receptors, Corticotropin-Releasing Hormone

Leptin-stimulated Stat3 activation in proopiomelanocortin (POMC)-expressing neurons of the hypothalamus plays an important role in maintenance of energy homeostasis. While Stat3 activation in POMC neurons is required for POMC expression, the role of elevated basal Stat3 activation as present in the development of obesity has not been directly addressed. Here, we have generated and characterized mice expressing a constitutively active version of Stat3 (Stat3-C) in POMC neurons (Stat3-C(POMC) mice). On normal chow diet, these animals develop obesity as a result of hyperphagia and decreased POMC expression accompanied by central leptin and insulin resistance. This unexpected finding coincides with POMC-cell-specific, Stat3-mediated upregulation of SOCS3 expression inhibiting both leptin and insulin signaling as insulin-stimulated PIP(3) (phosphatidylinositol-3,4,5 triphosphate) formation and protein kinase B (AKT) activation in POMC neurons as well as with the fact that insulin's ability to hyperpolarize POMC neurons is largely reduced in POMC cells of Stat3-C(POMC) mice. These data indicate that constitutive Stat3 activation is not sufficient to promote POMC expression but requires simultaneous PI3K (phosphoinositide 3-kinase)-dependent release of FOXO1 repression. In contrast, upon exposure to a high-fat diet, food intake and body weight were unaltered in Stat3-C(POMC) mice compared with control mice. Taken together, these experiments directly demonstrate that enhanced basal Stat3 activation in POMC neurons as present in control mice upon high-fat feeding contributes to the development of hypothalamic leptin and insulin resistance.

Topics: Agouti-Related Protein; Animals; Body Composition; Body Weight; Disease Models, Animal; Eating; Electrophoretic Mobility Shift Assay; Enzyme-Linked Immunosorbent Assay; Feedback; Gene Expression Regulation; Glucose Tolerance Test; Green Fluorescent Proteins; Hypothalamus; In Vitro Techniques; Insulin; Insulin Resistance; Leptin; Leukemia Inhibitory Factor; Membrane Proteins; Mice; Mice, Transgenic; Neural Inhibition; Neurons; Neuropeptide Y; Obesity; Patch-Clamp Techniques; Phosphatidylinositol 3-Kinases; Pro-Opiomelanocortin; Signal Transduction; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Transfection

A high-fat diet can increase adiposity, leptin secretion, and plasma fatty acid concentration. In hypertension, this scenario may accelerate cardiac hypertrophy and development of heart failure but could be protective by activating peroxisome proliferator-activated receptors and expression of mitochondrial oxidative enzymes. We assessed the effects of a high-fat diet on the development of left ventricular hypertrophy, remodeling, contractile dysfunction, and the activity of mitochondrial oxidative enzymes. Mice (n = 10-12/group) underwent transverse aortic constriction (TAC) or sham surgery and were fed either a low-fat diet (10% of energy intake as fat) or a high-fat diet (45% fat) for 6 wk. The high-fat diet increased adipose tissue mass and plasma leptin and insulin. Left ventricular mass and chamber size were unaffected by diet in sham animals. TAC increased left ventricular mass (approximately 70%) and end-systolic and end-diastolic areas (approximately 100% and approximately 45%, respectively) to the same extent in both dietary groups. The high-fat diet increased plasma free fatty acid concentration and prevented the decline in the activity of the mitochondrial enzymes medium chain acyl-coenzyme A dehydrogenase (MCAD) and citrate synthase that was observed with TAC animals on a low-fat diet. In conclusion, a high-fat diet did not worsen cardiac hypertrophy or left ventricular chamber enlargement despite increases in fat mass and insulin and leptin concentrations. Furthermore, a high-fat diet preserved MCAD and citrate synthase activities during pressure overload, suggesting that it may help maintain mitochondrial oxidative capacity in failing myocardium.

Topics: Acyl-CoA Dehydrogenase; Adiposity; Animals; Biomarkers; Blood Glucose; C-Reactive Protein; Citrate (si)-Synthase; Dietary Fats; Disease Models, Animal; Disease Progression; Fatty Acids, Nonesterified; Heart Failure; Hypertension; Hypertrophy, Left Ventricular; Inflammation Mediators; Insulin; Interleukin-6; Leptin; Male; Mice; Mice, Inbred C57BL; Mitochondria, Heart; Mitochondria, Muscle; Muscle, Skeletal; Myocardial Contraction; Myocardium; Oxidation-Reduction; RNA, Messenger; Time Factors; Triglycerides; Tumor Necrosis Factor-alpha; Ventricular Remodeling

Circulating leptin is elevated in some forms of obesity-related hypertension, associated with impaired baroreflex function. Leptin receptors are present on vagal afferent fibers and neurons within the solitary tract nucleus, providing an anatomic distribution consistent with baroreflex modulation. Although solitary tract nucleus microinjection of 144 fmol/60 nL of leptin had no significant effect on baroreflex sensitivity for control of the heart rate in urethane/chloralose-anesthetized Sprague-Dawley rats, 500 fmol of leptin impaired baroreflex sensitivity for bradycardia in response to increases in pressure (1.15+/-0.04 versus 0.52+/-0.12 ms/mm Hg; P<0.01). Transgenic ASrAOGEN rats with low brain angiotensinogen have an upregulation of the leptin receptor and p85 alpha mRNA in the dorsal medulla relative to Sprague-Dawley rats. Consistent with these observations, the response to leptin was enhanced in ASrAOGEN rats, because both the 144-fmol (1.46+/-0.08 versus 0.75+/-0.10 ms/mm Hg; P<0.001) and 500-fmol (1.36+/-0.32 versus 0.44+/-0.06 ms/mm Hg; P<0.05) leptin microinjections impaired baroreflex sensitivity. At these doses, leptin microinjection had no effect on resting pressure, heart rate, or the tachycardic response to decreases in pressure in Sprague-Dawley or ASrAOGEN rats. Thus, exogenous leptin at sites within the solitary tract nucleus impairs the baroreflex sensitivity for bradycardia induced by increases in arterial pressure, consistent with a permissive role in mediating increases in arterial pressure. Baroreflex inhibition was enhanced in animals with evidence of increased leptin receptor and relevant signaling pathway mRNA.

Topics: Analysis of Variance; Animals; Baroreflex; Bradycardia; Disease Models, Animal; Heart Rate; Leptin; Male; Microinjections; Probability; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Reference Values; RNA, Messenger; Sensitivity and Specificity; Solitary Nucleus; Sympathetic Nervous System

Spinal cord injury influences many hormones that are known to be involved in the modulation of neurotrophic, neurogenic, and neuroprotective events. Recent studies showed that leptin could be neuroprotective, enhancing neuronal survival in vitro and in vivo. The objective of this study was to evaluate the pattern of the serum leptin levels in rats during acute traumatic SCI.. Forty male Sprague-Dawley rats were divided randomly into 4 groups. In the control group, neither laminectomy nor SCI was performed; only laminectomy was performed without SCI in the sham group. In the cervical and thoracic spinal trauma groups, laminectomies were performed following the same trauma procedure. Blood samples were drawn 2, 6, 12, and 24 hours after the procedures and assayed immediately.. In the first 2 hours, levels of leptin were similar in control and sham-operated groups and higher in neurotrauma groups (P < 0.05). At the sixth hour, leptin levels increased in the sham-operated group, decreased in the neurotrauma groups (P < 0.05), and did not change in the control group (P > 0.05). At the 12th hour, the levels of leptin increased in all groups (P > 0.05). At the 24th hour, they decreased in the control, sham-operated, and cervical groups (P < 0.05); levels did not change in the thoracic group (P > 0.05). The decrease was higher in the control group than in the other groups (P < 0.05).. Activation of endogenous leptin secretion started immediately after the SCI. The level of neurologic lesion (either cervical or thoracic regions) affected the levels of serum leptin differently, but with the exception of the first 12-hour period, this difference did not reach a statistically significant level.

Topics: Analysis of Variance; Animals; Disease Models, Animal; Laminectomy; Leptin; Male; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries; Time Factors

To test the hypothesis that obesity resulting from deletion of the leptin gene or the leptin receptor gene results in increased knee osteoarthritis (OA), systemic inflammation, and altered subchondral bone morphology.. Leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) female mice compared with wild-type mice were studied, to document knee OA via histopathology. The levels of serum proinflammatory and antiinflammatory cytokines were measured using a multiplex bead immunoassay. Cortical and trabecular subchondral bone changes were documented by microfocal computed tomography, and body composition was quantified by dual x-ray absorptiometry.. Adiposity was increased by approximately 10-fold in ob/ob and db/db mice compared with controls, but it was not associated with an increased incidence of knee OA. Serum cytokine levels were unchanged in ob/ob and db/db mice relative to controls, except for the level of cytokine-induced neutrophil chemoattractant (keratinocyte chemoattractant; murine analog of interleukin-8), which was elevated. Leptin impairment was associated with reduced subchondral bone thickness and increased relative trabecular bone volume in the tibial epiphysis.. Extreme obesity due to impaired leptin signaling induced alterations in subchondral bone morphology without increasing the incidence of knee OA. Systemic inflammatory cytokine levels remained largely unchanged in ob/ob and db/db mice. These findings suggest that body fat, in and of itself, may not be a risk factor for joint degeneration, because adiposity in the absence of leptin signaling is insufficient to induce systemic inflammation and knee OA in female C57BL/6J mice. These results imply a pleiotropic role of leptin in the development of OA by regulating both the skeletal and immune systems.

Topics: Adiposity; Animals; Biomechanical Phenomena; Body Composition; Bone and Bones; Bone Density; Cytokines; Disease Models, Animal; Female; Inflammation; Joints; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity, Morbid; Osteoarthritis; Receptors, Leptin; Risk Factors; Signal Transduction

Topics: Animals; Biomechanical Phenomena; Disease Models, Animal; Humans; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Osteoarthritis; Osteoarthritis, Knee; Receptors, Leptin; Risk Factors

Understanding the early factors affecting obesity development in males and females may help to prevent obesity and may lead to the discovery of more effective treatments for those already obese. The Otsuka Long-Evans Tokushima Fatty (OLETF) rat model of obesity is characterized by hyperphagia-induced obesity, due to a spontaneous lack of CCK(1) receptors. In the present study, we focused on the behavioral and physiological aspects of obesity development from weaning to adulthood. We examined body weight, feeding efficiency, fat pad [brown, retroperitoneal, inguinal and epydidimal (in males)] weight, inguinal adipocyte size and number, leptin and oxytocin levels, body mass index, waist circumference, and females' estrous cycle structure. In the males, central hypothalamic gene expression was also examined. OLETF rats presented overall higher fat and leptin levels, larger adipocytes, and increased waist circumference and BMI from weaning until adulthood, compared with controls. Analysis of developmental patterns of gene expression for hypothalamic neuropeptides revealed peptide-specific patterns that may underlie or be a consequence of the obesity development. Analysis of the developmental trajectories toward obesity within the OLETF strain revealed that OLETF females developed obesity in a more gradual manner than the males, presenting delayed obesity-related "turning points," with reduced adipocyte size but larger postweaning fat pads and increased adipocyte hyperplasia compared with the males. Intake decrease in estrus vs. proestrus was significantly less in OLETF vs. Long-Evans Tokushima Otsuka females. The findings highlight the importance of using different sex-appropriate approaches to increase the efficacy of therapeutic interventions in the treatment and prevention of chronic early-onset obesity.

Topics: Adipocytes; Adipose Tissue; Age Factors; Aging; Animals; Blood Glucose; Body Mass Index; Body Weight; Chronic Disease; Disease Models, Animal; Disease Progression; Eating; Estrus; Feeding Behavior; Female; Gene Expression Regulation, Developmental; Hyperphagia; Hypothalamus; Leptin; Male; Neuropeptides; Obesity; Oxytocin; Rats; Rats, Inbred OLETF; Receptor, Cholecystokinin A; RNA, Messenger

The adipocytokine leptin has been proposed to increase cardiovascular risk in both obese and diabetic individuals. In the current study, therefore, we used apoE-deficient mice to examine the effects of leptin on both lesion size and calcification.. Mice were treated with once daily intraperitoneal injections of leptin (125 microg/mouse/d) for 2 months. The mice were then euthanized, and sections of the aortic root and thoracic aorta analyzed histomorphometrically. Measurements of lesion size and surface area occupied by atherosclerotic lesions did not reveal any differences between nontreated and leptin-treated animals. However, von Kossa staining of the aortic root demonstrated an 8.3+/-2.0-fold increase in lesion calcification as well as a 2.5+/-0.6-fold increase in valvular calcification in those animals treated with leptin. In addition, the percent total lesion area demonstrating ALP-positive staining was 5.4+/-2.1-fold greater in leptin-treated mice when compared to nontreated control mice. This increase in ALP staining was also accompanied by an increase in the expression of the osteoblast-specific markers, osteocalcin, and osteopontin.. Based on these observations, we conclude that leptin may increase cardiovascular risk by promoting osteogenic differentiation and thus vascular calcification.

Topics: Alkaline Phosphatase; Animals; Aorta; Aortic Valve; Apolipoproteins E; Atherosclerosis; Body Weight; Calcinosis; Cattle; Cell Differentiation; Cells, Cultured; Disease Models, Animal; Female; Humans; Leptin; Lipids; Mice; Mice, Knockout; Myocytes, Smooth Muscle; Osteoblasts; Osteocalcin; Osteopontin; Recombinant Proteins; Risk Factors

Breast cancer continues to be a major cause of cancer deaths in women. Estrogen, which is also produced by the adipose tissue, is held responsible for the elevated risk of breast cancer in obese women. However, the adipose tissue secrets hormones and adipokines such as leptin and IGF-I and these substances could also contribute to an increased breast cancer risk for obese women. In this study, the impact of obesity on cell proliferation was investigated. The carcinogen 7, 12, dimethylbenz[a]anthracene (DMBA) was administered to normal weight and diet-induced obese female Sprague-Dawley rats. Cell proliferation was evaluated by immunohistological staining of BrdU-incorporation. In the mammary glands and inguinal lymphatic nodes of the obese rats, cell proliferation was significantly increased, indicating a significant influence of obesity on breast cancer. Effects of leptin, estrogen, and IGF-I on the proliferation of MCF-7 cells in vitro were assessed using an MTT assay. Cell culture experiments demonstrated a mitogenic role of these three mediators on cell proliferation. Our data demonstrate a stimulative effect of substances produced by the adipose tissue on breast cancer. Body weight specific cell proliferation suggests that obesity-related adipokines and mediators enhance cell proliferation and increase the risk for breast cancer.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Adenocarcinoma; Analysis of Variance; Animals; Body Weight; Breast Neoplasms; Carcinogens; Cell Line, Tumor; Cell Proliferation; Dietary Fats; Disease Models, Animal; Estradiol; Female; Groin; Humans; Immunohistochemistry; Insulin-Like Growth Factor I; Leptin; Lymph Nodes; Lymphatic Metastasis; Mammary Neoplasms, Experimental; Obesity; Random Allocation; Rats; Rats, Sprague-Dawley; Time Factors

Yellow KK mice carrying the 'yellow obese' gene Ay are a well established polygenic model for human non-insulin dependent diabetes mellitus. These animals develop marked adiposity and decreased glucose tolerance relative to their control littermates, KK mice. The authors monitored glucose tolerance in KK-Ay mice over time and observed a significant (P

Topics: Age Factors; Amyloid; Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Glucagon; Glucagon-Like Peptide 1; Glucose; Insulin; Islet Amyloid Polypeptide; Leptin; Male; Mice; Mice, Inbred ICR

The aim of this study was to examine the effect of Chlorella vulgaris on glucose metabolism in rats fed a high fat diet. Sixty 6-week-old male Wistar rats were divided into two groups: normal diet group (N group) and high fat diet group (H group); then the rats in each group were further divided into three subgroups and fed either Chlorella-free diets or diets with 5% (C5) or 10% (C10) (wt/wt) Chlorella for 9 weeks. Serum leptin concentration was significantly lower in the NC10 and HC10 groups than in the N and H groups. The fasting glucose concentration and homeostasis model assessment of insulin resistance of the HC10 group were significantly lower than those of the H group. Glutamate transporter 4 protein expression was significantly higher in the HC10 group than the H group. In conclusion, 10% Chlorella intake was more effective for blood glucose regulation than 5% Chlorella intake in rats fed a high fat diet. Chlorella intake may prevent insulin resistance in Wistar rats fed a high fat diet.

Topics: Animals; Blood Glucose; Chlorella vulgaris; Diet; Dietary Fats; Disease Models, Animal; Glucose Transporter Type 4; Hypoglycemic Agents; Insulin Resistance; Leptin; Male; Models, Animal; Obesity; Rats; Rats, Wistar

Rats with diet-induced obesity (DIO) usually experience hyperleptinemia. Thus, leptin produced by adipocytes does not deplete adipocyte fat, which implying a leptin resistance in adipocytes during overnutrition. Here, we induced hyperleptinemia in rats by feeding them a diet consisting of 45% fat. In epididymal adipose tissues, the mRNA and protein levels of a putative leptin resistant factor, suppressor of cytokine signaling 3 (SOCS-3), were increased. The mRNA levels of SOCS-3 in adipocytes differentiated from adipose-derived stromal cells (ADSCs) were higher in DIO rats than in rats on a 10% fat diet. Using SOCS-3 short hairpin RNA lentivirus interference, we found decreased expression of acetyl-CoA carboxylase mRNA (a marker of de novo lipogenesis) and increased expression of acetyl-CoA oxidase mRNA (a marker of fat oxidation) in SOCS-3-knockdown adipocytes after incubation with 50 nM leptin for 6 h. We conclude that the SOCS-3 knockdown may have increased the leptin-mediated in situ fatty acid oxidation in the DIO adipocytes, and therefore, SOCS-3 might be an excellent target for therapeutic intervention for obesity.

Topics: Adipocytes; Animals; Cells, Cultured; Diet, Atherogenic; Disease Models, Animal; Down-Regulation; Drug Resistance; Fatty Acids; Gene Knockdown Techniques; Leptin; Lipid Metabolism; Male; Obesity; Oxidation-Reduction; Rats; Rats, Wistar; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins

To study the effects and its mechanisms of total flavonoids of Litsea coreana (TFLC) on insulin resistance (IR) in rats with hyperlipidemia.. The rats were fed with high fat emulsion to make IR models. The effects of TFLC on the state of impaired glucose tolerance (IGT), fasting serum glucose (FSG), fasting serum insulin (FINS), fasting serum lipids (TC, TG, LDL-C, HDL-C), free fatty acid (FFA) and Leptin were observed,and the index of insulin sensitivity (ISI) was calculated.. TFLC could significantly improve the state of IGT and depress the level of FSG, FINS, TC, TG, LDL-C, FFA and leptin of model rats, which could also increase the content of HDL-C and ISI significantly and enhance the sensitivity of insulin.. TFLC has obvious effects on increasing insulin sensitivity and improving the insulin resistance in rats with hyperlipidemia,which may contribute to the regulating effects on the disturbance of lipid metabolism and the decrease of leptin level.

Topics: Animals; Blood Glucose; Dietary Fats; Disease Models, Animal; Drugs, Chinese Herbal; Flavonoids; Glucose Tolerance Test; Hyperlipidemias; Insulin; Insulin Resistance; Leptin; Lipids; Litsea; Male; Plants, Medicinal; Rats; Rats, Sprague-Dawley

Obesity is a risk factor for postmenopausal breast cancer, particularly for development of estrogen-receptor (ER)-positive tumors. Additionally, obesity is implicated in breast cancer progression. However, few studies address mechanisms of action of how obesity mediates these responses. Our goal was to address how obesity and/or elevated serum leptin affects tumor formation from ER-positive T47-D cells. In Study 1 ovariectomized CD-1 nude female mice were injected with goldthioglucose (GTG) at 0.5 mg/g body weight in saline or the vehicle at 6 weeks of age. At 10 weeks of age mice were inoculated with T47-D cells and implanted with estrogen pellets. In Study 2 mice were injected with 0.3 mg/g GTG or the vehicle. At 10 weeks of age cells were inoculated and mice were implanted with estrogen or placebo pellets. Mice were followed until 30 weeks of age. Some GTG mice became obese and others were non-responders. In Study 1 no mice developed tumors. In Study 2 mice with placebo pellets developed more tumors than mice with estrogen pellets, 50% vs. 13%. GTG-obese mice with placebo pellets had a 100% tumor incidence compared to 50% and 20% for GTG-lean and controls without estrogen. Serum leptin was higher in obese compared to lean mice and adiponectin was not affected by body weight. Adiponectin:leptin ratio was significantly reduced in obese compared to lean mice. Leptin, leptin receptor and signaling protein expression were determined in mammary and tumor tissue. Leptin and STAT3 were most abundant in tumors. These findings suggest that in vivo estrogen suppressed proliferation of T47-D cells but without supplemental estrogen obesity enhanced tumor development. The exact reason for this is not presently clear.

Topics: Animals; Breast Neoplasms; Disease Models, Animal; Estradiol; Estrogens; Female; Leptin; Mice; Mice, Nude; Mice, Obese; Neoplasm Transplantation; Ovariectomy; Receptors, Estrogen

Gene-targeted deletion of the voltage-gated potassium channel, Kv1.3, results in 'super-smeller' mice that have altered firing patterns of mitral cells in the olfactory bulb, modified axonal targeting to glomerular synaptic units, and behaviorally have an increased ability to detect and discriminate odors. Moreover, the Kv1.3-null mice weighed less than their wild-type counterparts, have modified ingestive behaviors, and are resistant to fat deposition following a moderately high-fat dietary regime. In this study, we investigate whether or not gene-targeted deletion of Kv1.3 (Shaker family member) can abrogate weight gain in a genetic model of obesity, the melanocortin-4 receptor-null mouse (MC4R-null).. Mice with double gene-targeted deletions of Kv1.3 and MC4R were generated by interbreeding Kv1.3 (Kv)- and MC4R-null mouse lines to homozygosity. Developmental weights, nose to anus length, fat pad weight, fasting serum chemistry, oxygen consumption, carbon dioxide respiration, locomotor activity and caloric intake were monitored in control, Kv-null, MC4R-null and Kv/MC4R-null mice. Physiological and metabolic profiles were acquired at postnatal day 60 (P60) in order to explore changes linked to body weight at the reported onset of obesity in the MC4R-null model.. Gene-targeted deletion of Kv1.3 in MC4R-null mice reduces body weight by decreasing fat deposition and subsequent fasting leptin levels, without changing the overall growth, fasting blood glucose or serum insulin. Gene-targeted deletion of Kv1.3 in MC4R-null mice significantly extended lifespan and increased reproductive success. Basal or light-phase mass-specific metabolic rate and locomotor activity were not affected by genetic deletion of Kv1.3 in MC4R-null mice but dark-phase locomotor activity and mass-specific metabolism were significantly increased resulting in increased total energy expenditure.. Gene-targeted deletion of Kv1.3 can reduce adiposity and total body weight in a genetic model of obesity by increasing both locomotor activity and mass-specific metabolism.

Topics: Adiposity; Animals; Blood Glucose; Calorimetry, Indirect; Disease Models, Animal; Drinking; Energy Intake; Female; Fertility; Gene Deletion; Growth; Homeostasis; Insulin; Kv1.3 Potassium Channel; Leptin; Locomotion; Longevity; Male; Mice; Mice, Knockout; Obesity; Oxygen Consumption; Receptor, Melanocortin, Type 4; Weight Gain

The objectives of this study were to identify potential alterations in gene expression of melanocortin-4 receptor (MC4-R), proopiomelanocortin (POMC), and Agouti-related protein (AgRP) in mouse hypothalamus under a chronic peripheral infusion of leptin or at early (8 weeks) and advanced (16 weeks) phases of diet-induced obesity. Control or diet-induced obesity mice (8 or 16 weeks of high-fat diet) were either treated or not treated with leptin. Metabolic features were analyzed and expression of the genes of interest was measured by quantitative reverse transcriptase-PCR (RT-qPCR) and western blot. We reported that in control mice, but not in obese mice, leptin infusion induced an increase in POMC mRNA level as well as in MC4-R mRNA level suggesting that leptin could act directly and/or through alpha-melanocyte-stimulating hormone (alpha-MSH). This hypothesis was reinforced after in vitro studies, using the mouse hypothalamic GT1-7 cell line, since both leptin and Norleucine(4), D-Phenylalanine(7)-alpha-MSH (NDP-alpha-MSH) treatments increased MC4-R expression. After 8 weeks of high-fat diet, nondiabetic obese mice became resistant to the central action of leptin and their hypothalamic content of POMC and AgRP mRNA were decreased without modification of MC4-R mRNA level. After 16 weeks of high-fat diet, mice exhibited more severe metabolic disorders with type 2 diabetes. Moreover, hypothalamic expression of MC4-R was highly increased. In conclusion, several alterations of the melanocortin system were found in obese mice that are probably consecutive to their central resistance to leptin. Moreover, when the metabolic status is highly degraded (with all characteristics of a type 2 diabetes), other regulatory mechanisms (independent of leptin) can also take place.

Topics: Agouti-Related Protein; alpha-MSH; Animals; Cell Line; Diabetes Mellitus, Type 2; Disease Models, Animal; Hypothalamus; Infusions, Parenteral; Leptin; Male; Melanocortins; Mice; Mice, Inbred C57BL; Norleucine; Obesity; Pro-Opiomelanocortin; Receptor, Melanocortin, Type 4; RNA, Messenger

Leptin, a hormone mainly generated by adipocytes, acts centrally in the hypothalamus to regulate body weight and energy expenditure. However, there is strong evidence that leptin is also involved in cell-mediated immunity and cytokine crosstalk. In the present study the effects of diet-induced obesity and central and peripheral leptin treatment on leukocyte subsets and cytokine production was investigated. Leptin was injected either intravenously (i.v.) or intracerebroventricularly (i.c.v.) in male endotoxaemic or vehicle-treated healthy LEW-rats. Numbers of blood leukocyte subsets were analysed by FACS and cytokines (TNF-alpha and IL-6) by ELISA. Results showed that peripheral rather than central leptin treatment was able to significantly increase numbers of granulocytes, NK cells and monocytes. Three-colour staining revealed that the increase of ED9(+) monocytes was most likely due to the mobilization of two distinct monocyte subsets, predominantly ED9(+)CD4(-)NKR-P1A(+) and ED9(+)CD4(+)NKR-P1A(+). ELISA analysis revealed significantly elevated TNF-alpha levels in obese animals compared to their lean littermates, while IL-6 failed to show notable changes. In conclusion, the data of the present study revealed that leptin application induces a nutrition- and application-site dependent increase of circulating NK cells, granulocytes and specific monocyte subsets.

Topics: Animals; Disease Models, Animal; Endotoxemia; Energy Intake; Granulocytes; Injections, Intravenous; Injections, Intraventricular; Killer Cells, Natural; Leptin; Leukocyte Count; Male; Monocytes; Obesity; Rats; Rats, Inbred Lew; Recombinant Proteins; Thinness; Tumor Necrosis Factor-alpha

Topics: alpha-MSH; Animals; Disease Models, Animal; Down-Regulation; Genetic Predisposition to Disease; Hypertension; Leptin; Melanocortins; Protein Precursors; Rats; Rats, Inbred SHR; Rats, Wistar; Thyrotropin-Releasing Hormone

Obesity is clearly an independent risk factor for increased severity of acute pancreatitis (AP), although the mechanisms underlying this association are unknown. Adipokines (including leptin and adiponectin) are pleiotropic molecules produced by adipocytes that are important regulators of the inflammatory response. We hypothesized that the altered adipokine milieu observed in obesity contributes to the increased severity of pancreatitis. Lean (C57BL/6J), obese leptin-deficient (LepOb), and obese hyperleptinemic (LepDb) mice were subjected to AP by six hourly intraperitoneal injections of cerulein (50 microg/kg). Severity of AP was assessed by histology and by measuring pancreatic concentration of the proinflammatory cytokines IL-1beta and IL-6, the chemokine MCP-1, and the marker of neutrophil activation MPO. Both congenitally obese strains of mice developed significantly more severe AP than wild-type lean animals. Severity of AP was not solely related to adipose tissue volume: LepOb mice were heaviest; however, LepDb mice developed the most severe AP both histologically and biochemically. Circulating adiponectin concentrations inversely mirrored the severity of pancreatitis. These data demonstrate that congenitally obese mice develop more severe AP than lean animals when challenged by cerulein hyperstimulation and suggest that alteration of the adipokine milieu exacerbates the severity of AP in obesity.

Topics: Acute Disease; Adipokines; Adiponectin; Amylases; Animals; Blood Glucose; Body Weight; Ceruletide; Chemokines; Cytokines; Disease Models, Animal; Female; Insulin; Leptin; Lung; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Pancreas; Pancreatitis; Peroxidase; Severity of Illness Index

Leptin-resistant rats, when given a high-fat (HF) diet, have a delayed normalization of caloric intake and greater weight gain than those on a chow diet. Because aged, obese rats are leptin resistant, these data predict that they will also have a delayed normalization of caloric intake and exacerbated weight gain when provided a HF diet. To investigate this hypothesis, along with the consequences of a HF diet on voluntary wheel running, we compared various ages of rats on a HF or chow diet. HF-fed young rats spontaneously divided into diet-induced obese and diet-resistant rats. However, all aged rats were susceptible to the weight-gaining effects of HF feeding. Rate of initial weight gain was proportional to age, and peak caloric intake on the HF diet and the days required to normalize caloric intake to basal levels increased with age. Responsiveness to peripheral leptin before HF feeding revealed a dose-response decrease in food intake and body weight in the young but no responses in the aged to even the highest dose, 0.5 mg/day. In addition, both age and HF feeding decreased the tendency for wheel running, suggesting the propensity for inactivity with age and HF feeding may contribute to age-related obesity and accelerate the rate of diet-induced obesity. These results demonstrate that aged rats are more susceptible to the detrimental effects of a HF diet.

Topics: Adipose Tissue, Brown; Age Factors; Aging; Animals; Body Composition; Dietary Fats; Disease Models, Animal; Dose-Response Relationship, Drug; Energy Intake; Hyperphagia; Hypothalamus; Ion Channels; Leptin; Male; Mitochondrial Proteins; Motor Activity; Obesity; Physical Conditioning, Animal; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Rats; Rats, Inbred F344; RNA, Messenger; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Uncoupling Protein 1; Weight Gain

Studies indicate that an association exists between periodontitis and type 2 diabetes mellitus (T2DM) and/or obesity, with chronic inflammation hypothesized as the common denominator. The purpose of this study was to determine the causal effect of periodontitis and the concomitant impact of diet on the onset of insulin resistance (IR) and T2DM using a rat model system that simulates human obesity and T2DM.. Twenty-eight, 5-week-old female Zucker diabetic fatty (ZDF, fa/fa) rats were divided into four groups of seven animals: high-fat fed-periodontitis (HF/P), high-fat fed-no periodontitis (HF/C), low-fat fed-periodontitis (LF/P), and low-fat fed-no periodontitis (LF/C). Periodontitis was induced by ligature placement. Fasting plasma insulin and glucose levels were measured, and glucose tolerance tests were performed to assess glucose homeostasis, IR, and the onset of T2DM. The level of tumor necrosis factor-alpha (TNF-alpha), leptin, triglycerides, and free fatty acids were determined in week 13 at sacrifice.. HF/P rats developed more severe IR compared to HF/C rats (P <0.01) and LF/P or LF/C rats (P <0.001) as measured by fasting insulin levels and homeostasis model assessment analysis. The onset of severe IR occurred approximately 3 weeks earlier in HF/P rats compared to HF/C rats. HF/P rats developed impaired (110 to 125 mg/dl) and frank fasting hyperglycemia (>125 mg/dl) 2 weeks earlier than HF/C rats. There was no difference in the severity and onset of IR and T2DM between LF/P and LF/C rats. The level of TNF-alpha was significantly higher in HF/P rats compared to HF/C rats (P <0.01).. Periodontitis accelerated the onset of severe IR and impaired glucose homeostasis in high-fat fed ZDF rats.

Topics: Alveolar Bone Loss; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Diet, Fat-Restricted; Dietary Fats; Disease Models, Animal; Fasting; Fatty Acids, Nonesterified; Female; Glucose Tolerance Test; Homeostasis; Hyperglycemia; Insulin; Insulin Resistance; Leptin; Periodontitis; Rats; Rats, Zucker; Time Factors; Triglycerides; Tumor Necrosis Factor-alpha

The mammalian target of rapamycin (mTOR) kinase is a key regulator of several cellular functions, including cell growth and differentiation. Because hypothalamic mTOR complex 1 (mTORC1) signaling has been implicated as a target of leptin in the regulation of energy balance, we investigated its role in obesity-induced leptin resistance. In contrast to rats maintained on a low-fat (LF) diet for 3 weeks, rats maintained on a high-fat (HF)-diet had no anorexic response to intracerebroventricular leptin. Western blot analysis revealed that leptin was unable to modulate hypothalamic mTORC1 signaling in the HF group, whereas it significantly induced phosphorylation of both S6 kinase 1 (S6K1) and S6 ribosomal protein (S6) in the LF group. Similar to leptin, the cytokine ciliary neurotrophic factor (CNTF) induces hypophagia and increases signal transduction activator of transcription 3 phosphorylation. However, CNTF and its analog CNTF(Ax15) activate leptin-like pathways in the hypothalamus, even in leptin-resistant states, including diet-induced obesity. Intracerebroventricular CNTF(Ax15) decreased 24 h food intake and body weight in rats on HF or LF diets and increased the phosphorylation of hypothalamic S6K1 and S6 in a comparable way in both diets. Importantly, mice lacking the expression of S6K1 (S6K1(-/-)) did not respond to the anorectic action of either leptin or CNTF(Ax15), implying a crucial role for S6K1 in modulating the actions of these two cytokines. Finally, exposure to HF diet decreased mTORC1 signaling within the hypothalamus. Overall, these findings point strongly to the possibility that reduced hypothalamic mTORC1 signaling contributes to the development of hyperphagia, weight gain, and leptin resistance during diet-induced obesity.

Topics: Animals; Behavior, Animal; Ciliary Neurotrophic Factor; Dietary Fats; Disease Models, Animal; Eating; Feeding Behavior; Leptin; Male; Median Eminence; Mice; Mice, Knockout; Obesity; Rats; Rats, Long-Evans; Ribosomal Protein S6 Kinases; Signal Transduction; Transcription Factors

The endocrine system plays an important role in the adaptation to hypoxia. The aim of this study was to assess the effect of chronic hypoxia on insulin, adiponectin, leptin, and ghrelin levels in a neonatal animal model. Sprague-Dawley rats were placed in a normobaric hypoxic environment at birth. Controls remained in room air. Rats were killed at 2 and 8 weeks of life. Insulin, adiponectin, leptin, and ghrelin were measured. At 2 weeks of life, there was no significant difference in insulin, adiponectin, and leptin levels between the hypoxic and control rats. The only statistically significant difference was found in ghrelin levels, which were lower in the hypoxic group (3.19 +/- 3.35 vs 24.52 +/- 5.09 pg/mL; P < .05). At 8 weeks of life, insulin was significantly higher in the hypoxic group (0.72 +/- 0.14 vs 0.44 +/- 0.26 ng/mL; P < .05) and adiponectin was significantly lower (1257.5 +/- 789.5 vs 7817.3 +/- 8453.7 ng/mL; P < .05). Leptin and ghrelin did not show significant difference in this age group, but leptin level per body weight was higher in the hypoxic group. Finally, we conclude that 2 weeks of continuous neonatal hypoxic exposure leads to a decrease in plasma ghrelin only with no significant change in insulin, adiponectin, and leptin and that 8 weeks of hypoxia leads to a decrease in adiponectin with an increase in insulin despite a significant decrease in weight.

Topics: Adiponectin; Animals; Animals, Newborn; Body Weight; Disease Models, Animal; Female; Ghrelin; Hematocrit; Hypoxia; Insulin; Leptin; Pregnancy; Rats; Rats, Sprague-Dawley; Statistics, Nonparametric

Macrophages (MPhis) utilize macropinocytosis to integrate immune and metabolic signals in order to initiate an effective immune response. Diabetes is characterized by metabolic abnormalities and altered immune function. Here we examine the influence of diabetes on macropinocytosis in primary mouse macrophages and in an in vitro diabetes model.. The data demonstrate that peritoneal MPhis from diabetic (db/db) mice had reduced macropinocytosis when compared to MPhis from non-diabetic (db/+) mice. Additionally, MPhis cultured in hyperglycemic conditions were less adept at macropinocytosis than those cultured in low glucose. Notably, AMP-activated protein kinase (AMPK) activity was decreased in MPhis cultured in hyperglycemic conditions. Activation of AMPK with leptin or 5-aminoimidazole-4-carboxamide-1-beta-riboside (AICAR) increased macropinocytosis and inhibition of AMPK with compound C decreased macropinocytosis.. Taken together, these findings indicate that MPhis from diabetic mice have decreased macropinocytosis. This decrease appears dependent on reduced AMPK activity. These results demonstrate a previously unrealized role for AMPK in MPhis and suggest that increasing AMPK activity in diabetic MPhis could improve innate immunity and decrease susceptibility to infection.

Topics: Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Animals; Cell Culture Techniques; Cell Line, Tumor; Diabetes Mellitus, Type 2; Disease Models, Animal; Energy Metabolism; Glucose; Hyperglycemia; Immunity; Leptin; Macrophage Activation; Macrophages, Peritoneal; Mice; Pinocytosis; Pyrazoles; Pyrimidines; Ribonucleosides

Hyperleptinemia accompanying obesity affects endothelial nitric oxide (NO) and is a serious factor for vascular disorders. NO, superoxide (O(2)(-)), and peroxynitrite (ONOO(-)) nanosensors were placed near the surface (5+/-2 microm) of a single human umbilical vein endothelial cell (HUVEC) exposed to leptin or aortic endothelium of obese C57BL/6J mice, and concentrations of calcium ionophore (CaI)-stimulated NO, O(2)(-), ONOO(-) were recorded. Endothelial NO synthase (eNOS) expression and L-arginine concentrations in HUVEC and aortic endothelium were measured. Leptin did not directly stimulate NO, O(2)(-), or ONOO(-) release from HUVEC. However, a 12-h exposure of HUVEC to leptin increased eNOS expression and CaI-stimulated NO (625+/-30 vs. 500+/-24 nmol/l control) and dramatically increased cytotoxic O(2)(-) and ONOO(-) levels. The [NO]-to-[ONOO(-)] ratio ([NO]/[ONOO(-)]) decreased from 2.0+/-0.1 in normal to 1.30+/-0.1 in leptin-induced dysfunctional endothelium. In obese mice, a 2.5-fold increase in leptin concentration coincided with 100% increase in eNOS and about 30% decrease in intracellular L-arginine. The increased eNOS expression and a reduced l-arginine content led to eNOS uncoupling, a reduction in bioavailable NO (250+/-10 vs. 420+/-12 nmol/l control), and an elevated concentration of O(2)(-) (240%) and ONOO(-) (70%). L-Arginine and sepiapterin supplementation reversed eNOS uncoupling and partially restored [NO]/[ONOO(-)] balance in obese mice. In obesity, leptin increases eNOS expression and decreases intracellular l-arginine, resulting in eNOS an uncoupling and depletion of endothelial NO and an increase of cytotoxic ONOO(-). Hyperleptinemia triggers an endothelial NO/ONOO(-) imbalance characteristic of dysfunctional endothelium observed in other vascular disorders, i.e., atherosclerosis and diabetes.

Topics: Animals; Arginine; Biosensing Techniques; Calcium; Disease Models, Animal; Endothelial Cells; Endothelium, Vascular; Enzyme Inhibitors; Humans; Ionophores; Leptin; Male; Mice; Mice, Inbred C57BL; Nanotechnology; Nitric Oxide; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Obesity; Peroxynitrous Acid; Reactive Oxygen Species; Superoxides; Time Factors

Epidemiological evidence together with experimental models shows a direct relationship between fetal and early postnatal growth patterns and an increased risk of adult metabolic disease. Maternal health and nutrition are key determinants in influencing infant growth but the precise molecular mechanisms underlying this relationship are unclear, although it is evident that there are critical time windows when these effects are important. Animal models show mechanistic parallels with human populations and highlight that the early environment represents a therapeutic window for protection from obesity and metabolic disease. The observation that developmental programming can be reversed has been demonstrated in studies in which both maternal and neonatal leptin treatment prevents the induction of the adverse metabolic phenotype. Given that orally administered peptides are absorbed intact by the new born, the prospect of providing supplemental leptin either as drops or in milk deserves serious consideration as a means of reducing or reversing the obesity and type 2 diabetes epidemic.

Topics: Adult; Animals; Disease Models, Animal; Feeding Behavior; Female; Humans; Infant; Infant, Newborn; Leptin; Metabolic Syndrome; Obesity; Pregnancy; Prenatal Exposure Delayed Effects

This study investigated the effects of rosiglitazone on nutritionally programmed chronic disease, with a focus on blood pressure (BP) and aortic wall structural remodeling. Wistar pregnant rats were fed one of two diets: a normal protein diet (19% protein; NP rats) or low-protein diet (5% protein; LP rats). Male offspring at 3 months of age were randomly divided into four groups: NP offspring treated with rosiglitazone (NPR); untreated NP offspring (NP); LP offspring treated with rosiglitazone (LPR); untreated LP offspring (LP). Rosiglitazone was administered at a dose of 5 mg/kg/d until 6 months of age. BP was elevated in LP offspring. Rosiglitazone reduced BP beginning in the first week of treatment in the LPR offspring. The insulin sensitivity was increased in LP offspring, and was not altered by rosiglitazone. LP offspring exhibited a 40% reduction in the amount of elastic fibers in the aorta wall compared with NP offspring (p < 0.01), and the quantity of elastic fibers was not altered by rosiglitazone. The smooth muscle cells, elastic lamellae, circumferential wall tension (CWT) and tensile stress (TS) were increased in LP offspring, indicating increased blood flow in the aorta. Rosiglitazone reduced both CWT and TS by 30% compared to the levels in untreated LP offspring (p < 0.01 for both). Rosiglitazone restored the expressions of angiotensin II type 1 receptor and endothelial nitric oxide synthase nearly to the levels in the NP offspring. ANOVA disclosed a significant two-factor interaction between protein content in the diet and rosiglitazone treatment (p < 0.001 for CWT and p < 0.00001 for TS, two-way ANOVA). We conclude that rosiglitazone has beneficial effects in reducing the BP and the aortic tunica media hypertrophy with consequent balance of the wall stress in metabolically programmed offspring.

Topics: Animals; Aorta; Blood Glucose; Blood Pressure; Carbohydrate Metabolism; Diet, Protein-Restricted; Disease Models, Animal; Elasticity; Female; Hypertension; Hypertrophy; Insulin; Leptin; Male; Nitric Oxide Synthase Type III; PPAR gamma; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Rosiglitazone; Thiazolidinediones; Tunica Media

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

Leptin is an adipose hormone with well characterized roles in regulating food intake and energy balance. A novel neuroprotective role for leptin has recently been discovered; however, the underlying mechanisms are not clearly defined. The purpose of this study was to determine whether leptin protects against delayed neuronal cell death in hippocampal CA1 following transient global cerebral ischemia in rats and to study the signaling mechanism responsible for the neuroprotective effects of leptin. Leptin receptor antagonist, protein kinase inhibitors and western blots were used to assess the molecular signaling events that were altered by leptin after ischemia. The results revealed that intracerebral ventricle infusion of leptin markedly increased the numbers of survival CA1 neurons in a dose-dependent manner. Infusion of a specific leptin antagonist 10 min prior to transient global ischemia abolished the pro-survival effects of leptin, indicating the essential role of leptin receptors in mediating this neuroprotection. Both the Akt and extracellular signal-related kinase 1/2 (ERK1/2) signaling pathways appear to play a critical role in leptin neuroprotection, as leptin infusion increased the phosphorylation of Akt and ERK1/2 in CA1. Furthermore, pharmacological inhibition of either pathway compromised the neuroprotective effects of leptin. Taken together, the results suggest that leptin protects against delayed ischemic neuronal death in the hippocampal CA1 by maintaining the pro-survival states of Akt and ERK1/2 MAPK signaling pathways.