leptin and Hyperlipidemias

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

In this review, we attempt to deduce teleologically the physiological mission of leptin. Because overnutrition and diet-induced obesity are the only known causes of hyperleptinemia, we contrast the differences in overnutrition in normally leptinized rodents, in which the added lipids are confined to adipocytes, with those of unleptinized rodents, in which the added lipids are distributed in liver, pancreatic islets, and heart and skeletal muscle, causing organ dysfunction and cell death with a disease cluster resembling metabolic syndrome. We focus here on lipid-induced cardiac dysfunction and the remarkable ability of hyperleptinemia to prevent it. We conclude that the hyperleptinemia of overnutrition prevents the ectopic lipid deposition by: (1) acting on hypothalamic appetite centers to limit the caloric surplus to fit the available adipocyte storage capacity and, (2) upregulating of fatty acid oxidation and downregulating lipogenesis in peripheral tissues to minimize ectopic lipid deposition. The causes of failure of this system and its clinical consequences are discussed.

Topics: Animals; Cardiotonic Agents; Cardiovascular Diseases; Humans; Hyperlipidemias; Leptin; Models, Cardiovascular

Fructose intake and the prevalence of obesity have both increased over the past two to three decades. Compared with glucose, the hepatic metabolism of fructose favors lipogenesis, which may contribute to hyperlipidemia and obesity. Fructose does not increase insulin and leptin or suppress ghrelin, which suggests an endocrine mechanism by which it induces a positive energy balance. This review examines the available data on the effects of dietary fructose on energy homeostasis and lipid/carbohydrate metabolism. Recent publications, studies in human subjects, and areas in which additional research is needed are emphasized.

Topics: Beverages; Diabetes Mellitus, Type 2; Energy Metabolism; Fructose; Ghrelin; Glucose; Humans; Hyperlipidemias; Insulin; Insulin Resistance; Leptin; Obesity; Peptide Hormones

Topics: Animals; Body Mass Index; Gastric Mucosa; Helicobacter Infections; Helicobacter pylori; Humans; Hyperlipidemias; Leptin; Obesity

The authors presents the state of knowledge on the prevalence and proposed mechanisms leading to weight gain during treatment with atypical antipsychotics. A short review on the therapeutic approaches is also supplied.

Topics: Antipsychotic Agents; Body Weight; Clozapine; Dibenzothiazepines; Humans; Hyperlipidemias; Leptin; Piperazines; Psychotic Disorders; Quetiapine Fumarate; Risperidone; Thiazoles; Weight Gain

Adverse metabolic effects, such as diabetes mellitus, lipid abnormalities and weight gain, have increasingly been recognised with the use of the newer, so-called atypical antipsychotic drugs. This article reviews the current literature in the field and attempts to answer the question of whether the atypical antipsychotics differ in their effects on glucose-insulin homeostasis and lipid metabolism. It also addresses how then to manage the use of the atypical antipsychotics that do interfere with these metabolic systems. Differences in effects of atypical antipsychotics on leptin levels are also summarised and put into context; bodyweight gain associated with atypical antipsychotics is reviewed elsewhere. In summary, there are no large controlled trials published quantifying the prevalence of adverse effects on glucose-insulin homeostasis and lipid metabolism in patients receiving atypical antipsychotics. Nevertheless, the published articles and case reports reviewed in this article give a fairly good view of those adverse effects occurring with clozapine, olanzapine and risperidone, whereas little data are available regarding quetiapine, ziprasidone and zotepine, and no data exist for amisulpride and aripiprazole. Estimated rankings of the atypical agents, based on the available literature, show that the relative risk of glucose intolerance/diabetes mellitus, hyperlipidaemia and hyperleptinaemia is highest for clozapine and olanzapine, moderately high for quetiapine, rather low for risperidone and lowest for ziprasidone. Since adverse metabolic effects of atypical antipsychotics may have a negative influence on both the antipsychotic treatment outcome as well as the physical health of the patient, these effects have to be recognised and adequately managed. In this review, recommendations for prevention and treatment of the adverse metabolic effects are outlined.

Topics: Antipsychotic Agents; Glucose Metabolism Disorders; Humans; Hyperlipidemias; Leptin; Treatment Outcome

In the last few years, there has been increasing interest in the physiological role of acylation-stimulating protein (ASP). Recent studies in rats and mice, in particular in C3 (-/-) mice that are ASP deficient, have advanced our understanding of the role of ASP. Of note, the background strain of the mice influences the phenotype of delayed postprandial triglyceride clearance in ASP-deficient mice. Administration of ASP in all types of lean and obese mice studied to date, however, enhances postprandial triglyceride clearance. On the other hand, regardless of the background strain, ASP-deficient mice demonstrate reduced body weight, reduced leptin and reduced adipose tissue mass, suggesting that ASP deficiency results in protection against development of obesity. In humans, a number of studies have examined the relationship between ASP, obesity, diabetes and dyslipidemia as well as the influence of diet, exercise and pharmacological therapy. While many of these studies have small subject numbers, interesting observations may help us to better understand the parameters that may influence ASP production and ASP action. The aim of the present review is to provide a comprehensive overview of the recent literature on ASP, with particular emphasis on those studies carried out in rodents and humans.

Topics: Adipose Tissue; Animals; Blood Proteins; Body Weight; Cardiovascular Diseases; Complement C3; Complement C3a; Complement Factor B; Complement Factor D; Diabetes Mellitus; Humans; Hyperlipidemias; Insulin Resistance; Leptin; Mice; Mice, Knockout; Models, Animal; Obesity; Postprandial Period; Rats; Serine Endopeptidases; Triglycerides

It is established that plasma leptin is associated with satiety and that leptin stimulates lipid metabolism, and increases energy expenditure. These effects implicate leptin as a major regulator of energy homeostasis, which may serve to limit excess energy storage. As plasma leptin concentrations are tightly coupled with fat mass in humans, decreases in adipose mass with weight loss coincide with decreased concentrations of circulating leptin. However, due to many confounding factors, the effects of exercise on circulating leptin are less clear. The data from investigations examining single exercise bouts suggest that serum leptin concentrations are unaltered by short duration (41 minutes or less), non-exhaustive exercise, but may be affected by short duration, exhaustive exercise. More convincingly, studies investigating long duration exercise bouts indicate that serum leptin concentrations are reduced with exercise durations ranging from one to multiple hours. These findings raise speculation that exercise-associated reductions in leptin may be due to alterations in nutrient availability or nutrient flux at the level of the adipocytes, the primary site of leptin production and secretion. Thus, one purpose of this review is to discuss the effects of exercise on circulating leptin concentrations with special emphasis on studies that have examined single exercise bouts that are associated with high levels of energy expenditure and energy deficit. In addition, a 'nutrient sensing pathway' (the hexosamine biosynthetic pathway), which regulates leptin gene expression, will be discussed as a possible mechanism by which exercise-induced energy deficit may modulate serum leptin concentrations.

Topics: Adipose Tissue; Energy Metabolism; Exercise; Homeostasis; Humans; Hyperlipidemias; Leptin; Lipid Metabolism; Obesity; Satiety Response

Topics: Adipose Tissue; Cardiovascular Diseases; Complement Factor D; Hormones, Ectopic; Humans; Hyperlipidemias; Hypertension; Intercellular Signaling Peptides and Proteins; Leptin; Obesity; Renin-Angiotensin System; Resistin; Serine Endopeptidases; Tumor Necrosis Factor-alpha

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

Topics: Adiponectin; Adipose Tissue; Animals; Arteriosclerosis; Cytokines; Diabetes Mellitus; Homeostasis; Humans; Hyperlipidemias; Intercellular Signaling Peptides and Proteins; Leptin; Metabolic Diseases; Plasminogen Activator Inhibitor 1; Proteins; Tumor Necrosis Factor-alpha

Topics: Animals; Bezafibrate; Biguanides; Fatty Acids, Nonesterified; Humans; Hyperglycemia; Hyperinsulinism; Hyperlipidemias; Hypertension; Hypoglycemic Agents; Hypolipidemic Agents; Insulin Resistance; Leptin; Life Style; Metabolic Syndrome; Pioglitazone; Thiazoles; Thiazolidinediones; Tumor Necrosis Factor-alpha

The first unifying definition for the metabolic syndrome was proposed by WHO in 1998. In accordance to this, patients with type 2 diabetes mellitus or impaired glucose tolerance have the syndrome if they fulfil two of the criteria: hypertension, dyslipidaemia, obesity/abdominal obesity and microalbuminuria. Persons with normal glucose tolerance (NGT) should also be insulin resistant. About 40% of persons with impaired glucose tolerance (IGT) and 70% of patients with type 2 diabetes have features of the syndrome. Importantly, presence of the dysmetabolic syndrome is associated with reduced survival, particularly because of increased cardiovascular mortality. The dysmetabolic syndrome most likely results from interplay between several genes and an affluent environment. Compatible with the thrifty gene theory, common variants in genes regulating lipolysis, thermogenesis and glucose uptake in skeletal muscle account for a large part of such thrifty genes. However, hitherto unknown genes may still be identified by random gene approaches.

Topics: Abdomen; Adult; Age Distribution; Aged; Animals; Carrier Proteins; Diabetes Mellitus, Type 2; Genotype; Humans; Hyperlipidemias; Hypertension; Insulin Resistance; Leptin; Middle Aged; Mutation; Obesity; Phenotype; Prevalence; Pro-Opiomelanocortin; Receptor, Melanocortin, Type 4; Receptors, Cell Surface; Receptors, Leptin; Receptors, Peptide; Syndrome

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

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

Obesity is characterized by elevated lipids, insulin resistance and relative hypogonadotropic hypogonadism, reducing fertility and increasing risk of pregnancy complications and birth defects. We termed this phenotype 'Reprometabolic Syndrome' and showed that it can be recapitulated by acute infusions of lipid/insulin into healthy, normal weight, eumenorrheic women. Herein, we examined the broader impact of hyperlipidemia and euglycemic hyperinsulinemia on anterior pituitary trophic hormones and their targets.. Serum FSH, LH, TSH, growth hormone (GH), prolactin (PRL), thyroid hormones (free T4, total T3), cortisol, IGF-1, adiponectin, leptin and creatinine were measured in a secondary analysis of an interventional crossover study of 12 normal weight cycling women who underwent saline and heparin (control) infusion, or a euglycemic insulin infusion with heparin and Intralipid® (lipid/insulin), between days 2-5 in sequential menstrual cycles.. In contrast to the decrease in gonadotropins, FSH and LH, infusion of lipid/insulin had no significant effects on other trophic hormones; TSH, PRL or GH. Thyroid hormones (fT4 and total T3), cortisol, IGF-1, adiponectin and creatinine also did not differ between saline or lipid/insulin infusion conditions. Leptin increased in response to lipid/insulin (p<0.02).. Acute hyperlipidemia and hyperinsulinemia exerted differential, cell type specific effects on the hypothalamic-pituitary-gonadal, adrenal and thyroid axes. Elucidation of mechanisms underlying the selective modulation of pituitary trophic hormones, in response to changes in diet and metabolism, may facilitate therapeutic intervention in obesity-related neuroendocrine and reproductive dysfunction.

Topics: Adiponectin; Creatinine; Cross-Over Studies; Female; Follicle Stimulating Hormone; Growth Hormone; Heparin; Human Growth Hormone; Humans; Hydrocortisone; Hyperinsulinism; Hyperlipidemias; Insulin; Insulin-Like Growth Factor I; Leptin; Lipids; Luteinizing Hormone; Obesity; Pituitary Hormones; Pregnancy; Prolactin; Thyroid Hormones; Thyrotropin

Medications leveraging the leptin, PCSK9, ANGPTL3 and FABP4 pathways are being developed for the treatment of insulin resistance and/or lipid disorders. To evaluate whether these pathways are independent from each other, we assessed the levels of PCSK9, ANGPTL3 and FABP4, in normal subjects and subjects exhibiting HIV and highly active antiretroviral therapy (HAART) induced metabolic syndrome with lipoatrophy and hypoleptinemia. Studies were performed at baseline and during food deprivation for three days with either a placebo or leptin administration at physiological replacement doses to correct fasting induced acute hypoleptinemia and in pharmacological doses.. PCSK9, ANGPTL3, FABP4 levels and their correlations to lipoproteins-metabolites were assessed in randomized placebo controlled cross-over studies: a) in 15 normal-weight individuals undergoing three-day admissions in the fed state, in complete fasting with placebo and in complete fasting with leptin treatment in physiologic replacement doses (study 1), b) in 15 individuals day baseline in a fed and three fasting admissions for three days with leptin administered in physiologic, supraphysiologic and pharmacologic doses (study 2), c) in 7 hypoleptinemic men with HIV and HAART-induced lipoatrophy treated with leptin or placebo for two months in the context of a cross over randomized trial (study 3).. Circulating ANGPTL3, PCSK9 and FABP4 were markedly elevated in HIV-lipoatrophy and not affected by leptin treatment. PCSK9 levels correlated with lipids and markers of lipid utilization and lipolysis. ANGPTL3 levels correlated with HDL particles and their lipid composition. FABP4 levels were negatively associated with HDL diameter (HDL-D) and composition. PCSK9 and ANGPTL3 levels decreased during food deprivation by ~65 % and 30 % respectively. Leptin administration at physiologic, supraphysiologic and pharmacologic doses did not affect PCSK9, ANGPTL3 and FABP4 levels.. PCSK9, ANGPTL3 and FABP4 levels are associated with markers of lipid metabolism and are higher in HIV-lipoatrophy. PCSK9 and ANGPTL3 but not FABP4 decrease in response to food deprivation. PCSK9 and ANGPTL3 regulation is leptin-independent, suggesting independent pathways for lipid regulation. Thus, combining treatments of leptin with PCSK9 and/or ANGPTL3 inhibitors for metabolic diseases should have additive effects and merit further investigation.. ClinicalTrials.gov no. NCT00140231, NCT00140205, NCT00140244.

Topics: Angiopoietin-Like Protein 3; Angiopoietin-like Proteins; Fasting; HIV Infections; Humans; Hyperlipidemias; Leptin; Lipids; Lipodystrophy; Male; Metabolic Diseases; Proprotein Convertase 9

An aim of weight loss is to reduce the risk of type 2 diabetes (T2D) in obese subjects. However, the relation with long-term glycemic improvement remains unknown.. We evaluated the changes in lipid composition during weight loss and their association with long-term glycemic improvement.. We investigated the plasma lipidome of 383 obese, nondiabetic patients within a randomized, controlled dietary intervention in 8 European countries at baseline, after an 8-wk low-caloric diet (LCD) (800-1000 kcal/d), and after 6 mo of weight maintenance.. After weight loss, a lipid signature identified 2 groups of patients who were comparable at baseline but who differed in their capacities to lose weight and improve glycemic control. Six months after the LCD, one group had significant glycemic improvement [homeostasis model assessment of insulin resistance (HOMA-IR) mean change: -0.92; 95% CI: -1.17, -0.67)]. The other group showed no improvement in glycemic control (HOMA-IR mean change: -0.26; 95% CI: -0.64, 0.13). These differences were sustained for ≥1 y after the LCD. The same conclusions were obtained with other endpoints (Matsuda index and fasting insulin and glucose concentrations). Significant differences between the 2 groups were shown in leptin gene expression in adipose tissue biopsies. Significant differences were also observed in weight-related endpoints (body mass index, weight, and fat mass). The lipid signature allowed prediction of which subjects would be considered to be insulin resistant after 6 mo of weight maintenance [validation's receiver operating characteristic (ROC) area under the curve (AUC): 71%; 95% CI: 62%, 81%]. This model outperformed a clinical data-only model (validation's ROC AUC: 61%; 95% CI: 50%, 71%; P = 0.01).. In this study, we report a lipid signature of LCD success (for weight and glycemic outcome) in obese, nondiabetic patients. Lipid changes during an 8-wk LCD allowed us to predict insulin-resistant patients after 6 mo of weight maintenance. The determination of the lipid composition during an LCD enables the identification of nonresponders and may help clinicians manage metabolic outcomes with further intervention, thereby improving the long-term outcome and preventing T2D. This trial was registered at clinicaltrials.gov as NCT00390637.

Topics: Adiposity; Adult; Biomarkers; Biopsy, Needle; Body Mass Index; Body Weight Maintenance; Cohort Studies; Diet, Reducing; Europe; Gene Expression Regulation; Glycemic Index; Humans; Hyperlipidemias; Insulin Resistance; Leptin; Models, Biological; Obesity; Patient Dropouts; Risk Factors; ROC Curve; Subcutaneous Fat, Abdominal; Weight Loss

To explore the efficacy and effect mechanism of the combined therapy of acupuncture and tapping method in the treatment of obesity and hyperlipidemia of liver qi stagnation and spleen deficiency pattern in the patients.. One hundred and four female patients were randomized into a combined therapy of acupuncture and tapping (combined therapy group) group method and an acupuncture group, 52 cases in each group. In the acupuncture group, acupuncture was applied to Qimen (LR 14), Taichong (LR 3), Zhangmen (LR 13), Taibai (SP 3), Zusanli (ST 36), Geshu (BL 17), Ganshu (BL 18), Pishu (BL 20), etc. In the combined therapy group, on the basis of acupuncture treatment, the tapping method with plum blossom needle was used at each acupoint. The treatment was given once every two days, continuously for 3 months in the two groups. The indices were observed, including the obesity indices, such as body mass, body mass index (BMI), body fat percentage (F%) and obesity degree (A); the blood lipid levels such as total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL) and high density lipoprotein (HDL); the fat-islet axie relevant indices such as fasting plasma glucose (FBS), fasting leptin (FLP), fasting insulin (FINS), insulin sensitive index (ISI), insulin resistance in- dex (Homa IR), insulin secretion index (Homa-β) and autonomic nerve function index (Y value) before and after treatment in the patients of two groups. The efficacy was compared between the two groups.. The total effective rates were 96.2% (50/52) and 84.6% (44/52) in the combined therapy group and the acupuncture group respectively, without significant difference in comparison (P > 0.05). Obesity indices, blood lipid indices, fat-islet axie relevant indices and autonomic nerve function indices were all improved after treatment as compared with those before treatment in the two groups (P < 0.01, P < 0.05), and the improvements in the combined therapy group were much more significant (P < 0.01, P < 0.05).. The combined therapy of acupuncture and tapping method achieves the double effects of weight loss and lipid loss in the treatment of obesity combined with hyperlipidemia. The effect mechanism is possibly related to the positive regulations of blood glucose, lipid metabolism and fat-islet axie in the patients.

Topics: Acupuncture Points; Acupuncture Therapy; Adult; Blood Glucose; Female; Humans; Hyperlipidemias; Insulin; Leptin; Liver; Middle Aged; Obesity; Qi; Spleen; Treatment Outcome; Triglycerides; Young Adult

Plasma non-esterified fatty acids (NEFAs) activate the sympathetic nervous system and increase vascular resistance and blood pressure (BP); however, the response with ageing is not known. The objectives of this study were to characterize the cardiovascular, neural and endocrine responses to acute elevation of NEFA concentration. Seventeen healthy older volunteers (7 male and 10 female; age, 69 +/- 1 years; body mass index, 24 +/- 0 kg m(2); values are means +/- s.e.m.) received a 4 h intravenous infusion of the lipid emulsion Intralipid 20% or placebo (single-blind, randomized, balanced order) on two different days separated by at least 2 weeks. Muscle sympathetic nerve activity (MSNA), heart rate (HR), BP, cardiac output, leptin, insulin, aldosterone, angiotensin II and F(2)-isoprostanes were measured. The change in HR (+8.8 +/- 0.9 versus +3.0 +/- 0.9 beats min(1)), systolic BP (+13.9 +/- 2.2 versus +6.6 +/- 2.4 mmHg) and diastolic BP (+7.4 +/- 1.5 versus +1.3 +/- 0.8 mmHg) was significantly greater after Intralipid versus placebo infusions (P < 0.001). Lipid infusion increased MSNA burst frequency (+6.7 +/- 1.6 bursts min(1)), total MSNA (+45%; P < 0.001) and concentrations of insulin (+40%), aldosterone (+50%) and F(2)-isoprostanes (+80%), but not leptin. Hyperlipidaemia caused directionally opposite responses for insulin (increased) and calf vascular resistance (decreased) in men, whereas insulin and calf vascular resistance responses were severely blunted and non-existent, respectively, in women. We conclude that direct vascular mechanisms and central sympathetic activation contribute to the NEFA pressor response; though absolute values are higher, the change is not different compared with previous studies in a younger population.

Topics: Aged; Aging; Aldosterone; Blood Pressure; Cardiac Output; Epinephrine; Fat Emulsions, Intravenous; Fatty Acids, Nonesterified; Female; Heart Rate; Hemodynamics; Humans; Hyperlipidemias; Insulin; Leg; Leptin; Male; Middle Aged; Muscle, Skeletal; Regional Blood Flow; Sympathetic Nervous System; Vascular Resistance

Little is known about the effects of alterations in fatty acid classes on adiponectin, a hormone secreted by the adipocyte known to be important in the development of diabetes and cardiovascular disease (CVD). Any factor, including diet, that may positively influence adiponectin gene expression or increase circulating levels might be useful for improving such metabolic abnormalities. We investigated the effects of alterations in dietary fatty acid saturation on fasting serum adiponectin and associated peptides.. Double-blind, randomized, crossover, 2 x 3-week residential intervention trial where 18 mildly hyperlipidemic adult men were provided with a high saturated:unsaturated fat (SFA:USFA) and lower SFA:USFA treatment separated by an uncontrolled 4-week washout. Only fatty acid profile was altered between treatments. Fasting blood samples were collected on days 0, 1, 7, 14, 21, 22 of each intervention period for the measurement of adiponectin, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsC-RP), leptin, and ghrelin.. Body weight was kept constant (+/-1 kg) throughout each treatment. There was no detectable difference in fasting adiponectin at baseline (mean day 0 + day 1) between the treatment groups (mean +/- s.d.; high(SFA:USFA) = 7.0 +/- 1.7 vs. low(SFA:USFA) = 6.7 +/- 1.4 microg/ml, P > 0.05). There were neither significant between-treatment effects of fatty acid saturation (diet x time, P > 0.05) on serum adiponectin nor any significant between-treatment effects on serum TNF-alpha, IL-6, hsC-RP, leptin, or ghrelin (P > 0.05).. Fasting serum adiponectin was not detectably affected by alterations in dietary fatty acid profile in mildly hyperlipidemic men. There was no evidence that an increase in SFA content of the diet significantly worsened fasting serum adiponectin over a 3-week intervention period.

Topics: Adiponectin; Adult; Aged; Biomarkers; C-Reactive Protein; Cross-Over Studies; Diet Records; Dietary Fats; Double-Blind Method; Fasting; Fatty Acids; Fatty Acids, Unsaturated; Ghrelin; Humans; Hyperlipidemias; Interleukin-6; Leptin; Male; Middle Aged; Severity of Illness Index; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

In addition to lipid lowering, further pleotropic effects of statins have been postulated. We aimed to study if the various pleotropic effects are due indirectly to the modulation of adipocytokines.. We studied the effect of atorvastatin on insulin sensitivity and the plasma adiponectin and leptin concentrations. Our randomized open labeled study had 29 hyperlipidemic Type 2 diabetic patients (14 females, 15 males, mean age 60.0+/-2.2 yr). They were randomized into three 12-week atorvastatin intervention types. Each day patients were given either 10 mg (no.=10), 20 mg (no.=10) or 40 mg (no.=9). Evaluations were performed before and after intervention.. All baseline characteristics were statistically identical in the 3 groups. Drop in total cholesterol, LDL-cholesterol, and triglyceride levels were measured at the end. With 10 mg the drop was 30%, 37%, and 30%. The 20 mg group was 43%, 54%, and 34%. The 40 mg group was 42%, 51%, and 27%. Groups had no significant change of body mass index, HDLcholesterol, and glycated hemoglobin levels. Also, levels of insulin, adiponectin, leptin, homeostasis model assessment index (HOMA) and Quantitative Insulin Sensitivity Check Index (QUICKI) stayed the same. Pooled parameters of all 29 patients showed no difference in levels of insulin, adiponectin, leptin, HOMA, and QUICKI before and after treatment.. Atorvstatin does not affect insulin sensitivity and the adiponectin or leptin levels in hyperlipidemic Type 2 diabetes.

Topics: Adiponectin; Aged; Anticholesteremic Agents; Atorvastatin; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Glycated Hemoglobin; Heptanoic Acids; Humans; Hyperlipidemias; Insulin Resistance; Leptin; Male; Middle Aged; Pyrroles

Conjugated linoleic acid (CLA) is a group of dietary fatty acids with antiobesity and antidiabetic effects in some animals. The trans10cis12 (t10c12) CLA isomer seems to cause these effects, including improved insulin sensitivity. Whether such isomer-specific effects occur in humans is unknown. The aim of this study was to investigate whether t10c12 CLA or a commercial CLA mixture could improve insulin sensitivity, lipid metabolism, or body composition in obese men with signs of the metabolic syndrome.. In a randomized, double-blind controlled trial, abdominally obese men (n = 60) were treated with 3.4 g/day CLA (isomer mixture), purified t10c12 CLA, or placebo. Euglycemic-hyperinsulinemic clamp, serum hormones, lipids, and anthropometry were assessed before and after 12 weeks of treatment.. Baseline metabolic status was similar between groups. Unexpectedly, t10c12 CLA increased insulin resistance (19%; P < 0.01) and glycemia (4%; P < 0.001) and reduced HDL cholesterol (-4%; P < 0.01) compared with placebo, whereas body fat, sagittal abdominal diameter, and weight decreased versus baseline, but the difference was not significantly different from placebo. The CLA mixture did not change glucose metabolism, body composition, or weight compared with placebo but lowered HDL cholesterol (-2%; P < 0.05).. These results reveal important isomer-specific metabolic actions of CLA in abdominally obese humans. A CLA-induced insulin resistance has previously been described only in lipodystrophic mice. Considering the use of CLA-supplements among obese individuals, it is important to clarify the clinical consequences of these results, but they also provide physiological insights into the role of specific dietary fatty acids as modulators of insulin resistance in humans.

Topics: Adult; Aged; Body Composition; Diabetes Mellitus; Double-Blind Method; Humans; Hyperlipidemias; Insulin Resistance; Isomerism; Leptin; Linoleic Acid; Lipoproteins; Male; Metabolic Syndrome; Middle Aged; Obesity

The clinical efficacy of bezafibrate was examined with special reference to glucose metabolism in patients with type 2 diabetes mellitus (DM2). In protocol 1, 342 patients with DM2 and hyperlipidemias were randomly divided into 2 groups, 16-week bezafibrate treatment (n = 174) and no bezafibrate treatment (n = 168). In protocol 2, 20 DM2 patients were randomly divided into 2 groups, 8-week bezafibrate treatment (n = 10) and no bezafibrate treatment (n = 10), and a meal tolerance test (MTT) was performed. In protocol 1, bezafibrate treatment significantly reduced the fasting levels of triglyceride (TG) by 50% +/- 1.6%, total cholesterol (TC) by 12% +/- 1.1%, plasma glucose (PG) from 151.3 +/- 3.5 to 128.6 +/- 3.4 mg/dL, and hemoglobin A1c (HbA1c) from 7.2% +/- 0.1% to 6.9% +/- 0.1%, and significantly increased high-density lipoprotein cholesterol (HDL-C) by 20% +/- 0.8%. In protocol 2, fasting TG, PG, and insulin levels were significantly reduced by bezafibrate treatment. Moreover, in the MTT, postprandial increments of TG were significantly blunted after bezafibrate treatment, whereas postprandial PG and insulin levels were not significantly changed. Leptin levels were significantly decreased, while tumor necrosis factor alpha (TNF-alpha) levels were not changed. In conclusion, both hyperglycemia and hyperlipidemia can be improved by bezafibrate treatment in DM2.

Topics: Bezafibrate; Blood Glucose; Cholesterol; Cholesterol, HDL; Diabetes Mellitus, Type 2; Fasting; Female; Glycated Hemoglobin; Humans; Hyperlipidemias; Hypolipidemic Agents; Leptin; Male; Middle Aged; Triglycerides; Tumor Necrosis Factor-alpha

The effects of celiprolol on fasting plasma leptin levels, glucose tolerance, and insulin sensitivity were studied in a randomized, investigator-masked, and parallel clinical trial. Modified oral glucose tolerance tests (OGTT) were performed during the previous antihypertensive monotherapy (beta- or Ca-blocker, or ACE inhibitor), and 6 and 12 months after randomization to celiprolol (200-400 mg daily) or to control group, where the therapy was kept unchanged. One hundred sixty-nine dyslipidemic and hypertensive nondiabetics with an age range of 42-65 years and an average body mass index of 28.4 kg/m2 completed the study according to the protocol. The mean circulating leptin level decreased from 7.5 to 6.6 ng/mL in men (p < 0.05) and from 23.0 to 19.7 ng/mL in women during the 12-month celiprolol treatment. The incremental glucose area under the curve (AUC) in the 2-hour OGTT decreased from 3.8 to 3.0 h* mmol/L (p < 0.01), and insulin AUC decreased from 134 to 99 h* mU/L (p < 0.01). The insulin sensitivity index increased by 22% (p < 0.01) and the serum triglyceride level decreased by 15% in the celiprolol group. Changes in serum cholesterol were clinically insignificant. In the control group, no significant change was seen in any measured variable. A decrease in leptin levels in the celiprolol group was associated with improved insulin sensitivity, while the weight of the moderately obese patients did not change. The clinical significance of a 14% decrease in fasting plasma leptin level remains to be elucidated. The results suggest amelioration of leptin resistance during long-term celiprolol therapy.

Topics: Adrenergic beta-Antagonists; Celiprolol; Fasting; Female; Glucose Tolerance Test; Humans; Hyperlipidemias; Hypertension; Insulin; Leptin; Male; Middle Aged; Obesity; Patient Compliance

A syndrome of lipodystrophy, associated with hypertriglyceridaemia, hypercholesterolaemia, hyperinsulinaemia and peripheral insulin resistance has been reported in protease inhibitor (PI)-treated HIV-infected patients. Because lipid metabolism, fat mass distribution and insulin resistance are partly regulated by steroid hormones, we questioned whether lipodystrophy is related to hormonal perturbations.. To evaluate serum lipid and steroid hormone concentrations in HIV-positive men on highly active antiretroviral therapy (HAART) in order to determine whether dyslipidaemia, peripheral loss of fatty tissue and central fat accumulation are related to steroid hormone modifications.. A cross-sectional study.. Thirty-seven HIV-1-positive men on HAART, 23 of whom had symptoms of lipodystrophy, according to a subjective clinical score of lipodystrophy (SCSL), were tested. Serum concentrations of cholesterol, triglycerides and their subclasses, apolipoproteins and steroid hormones, including cortisol, dehydroepiandrosterone (DHEA), DHEA sulphate, androstenedione, testosterone and dihydrotestosterone were measured.. Serum cholesterol, very low density lipoprotein (VLDL) cholesterol, triglycerides, VLDL triglycerides, high density lipoprotein (HDL) and low density lipoprotein (LDL) triglycerides, apolipoprotein B (ApoB) and atherogenic ratios of cholesterol:HDL cholesterol, LDL cholesterol:HDL cholesterol and ApoB:apolipoprotein A1 (ApoA1) were significantly increased in lipodystrophy-positive compared with lipodystrophy-negative men. The serum cortisol level was similar in lipodystrophy-positive versus lipodystrophy-negative men, but was elevated compared with controls. Serum DHEA was significantly lower in lipodystrophy-positive versus lipodystrophy-negative men and, consequently, the cortisol:DHEA ratio was increased in lipodystrophy-positive patients. A positive correlation was found between the cortisol:DHEA ratio and increased levels of atherogenic lipids. In addition, the SCSL was positively correlated with dyslipidaemia and the cortisol:DHEA ratio.. This study demonstrates an association between the cortisol:DHEA ratio, lipid alterations and lipodystrophy. This syndrome might result from an imbalance between peripheral lipolysis and lipogenesis, both regulated by cortisol and DHEA.

Topics: Adult; Androgens; Anti-HIV Agents; Blood Glucose; Cross-Sectional Studies; HIV Infections; Humans; Hydrocortisone; Hyperlipidemias; Insulin; Leptin; Lipodystrophy; Male; Middle Aged

Hyperlipidemia is one of the metabolic disorders posing great threat to human health. Our previous studies have shown that the nutritional properties of peanut meal after fermentation are markedly improved, and can effectively improve hyperlipidemia caused by high-fat diet in mice. In this study, in order to facilitate the further utilization of peanut meal, the effect of peanut polypeptide (PP) from peanut meal mixed fermentation on lipid metabolism in mice fed with high-fat diet (HFD) and its possible mechanism were investigated. Fifty male C57BL/6J mice were randomly divided into five groups: normal control group (N), high-fat model group (M), PP low-dose group (PL), PP high-dose group (PH), and atorvastatin positive control group (Y).. The results show that PP supplementation can effectively reduce the body weight of mice, decrease the serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and leptin levels (P < 0.05), increase the high-density lipoprotein cholesterol (HDL-C) levels (P < 0.05), up-regulate the expression levels of ileal tight junction proteins ZO-1 and occludin (P < 0.05), reduce the hepatocyte injury and lipid accumulation caused by high-fat diet and increase the species richness of intestinal flora.. PP can significantly improve hyperlipidemia and regulate intestinal flora disorders caused by hyperlipidemia. The possible mechanism may be related to the reduction of serum leptin levels and up-regulating the expression levels of the ileal tight junction proteins ZO-1 and occludin. This study provides evidence for its regulatory role in lipid metabolism and intestinal function, and provides a research basis for the potential nutritional benefits of underutilized food by-products. © 2023 Society of Chemical Industry.

Topics: Animals; Arachis; Cholesterol, LDL; Diet, High-Fat; Fermentation; Gastrointestinal Microbiome; Humans; Hyperlipidemias; Leptin; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Occludin

To measure and compare serum levels of leptin and lipid profile parameters in primigravida women with PE and normotensive primigravida.. Analytical cross-sectional study.. Department of Physiology and Cell Biology, University of Health Sciences, Lahore, from 2018 to 2020.. Preeclamptic (PE, group A) and normal primigravida (PG, group B) with gestational age 30-36 weeks were recruited from tertiary care hospitals. After written and informed consent, blood samples were taken. Serum was separated and stored at -80oC until processed. CBC and lipid profile of each patient was also done using automated lab machines. Serum levels of leptin were calculated by ELISA. The data was entered and analysed in SPSS version 20.. The mean serum levels of leptin (ng/ml) in PE (group A) were significantly raised compared to normotensive PG (group B) at 33.44±12.91 and 4±6.20 respectively (p.

Topics: Cross-Sectional Studies; Female; Humans; Hyperlipidemias; Infant; Leptin; Lipids; Pre-Eclampsia

This study aims to explore the protective role of ethanol extract from Chimonanthus nitens Oliv. leaf (COE) in hyperlipidemia via the leptin/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway.. Male Sprague‒Dawley rats were randomly divided into 6 groups (n = 8): normal-fat diet (NMD), high-fat diet (HFD), HFD treated with simvastatin (SIM, 5 mg/kg/day), and HFD treated with COE (40, 80, 160 mg/kg/day). Lipid parameters, oxidative stress factors, serum leptin, body weight, hepatic wet weight and liver index were measured. Proteins in the leptin/JAK2/STAT3 pathway in liver tissues were determined using western blotting. Additionally, the expression levels of cytochrome P450 family 7 subfamily A member 1 (CYP7A1) and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) were quantified using western blotting and quantitative real-time polymerase chain reaction (qPCR).. COE decreased HFD-induced increases in body weight, hepatic wet weight and the liver index. HFD-induced hyperlipidemia and oxidative stress were observed in rat serum and livers. Additionally, COE repressed these two symptoms in rats fed a HFD. Moreover, COE caused CYP7A1 upregulation and HMGCR downregulation in HFD-fed rats. Mechanistically, COE induced the expression of leptin receptor (OB-Rb) and JAK2 and STAT3 phosphorylation in HFD-treated rats.. COE activates the leptin/JAK2/STAT3 pathway, leading to an improvement in liver function and lipid metabolism and ultimately alleviating hyperlipidemia in rats. Therefore, COE may be a potential hypolipidemic drug for the treatment of hyperlipidemia.

Topics: Animals; Body Weight; Diet, High-Fat; Ethanol; Hyperlipidemias; Janus Kinase 2; Leptin; Liver; Male; Plant Leaves; Rats; Rats, Sprague-Dawley; STAT3 Transcription Factor

Topics: Adiponectin; Animals; Antioxidants; Auricularia; Body Weight; Cytoprotection; Fungal Polysaccharides; Hyperlipidemias; Hypolipidemic Agents; Insulin; Leptin; Liver; Male; Mice

The mechanisms whereby obesity differentially affects males and females are unclear. Because macrophages are functionally the most important cells in obesity-induced inflammation, we sought to determine reasons for male-specific propensity in macrophage migration. We previously determined that male mice fed a high-fat diet exhibit macrophage infiltration into the hypothalamus, whereas females were protected irrespective of ovarian estrogen, in this study, we show that males accumulate more macrophages in adipose tissues that are also more inflammatory. Using bone marrow cells or macrophages differentiated in vitro from male and female mice fed control or high-fat diet, we demonstrated that macrophages derived from male mice are intrinsically more migratory. We determined that males have higher levels of leptin in serum and adipose tissue. Serum CCL2 levels, however, are the same in males and females, although they are increased in obese mice compared with lean mice of both sexes. Leptin receptor and free fatty acid (FFA) receptor, GPR120, are upregulated only in macrophages derived from male mice when cultured in the presence of FFA to mimic hyperlipidemia of obesity. Unless previously stimulated with LPS, CCL2 did not cause migration of macrophages. Leptin, however, elicited migration of macrophages from both sexes. Macrophages from male mice maintained migratory capacity when cultured with FFA, whereas female macrophages failed to migrate. Therefore, both hyperlipidemia and hyperleptinemia contribute to male macrophage-specific migration because increased FFA induce leptin receptors, whereas higher leptin causes migration. Our results may explain sex differences in obesity-mediated disorders caused by macrophage infiltration.

Topics: Animals; Cell Movement; Chemokine CCL2; Fatty Acids, Nonesterified; Female; Hyperlipidemias; Inflammation; Leptin; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Multifactorial Inheritance; Obesity; Sex Characteristics; Sex Factors

The effects of the administration of bamboo shoot (Phyllostachys edulis) dietary fiber (BSDF) on high-fat diet (HDF) induced hyperlipidemia were studied with SD rat models. The results indicated that the body weight of rats and the mass of their adipose tissue were significantly (P < 0.05) decreased after the combination treatment of soluble dietary fiber (SDF) and insoluble dietary fiber (IDF). The levels of total cholesterol, triglyceride, and low-density lipoprotein cholesterol were significantly (P < 0.05) decreased by 30.20%, 53.28% and 35.63%, respectively, compared to those of the model group. The levels of serum alanine aminotransferase, aspartate aminotransferase, leptin, and insulin-like growth factor-1 of the SDF + IDF group were also significantly lower than those of the HDF model group (P < 0.05). Additionally, the perirenal fat percentage and body fat percentage in the SDF + IDF group were reduced by 31.61% and 25.09%, respectively. IDF exhibited better hypolipidemic ability than SDF in HFD induced rats at the same dose, while SDF and IDF showed a synergistic hyperlipidemia prevention effect. The mRNA expression levels of lipid synthesis genes SREBP-1c and FAS were significantly down-regulated by SDF + IDF treatment (P < 0.05). These results suggested that BSDF composed of IDF and SDF, with potential hypolipidemic effects, could be used in the production of health-beneficial food.

Topics: Adipose Tissue; Alanine Transaminase; Animals; Aspartate Aminotransferases; Blood Glucose; Body Weight; Cholesterol; Diet, High-Fat; Dietary Fiber; Down-Regulation; Hyperlipidemias; Leptin; Lipoproteins, LDL; Liver; Male; Plant Shoots; Rats; Rats, Sprague-Dawley; Sasa; Triglycerides

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

Decreased expression of mitochondrial frataxin (FXN) causes Friedreich's ataxia (FRDA), a neurodegenerative disease with type 2 diabetes (T2D) as severe comorbidity. Brown adipose tissue (BAT) is a mitochondria-enriched and anti-diabetic tissue that turns excess energy into heat to maintain metabolic homeostasis. Here we report that the FXN knock-in/knock-out (KIKO) mouse shows hyperlipidemia, reduced energy expenditure and insulin sensitivity, and elevated plasma leptin, recapitulating T2D-like signatures. FXN deficiency leads to disrupted mitochondrial ultrastructure and oxygen consumption as well as lipid accumulation in BAT. Transcriptomic data highlights cold intolerance in association with iron-mediated cell death (ferroptosis). Impaired PKA-mediated lipolysis and expression of genes controlling mitochondrial metabolism, lipid catabolism and adipogenesis were observed in BAT of KIKO mice as well as in FXN-deficient T37i brown and primary adipocytes. Significant susceptibility to ferroptosis was observed in adipocyte precursors that showed increased lipid peroxidation and decreased glutathione peroxidase 4. Collectively our data point to BAT dysfunction in FRDA and suggest BAT as promising therapeutic target to overcome T2D in FRDA.

Topics: Adipocytes; Adipose Tissue, Brown; Animals; Cold Temperature; Cyclic AMP-Dependent Protein Kinases; Diabetes Mellitus, Type 2; Ferroptosis; Frataxin; Friedreich Ataxia; Hyperlipidemias; Insulin Resistance; Iron-Binding Proteins; Leptin; Lipid Metabolism; Lipolysis; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Electron, Transmission; Mitochondria; Oxidative Stress; Phospholipid Hydroperoxide Glutathione Peroxidase; RNA-Seq; Thermogenesis

To determine the efficacy of Corchorus olitorius (C. olitorius) leaf extract in the prevention of metabolic syndrome induced in rats by high-fat diet (HFD) and compare it with that of orlistat.. Phytochemical analysis was performed. Effect of orlistat and C. olitorius extract on lipase activity and acute food intake were investigated. Body weight, biochemical parameters and histopathological examination were demonstrated.. Corchorus olitorius extract inhibited the pancreatic lipase activity, but orlistat was more potent. Cumulative food intake has not changed by the tested agents. In obese rats, C. olitorius or orlistat significantly decreased weight gain and visceral white adipose tissue. They exhibited a significant reduction in serum glucose, total cholesterol, triglycerides, low density lipoprotein cholesterol, free fatty acids, IL-1β, tumour necrosis factor-α (TNF-α), insulin and leptin levels of obese rat groups while high density lipoprotein cholesterol and adiponectin levels were significantly increased by them. Histopathological examination of the liver revealed that C. olitorius was more effective than orlistat in the alleviating of steatosis and adipocyte hypertrophy shown in obese control rats.. Corchorus olitorius is effective as orlistat in preventing obesity, hyperlipidaemia, steatosis and insulin resistance. These actions may be mediated by inhibiting of lipase activity, TNF-α, IL-1β and leptin resistance along with increasing of adiponectin.

Topics: Adiponectin; Animals; Anti-Obesity Agents; Corchorus; Cytokines; Diet, High-Fat; Hyperlipidemias; Insulin; Insulin Resistance; Leptin; Lipase; Male; Metabolic Syndrome; Obesity; Orlistat; Plant Extracts; Plant Leaves; Rats; Rats, Sprague-Dawley; Weight Gain

Ethanolic extract of leaves of Morus alba L. (M. alba), known as white mulberry, was orally administered (100 mg/kg b.wt) for 8 weeks to female Wistar rats that were fed a high-cholesterol diet (HCD), to investigate the potential of M. alba leaves in attenuation of obesity, dyslipidemia, insulin resistance, and deficits in mood, cognitive as well as motor activity that are linked to the adipokines secretions of visceral adipose tissue. Results showed that M. alba diminished body weight gain, hypercholesterolemia, hypertriglyceridemia, atherogenic (AI) & coronary artery indices (CRI), and ameliorated glucose level and insulin resistance index in rats on HCD, compared with untreated HCD rats. Moreover, M. alba administration significantly decreased serum leptin and resistin contents as well as their mRNA expression in visceral adipose tissue, but significantly increased serum adiponectin level, and its mRNA expression in visceral adipose tissue in rats fed on HCD, compared to those in untreated HCD group. Regarding behavioral alterations, M. alba attenuated motor deficit, declined memory, depression and anxiety-like behavior, as well in rats on HCD, compared to that noticed in untreated HCD rats. The current data showed that serum leptin and resistin showed a positive correlation with and body weight gain, triglycerides (TG), AI as well as CRI, but showed a negative correlation with exploration, declined memory, depression- and anxiety-like behavior. Conversely, serum adiponectin showed a negative correlation with and body weight gain, TG, AI as well as CRI, but showed a positive correlation with locomotor activity, exploration, declined memory, and depression- and anxiety-like behavior. In conclusion, M. alba leaves supplementation could attenuate adiposity, insulin resistance behavioral deficits via down-regulation of regulation of gene expression of leptin, resistin, but up-regulation of adiponectin gene expression in the visceral adipose tissue of rats fed a high-cholesterol diet.

Topics: Adiponectin; Adiposity; Animals; Behavior, Animal; Blood Glucose; Cholesterol, Dietary; Female; Gene Expression; Hyperlipidemias; Insulin Resistance; Leptin; Morus; Plant Extracts; Plant Leaves; Rats; Rats, Wistar; Resistin; Weight Gain

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

Chemerin (also known as tazarotene-induced gene 2 and retinoic acid receptor responder 2) has been identified as an adipokine that exerts effects on many biological processes, including adipogenesis, angiogenesis, inflammation, immune responses, and food intake. This variety of effects has led to its implication in obesity and co-morbidities including diabetes and a risk of cardiovascular disease. The biological effects are mostly mediated by a so-called G protein-coupled receptor, chemokine-like receptor 1 (CMKLR1). Given the association of chemerin with obesity and related diseases, we decided to study in detail the regulation of chemerin and CMKLR1 expression in white adipose tissue (WAT). Specifically, we focused on their expression levels in physiological and pathophysiological settings involved in energy balance: e.g., fasting, postnatal development, and gender. We used Sprague Dawley rats with different nutritional statuses, levels of hormonal deficiency, and states of development as well as ob/ob (leptin-deficient) mice. We analysed the protein expression of both the ligand and receptor (chemerin and CMKLR1) in gonadal WAT by western blotting. We found that chemerin and CMKLR1 protein levels were regulated in WAT by different conditions associated with metabolic changes such as nutritional status, sex steroids, pregnancy, and food composition. Our data indicate that regulation of the expression of this new adipokine and its receptor by nutritional status and gonadal hormones may be a part of the adaptive mechanisms related to altered fat mass and its metabolic complications.

Topics: Adipose Tissue, White; Animals; Chemokines; Diet, High-Fat; Eating; Female; Gonadal Steroid Hormones; Hyperlipidemias; Intercellular Signaling Peptides and Proteins; Leptin; Male; Nutritional Status; Pregnancy; Rats, Sprague-Dawley; Receptors, Chemokine; Sex Characteristics

Lipodystrophy syndromes are rare disorders of deficient adipose tissue. Metreleptin, a human analog of leptin, improved metabolic abnormalities in mixed cohorts of children and adults with lipodystrophy and low leptin.. Determine effects of metreleptin on diabetes, hyperlipidemia, nonalcoholic fatty liver disease (NAFLD), growth, and puberty in pediatric patients with lipodystrophy and low leptin.. Prospective, single-arm, open-label studies with continuous enrollment since 2000.. National Institutes of Health, Bethesda, Maryland.. Fifty-three patients aged 6 months to <18 years with lipodystrophy, leptin level <8 ng/mL (male patients) or <12 ng/mL (female patients), and ≥1 metabolic abnormality (diabetes, insulin resistance, or hypertriglyceridemia).. Subcutaneous metreleptin injections (0.04 to 0.19 mg/kg/d).. Change in A1c, lipid, and transaminase levels after a mean ± standard deviation (SD) of 12 ± 0.2 months and 61 ± 39 months. Changes in liver histology, growth, and pubertal development throughout treatment.. After 12 months, the A1c level (mean ± SD) decreased from 8.3% ± 2.4% to 6.5% ± 1.8%, and median triglyceride level decreased from 374 mg/dL [geometric mean (25th,75th percentile), 190, 1065] to 189 mg/dL (112, 334; P < 0.0001), despite decreased glucose- and lipid-lowering medications. The median [geometric mean (25th,75th percentile)] alanine aminotransferase level decreased from 73 U/L (45, 126) to 41 U/L (25, 59; P = 0.001), and that of aspartate aminotransferase decreased from 51 U/L (29, 90) to 26 U/L (18, 42; P = 0.0002). These improvements were maintained over long-term treatment. In 17 patients who underwent paired biopsies, the NAFLD activity score (mean ± SD) decreased from 4.5 ± 2.0 to 3.4 ± 2.0 after 3.3 ± 3.2 years of metreleptin therapy (P = 0.03). There were no clinically significant changes in growth or puberty.. Metreleptin lowered A1c and triglyceride levels, and improved biomarkers of NAFLD in pediatric patients with lipodystrophy. These improvements are likely to reduce the lifetime burden of disease.

Topics: Adolescent; Alanine Transaminase; Aspartate Aminotransferases; Blood Glucose; Body Height; Child; Child, Preschool; Cohort Studies; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hyperlipidemias; Hypoglycemic Agents; Hypolipidemic Agents; Infant; Insulin Resistance; Leptin; Lipodystrophy; Liver; Male; Non-alcoholic Fatty Liver Disease; Prospective Studies; Puberty; Triglycerides

Growth factor signaling via insulin receptor (IR) and IGF-1 receptor (IGF1R) plays several important roles in the pathogenesis of metabolic syndrome and diabetes. OSI-906 (linsitinib), an anti-tumor drug, is an orally bioavailable dual inhibitor of IR and IGF1R. To investigate the recovery from metabolic changes induced by the acute inhibition of IR and IGF1R in adult mice, mice were treated with OSI-906 or a vehicle for 7 days and the results were analyzed on the last day of injection (Day 7) or after 7 or 21 days of withdrawal (Day 14 or Day 28). On day 7, the visceral white fat mass was significantly reduced in mice treated with OSI-906 accompanied by a reduced expression of leptin and an increased expression of the lipolysis-related genes Lpl and Atgl. Interestingly, the lipoatrophy and the observed changes in gene expression were completely reversed on day 14. Similarly, liver steatosis and β cell proliferation were transiently observed on day 7 but had disappeared by day 14. Taken together, these results suggest that this model for the acute inhibition of systemic IR/IGF1R signaling may be useful for investigating the recovery from metabolic disorders induced by impaired growth factor signaling.

Topics: Animals; Cell Proliferation; Dietary Supplements; Energy Metabolism; Fatty Liver; Hyperglycemia; Hyperinsulinism; Hyperlipidemias; Imidazoles; Insulin-Secreting Cells; Leptin; Lipodystrophy; Mice; Pyrazines; Safety-Based Drug Withdrawals; Time Factors; Tomography, X-Ray Computed

Leptin and its receptor play several physiological roles in the canine gallbladder, and the dysregulation of leptin might play a role in the pathogenesis of gallbladder diseases such as gallbladder mucocele. Previous studies revealed a positive association between hyperlipidemia and gallstones in humans. However, the latter is still unclear in dogs with cholelithiasis. In this study, we examined the differences in leptin, leptin receptor, total cholesterol, and triglyceride levels between healthy dogs and dogs with cholelithiasis, and evaluated the correlation between leptin and hyperlipidemia. Twenty-eight healthy dogs and 34 client-owned dogs with cholelithiasis were enrolled in the study. Leptin concentrations and lipid profiles were determined from sera, and leptin and leptin receptor expression levels were quantified in gallbladder tissue. In dogs with cholelithiasis, serum concentrations of leptin (p < 0.001), total cholesterol (p < 0.001), and triglycerides (p < 0.001) were significantly higher compared with those in healthy dogs. Positive correlations were observed between serum leptin and total cholesterol (95% confidence interval (CI) = 0.61-0.89, r = 0.725, p < 0.001), and between leptin and triglycerides (95% CI = 0.63-0.89, r = 0.782, p < 0.001) in the cholelithiasis group. Hypercholesterolemia (Odds Ratio (OR) = 9.720; 95% CI = 1.148-82.318) and hypertriglyceridemia (OR = 12.913; 95% CI = 1.548-107.722) were shown to be risk factors for gallstone disease. In cholelithiasis patients who underwent cholecystectomy, serum leptin levels were significantly higher than in patients that had not undergone surgery (p < 0.001). Leptin and leptin receptor expression was upregulated in the gallbladder tissues of cholelithiasis patients (p < 0.01 and p < 0.001, respectively). These results indicate that increased serum leptin concentrations and hyperlipidemia (hypercholesterolemia or hypertriglyceridemia) are associated with canine cholelithiasis and that homeostatic imbalance of these parameters might affect the pathogenesis of gallstones.

Topics: Animals; Cholelithiasis; Dog Diseases; Dogs; Hyperlipidemias; Leptin

The phosphoinositide phosphatase, myotubularin-related protein 14 (MTMR14), has been reported to play an important role in the regulation of muscle performance, autophagy, and aging in mice. We previously showed that MTMR14-knockout (KO) mice gain weight earlier than their wild-type (WT) littermates even on a normal chow diet (NCD), suggesting that this gene might also be involved in regulating metabolism. In the present study, we evaluated the effect of MTMR14 deficiency on high-fat diet (HFD)-induced obesity, lipid accumulation, metabolic disorders, and inflammation in WT and MTMR14-KO mice fed with NCD or HFD. To this end, MTMR14-KO mice fed with HFD showed significantly increased body weight, blood glucose levels, serum triglyceride (TG) levels, and total cholesterol (TC) levels as compared to their age-matched WT control. Additionally, lipid accumulation also increased in the KO mice. Simultaneously, the expression of metabolism-associated genes (Glut4, adiponectin, and leptin) was different in the liver, muscle, and fatty tissue of MTMR14-KO mice fed with HFD. More importantly, the expression of several inflammation-associated genes (TNF-α, IL-6, IL-1β, and MCP-1) dramatically increased in the liver, muscle, and fatty tissue of MTMR14-KO mice relative to control. Taken together, these results suggest that MTMR14 deficiency accelerates HFD-induced metabolic dysfunction and inflammation. Furthermore, the results showed that exacerbated metabolic dysfunction and inflammation may be regulated via the PI3K/Akt and ERK signaling pathways.

Topics: Adiponectin; Adipose Tissue; Animals; Cytokines; Diet, High-Fat; Gene Expression Regulation; Glucose Transporter Type 4; Hyperglycemia; Hyperlipidemias; Leptin; Lipid Metabolism; Liver; Male; Mice, Inbred C57BL; Mice, Knockout; Muscle, Skeletal; Obesity; Phosphoric Monoester Hydrolases; Random Allocation; Weight Gain

Modified Lingguizhugan Decoction (MLD) came from famous Chinese medicine Linggui Zhugan Decoction. The MLD is used for the treatment of metabolic syndrome in the clinical setting. Our study focuses on the comprehensive treatment of MLD incorporated with dietary restriction and exercise in a rat model of the metabolic syndrome (MS).. Rats were divided into five groups: control group (Cont), high-fat diet group (HFD), high-fat diet incorporated with dietary restriction group (HFD-DR), exercise incorporated with dietary restriction group (HFD-DR-Ex) and MLD incorporated with dietary restriction and exercise group (HFD-DR-Ex-MLD). Treatments were conducted for 1 week after feeding high-fat diet for 12 weeks. The effects of treatments on high fat diet-induced obesity, hyperglycemia, hyperlipidemia, hypertension, hepatic injury and insulin resistance in rats of MS were examined. In addition, the tumor necrosis factor-α (TNF-α), leptin and protein kinase B (PKB) in rats serum and liver were also examined by enzyme-linked immunosorbent assay (ELISA).. After a week's intervention by dietary restriction, dietary restriction incorporated with exercise or MLD, compared with HFD rats, the relative weight of liver and fat, levels of triglyceride, total cholesterol, low-density lipoprotein, free fatty acid, aspartate aminotransferase, glutamic-pyruvic transaminase and alkaline phosphatase, insulin, were significantly decreased (p < 0.05 or 0.01). This treatment also inhibited abnormal increases of TNF-α, leptin and PKB in serum and liver.. MLD incorporated with dietary restriction and exercise treatment exhibit effects in alleviating high-fat diet-induced obesity, hyperglycemia, hyperlipidemia, hypertension, hepatic injury and insulin resistance, which are possibly due to the down-regulation of TNF-α, leptin and PKB.

Topics: Adipose Tissue; Animals; Blood Pressure; Caloric Restriction; Drugs, Chinese Herbal; Hyperglycemia; Hyperlipidemias; Hypertension; Insulin; Leptin; Lipids; Liver; Magnoliopsida; Male; Metabolic Syndrome; Obesity; Physical Conditioning, Animal; Phytotherapy; Poria; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Hyaluronan has diverse biological activities depending on its molecular size. The hyaluronan fragments (50 kDa) can decrease adipogenic differentiation in vitro. However, in vivo anti-obesitic effects of hyaluronan fragments have not been elucidated. Therefore, we examined the anti-obesity effects of hyaluronan fragments on high-fat diet induced obesity in C57BL/6 mice. Oral administration of hyaluronan fragments (200 mg/kg for 8 weeks) decreased body weight, adipose tissues, serum lipid (low-density lipoprotein cholesterol, triglyceride), and leptin level. Hyaluronan fragments decreased the hypertrophy of adipose tissue and ameliorated liver steatosis. The mRNA expression of leptin was reduced in adipocyte by treatment with hyaluronan fragments. Additionally, hyaluronan fragments enhanced the mRNA expression of PPAR-α and its target genes UCP-2 and decreased mRNA expression of PPAR- γ and fatty acid synthase in liver. In conclusions, hyaluronan fragments had marked effects on inhibiting the development of obesity in obese mice fed the high-fat diet. It suggested that enhancing PPAR-α and suppressing PPAR-γ expression are two possible mechanisms for the anti-obesitic effect of hyaluronan fragments.

Topics: Adipocytes; Adiponectin; Animals; Body Weight; Diet, High-Fat; Fatty Liver; Hyaluronic Acid; Hyperlipidemias; Leptin; Lipid Metabolism; Lipids; Lipoproteins, LDL; Liver; Mice; Mice, Inbred C57BL; Mice, Obese; Molecular Weight; Obesity; PPAR alpha; Real-Time Polymerase Chain Reaction; Triglycerides

To determine the roles of insulin and insulin-like growth factor 1 (IGF-1) action in adipose tissue, we created mice lacking the insulin receptor (IR), IGF-1 receptor (IGF1R), or both using Cre-recombinase driven by the adiponectin promoter. Mice lacking IGF1R only (F-IGFRKO) had a ∼25% reduction in white adipose tissue (WAT) and brown adipose tissue (BAT), whereas mice lacking both IR and IGF1R (F-IR/IGFRKO) showed an almost complete absence of WAT and BAT. Interestingly, mice lacking only the IR (F-IRKO) had a 95% reduction in WAT, but a paradoxical 50% increase in BAT with accumulation of large unilocular lipid droplets. Both F-IRKO and F-IR/IGFRKO mice were unable to maintain body temperature in the cold and developed severe diabetes, ectopic lipid accumulation in liver and muscle, and pancreatic islet hyperplasia. Leptin treatment normalized blood glucose levels in both groups. Glucose levels also improved spontaneously by 1 year of age, despite sustained lipodystrophy and insulin resistance. Thus, loss of IR is sufficient to disrupt white fat formation, but not brown fat formation and/or maintenance, although it is required for normal BAT function and temperature homeostasis. IGF1R has only a modest contribution to both WAT and BAT formation and function.

Topics: Adipose Tissue; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Hyperglycemia; Hyperlipidemias; In Vitro Techniques; Insulin; Insulin-Secreting Cells; Leptin; Lipodystrophy; Mice; Mice, Knockout; Oxygen Consumption; Radioimmunoprecipitation Assay; Receptor, IGF Type 1; Receptor, Insulin; Succinate Dehydrogenase

Liraglutide, a glucagon-like peptide-1 (GLP-1) analogue, is an antidiabetic drug. It has been shown to improve endothelial dysfunction, but the mechanism remains somewhat unclear. Leptin can also improve endothelial function. Cardiovascular disease (CVD) is linked to hyperleptinemia, and leptin resistance, how liraglutide influences the effect of leptin on endothelial function, is never reported. We used palmitic acid (PA) to mimic hyperlipidemia in endothelial cells to explore the cardio-protective mechanism of liraglutide and its impact on the role of leptin.. Human umbilical vein endothelial cells (HUVECs) were incubated with PA for 16 h and then were treated with liraglutide for 30 min.. PA elevated not only phosphorylation of JNK and IKKα/β, but also the expression of IL-6 in HUVECs. These effects of PA were reversed by liraglutide. In addition, liraglutide increased phosphorylation of eNOS, AMPK, and the release of NO but had no effect on PKC phosphorylation. In addition, leptin elevated eNOS phosphorylation but was abrogated by PA. However, in the presence of liraglutide, leptin regained its function of elevating eNOS phosphorylation. Last, we found that liraglutide inhibited PA-elevated SOCS3, which is a marker of leptin resistance.. GLP-1 impairs endothelial inflammatory signals, improves endothelial function, and reverses leptin resistance.

Topics: AMP-Activated Protein Kinases; Endothelial Cells; Enzyme Activation; Human Umbilical Vein Endothelial Cells; Humans; Hyperlipidemias; Hypoglycemic Agents; Leptin; Liraglutide; Palmitic Acid

We previously reported that dietary intake of shiitake mushroom (SM; Lentinus edodes) decreased serum concentrations of polar lipids in male rats.. This study evaluated the dietary effects of SM on serum cholesterol-related and serum antioxidant indexes in rats of both sexes.. Sprague-Dawley rats [38 dams and their offspring (20 males and 20 females/diet)] were fed diets containing 0 (control), 1%, 4%, or 10% (wt:wt) SM powder from gestation day 4 through to postnatal day (PND) 126. Biochemical indexes were monitored during the midgrowth phase (PNDs 50-66).. The food consumption by offspring fed the control diet and diets supplemented with SM was not different when measured on PND 65. However, the 4% and 10% SM diets resulted in male rats with 7% lower body weights than those of the other 2 groups on PND 66. SM consumption dose-dependently decreased the concentrations of lipidemia-related factors in sera, irrespective of sex. At PND 50, serum concentrations of total cholesterol, HDL cholesterol, and non-HDL cholesterol in SM-fed male and female rats were generally lower (3-27%) than those in the corresponding control groups. Consumption of the 10% SM diet resulted in significantly decreased (55%) serum triglyceride concentrations relative to the control groups for both sexes. The 10% SM diet elicited a 62% reduction of serum leptin concentrations in females but not in males, and this same diet increased serum insulin (137%) and decreased serum glucose (15%) in males compared with controls. Serum lipophilic antioxidant capacity in males and females fed SM diets was generally lower (31-86%) than that in the control groups.. SM decreased the concentrations of lipidemia-related factors in rat sera irrespective of sex. The SM-elicited reduction of lipophilic antioxidant capacity irrespective of sex may reflect a lower pro-oxidative state and, hence, improved metabolic profile.

Topics: Animal Nutritional Physiological Phenomena; Animals; Antioxidants; Diet; Dose-Response Relationship, Drug; Female; Hyperlipidemias; Insulin; Leptin; Lipids; Male; Maternal Nutritional Physiological Phenomena; Pregnancy; Prenatal Exposure Delayed Effects; Random Allocation; Rats; Rats, Sprague-Dawley; Shiitake Mushrooms

Beneficial effects of green tea (Camellia sinensis, Theaceae) extracts against obesity have been reported; however, the anti-obesity ability of the major components of green tea, polysaccharides, polyphenols and caffeine is not clear. Therefore, experiments with total green tea extracts, polyphenols, polysaccharides, caffeine, and a complex of polysaccharide and polyphenol at a dose of 400 or 800 mg kg⁻¹ were conducted on high-fat diet fed rats for 6 weeks to investigate their anti-obesity effects. The results indicated that polyphenols and polysaccharides were responsible for the suppressive effect of green tea extracts on body weight increase and fat accumulation. Moreover, polyphenols, polysaccharides, or caffeine can improve blood lipid and antioxidant levels, and effectively reduce rat serum leptin levels, inhibit the absorption of fatty acids, and markedly reduce the expression levels of the IL-6 and TNF-α gene. Furthermore, it was shown that polysaccharides and polyphenols were synergistic in reduction of serum leptin levels and in anti-inflammatory activity. These results suggest that the polysaccharide combination with polyphenols might be a potential therapy against obesity.

Topics: Adipose Tissue, White; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Obesity Agents; Caffeine; Camellia sinensis; Cytokines; Dietary Supplements; Food Handling; Hyperlipidemias; Hypolipidemic Agents; Leptin; Liver; Male; Obesity; Plant Extracts; Plant Leaves; Polyphenols; Polysaccharides; Random Allocation; Rats, Sprague-Dawley; Specific Pathogen-Free Organisms

A maternal high-fat (HF) diet during pregnancy and lactation can result in adverse metabolic and reproductive outcomes in female offspring independent of postnatal diet. Interventions during critical windows of developmental plasticity may prevent developmental programming in offspring. The effects of maternal supplementation with the anti-inflammatory lipid conjugated linoleic acid (CLA) on early-onset puberty, metabolic dysfunction, and estrous cycle dysfunction was assessed. Sprague-Dawley rats were randomly assigned to a purified control diet (CD; 10% kcal from fat), CD with CLA (CLA; 10% kcal from fat, 1% CLA), HF (45% kcal from fat) or HF with CLA (HFCLA; 45% kcal from fat, 1% CLA). Diets were fed ad libitum for 10 days prior to time mating and throughout gestation and lactation. Offspring plasma/tissues were taken at Day 24 (prepubertal) or Day 150 (adult). Puberty was assessed from Day 26 and estrous cycle from Day 128. Female offspring from HF mothers had lower birth weights but by Postnatal Day 24 had exhibited catch-up growth concomitant with increased fat mass, hyperleptinemia, and dyslipidemia. Maternal CLA supplementation reversed these effects. Early-onset puberty was only observed in HF offspring; this was reversed in HFCLA offspring. In adulthood, despite no evidence of glucose intolerance or altered insulin sensitivity, HF offspring displayed increased fat mass, dyslipidemia, disrupted estrous cyclicity. and hyperleptinemia; this was reversed by maternal CLA supplementation. Data presented in this study demonstrate the importance of diet in women of reproductive age and during pregnancy on reproductive and metabolic parameters in their offspring and that supplementation with CLA during critical windows of development may represent a therapeutic strategy in the prevention of early-life programming of metabolic and reproductive dysfunction.

Topics: Animals; Diet, High-Fat; Dietary Supplements; Female; Hyperlipidemias; Lactation; Leptin; Linoleic Acids, Conjugated; Maternal Nutritional Physiological Phenomena; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Sexual Maturation

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

Obesity is characterized by hyperleptinemia and decreased response to exogenous leptin. This has been widely attributed to the development of leptin resistance, a state of impaired leptin signaling proposed to contribute to the development and persistence of obesity. To directly determine endogenous leptin activity in obesity, we treated lean and obese mice with a leptin receptor antagonist. The antagonist increased feeding and body weight (BW) in lean mice, but not in obese models of leptin, leptin receptor, or melanocortin-4 receptor deficiency. In contrast, the antagonist increased feeding and BW comparably in lean and diet-induced obese (DIO) mice, an increase associated with decreased hypothalamic expression of Socs3, a primary target of leptin. These findings demonstrate that hyperleptinemic DIO mice retain leptin suppression of feeding comparable to lean mice and counter the view that resistance to endogenous leptin contributes to the persistence of DIO in mice.

Topics: Animals; Body Weight; Diet; Hyperlipidemias; Leptin; Mice; Mice, Knockout; Mice, Obese; Obesity; Receptor, Melanocortin, Type 4; Receptors, Leptin; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins

Obesity is a common cause of hyperlipidemia, which is a major coronary risk factor. Previous studies have shown red yeast rice (RYR) effectiveness in lowering low-density lipoprotein cholesterol. The aim of this study was to investigate the effects of RYR on obesity and hyperlipidemia. Mice were randomly separated into five groups: the control group with a normal diet, the high-fat diet (HFD) group fed a HFD without any treatment, and HFD-fed groups supplemented with RYR (1 g/kg/day for 8 weeks, 1 g/kg/day for 12 weeks, and 2.5 g/kg/day for 8 weeks). Body weight was recorded twice and food intake thrice weekly. Liver and fat pads were surgically removed and weighed. The levels of lipid parameters, liver enzymes, and leptin levels were measured. The HFD feeding resulted in obesity, which was associated with increases in body weight, liver weight, fat pad weight, liver enzymes, and plasma leptin levels with the development of hyperlipidemia. RYR prevented weight gain and fat pad weight in mice fed a HFD. RYR alleviated blood lipid parameters, liver enzymes, and leptin levels, and improved atherogenic index. These findings suggest that RYR has therapeutic potential in treating obesity and hyperlipidemia.

Topics: Adipose Tissue; Alanine Transaminase; Animals; Aspartate Aminotransferases; Biological Products; Body Weight; Diet; Diet, High-Fat; Hyperlipidemias; Leptin; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity; Organ Size

Four-week-old female Wistar rats were divided into two groups and fed a control diet (C) or a hyperlipidic diet (H) for 4 weeks. Rats from each group underwent ovariectomy (OVX) or sham surgery (SHAM). They received C or H for the next four weeks. The body weight gain (BW), food efficiency (FE), and carcass lipid content were higher in the OVX H than in the SHAM H. The OVX H exhibited a higher serum leptin level than other groups. IL-6, TNF-α, and IL-10 content of mesenteric (MES) adipose tissue was lower in the OVX H than in the OVX C. IL-6, TNF-α, and IL-10 content of retroperitoneal (RET) adipose tissue was lower in the SHAM H than in the SHAM C. The SHAM H showed decreased TG relative to the SHAM C. Similar results were obtained in relation to IL-6Rα, TNFR1, TLR-4, and MyD88 contents in the MES and RET white adipose tissue among the groups. A hyperlipidic diet for 8 weeks combined with short-term ovariectomy decreases the cytokine content of MES adipose tissues but increases BW, enhancing FE and elevating serum leptin levels. These suggest that the absence of estrogens promotes metabolic changes that may contribute to installation of a proinflammatory process induced by a hyperlipidic diet.

Topics: Adipose Tissue; Adiposity; Animals; Blood Glucose; Body Weight; Cytokines; Diet; Female; Hyperlipidemias; Insulin; Leptin; Mesentery; Ovariectomy; Rats; Rats, Wistar

Obesity is a multifactorial disorder which is closely associated with hyperlipidemia. Avocados are edible fruits traditionally consumed for various health benefits including body weight reduction.. To determine the hypolipidemic and anti-obesity effect of hydro-alcoholic fruit extract of avocado (HFEA) in rats fed with high fat diet (HFD).. Male Sprague Dawley rats were divided into four groups. Groups 1 and 2 rats were fed with normal diet. Groups 3 and 4 rats were fed with HFD for 14 weeks. In addition, Groups 2 and 4 rats were co-administered with 100 mg/kg body weight of HFEA from 3rd week onwards.. The HFEA was subjected to HPLC to quantify the major phytonutrients. Body mass index (BMI), adiposity index (ADI), total fat pad mass (TFP), blood lipid levels were determined in all the groups of rats. The mRNA expression of fatty acid synthase (FASN), lipoprotein lipase (LPL), fibroblast growth factor 21 (FGF21) and leptin was also assessed.. HFEA was found to contain flavonoids: rutin-141.79, quercetin-5.25, luteolin-165, phenolic compounds: gallic acid-198.57, ellagic acid-238.22, vanillic acid-4.79 and phytosterols: betasitosterol-70, stigmasterol-12.5 (mg/100 g). HFEA reduced BMI, ADI, TFP, blood cholesterol, triglycerides, and LDL in rats fed with HFD. Serum leptin was found reduced in HFEA co-administered rats. The mRNA expression of FASN, LPL, and leptin in subcutaneous and visceral adipose tissue was found to be significantly reduced in HFEA co-administered rats. The gene expression of fibroblast growth factor-21 (FGF21) was found to be significantly increased in HFEA treated rats when compared to HFD control rats.. The hypolipidemic effect of HFEA may be partly due to its modulating effect on endogenous fat synthesis and adiponectin formation through the transcription factor FGF21. The results also show that avocado fruit extract has profound influence on leptin activity, which controls satiety and hunger to regulate the food intake.

Topics: Animals; Body Mass Index; Chemical Fractionation; Cholesterol; Diet, High-Fat; Fatty Acid Synthase, Type I; Fibroblast Growth Factors; Flavonoids; Fruit; Hyperlipidemias; Hypolipidemic Agents; Leptin; Lipoprotein Lipase; Male; Obesity; Persea; Phenols; Phytosterols; Plant Extracts; Rats; Rats, Sprague-Dawley; Triglycerides

Leptin, an adipokine elevated in obesity, may be related to an adverse cardiovascular risk profile in childhood. However, evidence for this relationship in pre-pubertal children is scarce. We aimed to analyze the relationship between leptin levels and lipid and insulin profiles in Spanish children.. Our population-based sample included 389 males and 369 females aged 6-8 years. Lipid levels were determined by standard methods, insulin by radioimmunoassay and leptin by sandwich ELISA. Leptin levels were higher in girls (8.6 ng/ml) than boys (4.7 ng/ml) (p < 0.001). Leptin increased from ages 6 to 8 in girls, but remained steady in boys. In both sexes, leptin increased significantly (p < 0.001) across weight category from normal weight to obese. Children in the highest tertile of leptin concentration showed significantly (p < 0.01) lower levels of HDL-cholesterol (HDL-C) and apolipoprotein-AI (apo-AI) and significantly higher triglyceride (TG) levels than children in lower tertiles. However, in linear regression analysis, after adjustment for body mass index (BMI), leptin only accounted for 1.5% of the variance of HDL-C in boys, and 2.6% of the variance of apo-AI in girls. Leptin was strongly and positively correlated with insulin and HOMA. Upon regression analysis, leptin contributed to over 20% of the variability in insulin and HOMA, independent of BMI.. Leptin levels show sex differences in pre-pubertal children. In this age group, leptin levels are strongly related to insulin, and affect lipid profile -namely HDL-C, apo-AI and TG- particularly when leptin levels are high.

Topics: Age Factors; Anthropometry; Apolipoprotein A-I; Body Mass Index; Cardiovascular Diseases; Child; Cholesterol, HDL; Cohort Studies; Cross-Sectional Studies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hyperlipidemias; Insulin; Insulin Resistance; Leptin; Linear Models; Male; Metabolic Syndrome; Multivariate Analysis; Risk Assessment; Sex Factors; Spain

Ficus carica has been traditionally used for the treatment of several metabolic syndrome-related health problems. It was the objective of this study to investigate the preventive effects of a Ficus carica (FC) leaf extract on hyperlipidemia in high fat diet (HFD)-induced obese male rats. Male Sprague-Dawley rats (180-200 g) were fed with a regular diet, HFD or a HFD + oral treatment of either 50 mg/kg or 100 mg/kg of FC or 30 mg/kg pioglitazone for six weeks. A range of parameters was evaluated including body weight development, plasma levels of total cholesterol, triglycerides (TG), low-density-lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), adiponectin, leptin, glucose, insulin, interleukin-6 (IL-6), atherogenic index (AI) and the coronary risk index (CRI). FC significantly lowered TG and IL-6 levels and elevated HDL cholesterol (p < 0.05). The effects of FC on lipid parameters were more pronounced than those of the positive control pioglitazone. FC significantly lowered AI and CRI (p < 0.01) while it had no effect on adiponectin and leptin levels. Our results demonstrate that preventive treatment with FC significantly improved the lipid profile and decreased adipogenic risk factors in HFD rats most likely mediated through an increase in HDL-C levels.

Topics: Adiponectin; Animals; Blood Glucose; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Diet, High-Fat; Ficus; Hyperlipidemias; Insulin; Interleukin-6; Leptin; Male; Obesity; Pioglitazone; Plant Extracts; Plant Leaves; Rats; Rats, Sprague-Dawley; Thiazolidinediones; Triglycerides

We conducted this investigation in order to examine the anti-obesity and hypolipidaemic effects of Nelumbo nucifera seed ethanol extract (NSEE) in vitro and in vivo.. To study the anti-obesity effect of NSEE in vitro and in vivo, human pre-adipocytes were treated with NSEE, and male Sprague-Dawley rats were fed with a normal diet and a high-fat diet with or without NSEE, respectively.. In vitro treatment with NSEE resulted in inhibition of lipid accumulation and decreased expression of peroxisome proliferator-activated receptor gamma (PPARγ), glucose transporter 4 (GLUT4), and leptin in cultured human adipocytes, indicating that it inhibited the differentiation of pre-adipocytes into adipocytes. Administration of NSEE resulted in significantly reduced body weight gain and adipose tissue weights in rats. Serum triglyceride and leptin level of the high-fat diet + NSEE group was significantly lower, compared to the high-fat group.. These results demonstrate an inhibitory effect of NSEE on adipogenesis. In addition, NSEE had a beneficial effect, reducing adipose tissue weights, ameliorating blood lipid profile, and modulating serum leptin level in rats fed a high-fat diet. Therefore, we suggest that lotus seed has a potential to be developed as an effective agent against obesity-related diseases.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Adipose Tissue; Animals; Anti-Obesity Agents; Diet, High-Fat; Glucose Transporter Type 4; Hyperlipidemias; Hypolipidemic Agents; Leptin; Male; Mice; Nelumbo; Obesity; Phytotherapy; Plant Extracts; PPAR gamma; Rats; Rats, Sprague-Dawley; Seeds; Triglycerides; Weight Gain

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

AT₁ receptor antagonists decrease body weight gain in models of murine obesity. However, fewer data are available concerning the anti-obesity effects of these antagonists, given as a treatment after obesity had been established.. In spontaneously hypertensive rats, obesity was established by cafeteria diet (CD) feeding for 19 weeks. Rats were then were treated with telmisartan (8 mg·kg⁻¹·d⁻¹) or amlodipine (10 mg·kg⁻¹·d⁻¹; serving as blood pressure control) or telmisartan + amlodipine (2 + 10 mg·kg⁻¹·d⁻¹; to control for dose-dependency) for 17 weeks. Rats receiving only chow (C(chow)) or CD-fed rats treated with vehicle (C(CD)) served as controls.. The CD feeding induced obesity, hyperphagia, hyperlipidaemia, and leptin and insulin resistance. Telmisartan reduced the CD-induced increase in body weight and abdominal fat mass. Whereas energy intake was higher rather than lower, the respiratory ratio was lower. After telmisartan, leptin-induced energy intake was reduced and respiratory ratio was increased compared with C(CD) rats. Telmisartan also decreased plasma levels of triglycerides, free fatty acids and low-density lipoprotein. Amlodipine alone or the combination telmisartan + amlodipine did not affect body weight and eating behaviour. Telmisartan, but not amlodipine and telmisartan + amlodipine, improved glucose utilization. The decrease in BP reduction was almost the same in all treatment groups.. Telmisartan exerted anti-obesity effects and restored leptin sensitivity, given as a treatment to rats with obesity. Such effects required high doses of telmisartan and were independent of the decrease in blood pressure.

Topics: Amlodipine; Angiotensin II Type 1 Receptor Blockers; Animals; Anti-Obesity Agents; Antihypertensive Agents; Behavior, Animal; Benzimidazoles; Benzoates; Diet, High-Fat; Dietary Sucrose; Drug Therapy, Combination; Energy Intake; Hyperlipidemias; Hypertension; Hypolipidemic Agents; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Obesity; Random Allocation; Rats; Rats, Inbred SHR; Telmisartan; Weight Gain

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

High-protein (HP) diets are effective anti-steatotic treatment options for patients with non-alcoholic fatty liver disease, but whether these diets also decrease steatosis in hyperlipidaemic conditions is not known. The aim of the present study was to determine the effects of a HP diet on hepatic steatosis and inflammation in hyperlipidaemic mice. Hyperlipidaemic male and female APOE2 knock-in (APOE2ki) mice were fed a semi-synthetic low-protein (LP) or HP diet in combination with a low-fat diet or a high-fat diet for 3 weeks. The HP diets reduced hepatic fat and cholesterol concentrations to 40-55 % of those induced by the corresponding LP diets and attenuated hepatic inflammation mildly. The VLDL-associated plasma cholesterol concentrations decreased to 60-80 %, but those of TAG increased 3-4-fold. APOE2-mediated restriction of fat import into the liver did not modify the effects of a HP diet previously observed in wild-type mice. Female APOE2ki mice exhibited a higher expression of lipogenic, cholesterol-synthesising, inflammatory and cell-stress genes than wild-type female or male APOE2ki mice, but a similar response to HP diets. Low Apob expression and unchanged plasma APOB100 concentrations suggest that HP diets increase the plasma concentrations of TAG by slowing their clearance. The decrease in plasma leptin and hepatic fat and glycogen concentrations and the increase in fatty acid-oxidising gene and phosphoenolpyruvate carboxykinase 1 protein expression suggest a HP diet-mediated increase in mitochondrial metabolism. In conclusion, a HP diet reduces hepatic lipid content in dyslipidaemic mice and lowers the activation status of inflammatory cells in the liver.

Topics: Animals; Apolipoprotein B-100; Apolipoprotein E2; Cholesterol; Diet, Fat-Restricted; Diet, High-Fat; Diet, Protein-Restricted; Dietary Proteins; Female; Gene Knock-In Techniques; Hepatitis; Hyperlipidemias; Leptin; Lipid Metabolism; Liver; Liver Glycogen; Male; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria, Liver; Non-alcoholic Fatty Liver Disease; Triglycerides

Obesity has become a public health concern due to its positive association with the incidence of many diseases, and coffee components including chlorogenic acid (CGA) and caffeine have been demonstrated to play roles in the suppression of fat accumulation. To investigate the mechanism by which CGA and caffeine regulate lipid metabolism, in the present study, forty mice were randomly assigned to four groups and fed diets containing no CGA or caffeine, CGA, caffeine, or CGA+caffeine for 24 weeks. Body weight, intraperitoneal adipose tissue (IPAT) weight, and serum biochemical parameters were measured, and the activities and mRNA and protein expression of lipid metabolism-related enzymes were analysed. There was a decrease in the body weight and IPAT weight of mice fed the CGA+caffeine diet. There was a significant decrease in the serum and hepatic concentrations of total cholesterol, TAG and leptin of mice fed the CGA+caffeine diet. The activities of carnitine acyltransferase (CAT) and acyl-CoA oxidase (ACO) were increased in mice fed the caffeine and CGA+caffeine diets, while the activity of fatty acid synthase (FAS) was suppressed in those fed the CGA+caffeine diet. The mRNA expression levels of AMP-activated protein kinase (AMPK), CAT and ACO were considerably up-regulated in mice fed the CGA+caffeine diet, while those of PPARγ2 were down-regulated. The protein expression levels of AMPK were increased and those of FAS were decreased in mice fed the CGA+caffeine diet. These results indicate that CGA+caffeine suppresses fat accumulation and body weight gain by regulating the activities and mRNA and protein expression levels of hepatic lipid metabolism-related enzymes and that these effects are stronger than those exerted by CGA and caffeine individually.

Topics: Acyl-CoA Oxidase; Adiposity; Animals; Caffeine; Carnitine Acyltransferases; Chlorogenic Acid; Dietary Supplements; Enzyme Induction; Enzyme Repression; Fatty Acid Synthases; Fatty Liver; Female; Gene Expression Regulation, Enzymologic; Hyperlipidemias; Intra-Abdominal Fat; Leptin; Lipid Metabolism; Liver; Mice; Mice, Inbred ICR; Organ Size; Random Allocation

Soybean-derived PC is an essential cell membrane phospholipid that is composed of unsaturated fatty acids, including oleic acid. The present study aimed to evaluate the potential alleviation effects of soybean PC on high fat diet (HFD)-induced obesity and its related complications.. We fed C57BL/6 mice a HFD for 12 weeks and administered PC orally for 8 or 12 weeks at different doses. At the end of the experiment, blood was prepared for biochemical analysis and leptin ELISA. Aorta, epididymal and mesenteric fat and liver were removed surgically, weighed and observed for histological or immunohistochemical changes.. PC significantly prevented body weight gain and lipid accumulation and alleviated hyperlipidemia by decreasing triglyceride (TG) and total cholesterol (TC) levels and the atherogenic index in serum or by increasing the HDL/TC ratio. Aortic apoE expression and serum leptin levels were suppressed by PC treatment in the HFD-induced obese mouse model. Elevated serum aspartate aminotransferase and alanine aminotransferase levels in HFD-fed mice were decreased in the PC groups. PC treatment significantly decreased HFD-induced liver weight and hepatic lipid accumulation.. PC treatment alleviated HFD-induced obese status and obesity-related complications such as hyperlipidemic changes that induce cardiovascular disease and NAFLD.

Topics: Adipocytes; Animals; Apolipoproteins E; Diet, High-Fat; Hyperlipidemias; Leptin; Male; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity; Phosphatidylcholines; Weight Gain

Various mushrooms have been used in folk medicine for the treatment of lifestyle diseases in eastern countries, and several compounds that modulate the immune system, lower blood lipid levels, and inhibit tumor and viral action have been isolated. The fruiting body of Panellus serotinus (Mukitake) is recognized in Japan as one of the most delicious edible mushrooms, and previous studies have demonstrated that the dietary intake of powdered whole Mukitake or Mukitake extracts prevents the development of non-alcoholic fatty liver disease (NAFLD) in leptin-resistant db/db mice. In the present study, we evaluated the effect of the Mukitake diet on the pathogenesis of metabolic disorders in leptin-deficient ob/ob mice.. After 4 weeks of feeding, hepatomegaly, hepatic lipid accumulation, and elevated hepatic injury markers in the serum were markedly alleviated in Mukitake-fed ob/ob mice compared with control mice. Moreover, the mild hyperlipidemia in control ob/ob mice was attenuated and the elevated atherogenic index was reduced in Mukitake-fed ob/ob mice. These effects were partly attributable to the suppression of hepatic lipogenic enzyme activity due to the Mukitake diet.. The current results showed that Mukitake supplementation is beneficial for the alleviation of NAFLD and dyslipidemia in obese, diabetic ob/ob mice.

Topics: Agaricales; Animals; Carnitine O-Palmitoyltransferase; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus; Fatty Acid Synthases; Food, Formulated; Fruiting Bodies, Fungal; Glucosephosphate Dehydrogenase; Hepatomegaly; Hyperlipidemias; Leptin; Lipid Metabolism; Male; Mice; Mice, Knockout; Mice, Obese; Obesity; Phosphatidate Phosphatase; Powders; Triglycerides

The induction of hyperlipidemia using poloxamer 407 (P407) is gaining use for studying the effect of the condition on drug pharmacokinetics. Although a single intraperitoneal dose of P407 causes a rapid onset of hyperlipidemia, the initial lipid concentrations are much higher than seen in humans. The hyperlipidemia is also reversible in nature. Here, pharmacokinetic methods were used to assess the P407 dose response on serum lipids, adipokines and cytokines.. Single 0.5 and 1 g/kg doses of P407 were injected into rats followed by blood collection at various times for up to 12 d. Serum was assayed for lipids, selected adipokines and cytokines.. As expected, large increases in lipid levels were seen by 36 h after dosing. Using area under the concentration vs. time curve as a measure of systemic lipid exposure, P407 increased serum baseline corrected serum lipids in a nearly dose proportional fashion. The maximum increase in lipids was observed at ~36 h, with most lipids remaining elevated for up to ~180 h, although for the 1 g/kg dose triglyceride concentrations had still not quite returned to baseline by 12 days postdose. In addition to changes in lipids, P407 significantly increased serum leptin and decreased the serum adiponectin concentrations but did not affect cytokine levels.. Depending on study aims, for the use of the model it may be beneficial to perform single-dose assessments at time points later than 36 h when the lipoprotein concentrations will be more similar to those seen in patient with hyperlipidemia.

Topics: Adiponectin; Animals; Hyperlipidemias; Interleukin-6; Leptin; Lipids; Male; Poloxamer; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Leptin is a hormone secreted from adipocytes. It regulates metabolism and energy homeostasis through the leptin receptor (LEPR) which is localized centrally in hypothalamus as well as in peripheral tissues. The aim of this study was to investigate the association of leptin receptor gene Q223R polymorphism on obesity in association with body mass index (BMI), lipid parameters, plasma leptin levels and homeostasis model assessment of insulin resistance (HOMA-IR).. The study included 110 obese and 90 non-obese subjects. The LEPR Q223R polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Plasma leptin levels, serum lipid and antropometric parameters were measured.. No association was found between LEPR gene Q223R polymorphism and BMI in both study and control groups. Strikingly study group with non-obese subjects and with the RR genotype (homozygous mutant) had significantly higher serum total cholesterol (p<0.001) and low density lipoprotein cholesterol (LDL-cholesterol) levels (p<0.05) than QR (heterozygous) and QQ (wild type) genotypes. In obese group, subjects with the RR genotypes had significantly higher triglycerides (p<0.05) levels, waist (p<0.05) and hip circumferences (p<0.001) than the QQ and QR genotypes.. Our results suggest that the LEPR gene Q223R polymorphism has an association with waist and hip circumferences in obese group but no direct association with obesity although there is a significant influence on lipid profile both in obese and non-obese subjects.

Topics: Adult; Blood Glucose; Body Mass Index; Case-Control Studies; Cholesterol, HDL; Cholesterol, LDL; Fasting; Female; Genotype; Humans; Hyperlipidemias; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Prospective Studies; Receptors, Leptin; Triglycerides; Waist Circumference

Polygonatum odoratum (Mill.) Druce belongs to the genus Polygonatum family of plants. In traditional Chinese medicine, the root of Polygonatum odoratum, Rhizoma Polygonati Odorati, is used both for food and medicine to prevent and treat metabolic disorders such as hyperlipidemia, hyperglycemia, obesity and cardiovascular disease. However, there is no solid experimental evidence to support these applications, and the underlying mechanism is also needed to be elucidated. Here, we examined the effect of the extract of Rhizoma Polygonati Odorati (ER) on metabolic disorders in diet-induced C57BL/6 obese mice. In the preventive experiment, the ER blocked body weight gain, and lowered serum total cholesterol (TC), triglyceride (TG) and fasting blood glucose, improved glucose tolerance test (GTT) and insulin tolerance test (ITT), reduced the levels of serum insulin and leptin, and increased serum adiponectin levels in mice fed with a high-fat diet significantly. In the therapeutic study, we induced obesity in the mice and treated the obese mice with ER for two weeks. We found that ER treatments reduced serum TG and fasting blood glucose, and improved glucose tolerance in the mice. Gene expression analysis showed that ER increased the mRNA levels of peroxisome proliferator-activated receptors (PPAR) γ and α and their downstream target genes in mice livers, adipose tissues and HepG2 cells. Our data suggest that ER ameliorates metabolic disorders and enhances the mRNA expression of PPARs in obese C57BL/6 mice induced by high-fat diet.

Topics: Adiponectin; Animals; Blood Glucose; Diet, High-Fat; Drugs, Chinese Herbal; Fasting; Female; Hyperlipidemias; Insulin; Insulin Resistance; Leptin; Liver; Mice; Mice, Inbred C57BL; Obesity; Polygonatum; PPAR alpha; PPAR gamma; Triglycerides; Up-Regulation

Although green tea extract has been reported to suppress hyperlipidemia, it is unclear how tea extracts prepared from green, oolong, black and pu-erh teas modulate fatty acid synthase expression in rats fed on a high-fructose diet. In this animal study, we evaluated the hypolipidemic and hypoleptinemia effect of these four different tea leaves fed to male Wistar rats for 12 weeks. The results showed that a fructose-rich diet significantly elevated serum triacylglycerols, cholesterol, insulin, and leptin concentrations, as compared with those in the control group. Interestingly, consuming tea leaves for 12 weeks almost normalized the serum triacylglycerols concentrations. Again, rats fed with fructose/green tea and fructose/pu-erh tea showed the greatest reduction in serum TG, cholesterol, insulin and leptin levels. In contrast, serum cholesterol and insulin concentrations of the fructose/oolong tea-fed rats did not normalize. The relative epididymal adipose tissue weight was lower in all rats supplemented with tea leaves than those fed with fructose alone. There was molecular evidence of improved lipid homeostasis according to fatty acid synthase (FAS) protein expression. Furthermore, supplementation of green, black, and pu-erh tea leaves significantly decreased hepatic FAS mRNA and protein levels, and increased AMPK phosphorylation, compared with those of rats fed with fructose only. These findings suggest that the intake of green, black, and pu-erh tea leaves ameliorated the fructose-induced hyperlipidemia and hyperleptinemia state in part through the suppression of FAS protein levels and increased AMPK phosphorylation.

Topics: Adipose Tissue; Alanine Transaminase; AMP-Activated Protein Kinases; Animals; Antioxidants; Aspartate Aminotransferases; Blood Glucose; Body Weight; Cholesterol; Diet; Dietary Supplements; Fatty Acid Synthases; Fructose; Hyperlipidemias; Insulin; Leptin; Lipid Metabolism; Liver; Male; Phosphorylation; Plant Extracts; Plant Leaves; Rats; Rats, Wistar; RNA, Messenger; Tea; Triglycerides

n-3 Polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and taurine are functional compounds abundantly present in seafoods. In this study, we examined the combined effects of EPA- and DHA-rich fish oil and taurine on white adipose tissue (WAT) weight and blood glucose levels in diabetic/obese KK-A(y) mice. After a 4-wk administration of experimental diets (soybean oil or fish oil, supplemented with 0%, 2%, or 4% taurine), the increase in WAT weight of the mice fed the "fish oil + 4% taurine" diet was significantly suppressed compared to the "soybean oil + 4% taurine" and "fish oil only" diets. Serum triglycerides, free fatty acids, and total cholesterol levels decreased by fish oil administration. In addition, fish oil and taurine increased the activity of acyl-CoA oxidase, which is the rate-limiting enzyme of peroxisomal β-oxidation, increased in the liver of KK-A(y) mice. The activity of fatty acid synthase decreased by fish oil diets. Furthermore, blood glucose and insulin levels were significantly lower in the mice fed fish oil than in the soybean oil-fed mice. In fish oil + 4% taurine group, hyperglycemia and hyperinsulinemia were effectively improved in KK-A(y) mice compared to the fish oil only groups. In particular, the combination of fish oil and taurine enhanced the glucose transporter 4 (GLUT4) distribution in the plasma membrane of muscle tissue. These results suggest that EPA- and DHA-rich fish oil, especially in combination with taurine, exhibits preventive effects on WAT weight gain and hyperglycemia in diabetic/obese KK-A(y) mice.

Topics: Acyl-CoA Oxidase; Adipose Tissue, White; Adiposity; Animals; Diabetes Mellitus, Type 2; Fatty Acid Synthases; Fatty Acids, Omega-3; Fish Oils; Functional Food; Glucose Transporter Type 4; Hyperglycemia; Hyperinsulinism; Hyperlipidemias; Leptin; Liver; Male; Mice; Mice, Obese; Muscle, Skeletal; Obesity; Seafood; Taurine

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

Skeletal muscle resistance to the key metabolic hormones, leptin and insulin, is an early defect in obesity. Suppressor of cytokine signaling 3 (SOCS3) is a major negative regulator of both leptin and insulin signaling, thereby implicating SOCS3 in the pathogenesis of obesity and associated metabolic abnormalities. Here, we demonstrate that SOCS3 mRNA expression is increased in murine skeletal muscle in the setting of diet-induced and genetic obesity, inflammation, and hyperlipidemia. To further evaluate the contribution of muscle SOCS3 to leptin and insulin resistance in obesity, we generated transgenic mice with muscle-specific overexpression of SOCS3 (MCK/SOCS3 mice). Despite similar body weight, MCK/SOCS3 mice develop impaired systemic and muscle-specific glucose homeostasis and insulin action based on glucose and insulin tolerance tests, hyperinsulinemic-euglycemic clamps, and insulin signaling studies. With regards to leptin action, MCK/SOCS3 mice exhibit suppressed basal and leptin-stimulated activity and phosphorylation of alpha2 AMP-activated protein kinase (α2AMPK) and its downstream target, acetyl-CoA carboxylase (ACC). Muscle SOCS3 overexpression also suppresses leptin-regulated genes involved in fatty acid oxidation and mitochondrial function. These studies demonstrate that SOC3 within skeletal muscle is a critical regulator of leptin and insulin action and that increased SOCS may mediate insulin and leptin resistance in obesity.

Topics: Adenylate Kinase; Animals; Homeostasis; Hyperlipidemias; Inflammation; Insulin; Leptin; Mice; Mice, Transgenic; Muscle, Skeletal; Obesity; RNA, Messenger; Signal Transduction; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins

The aim of this study was to evaluate the relationship between plasma leptin and lipid levels in breeding mares and their newborn foals. The study was conducted on 17 Polish cold-blood mares and their newborn foals. The mares were divided into two groups, according to the course of delivery. These groups were seven mares which had a normal delivery and 10 mares which had required veterinary intervention during their delivery. Blood samples were taken from the jugular vein of both the mares and their foals. The blood samples were taken within 30 min after delivery, as well as on four successive mornings directly afterwards. In obtained plasma samples, the leptin, triacylglycerols (TG) and free fatty acid (FFA) concentrations were measured. The leptin and TG levels in the plasma sampled on the day of delivery and the two following days were significantly higher in mares which received veterinary intervention during the delivery, when compared to the results obtained from the plasma of mares which had normal delivery. The results obtained from foals did not show any statistical differences. In conclusion, the conducted tests have shown that post-parturient hyperlipidemia and hyperleptinemia in mares did not influence the lipid status and plasma leptin level in newborn foals.

Topics: Animals; Animals, Newborn; Female; Horse Diseases; Horses; Hyperlipidemias; Leptin; Lipase; Overweight; Postpartum Period

Iberian pig is the most abundant Mediterranean swine. The lack of knowledge of the reproductive physiology of Mediterranean genotypes, with predisposition to obesity, led us to evaluate the influence of body condition and metabolic status at weaning on the resumption of follicular growth and the appearance of post-weaning oestrus. Females failing to display post-weaning oestrus showed a high decrease in backfat mass during lactation; backfat depth at weaning was therefore lower than in sows becoming in oestrus. Females not bearing oestrus behaviour showed lower plasma leptin levels and higher ghrelin concentrations at weaning. Moreover, these sows evidenced dyslipidemic profile (increased triglyceridemia and cholesterolemia) and mobilization of fat reserves. Hence, changes in metabolic regulation of Iberian pigs may originate large effects on the resumption of ovulatory activity after weaning.

Topics: Adiposity; Animals; Blood Glucose; Estrus; Female; Ghrelin; Hyperlipidemias; Leptin; Lipids; Obesity; Sus scrofa; Swine Diseases; Weaning

The Chinese formula Tang-Min-Ling (TML), an improved product of the decoction of Dachaihu which has a history of more than 2000 years, has main constituents of Coptis chinensis Franch, Scutellaria baicalensis Georgi, Rheum officinale Baill and Bupleurum chinense DC. A multi-central randomized controlled investigation performed previously by us has showed that TML has positive effects on regulating glycometabolism in type 2 diabetes (T2DM) patients, but the mechanisms remain unclear. Using Otsuka Long-Evans Tokushima Fatty (OLETF) rats as an animal model with rosiglitazone as a positive control, we were able to detect TML's effect on the serum glucose, serum lipid, serum leptin and adiponcetin after oral administration for 12 weeks. We were also able to detect the insulin resistance level by a glucose clamp test and study the mechanisms of TML in improving insulin resistance by detecting skeletal muscle AMP-activated protein kinase (AMPK) and glucose transporter 4 (GLUT4). Results showed that TML significantly reduced the glucose area under a curve of the oral glucose tolerance test, and had a positive effect in regulating serum lipid metabolism. TML treatment also significantly reduced the serum leptin level, but it had no effect on the serum adiponectin level. The AMPK enzymatic activity and GLUT4 expression in Skeletal Muscle were also upregulated in the TML group. The results suggest that the Chinese medicine TML, which contains Coptis chinensis Franch as one of its components, improves glycometabolism and its possible mechanisms may involve in improvement of insulin resistance of OLETF rats.

Topics: Adiponectin; AMP-Activated Protein Kinases; Animals; Area Under Curve; Blood Glucose; Bupleurum; Coptis; Diabetes Mellitus, Type 2; Drugs, Chinese Herbal; Glucose Tolerance Test; Glucose Transporter Type 4; Hyperlipidemias; Hypoglycemic Agents; Insulin Resistance; Leptin; Lipid Metabolism; Lipids; Muscle, Skeletal; Phytotherapy; Rats; Rats, Inbred OLETF; Rheum; Rosiglitazone; Scutellaria baicalensis; Thiazolidinediones

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

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

Chronic intermittent hypoxia (IH) during sleep can result from obstructive sleep apnea (OSA), a disorder that is particularly prevalent in obesity. OSA is associated with high levels of circulating leptin, cardiovascular dysfunction, and dyslipidemia. Relationships between leptin and cardiovascular function in OSA and chronic IH are poorly understood. We exposed lean wild-type (WT) and obese leptin-deficient ob/ob mice to IH for 4 wk, with and without leptin infusion, and measured cardiovascular indices including aortic vascular stiffness, endothelial function, cardiac myocyte morphology, and contractile properties. At baseline, ob/ob mice had decreased vascular compliance and endothelial function vs. WT mice. We found that 4 wk of IH decreased vascular compliance and endothelial relaxation responses to acetylcholine in both WT and leptin-deficient ob/ob animals. Recombinant leptin infusion in both strains restored IH-induced vascular abnormalities toward normoxic WT levels. Cardiac myocyte morphology and function were unaltered by IH. Serum cholesterol and triglyceride levels were significantly decreased by leptin treatment in IH mice, as was hepatic stearoyl-Coenzyme A desaturase 1 expression. Taken together, these data suggest that restoring normal leptin signaling can reduce vascular stiffness, increase endothelial relaxation, and correct dyslipidemia associated with IH.

Topics: Acetylcholine; Animals; Chronic Disease; Hyperlipidemias; Hypoxia; Leptin; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Myocytes, Cardiac; Signal Transduction; Stearoyl-CoA Desaturase; Vascular Resistance

The purpose of this work was to study the central mechanisms involved in food intake regulation and leptin resistance during gestation in the rat. Sprague Dawley rats of 7, 13, and 18 d of pregnancy [days of gestation (G) 7, G13, and G18] were used and compared with nonpregnant animals in diestrus-1. Food intake was already increased in G7, before hyperleptinemia and central leptin resistance was established in midpregnancy. Leptin resistance was due to a reduction in leptin transport through the blood-brain barrier (BBB) and to alterations in leptin signaling within the hypothalamus based on an increase in suppressor of cytokine signaling 3 levels and a blockade of signal transducer and activator of transcription-3 phosphorylation (G13), followed by a decrease in LepRb and of Akt phosphorylation (G18). In early gestation (G7), no change in hypothalamic neuropeptide Y (NPY), agouti-related peptide (AgRP), or proopiomelanocortin (POMC) expression was shown. Nevertheless, an increase in NPY and AgRP and a decrease in POMC mRNA were observed in G13 and G18 rats, probably reflecting the leptin resistance. To investigate the effect of maternal vs. placental hormones on these mechanisms, we used a model of pseudogestation. Rats of 9 d of pseudogestation were hyperphagic, showing an increase in body and adipose tissue weight, normoleptinemia, and normal responses to iv/intracerebroventricular leptin on hypothalamic leptin signaling, food intake, and body weight. Leptin transport through the BBB, and hypothalamic NPY, AgRP and POMC expression were unchanged. Finally, the transport of leptin through the BBB was assessed using a double-chamber culture system of choroid plexus epithelial cells or brain microvascular endothelial cells. We found that sustained high levels of prolactin significantly reduced leptin translocation through the barrier, whereas progesterone and β-estradiol did not show any effect. Our data demonstrate a dual mechanism of leptin resistance during mid/late-pregnancy, which is not due to maternal hormones and which allows the maintenance of hyperphagia in the presence of hyperleptinemia driven by an increase in NPY and AgRP and a decrease in POMC mRNA. By contrast, in early pregnancy maternal hormones induce hyperphagia without the regulation of hypothalamic NPY, AgRP, or POMC and in the absence of leptin resistance.

Topics: Agouti-Related Protein; Animals; Animals, Newborn; Blood-Brain Barrier; Blotting, Western; Body Weight; Cells, Cultured; Eating; Enzyme-Linked Immunosorbent Assay; Female; Hyperlipidemias; Hyperphagia; Hypothalamus; In Situ Hybridization; Infusions, Intraventricular; Injections, Intravenous; Leptin; Neuropeptide Y; Pregnancy; Pro-Opiomelanocortin; Progesterone; Rats; Rats, Sprague-Dawley

To develop a therapeutic agent for obesity-related metabolic disorders, a mixture of dietary components was prepared, including grape extract, green tea extract and l-carnitine (RGTC), and its effects on obesity, hyperlipidemia and non-alcoholic fatty liver disease examined. The RGTC dramatically inhibited the high-fat diet (HFD)-induced increase in body weight and fat in C57BL/6 mice, whereas food consumption was not affected by RGTC treatment. The RGTC also concentration-dependently suppressed the HFD-induced increase in plasma lipids, such as low-density lipoprotein cholesterol and triglycerides. In addition, increases in liver weight and liver steatosis were returned to normal by RGTC treatment in HFD-fed C57BL/6 mice. The plasma levels of glutamic-oxaloacetic transaminase and glutamic-pyruvic transaminase were also significantly down-regulated by RGTC treatment. These results suggest that RGTC suppressed HFD-induced obesity, hyperlipidemia and non-alcoholic fatty liver disease, suggesting that RGTC supplementation might be a promising adjuvant therapy for the treatment of these metabolic disorders.

Topics: Adipose Tissue; Alanine Transaminase; Animals; Aspartate Aminotransferases; Body Weight; Carnitine; Diet, High-Fat; Fatty Liver; Hyperlipidemias; Leptin; Lipids; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity; Plant Extracts; Tea; Vitis

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

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

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

Hyperlipidemia associated with obesity is closely related to the development of atherosclerosis. Both n-3 polyunsaturated fatty acids (PUFAs) and long-chain monounsaturated fatty acids (MUFAs; i.e., C20:1 and C22:1 isomers) supplementation modulate risk factors for metabolic syndrome via multiple mechanisms, including the restoration of impaired lipid metabolism. We therefore examined the effects of pollock oil, which contains a considerable amount of n-3 PUFAs as well as long-chain MUFAs, on plasma hyperlipidemia and hepatic steatosis in diet-induced obese mice.. Male C57BL/6J mice (24-26 g) were divided into two groups (n = 10/group) and were fed a high-fat diet containing 32% lard (control group) or 17% lard plus 15% pollock oil (experimental group) for 6 weeks. For both groups, fat comprised 60% of the total caloric intake.. Although body and liver masses for the two groups did not differ significantly, hepatic lipids concentrations (triglycerides and total cholesterols) were lower (P < 0.05) after pollock oil ingestion. After 2 weeks on the specified diets, plasma lipid levels (total cholesterol, LDL cholesterol, and triglycerides) significantly decreased (P < 0.05) in the experimental group compared with the control group, although plasma HDL cholesterol levels did not differ. At the end of 6 weeks, plasma adiponectin levels increased (P < 0.05), whereas plasma resistin and leptin levels decreased (P < 0.05) in the experimental mice. Increased levels of long-chain MUFAs and n-3 PUFAs in plasma, liver and adipose tissue by ingesting pollock oil were possibly correlated to these favorable changes. Expression of hepatic genes involved in cholesterol metabolism (SREBP2, HMGCR, and ApoB) and lipogenesis (SREPB1c, SCD-1, FAS, and Acacα) was suppressed in the experimental group, and may have favorably affected hyperlipidemia and hepatic steatosis induced by the high-fat diet.. We demonstrated that pollock oil supplementation effectively improved hyperlipidemia, attenuated hepatic steatosis, and downregulated the express of hepatic genes involved in cholesterol and lipid metabolism in mice with diet-induced obesity.

Topics: Adiponectin; Animals; Dietary Fats; Down-Regulation; Fatty Acid Synthases; Fatty Liver; Fish Oils; Gadiformes; Hydroxymethylglutaryl CoA Reductases; Hyperlipidemias; Intra-Abdominal Fat; Leptin; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Random Allocation; Resistin; RNA, Messenger; Stearoyl-CoA Desaturase; Sterol Regulatory Element Binding Proteins

Our aim was to assess the reaction of TNFalpha, resistin, leptin and adiponectin to lipid infusion. Eight healthy subjects underwent a 24-hour lasting infusion of lipid emulsion. Plasma concentrations and expressions of selected cytokines in subcutaneous fat were measured. TNFalpha plasma concentration did not change during the first 4 hours of hypertriglyceridemia, but a significant increase after 24 hours was detected (p<0.001 for 0; 30; 240 min vs. 24 h). Plasma concentration of resistin significantly increased at 30 min of infusion and remained elevated (p<0.01 for 0 min vs. 30; 240 min; p<0.001 for 0 min vs. 24 h). Plasma concentrations of leptin and adiponectin did not show any significant changes. Although the expression of resistin in the subcutaneous adipose tissue tended to increase, the change was not significant. Expressions of TNFalpha, leptin and adiponectin were unaffected. In conclusions, our results indicate that acutely induced hyperlipidemia could influence the secretion of TNFalpha and resistin.

Topics: Adipokines; Adiponectin; Adult; Biomarkers; Fat Emulsions, Intravenous; Fatty Acids, Nonesterified; Gene Expression Regulation; Humans; Hyperlipidemias; Infusions, Intravenous; Leptin; Male; Resistin; Subcutaneous Fat; Time Factors; Triglycerides; Tumor Necrosis Factor-alpha; Young Adult

Previous studies have identified a single-nucleotide polymorphism in the gene encoding peroxisome proliferator-activated receptor-delta (PPARD), rs2016520, that is associated with changes in metabolic disease in some but not all studies, which suggests that PPARD agonists may have therapeutic benefits for the treatment of metabolic disorders, including dyslipidemia, type 2 diabetes, and obesity.. The objective of the study was to determine whether rs2016520 or other single-nucleotide polymorphism in the PPARD locus influenced the risk of developing various characteristics of metabolic disease.. Haplotype tagging analysis across PPARD was performed in 11,074 individuals from the Welcome Trust U.K. Type 2 Diabetes Case Control Collection.. In subjects with and without type 2 diabetes, rs2016520 was associated with body mass index, high-density lipoprotein cholesterol, leptin, and TNFalpha and was dependent on gender.. The current results suggest differential effects of PPARdelta in males and females.

Topics: Adiponectin; Adolescent; Adult; Aged; Aged, 80 and over; Body Mass Index; Cholesterol; Cohort Studies; Diabetes Mellitus, Type 2; Female; Gene Frequency; Genotype; Haplotypes; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Leptin; Lipids; Male; Middle Aged; Phenotype; Polymorphism, Single Nucleotide; PPAR delta; Reverse Transcriptase Polymerase Chain Reaction; Sex Characteristics; Tumor Necrosis Factor-alpha; Young Adult

The effect of Eriobotrya japonica Lindl. (loquat) on insulin resistance was examined in mice fed a high-fat (HF) diet. First, the mice were divided randomly into two groups: the control (CON) group was fed a low-fat diet, whereas the experimental group was fed with a 45% HF diet for 10 weeks. After 6 weeks of induction, the HF group was subdivided into five groups and was given orally loquat or not for 4 weeks afterward. It was demonstrated that loquat was effective in ameliorating the HF diet-induced hyperglycemia, hyperleptinemia, hyperinsulinemia and hypertriglyceridemia, as well as in decreasing the levels of free fatty acid (FFA), but increasing the adipose PPARγ (peroxisomal proliferator-activated receptor γ) and hepatic PPARα mRNA levels. Loquat significantly decreased the body weight gain, weights of white adipose tissue and visceral fat accompanying the suppressed leptin mRNA levels. Loquat not only suppressed the hepatic mRNA levels of enzymes involved in fatty acid and triacylglycerol synthesis and lowered the sterol regulatory element binding protein-1c (SREBP-1c) mRNA level, but also affected fatty acid oxidation enzyme levels. These regulations may contribute to triacylglycerol accumulation in white adipose tissue. The findings provide a nutritional basis for the use of loquat as a functional food factor that may have benefits for the prevention of hyperlipidemia and diabetes.

Topics: Adipokines; Adipose Tissue; Administration, Oral; AMP-Activated Protein Kinases; Animals; Eriobotrya; Fatty Acids, Nonesterified; Glucose Tolerance Test; Hyperinsulinism; Hyperlipidemias; Hypertriglyceridemia; Insulin Resistance; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Phytotherapy; Plant Extracts; PPAR gamma; RNA, Messenger; Sterol Regulatory Element Binding Protein 1; Weight Gain

Histamine has been proposed to be an important regulator of energy intake and expenditure. The aim of this study was to evaluate histamine regulation of glucose and lipid metabolism and development of nonalcoholic steatohepatitis (NASH) with a hyperlipidemic diet. Histamine regulation of glucose and lipid metabolism, adipocytokine production, and development of hyperlipidemia-induced hepatic injury were studied in histamine H1 (H1R(-/-)) and H2 (H2R(-/-)) receptor knockout and wild-type mice. H1R(-/-) mice showed mildly increased insulin resistance. In contrast, H2R(-/-) mice manifested profound insulin resistance and glucose intolerance. High-fat/high-cholesterol feeding enhanced insulin resistance and glucose intolerance. Studies with two-deoxy-2-[(18)F]-fluoro-d-glucose and positron emission tomography showed a brain glucose allocation in H1R(-/-) mice. In addition, severe NASH with hypoadiponectinemia as well as hepatic triglyceride and free cholesterol accumulation and increased blood hepatic enzymes were observed in H2R(-/-) mice. H1R(-/-) mice showed an obese phenotype with visceral adiposity, hyperleptinemia, and less severe hepatic steatosis and inflammation with increased hepatic triglyceride. These data suggest that H1R and H2R signaling may regulate glucose and lipid metabolism and development of hyperlipidemia-induced NASH.

Topics: Adiponectin; Adipose Tissue; Animals; Body Weight; Dietary Fats; Fatty Acid Synthases; Fatty Liver; Fluorodeoxyglucose F18; Glucose; Histamine; Hyperlipidemias; Leptin; Lipid Metabolism; Liver; Mice; Mice, Knockout; Radiopharmaceuticals; Receptors, Histamine H1; Receptors, Histamine H2; Sterol Regulatory Element Binding Proteins

In order to examine the influence of obesity on metabolic disorder and liver pathogenesis of the Fatty Liver Shionogi (FLS) mouse, which develops hereditary fatty liver and spontaneous liver tumors, we established a new congenic strain named FLS-Lep(ob). The Lep(ob) gene of the C57BL/6JWakShi (B6)-Lep(ob)/Lep(ob) mouse was transferred into the genome of the FLS mouse, by backcross mating. FLS-Lep(ob)/Lep(ob) mice were maintained by intercrossing between Lep(ob)-heterozygous littermates. The FLS-Lep(ob)/Lep(ob) mice of both sexes developed remarkable hyperphagia, obesity and type 2 diabetes mellitus. At 12 weeks of age, glucosuria was detected in all male and female FLS-Lep(ob)/Lep(ob) mice. Biochemical examination demonstrated that the FLS-Lep(ob)/Lep(ob) mice have severe hyperlipidemia and hyperinsulinemia. The livers of FLS-Lep(ob)/Lep(ob) mice showed microvesicular steatosis and deposition of large lipid droplets in hepatocytes throughout the lobules. The steatohepatitis-like lesions including the multifocal mononuclear cell infiltration and clusters of foamy cells were observed earlier in FLS-Lep(ob)/ Lep(ob) mice than in FLS mice. B6-Lep(ob)/Lep(ob) mice did not show hepatic inflammatory change. Furthermore, FLS-Lep(ob)/Lep(ob) mice developed multiple hepatic tumors including hepatocellular adenomas and carcinomas following steatohepatitis. In conclusion, the FLS-Lep(ob)/Lep(ob) mice developed steatohepatitis and hepatic tumors following hepatic steatosis. The FLS-Lep(ob)/Lep(ob) mouse with obesity and type 2 diabetes mellitus might be a useful animal model for human non-alcoholic steatohepatitis (NASH).

Topics: Adenoma, Liver Cell; Animals; Carcinoma, Hepatocellular; Diabetes Mellitus, Type 2; Fatty Liver; Female; Gene Expression; Glucose Tolerance Test; Glycosuria; Hepatocytes; Hyperlipidemias; Insulin Resistance; Leptin; Lipids; Liver; Liver Neoplasms; Male; Mice; Mice, Congenic; Mice, Inbred C57BL; Obesity; RNA, Messenger

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

Glucocorticoid (GC) action depends on GC plasma concentration, cellular GC receptor expression, and the pre-receptor hormone metabolism catalyzed by 11β-hydroxysteroid dehydrogenase (11β-HSD). 11β-Hydroxysteroid dehydrogenase exists in 2 isoforms; 11β-HSD1 converts inactive cortisone to cortisol, and 11β-HSD2 converts cortisol to cortisone. Increasing evidence in humans and experimental animals suggests that altered tissue cortisol metabolism may predispose to diabetes mellitus (DM). Once DM is established, hyperglycemia and hyperlipidemia may further maintain the abnormal metabolism of cortisol. To gain further insight in this regard, healthy cats were infused for 10 d with lipids (n = 6) or saline (n = 5). At the end of the infusion period, tissue samples from adipose tissue (visceral, subcutaneous), liver, and muscle were collected to determine mRNA expression of 11β-HSD1, 11β-HSD2, and GC receptor by real-time reverse-transcriptase polymerase chain reaction; blood samples were collected to determine plasma cortisol and leptin concentrations. Lipid infusion resulted in greater 11β-HSD1 expression and lower GC receptor expression in visceral and subcutaneous adipose tissue, and lower 11β-HSD2 expression in visceral adipose tissue and liver. Plasma cortisol did not differ. Leptin and body weight increased in lipid-infused cats. In spite of comparable circulating cortisol levels, up-regulation of 11β-HSD1 and down-regulation of 11β-HSD2 expression may result in increased tissue cortisol concentrations in fat depots of hyperlipidemic cats. Down-regulation of GC receptor may represent a self-protective mechanism against increased tissue cortisol levels. In conclusion, hyperlipidemia has a profound effect on 11β-HSD expression and supports the connection between high lipid concentrations and tissue cortisol metabolism.

Topics: 11-beta-Hydroxysteroid Dehydrogenases; Adipose Tissue; Animals; Cat Diseases; Cats; Fatty Acids, Nonesterified; Gene Expression; Glucocorticoids; Glucose Tolerance Test; Hydrocortisone; Hyperlipidemias; Insulin; Leptin; Lipids; Liver; Male; Muscles; Receptors, Glucocorticoid; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

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

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

We investigated whether regular decaffeinated green tea intake could modulate body weight in an experimental model of obesity. Male leptin-deficient (ob/ob) mice and their C57BL/6J lean littermates (4 weeks of age; n 20/genotype) were assigned randomly to receive either decaffeinated green tea or vehicle, for 6 weeks. Body weights were recorded weekly and fluid intake was measured at each replacement. Blood was collected from the heart into collection tubes, with Li(+)-heparin as the anticoagulant. Administration of decaffeinated green tea to ob/ob mice significantly slowed their rate of weight gain, as compared with animals that were fed buffer alone. This effect is apparent after only 1 week of supplementation. No significant difference was recorded between C57BL/6J lean mice administrated decaffeinated green tea and those given buffer alone. Decaffeinated green tea consumption by ob/ob mice was also associated with significantly lower cholesterolemia, triglyceridemia, and adiponectin concentration. Fecal lipids did not change significantly throughout the experiment. In conclusion, administration of decaffeinated green tea might contribute to weight control and provides an opportunity for through-the-day consumption, without the excitatory effects of caffeine.

Topics: Adiponectin; Animals; Anti-Obesity Agents; Caffeine; Catechin; Cholesterol; Feces; Hyperlipidemias; Hypolipidemic Agents; Leptin; Lipid Metabolism; Lipids; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Plant Preparations; Tea; Triglycerides; Weight Gain

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

To investigate the association between smoking and leptin, and to discuss their influence on diabetes in a large-scale study of Japanese men.. A cross-sectional study was carried out in 2002. The subjects were 2836 men aged 35-66. Smoking history was investigated in a self-administered questionnaire. Blood leptin, glucose and insulin were measured.. Significant differences in leptin levels and homeostasis model assessment of insulin resistance (HOMA-IR) related to smoking status were observed (P=0.001 and P=0.008, respectively). The multivariate-adjusted geometric means of leptin in current, past and never smokers were 3.88, 4.08 and 4.12 ng/ml, respectively, while the means of HOMA-IR were 1.64, 1.61 and 1.49, respectively. The age-, body mass index-, and other lifestyle-adjusted prevalences of diabetes in current and never smokers were 9.2 and 4.7%, respectively. That of current smokers was significantly higher than in never smokers (P<0.001). The dose-dependent association found between the intensity of smoking and leptin levels in current smokers was statistically significant (P=0.030).. The present finding may explain in part an association among smoking, leptin levels and diabetes. Smoking is one of the important modifiable risk factors for the prevention of diabetes.

Topics: Adult; Alcohol Drinking; Cardiovascular Diseases; Cohort Studies; Cross-Sectional Studies; Energy Intake; Humans; Hyperlipidemias; Insulin Resistance; Japan; Leptin; Life Style; Male; Middle Aged; Smoking

To evaluate the relationships between leptin, soluble leptin receptor, lipid profiles, and LEPR gene polymorphisms in child and adolescent Thai subjects.. Cross-sectional study of Thai children and adolescents.. 116 male and 65 female at risk for overweight/overweight child and adolescent Thai subjects, and 33 male and 62 female healthy child and adolescent Thai subjects (age: 5-19 years).. Leptin levels, soluble leptin receptor levels, lipid profiles, LEPR gene polymorphisms.. Significantly higher levels of cholesterol, triglyceride, low-density lipoprotein cholesterol (LDL-C), and leptin levels were observed in at risk for overweight/overweight group. On the other hand, high-density lipoprotein cholesterol (HDL-C) and soluble leptin receptor levels were significantly lower in the same group. Serum soluble leptin receptor levels were significantly negatively correlated with leptin. The at risk for overweight/overweight subjects with the Lys656Lys homozygous wild type LEPR gene had significantly higher cholesterol and LDL-C levels than those with Lys656Asn heterozygous and Asn656Asn homozygous mutant type. In contrast, subjects with Lys656Lys homozygous wild type had significantly lower leptin levels than those with Lys656Asn heterozygous and Asn656Asn homozygous mutant type. There was a statistically significant association between body mass index (BMI) and hyperleptinemia (odds ratio; OR = 2.49, p = 0.000) and females had more increased risk of hyperleptinemia than males (OR = 15.74, p = 0.004) in adolescent Thai subjects.. The present study is the first report of Lys656Asn polymorphism of the LEPR gene associated with cholesterol, LDL-C, and leptin levels in Thai children and adolescents. Serum leptin levels were significantly higher in the at risk for overweight/overweight. In contrast, there were significantly lower soluble leptin receptor levels in the same group. In addition, there was a statistically significant association between BMI, sex, and hyperleptinemia in adolescent Thai subjects.

Topics: Adolescent; Adult; Body Mass Index; Child; Child, Preschool; Cholesterol; Cross-Sectional Studies; Female; Humans; Hyperlipidemias; Leptin; Lipids; Male; Obesity; Odds Ratio; Overweight; Polymorphism, Genetic; Receptors, Leptin; Risk Factors; Sex Distribution; Thailand

This study investigated the effect of curcumin (0.05-g/100-g diet) supplementation on a high-fat diet (10% coconut oil, 0.2% cholesterol, wt/wt) fed to hamsters, one of the rodent species that are most closely related to humans in lipid metabolism. Curcumin significantly lowered the levels of free fatty acid, total cholesterol, triglyceride, and leptin and the homeostasis model assessment of insulin resistance index, whereas it elevated the levels of high-density lipoprotein cholesterol and apolipoprotein (apo) A-I and paraoxonase activity in plasma, compared with the control group. The levels of hepatic cholesterol and triglyceride were also lower in the curcumin group than in the control group. In the liver, fatty acid beta-oxidation activity was significantly higher in the curcumin group than in the control group, whereas fatty acid synthase, 3-hydroxy-3-methylglutaryl coenzyme A reductase, and acyl coenzyme A:cholesterol acyltransferase activities were significantly lower. Curcumin significantly lowered the lipid peroxide levels in the erythrocyte and liver compared with the control group. These results indicate that curcumin exhibits an obvious hypolipidemic effect by increasing plasma paraoxonase activity, ratios of high-density lipoprotein cholesterol to total cholesterol and of apo A-I to apo B, and hepatic fatty acid oxidation activity with simultaneous inhibition of hepatic fatty acid and cholesterol biosynthesis in high-fat-fed hamsters.

Topics: Animals; Apolipoprotein A-I; Aryldialkylphosphatase; Cardiovascular Diseases; Cholesterol, HDL; Cricetinae; Curcumin; Dietary Fats; Fatty Acids; Hyperlipidemias; Hypolipidemic Agents; Insulin Resistance; Leptin; Lipid Peroxidation; Male; Mesocricetus

The metabolic syndrome is a group of disorders including obesity, insulin resistance, atherogenic dyslipidemia, hyperglycemia, and hypertension. To date, few animal models have been described to recapitulate the phenotypes of the syndrome. In this study, we generated and characterized two lines of triple-knockout mice that are deficient in either apolipoprotein E (Apoe(-/-)) or low-density lipoprotein receptor (Ldlr(-/-)) and express no leptin (Lep(ob/ob)) or apolipoprotein B-48 but exclusively apolipoprotein B-100 (Apob(100/100)). These two lines are referred to as Apoe triple-knockout-Apoe 3KO (Apoe(-/-)Apob(100/100)Lep(ob/ob)) and Ldlr triple-knockout-Ldlr 3KO (Ldlr(-/-)Apob(100/100)Lep(ob/ob)) mice. Both lines develop obesity, hyperinsulinemia, hyperlipidemia, hypertension, and atherosclerosis. However, only Apoe 3KO mice are hyperglycemic and glucose intolerant and are more obese than Ldlr 3KO mice. To evaluate the utility of these lines as pharmacological models, we treated both with leptin and found that leptin therapy ameliorated most metabolic derangements. Leptin was more effective in improving glucose tolerance in Ldlr 3KO than Apoe 3KO animals. The reduction of plasma cholesterol by leptin in Ldlr 3KO mice can be accounted for by its suppressive effect on food intake. However, in Apoe 3KO mice, leptin further reduced plasma cholesterol independently of its effect on food intake, and this improvement correlated with a smaller plaque lesion area. These effects suggest a direct role of leptin in modulating VLDL levels and, likewise, the lesion areas in VLDL-enriched animals. These two lines of mice represent new models with features of the metabolic syndrome and will be useful in testing therapies targeted for combating the human condition.

Topics: Animals; Apolipoprotein B-48; Apolipoproteins E; Disease Models, Animal; Hyperglycemia; Hyperlipidemias; Hypertension; Insulin Resistance; Leptin; Lipoproteins, VLDL; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Phenotype; Receptors, LDL

Forty-eight 67-day-old male Wistar rats (330+/-5g) were fed ad libitum either with a lipid enriched diet or a standard laboratory chow. Half of each sub-group was submitted to training. Training and difference in diet composition induced nonsignificant changes in body adiposity. Visceral fat (perirenal adipose tissue mass) was correlated with leptin (r=0.35, p=0.02) and insulin (r=0.38, p=0.01). Total body fat mass (measured by DEXA) was correlated with leptin only (r=0.58, p=0.003). Other correlations between perirenal adipose tissue or fat mass and adiponectin or insulin like growth factor 1 were nonsignificant. These results suggest that, in rat like in human, visceral fat development is linked with insulin insensitivity.

Topics: Adiponectin; Adipose Tissue; Animals; Body Weight; Dietary Fats; Hyperlipidemias; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Intra-Abdominal Fat; Leptin; Male; Organ Size; Physical Conditioning, Animal; Rats; Rats, Wistar

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

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

Resistin has been linked to components of the metabolic syndrome, including obesity, insulin resistance, and hyperlipidemia. We hypothesized that resistin deficiency would reverse hyperlipidemia in genetic obesity. C57Bl/6J mice lacking resistin [resistin knockout (RKO)] had similar body weight and fat as wild-type mice when fed standard rodent chow or a high-fat diet. Nonetheless, hepatic steatosis, serum cholesterol, and very low-density lipoprotein (VLDL) secretion were decreased in diet-induced obese RKO mice. Resistin deficiency exacerbated obesity in ob/ob mice, but hepatic steatosis was drastically attenuated. Moreover, the levels of triglycerides, cholesterol, insulin, and glucose were reduced in ob/ob-RKO mice. The antisteatotic effect of resistin deficiency was related to reductions in the expression of genes involved in hepatic lipogenesis and VLDL export. Together, these results demonstrate a crucial role of resistin in promoting hepatic steatosis and hyperlipidemia in obese mice.

Topics: Adiponectin; Animals; Blood Glucose; Body Weight; Cholesterol; Cohort Studies; Fatty Liver; Hyperlipidemias; Immunohistochemistry; Insulin; Leptin; Lipoproteins, VLDL; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Obesity; Resistin; Triglycerides

Obesity and hyperlipidemia are common findings after kidney transplantation (Tx), and may represent independent risk factors for development of atherosclerosis and chronic allograft nephropathy. In a prospective metabolic study, we monitored a total of 68 obese transplant patients (body mass index > 30 kg/m2) with dyslipidemia. We compared findings of a new therapeutic regimen 1 year (at baseline) and 2 years after renal transplantation. Using the Subjective Global Assessment, at the end of the first year an Individualized Hypoenergetic-Hypolipidemic diet was initiated. Subsequently, after withdrawal of corticosteroids IHHD was regularly supplemented with statins (atorvastatin 10-20 mg/day) and followed-up for 2 years. All patients were on a regimen of cyclosporin A or tacrolimus and mycophenolate mofetil. During the study period, there was a significant decrease in BMI (p<0.25) and an increase in adiponectin levels (p<0.01). Long-term therapy was associated with a significant decrease in serum leptin (p<0.01) and lipid metabolism parameters (p<0.01). Insulin clearance mean systolic and diastolic blood pressure, proteinuria and apo-lipoprotein E isoforms did not differ significantly. Based on our results, we can assume that obesity and hyperlipidemia after renal transplantation can be effectively treated by modified immunosuppression (corticosteroid withdrawal), statins and long-term diet (IHHD). The increased levels of adiponectin may be a marker of reduced atherosclerosis and chronic allograft nephropathy.

Topics: Adiponectin; Adult; Aged; Female; Humans; Hyperlipidemias; Kidney Transplantation; Leptin; Male; Metabolic Syndrome; Middle Aged; Obesity

SH2B1 (previously named SH2-B), a cytoplasmic adaptor protein, binds via its Src homology 2 (SH2) domain to a variety of protein tyrosine kinases, including JAK2 and the insulin receptor. SH2B1-deficient mice are obese and diabetic. Here we demonstrated that multiple isoforms of SH2B1 (alpha, beta, gamma, and/or delta) were expressed in numerous tissues, including the brain, hypothalamus, liver, muscle, adipose tissue, heart, and pancreas. Rat SH2B1beta was specifically expressed in neural tissue in SH2B1-transgenic (SH2B1(Tg)) mice. SH2B1(Tg) mice were crossed with SH2B1-knockout (SH2B1(KO)) mice to generate SH2B1(TgKO) mice expressing SH2B1 only in neural tissue but not in other tissues. Systemic deletion of the SH2B1 gene resulted in metabolic disorders in SH2B1(KO) mice, including hyperlipidemia, leptin resistance, hyperphagia, obesity, hyperglycemia, insulin resistance, and glucose intolerance. Neuron-specific restoration of SH2B1beta not only corrected the metabolic disorders in SH2B1(TgKO) mice, but also improved JAK2-mediated leptin signaling and leptin regulation of orexigenic neuropeptide expression in the hypothalamus. Moreover, neuron-specific overexpression of SH2B1 dose-dependently protected against high-fat diet-induced leptin resistance and obesity. These observations suggest that neuronal SH2B1 regulates energy balance, body weight, peripheral insulin sensitivity, and glucose homeostasis at least in part by enhancing hypothalamic leptin sensitivity.

Topics: Adaptor Proteins, Signal Transducing; Adipose Tissue; Animals; Base Sequence; Body Weight; DNA Primers; Energy Metabolism; Glucose; Homeostasis; Hyperlipidemias; Hypothalamus; Insulin Resistance; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Neurons; Obesity

Obesity and hyperlipidaemia are found very frequently after kidney transplantation (Tx) and may represent independent risk factors for development of atherosclerosis and chronic allograft nephropathy. In a prospective metabolic study, we monitored, a total of 68 obese transplant patients [body mass index (BMI) > 30 kg/m2] with dyslipidaemia over a period of 24 months. We compared the findings of a new therapeutic regimen 1 year (start of the study) and 2 years after renal transplantation. Based on a Subjective Global Assessment Scoring Sheet, we started at the end of the first year with an individualized hypoenergic-hypolipidaemic diet (IHHD). Subsequently, after corticoid withdrawal, IHHD was supplemented regularly with statins (atorvastatin 10-20 mg/day)) and followed-up for 2 years. All patients were on a regimen of cyclosporin A or tacrolimus and mycophenolate mofetil. During the study period, there was a significant decrease in BMI (p < 0.025) and an increase of the adiponectin level (p < 0.01). Long-term therapy was associated with a significant decrease in serum leptin (p < 0.01) and lipid metabolism parameters (p < 0.01). Inulin clearance, mean systolic and diastolic blood pressure, proteinuria, lipoprotein(a) and apo-lipoprotein E isoforms did not differ significantly. Based on our results, we assume that obesity and hyperlipidaemia after renal transplantation can be treated effectively by modified immunosuppression (corticosteroid withdrawal), statins and long-term diet (IHHD). The increased level of adiponectin may be a marker of reducing atherosclerotic and chronic allograft nephropathy processes.

Topics: Adiponectin; Atherosclerosis; Body Mass Index; Diet, Reducing; Hyperlipidemias; Kidney Transplantation; Leptin; Obesity; Prospective Studies

Leptin-induced increases in insulin sensitivity are well established and may be related to the effects of leptin on lipid metabolism. However, the effects of leptin on the levels of lipid metabolites implicated in pathogenesis of insulin resistance and the effects of leptin on lipid-induced insulin resistance are unknown. The current study addressed in rats the effects of hyperleptinemia (HL) on insulin action and markers of skeletal muscle (SkM) lipid metabolism in the absence or presence of acute hyperlipidemia induced by an infusion of a lipid emulsion. Compared with controls (CONT), HL increased insulin sensitivity, as assessed by hyperinsulinemic-euglycemic clamp ( approximately 15%), and increased SkM Akt ( approximately 30%) and glycogen synthase kinase 3 alpha ( approximately 52%) phosphorylation. These improvements in insulin action were associated with decreased SkM triglycerides (TG; approximately 61%), elevated ceramides ( approximately 50%), and similar diacylglycerol (DAG) levels in HL compared with CONT. Acute hyperlipidemia in CONT decreased insulin sensitivity ( approximately 25%) and increased SkM DAG ( approximately 33%) and ceramide ( approximately 60%) levels. However, hyperlipidemia did not induce insulin resistance or SkM DAG and ceramide accumulation in HL. SkM total fatty acid transporter CD36, plasma membrane fatty acid binding protein, acetyl Co-A carboxylase phosphorylation, and fatty acid oxidation were similar in HL compared with CONT. However, HL decreased SkM protein kinase C theta (PKC theta), a kinase implicated in mediating the detrimental effects of lipids on insulin action. We conclude that increases in insulin sensitivity induced by HL are associated with decreased levels of SkM TG and PKC theta and increased SkM insulin signaling, but not with decreases in other lipid metabolites implicated in altering SkM insulin sensitivity (DAG and ceramide). Furthermore, insulin resistance induced by an acute lipid infusion is prevented by HL.

Topics: Acute Disease; Animals; Ceramides; Diglycerides; Emulsions; Fat Emulsions, Intravenous; Fatty Acid-Binding Proteins; Glycogen Synthase Kinase 3; Hyperlipidemias; Insulin; Insulin Resistance; Isoenzymes; Leptin; Male; Muscle, Skeletal; Phospholipids; Protein Kinase C; Protein Kinase C-theta; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Safflower Oil; Signal Transduction; Soybean Oil; Triglycerides

The objectives of this study were to determine 1) whether the extent of weight loss is predictive of the degree of changes in hormone and lipid levels; 2) the interactions between energy regulating hormones after weight loss through an energy deficit/exercise protocol diet and exercise; 3) whether initial metabolic parameters are indicative of the extent of weight loss.. Thirty-five hyperlipidemic females (BMI 28-39 kg/m2) 35-60 years old participated in a six month weight loss trial. Weight loss resulted from a diet and exercise program that when combined produced a 30% energy deficit. Fasting plasma taken during 2 wk stabilization periods at the beginning and end of the study was analysed for lipids, hormone and glucose levels.. Average weight loss was 11.7 +/- 2.5 kg (p < 0.0001). TC, LDL-C, and triacylglycerols decreased 9.3 +/- 9.5% (p < 0.0001), 7.4 +/- 12.2% (p < 0.001), and 26.8 +/- 19.6% (p < 0.05), respectively, while HDL-C increased (p < 0.05) by 8.2 +/- 16.3%. Leptin levels declined (p < 0.001) 48.9 +/- 16.0% and ghrelin levels rose (p < 0.001) 21.2 +/- 26.7%. While overall levels of adiponectin did not differ, individual values changed such that weight loss predicted increases in adiponectin levels. Though initial weight did not predict weight loss, baseline lipid and insulin levels positively predicted weight loss.. Initial metabolic parameters may be predictors of weight loss. Beneficial effects of weight loss as achieved through diet and exercise on measured parameters indicate moderate weight loss reduces key risk factors of cardiovascular disease in overweight individuals.

Topics: Adiponectin; Adult; Blood Glucose; Cardiovascular Diseases; Combined Modality Therapy; Diet, Reducing; Energy Metabolism; Exercise; Female; Ghrelin; Humans; Hyperlipidemias; Leptin; Lipids; Middle Aged; Obesity; Peptide Hormones; Predictive Value of Tests; Risk Factors; Weight Loss

Regucalcin plays a multifunctional role as a regulatory protein in intracellular signaling pathway in many cell types. Regucalcin transgenic (TG) rats have been shown to experience hyperlipidemia with increasing age. This study was undertaken to determine whether lipid components in the adipose and liver tissues are changed in regucalcin TG rats in vivo. Female regucalcin TG rats were used at 7 or 50 weeks of age. Serum triglyceride or HDL-cholesterol concentrations were significantly increased in 7-week-old regucalcin TG rats as compared with those in 7-week-old normal rats. Serum triglyceride, total cholesterol, HDL-cholesterol, or free fatty acid concentrations were significantly increased in 50-week-old regucalcin TG rats. Meanwhile, triglyceride content in the adipose tissues was significantly increased in 50-week-old regucalcin TG rats,while the free fatty acid content was not significantly changed. Triglyceride, total cholesterol, or free fatty acid content in the liver tissues was significantly decreased in 50-week-old regucalcin TG rats. Liver glycogen content was significantly decreased in 7- or 50-week-old regucalcin TG rats. In addition, regucalcin mRNA and its protein levels were seen in the adipose tissues of normal rats. Those levels were not significantly changed in regucalcin TG rats at 50 weeks of age. Leptin mRNA expression in the adipose or liver tissues was significantly decreased in 50-week-old regucalcin TG rats. Adiponectin mRNA levels were not significantly changed in the adipose tissues of 50-week-old regucalcin TG rats, while the levels were significantly decreased in the liver tissues. This study demonstrates that the disorder of lipid metabolism in the adipose and liver tissues is induced in regucalcin TG rats with aging, and that the gene expression of leptin or adiponectin is suppressed in TG rats.

Topics: Adiponectin; Adipose Tissue; Aging; Animals; Animals, Genetically Modified; Base Sequence; Calcium-Binding Proteins; Carboxylic Ester Hydrolases; DNA, Complementary; Fatty Acids, Nonesterified; Female; Gene Expression; Hyperlipidemias; Intracellular Signaling Peptides and Proteins; Leptin; Lipid Metabolism; Liver; Rats; Rats, Sprague-Dawley; Recombinant Proteins; RNA, Messenger; Triglycerides

To investigate whether the perinatal and postnatal exposure of mice to bisphenol A (BPA) caused the development of obesity and/or hyperlipidemia.. Pregnant mice were exposed to BPA in drinking water at concentrations of either 1 microg/mL (LD group) or 10 microg/mL (HD group) from gestation day 10 and throughout the lactating period. After weaning, the pups were allowed free access to drinking water containing the appropriate concentrations of BPA. The body weight, adipose tissue weight, and serum lipid levels were measured in the offspring at postnatal day 31.. In females, the mean body weight increased by 13% in the LD group (p<0.05) and 11% in the HD group (p<0.05) compared with the control group. The mean adipose tissue weight increased by 132% in the LD group (p<0.01). The mean total cholesterol level increased by 33% in the LD group (p<0.01) and 17% in the HD group (p<0.05). In males, the mean body weight and mean adipose tissue weight increased by 22% (p<0.01) and 59% (p<0.01), respectively, in the HD group compared with the control group. The mean triacylglycerol level increased by 34% in the LD group (p<0.05).. The continuous exposure of mice to BPA during the perinatal and postnatal periods caused the development of obesity and hyperlipidemia.

Topics: Adipose Tissue; Animals; Benzhydryl Compounds; Blood Glucose; Body Weight; Cholesterol; Estrogens, Non-Steroidal; Female; Hyperlipidemias; Leptin; Male; Mice; Obesity; Phenols; Pregnancy; Prenatal Exposure Delayed Effects; Sex Factors

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

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

Diseases of the heart and blood vessels are a major cause of illness and disability worldwide. The relationship between ethanol consumption and cardiovascular disease are both complex and interconnected. Our aim of this study was to explore the effect of leptin on lipid metabolism in ethanol supplemented mice. Male Swiss mice (Mus musculas) weighing 25+/-2 g were administered ethanol (6.32 g kg(-1) body weight) for the first 30 days. Subsequently, ethanol fed mice were given intraperitoneal injections of exogenous mouse recombinant leptin (230 microg kg(-1) body weight) every alternate day for 15 days. Food and water intake and total body weight were measured every day and at the end of the experimental period of 45 days, plasma and cardiac lipids were analyzed. Exogenous leptin injections to ethanol fed mice significantly (P < 0.05) prevented the accumulation of total cholesterol, phospholipids (PL), triglycerides (TG) and free fatty acids (FFA) in the mouse heart and blood as compared to the untreated ethanol fed mice whereas, the plasma concentration of free cholesterol was significantly increased on leptin administration as compared to normal untreated mice. Moreover leptin administration significantly elevated the activities of cardiac lipoprotein lipase (LPL) and plasma lecithin cholesterol acyl transferase (LCAT) and significantly reduced the activities of cardiac HMG CoA reductase and cholesterol ester synthase (CES) on leptin administration to ethanol fed mice. Thus we could postulate that an increase in systemic leptin level prevents the accumulation of lipids in the plasma and heart of ethanol treated mice.

Topics: Animals; Disease Models, Animal; Ethanol; Heart; Hydroxymethylglutaryl CoA Reductases; Hyperlipidemias; Injections, Intraperitoneal; Leptin; Lipid Metabolism; Lipids; Lipoprotein Lipase; Male; Mice; Myocardium; Phosphatidylcholine-Sterol O-Acyltransferase

Fetal programming is now recognized as a key determinant of the adult phenotype, with major implications for adult-onset diseases including hypertension. Two mediators of fetal programming are maternal nutrition and fetal glucocorticoid exposure. Recent studies show that postnatal dietary manipulations can exacerbate programming effects, but whether programming effects can be attenuated by postnatal dietary manipulations, and thus provide a possible therapeutic strategy, is unknown. In this study, we tested the hypothesis that a postnatal diet enriched with long-chain omega-3 fatty acids attenuates programmed hyperleptinemia and hypertension. Pregnant rats were treated with dexamethasone (Dex) from d 13 to term, and offspring were cross-fostered to mothers on either a standard diet or a diet high in omega-3 fatty acids and remained on these diets postweaning. Maternal Dex reduced birthweight and delayed the onset of puberty in offspring. Hyperleptinemia (associated with elevated leptin mRNA expression in adipose tissue) and hypertension were evident in offspring by 6 months of age in Dex-exposed animals consuming a standard diet, but these effects were completely blocked by a high omega-3 diet. These results demonstrate for the first time that manipulation of postnatal diet can limit adverse outcomes of fetal programming, with programmed hyperleptinemia and hypertension prevented by a postnatal diet enriched with omega-3 fatty acids. This raises the possibility that dietary supplementation with omega-3 fatty acids may provide a viable therapeutic option for preventing and/or reducing adverse programming outcomes in humans.

Topics: Animals; Animals, Newborn; Body Weight; Dietary Fats; Energy Intake; Fatty Acids, Omega-3; Female; Hyperlipidemias; Hypertension; Leptin; Male; Pregnancy; Pregnancy, Animal; Rats; Rats, Wistar

Endogenously formed reactive oxygen species continuously damage cellular constituents including DNA. These challenges, coupled with exogenous exposure to agents that generate reactive oxygen species, are both associated with normal aging processes and linked to cardiovascular disease, cancer, cataract formation, and fatty liver disease. Although not all of these diseases have been definitively shown to originate from mutations in nuclear DNA or mitochondrial DNA, repair of oxidized, saturated, and ring-fragmented bases via the base excision repair pathway is known to be critical for maintaining genomic stability. One enzyme that initiates base excision repair of ring-fragmented purines and some saturated pyrimidines is NEIL1, a mammalian homolog to Escherichia coli endonuclease VIII. To investigate the organismal consequences of a deficiency in NEIL1, a knockout mouse model was created. In the absence of exogenous oxidative stress, neil1 knockout (neil1-/-) and heterozygotic (neil1+/-) mice develop severe obesity, dyslipidemia, and fatty liver disease and also have a tendency to develop hyperinsulinemia. In humans, this combination of clinical manifestations, including hypertension, is known as the metabolic syndrome and is estimated to affect >40 million people in the United States. Additionally, mitochondrial DNA from neil1-/- mice show increased levels of steady-state DNA damage and deletions relative to wild-type controls. These data suggest an important role for NEIL1 in the prevention of the diseases associated with the metabolic syndrome.

Topics: Animals; DNA Damage; DNA Glycosylases; DNA, Mitochondrial; Fatty Liver; Female; Gene Deletion; Hyperinsulinism; Hyperlipidemias; Kidney; Leptin; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Pedigree

Recent studies have provided evidence that leptin has significant effects on vascular development and repair. The aim was to determine the levels of leptin and lipid profile in diabetic postmenopausal women with and without the complication of ischemic heart disease and to develop correlation between them. Moreover, the relationship between leptin levels and extent of ischemic changes were determined.. One hundred twenty postmenopausal subjects between the ages of 45 and 60 years were included in the study. They were divided into three groups of forty subjects each. The first group comprised normal healthy controls, the second diabetic type 2 patients with no history of ischemic heart disease (I1ID), and the third diabetic patients with IHD. Serum leptin levels were determined by a Kit obtained from DRG and samples were analyzed on ELISA. Fasting and random blood glucose was determined by the glucose oxidase method, cholesterol, triglycerides, LDL cholesterol, and HDL cholesterol were also determined by kits obtained from Merck.. The results show that leptin and serum lipid levels increased significantly in diabetic patients with IHD compared with diabetic patients without IHD as well as normal subjects. Moreover; the sertum leptin level increased significantly in the diabetic patients with IHD who had positive findings in myocardial perfusion scan compared with those having negative findings.. Hyperleptinemia in diabetic patients shows that leptin contributes to the development of cardiovascular disease in diabetic patients.

Topics: Aged; Diabetes Mellitus, Type 2; Female; Humans; Hyperlipidemias; Leptin; Lipids; Middle Aged; Myocardial Ischemia; Postmenopause

Adipokines may serve as an important etiologic link between atherosclerosis and obesity. Because adipose tissue is one site of action of the lipid-lowering drug niacin, we investigated whether niacin treatment would affect not only lipids but also adipokines. Twenty-four patients were treated with extended-release niacin. During the first 4 weeks the daily dose was increased at weekly intervals from 375 to 1000 mg, which was maintained for 4 weeks. Thereafter, the dose was 1500 mg for another 6 weeks. Adiponectin increased by 54% and 94%, respectively, resistin was lowered only moderately, and leptin not at all. Because adiponectin has repeatedly been shown to be negatively associated with atherosclerotic risk, its pronounced increase may bring about additional atheroprotection by niacin beyond its improvement in lipids.

Topics: Adiponectin; Adult; Aged; Cholesterol; Cholesterol, HDL; Cytokines; Delayed-Action Preparations; Female; Humans; Hyperlipidemias; Hypolipidemic Agents; Leptin; Lipids; Male; Middle Aged; Niacin; Resistin; Triglycerides

A prospective clinical intervention study was performed to estimate the metabolic risk factors in patients with very severe obesity (VSO) vs. severe obesity (SO).. Two hundred twenty-eight VSO (BMI > or = 50 kg/m(2)) and 221 SO patients (BMI = 40 to 49.9 kg/m(2)) participated in the study (367 women and 82 men). Metabolic measurements included plasma lipids, glucose and insulin, hemoglobin A(1c), leptin, and sex hormones, as well as hepatic steatosis in a subgroup of patients. Subgroups of patients with non-insulin-dependent diabetes and hyperlipidemia (HLP) were examined.. The most unexpected result of our study was that VSO men showed significantly better lipid profiles than SO men. Furthermore, 18% of VSO men had no metabolic aberrations, whereas all SO men did. The advantageous metabolic status of VSO men was associated with sex hormone changes that favor gynoid fat distribution. The beneficial metabolic situation with VSO seems to be sex specific for men.. This study shows that the metabolic situation in VSO is not more severe than in the less obese cohort. These findings distinctly differ from the positive associations that have previously been reported between BMI, lipids, and other metabolic indices among individuals whose BMI is <40 kg/m(2).

Topics: Adult; Blood Glucose; Body Mass Index; Cohort Studies; Diabetes Mellitus, Type 2; Estradiol; Female; Glycated Hemoglobin; Humans; Hyperlipidemias; Insulin; Leptin; Lipids; Male; Metabolic Syndrome; Obesity, Morbid; Progesterone; Prospective Studies; Risk Factors; Sex Factors; Testosterone

We previously reported that diacylglycerol (DAG) as compared with triacylglycerol (TAG) suppressed increases in postprandial lipids in healthy volunteers. This study was to investigate the effects of DAG on postprandial lipids, particularly remnant lipoproteins in diabetics.. Emulsified DAG oil or TAG oil with a fatty acid composition similar to DAG oil was orally administered (30 g fat/m2 of body surface) to moderately controlled six diabetics, with hemoglobin A1c (HbA1c) below 8%, after fasting for at least 12 h in a randomized crossover manner. Serum cholesterol and TAG, lipids in remnant-like particles (RLP), and other lipid parameters including serum ketone bodies were measured prior to and 2, 4, and 6 h after fat loading.. DAG loading significantly suppressed increases in postprandial serum TAG and lipids in RLP as compared with TAG loading. The incremental area under the curve (IAUC) for serum TAG and that for lipids in RLP with DAG loading were also significantly smaller than those with TAG loading. However, changes in serum levels of insulin, free fatty acids, and ketone bodies during fat loading were essentially the same for DAG and TAG.. This pilot study suggests that substituting DAG intake for TAG may be beneficial to moderately controlled diabetics due to its effect in reducing postprandial hyperlipidemia.

Topics: Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 2; Diglycerides; Humans; Hyperlipidemias; Insulin; Ketone Bodies; Leptin; Lipoproteins, LDL; Plasminogen Activator Inhibitor 1; Postprandial Period

Eradication of Helicobacter pylori improves clinical symptoms and quality of life in patients with peptic ulcer.. To investigate the effect of eradication of H. pylori on body mass index and incidence of hyperlipidaemia in patients with peptic ulcer.. The study population comprised 50 patients (42 men, 8 women; mean age, 51 years; 28 gastric ulcer, 22 duodenal ulcer) who underwent physical and blood examination before and 1 year after undergoing eradication therapy and 100 sex- and age-matched control subjects. Body mass index, total cholesterol and triglyceride were measured before and 1 year after therapy.. The eradication therapy group showed a significant increase in body mass index (22.7+/-2.5 kg/m2 before eradication versus 23.6+/-2.6 kg/m2 after eradication, p < 0.01), serum total cholesterol (204.1+/-33.2 mg/dL versus 221.2+/-38.8 mg/dL, p < 0.01), and triglyceride. Additionally, the eradication therapy group showed a significant increase in the incidence of hypercholesterolemia (30% versus 58%, p<0.01), hypertriglyceridaemia (28% versus 44%, p < 0.01) and obesity (12% versus 22%, p <0.05) 12 months after therapy.. Our findings show that eradication of H. pylori significantly increases the incidence of hyperlipidaemia and obesity in patients with peptic ulcer.

Topics: Adult; Aged; Body Mass Index; Breath Tests; Comorbidity; Female; Helicobacter Infections; Helicobacter pylori; Humans; Hyperlipidemias; Leptin; Male; Middle Aged; Obesity; Peptic Ulcer; Quality of Life

Obesity is associated with marked increases in plasma leptin concentration, and hyperleptinemia is an independent risk factor for coronary artery disease. As a result, the purpose of this investigation was to test the following hypotheses: 1) leptin receptors are expressed in coronary endothelial cells; and 2) hyperleptinemia induces coronary endothelial dysfunction. RT-PCR analysis revealed that the leptin receptor gene is expressed in canine coronary arteries and human coronary endothelium. Furthermore, immunocytochemistry demonstrated that the long-form leptin receptor protein (ObRb) is present in human coronary endothelium. The functional effects of leptin were determined using pressurized coronary arterioles (<130 microm) isolated from Wistar rats, Zucker rats, and mongrel dogs. Leptin induced pharmacological vasodilation that was abolished by denudation and the nitric oxide synthase inhibitor N(omega)-nitro-l-arginine methyl ester and was absent in obese Zucker rats. Intracoronary leptin dose-response experiments were conducted in anesthetized dogs. Normal and obese concentrations of leptin (0.1-3.0 microg/min ic) did not significantly change coronary blood flow or myocardial oxygen consumption; however, obese concentrations of leptin significantly attenuated the dilation to graded intracoronary doses of acetylcholine (0.3-30.0 microg/min). Additional experiments were performed in canine coronary rings, and relaxation to acetylcholine (6.25 nmol/l-6.25 micromol/l) was significantly attenuated by obese concentrations of leptin (625 pmol/l) but not by physiological concentrations of leptin (250 pmol/l). The major findings of this investigation were as follows: 1) the ObRb is present in coronary arteries and coupled to pharmacological, nitric oxide-dependent vasodilation; and 2) hyperleptinemia produces significant coronary endothelial dysfunction.

Topics: Animals; Arterioles; Cells, Cultured; Coronary Circulation; Coronary Vessels; Dogs; Dose-Response Relationship, Drug; Endothelium, Vascular; Humans; Hyperlipidemias; Leptin; Nitric Oxide; Obesity; Rats; Rats, Zucker; Receptors, Cell Surface; Receptors, Leptin; Vasodilation

Metabolic syndrome is a common disorder in Taiwan. For this study 431 subjects were randomly selected from visitors to the Department of Health Management. Blood pressure, blood glucose, lipid, uric acid levels and anthropometric measurements with immunoreactive insulin (IRI) and leptin levels were all correlated. We randomly selected 431 subjects who visited the Department of Health Management. Whole body three-dimensional (3-D) laser scanner scans were employed for the anthropometric measurements. The metabolic index (MI) was designed using anthropometric parameters. Of the 431 subjects, 50% had displayed a body mass index (BMI) equal to or exceeding 25 kg/m2. Pearson correlation coefficient and multiple regression analysis revealed that MI constituted another index for correlating metabolic parameters by comparing MI with BMI and waist circumference to hip circumference ratio (WHR). Most data related to metabolic syndrome showed statistically significant differences between high and low IRI groups, comprising uric acid, total cholesterol, fasting plasma glucose, triglyceride, LDL, Chol/HDL ratio, and LDL/HDL ratio. Both IRI and leptin revealed statistical association with BMI, WHR, waist cross section area to hip cross section area ratio (WHAR), and MI in the study. Hypercholesterolemia appeared in 14.6% of the subjects. Elevated low-density lipoprotein (> or = 130 mg/dL) affected 36.9% of the subjects. In conclusion, MI calculated from 3-D body scanner correlated with many important metabolic risk factors and associated with clinical disorders like DM, hyperlipidemia, hyperuricemia and hypertension.

Topics: Adult; Aged; Aged, 80 and over; Anthropometry; Body Mass Index; Body Weights and Measures; Female; Humans; Hyperlipidemias; Imaging, Three-Dimensional; Incidence; Insulin; Lasers; Leptin; Male; Metabolic Syndrome; Middle Aged; Risk Factors; Waist-Hip Ratio

The CLOCK transcription factor is a key component of the molecular circadian clock within pacemaker neurons of the hypothalamic suprachiasmatic nucleus. We found that homozygous Clock mutant mice have a greatly attenuated diurnal feeding rhythm, are hyperphagic and obese, and develop a metabolic syndrome of hyperleptinemia, hyperlipidemia, hepatic steatosis, hyperglycemia, and hypoinsulinemia. Expression of transcripts encoding selected hypothalamic peptides associated with energy balance was attenuated in the Clock mutant mice. These results suggest that the circadian clock gene network plays an important role in mammalian energy balance.

Topics: Adipocytes; Animals; Body Weight; Brain; Circadian Rhythm; CLOCK Proteins; Dietary Fats; Energy Intake; Energy Metabolism; Feeding Behavior; Hepatocytes; Hyperglycemia; Hyperlipidemias; Insulin; Leptin; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Motor Activity; Mutation; Neuropeptides; Obesity; Trans-Activators; Weight Gain

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

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

Adenovirus-induced hyperleptinemia rapidly depletes body fat in normal rats without increasing free fatty acids and ketogenesis, implying that fat-storing adipocytes are oxidizing the fat. To analyze the ultrastructural changes of adipocytes accompanying this functional transformation, we examined the fat tissue by electron microscopy. After 14 days of hyperleptinemia, adipocytes had become shrunken, fatless, and encased in a thick basement-membrane-like matrix. They were crowded with mitochondria that were much smaller than those of brown adipocytes. Their gene expression profile revealed striking up-regulation of peroxisome proliferator-activated receptor gamma coactivator 1alpha (an up-regulator of mitochondrial biogenesis not normally expressed in white fat), increased uncoupling proteins-1 and -2, and down-regulation of lipogenic enzymes. Phosphorylation of both acetyl CoA carboxylase and AMP-activated protein kinase was increased, thus explaining the increase in fatty acid oxidation. The ability to transform adipocytes into unique fat-burning cells may suggest novel therapeutic strategies for obesity.

Topics: Adenoviridae; Adipocytes; Adipose Tissue; Animals; Biomarkers; Gene Expression Regulation; Hyperlipidemias; Leptin; Lipid Metabolism; Mitochondria; Oxidants; Oxidation-Reduction; Rats; Rats, Zucker; RNA, Messenger; Transcription Factors

Obesity is characterized by whole-body insulin resistance, yet the expression of many insulin-stimulated genes, including leptin, is elevated in obesity. These observations suggest that insulin resistance may depend on tissue type and gene. To address this hypothesis, we examined the regulation of immediate-early gene expression in liver and adipose tissue after injection of insulin and glucose, in lean insulin-sensitive, and in A(y)/a obese insulin-sensitive and obese insulin-resistant mice. Expression of hepatic jun-B mRNA was robustly increased after insulin injection in lean insulin-sensitive a/a mice and insulin-sensitive A(y)/a mice. In contrast, induction of hepatic jun-B and c-fos gene expression by insulin was markedly attenuated in obese insulin-resistant mice. Surprisingly, induction of adipose jun-B and c-fos gene expression by insulin was markedly enhanced in obese insulin-resistant mice. Furthermore, the expressions of jun-B and leptin were also enhanced in insulin-resistant mice after injection of glucose. Leptin mRNA was positively correlated with blood glucose levels and jun-B mRNA in lean but not insulin-resistant mice. Multiple regression analysis indicated that the correlation between leptin mRNA and jun-B mRNA was significant even after removing the effect of blood glucose, but the correlation between leptin mRNA and glucose was no longer significant after removing the effect of jun-B mRNA. These data suggest that some impairments in biosynthetic responses to insulin are manifest primarily in the liver, leading to hyperinsulinemia and stimulating the expression of some adipose insulin-stimulated genes, including leptin. These studies demonstrate the utility of immediate-early gene expression in the analysis of biosynthetic mechanisms of insulin resistance.

Topics: Adipose Tissue; Animals; Female; Gene Expression; Genes, Immediate-Early; Glucose; Hyperlipidemias; Insulin; Insulin Resistance; Leptin; Liver; Male; Mice; Mice, Obese; Obesity; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun

The phospholipid scramblases (PLSCR1 to PLSCR4) are a structurally and functionally unique class of proteins, which are products of a tetrad of genes conserved from Caenorhabditis elegans to humans. The best characterized member of this family, PLSCR1, is implicated in the remodeling of the transbilayer distribution of plasma membrane phospholipids but is also required for normal signaling through select growth factor receptors. Mice with targeted deletion of PLSCR1 display perinatal granulocytopenia due to defective response of hematopoietic precursors to granulocyte colony-stimulating factor and stem cell factor. To gain insight into the biologic function of another member of the PLSCR family, we investigated mice with targeted deletion of PLSCR3, a protein that like PLSCR1 is expressed in many blood cells but which, by contrast to PLSCR1, is also highly expressed in fat and muscle. PLSCR3(-/-) mice at 2 months of age displayed aberrant accumulation of abdominal fat when maintained on standard rodent chow, which was accompanied by insulin resistance, glucose intolerance, and dyslipidemia. Primary adipocytes and cultured bone-marrow-derived macrophages from PLSCR3(-/-) mice were engorged with neutral lipid, and adipocytes displayed defective responses to exogenous insulin. Plasma of PLSCR3(-/-) mice was elevated in non-high-density lipoproteins, cholesterol, triglycerides, nonesterified fatty acids, and leptin, whereas adiponectin was low. These data suggest that the expression of PLSCR3 may be required for normal adipocyte and/or macrophage maturation or function and raise the possibility that deletions or mutations affecting the PLSCR3(-/-) gene locus may contribute to the risk for lipid-related disorders in humans.

Topics: Adiponectin; Adipose Tissue; Animals; Carrier Proteins; Cells, Cultured; Glucose; Hematopoietic Stem Cells; Hyperlipidemias; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Membrane Proteins; Mice; Phospholipid Transfer Proteins; Phospholipids; Proteins

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

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

Orlistat is an inhibitor of lipase which splits triglycerides into free fatty acides and glycerol. This drug, by inhibiting hydrolysis of triglycerides, is the cause of significant loss of fat in the faeces. 13 obese and 15 nonobese subjects were examined. Obese subjects received orlistat (Xenical, F. Hoffmann La Roche Ltd, Switzerland) 3 x 120 mg/d. Treatment with orlistat for 16 weeks was followed by a significant fall of BMI and MAP, insulinemia, insulin/glucose ratio, leptinemia, serum total cholesterol, triglycerides, HDL-cholesterol and 25-OH-D concentration respectively. Orlistat did not influence significantly serum LDL-cholesterol concentration but unexpectedly increased plasma levels of folic acid, vitamin B12 and NPY.. (1) Monitoring of plasma 25-OH-D levels in obese patients on orlistat therapy seems to be mandatory. (2) In spite of significant changes (in opposite direction) in leptinemia and serum NPY level observed in obese subjects treated with orlistat, presence of a functional relationship between these hormones could not be confirmed.

Topics: Adult; Anti-Obesity Agents; Blood Glucose; Carbohydrates; Case-Control Studies; Cholesterol, HDL; Cholesterol, LDL; Enzyme Inhibitors; Female; Hormones; Humans; Hypercholesterolemia; Hyperlipidemias; Insulin; Lactones; Leptin; Lipase; Lipids; Male; Neuropeptide Y; Obesity; Orlistat; Poland; Time Factors; Treatment Outcome; Triglycerides; Vitamins; Weight Loss

Topics: Animals; Cholesterol; Hyperlipidemias; Leptin; Male; Mice; Mice, Inbred Strains

To explore the links between tumor necrosis factor alpha (TNFalpha) and leptin adipose tissue expression and low-grade systemic inflammation and to determine the relationship between inflammation and the degree of adiposity, the presence of type 2 diabetes, and other cardiovascular risk factors.. Ninety-one women (BMI 19 to 65 kg/m(2)) were divided into tertiles of CRP. Insulin resistance was calculated using the HOMA method. Albumin, fibrinogen, C-reactive protein (CRP), interleukin-6, sTNFR1, sTNFR2, and leptin levels were measured in serum and plasma samples. TNFalpha and leptin expression were measured by reverse transcription-polymerase chain reaction in abdominal subcutaneous adipose tissue samples.. CRP was positively related to BMI and upper distribution of adiposity. TNFalpha and leptin adipose tissue expression were higher in the upper tertile of CRP. Also, peripheral levels of both soluble TNFRs and leptin were higher in patients with the greatest inflammation degree. Diabetes, dislipidemia, and hypertension were most prevalent in patients in the upper CRP tertile. Inflammatory markers of diabetic women were significantly different from those of nondiabetic women, even after adjusting for differences in body fat. BMI, type 2 diabetes, and adipose TNFalpha mRNA levels were significant predictors of serum CRP levels (r(2) = 0.28, p < 0.001).. These results are in agreement with the hypothesis that the synthesis of adipose tissue TNFalpha and leptin could induce the production of interleukin-6, CRP, and other acute-phase reactants, thus contributing to the maintenance of chronic low-grade inflammation state involved in the progression of obesity and its associated comorbidities.

Topics: Adipose Tissue; Adult; Antigens, CD; Body Composition; Body Mass Index; C-Reactive Protein; Diabetes Mellitus, Type 2; Female; Gene Expression; Humans; Hyperlipidemias; Hypertension; Inflammation; Insulin Resistance; Interleukin-6; Leptin; Leukocyte Count; Receptors, Leptin; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; RNA, Messenger; Tumor Necrosis Factor-alpha

A major complication associated with the use of protease inhibitors (PIs) in treatment of HIV-infected patients is lipid abnormalities including dyslipidemia, lipodystrophy, and liver steatosis. Previous studies revealed that these abnormalities are associated with PI-induced accumulation of activated sterol regulatory element binding proteins (SREBPs) in the nucleus of liver and adipose tissues, resulting in constitutive activation of lipid metabolism genes. This study used the mouse model to determine the potential of polyunsaturated fatty acid (PUFA) diet or leptin replacement therapy to alleviate these PI-induced metabolic abnormalities. Results showed that feeding C57BL/6 mice with a PUFA-rich diet failed to normalize plasma cholesterol and triglyceride levels in ritonavir-treated mice. The PUFA-rich diet also had no effect on ritonavir-induced interscapular fat accumulation and liver steatosis. In contrast, daily administration of leptin significantly reversed the elevated plasma cholesterol level induced by ritonavir. Leptin replacement therapy also significantly reduced the ritonavir-induced interscapular fat mass and improved liver steatosis. Taken together, these data suggest that PI-induced lipid abnormalities, especially dyslipidemia, lipodystrophy, and liver steatosis, may be reduced with leptin replacement therapy.

Topics: Adipose Tissue; Animals; Azo Compounds; CCAAT-Enhancer-Binding Proteins; Cholesterol; Coloring Agents; Disease Models, Animal; DNA-Binding Proteins; Fat Necrosis; Fatty Acids, Unsaturated; HIV Protease Inhibitors; Hyperlipidemias; Leptin; Lipid Metabolism; Lipids; Lipodystrophy; Liver; Male; Mice; Mice, Inbred C57BL; Organ Size; Ritonavir; Sterol Regulatory Element Binding Protein 1; Transcription Factors; Triglycerides

Although recent evidence suggests that leptin can directly regulate a wide spectrum of peripheral functions, including fat metabolism, genetic examples are still needed to illustrate the physiological significance of direct actions of leptin in a given peripheral tissue. To this end, we used a technical knock-out approach to reduce the expression of leptin receptors specifically in white adipose tissue. The evaluation of leptin receptor reduction in adipocytes was based on real time PCR analysis of the mRNA levels, Western blot analysis of the proteins, and biochemical analysis of leptin signaling capability. Despite a normal level of leptin receptors in the hypothalamus and normal food intake, mutant mice developed increased adiposity, decreased body temperature, hyperinsulinemia, hypertriglyceridemia, impaired glucose tolerance and insulin sensitivity, as well as elevated hepatic and skeletal muscle triglyceride levels. In addition, a variety of genes involved in regulating fat and glucose metabolism were dysregulated in white adipose tissue. These include tumor necrosis factor-alpha, adiponectin, leptin, fatty acid synthase, sterol regulatory element-binding protein 1, glycerol kinase, and beta3-adrenergic receptor. Furthermore, the mutant mice are significantly more sensitive to high fat feeding with regard to developing obesity and severe insulin resistance. Thus, we provide a genetic model demonstrating the physiological importance of a peripheral effect of leptin in vivo. Importantly, this suggests the possibility that leptin resistance at the adipocyte level might be a molecular link between obesity and type 2 diabetes.

Topics: Adipocytes; Adipose Tissue; Animals; Base Sequence; Blotting, Western; Body Temperature; Dose-Response Relationship, Drug; Fatty Acids, Nonesterified; Female; Gene Expression Regulation; Genotype; Glucose; Glucose Tolerance Test; Hyperlipidemias; Hypothalamus; Insulin Resistance; Leptin; Liver; Male; Mice; Mice, Mutant Strains; Mice, Transgenic; Models, Genetic; Molecular Sequence Data; Muscle, Skeletal; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Antisense; RNA, Messenger; Temperature; Time Factors; Tissue Distribution; Transgenes; Triglycerides

Obesity is an important risk factor of atherosclerosis; however, the mechanism of proatherogenic effect of obesity is not definitely established. Recent studies suggest an important role of leptin in obesity associated complications. We investigated the effect of chronic hyperleptinemia on two antioxidant enzymes contained in plasma lipoproteins: paraoxonase 1 (PON1) and platelet activating factor-acetylhydrolase (PAF-AH). The study was performed on three groups of male Wistar rats: (1) control, fed ad libitum, (2) leptin treated, receiving leptin (0.25 mg/kg twice daily s.c. for 7 days), (3) pair-fed, in which food intake was identical as in leptin-treated animals. PON1 activity toward paraoxon, phenyl acetate, gamma-decanolactone and homogentisic acid lactone was lower in leptin-treated than in control group by 30.4, 30.8, 34.5 and 62%, respectively. Leptin increased plasma concentration and urinary excretion of isoprostanes by 46.4 and 49.2%, respectively. Leptin treatment had no effect on plasma lipid profile and glucose level. Plasma leptin was 208.8% higher in leptin-treated and 51.5% lower in pair-fed than in control group. These data indicate that hyperleptinemia induced by exogenous leptin administration markedly decreases plasma PON1 activity and induces oxidative stress. These mechanisms may be involved in atherogenesis in hyperleptinemic obese individuals.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Animals; Antimetabolites, Antineoplastic; Antioxidants; Aryldialkylphosphatase; Biomarkers; Cholinesterase Inhibitors; Chronic Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Hyperlipidemias; Isoprostanes; Lactones; Leptin; Male; Models, Cardiovascular; Oxidative Stress; Paraoxon; Phenylacetates; Rats; Rats, Wistar; Statistics as Topic

Obesity is known to predispose individuals to liver disease by increasing hepatic sensitivity to endotoxin. The aim of the present study was to determine the effect of mouse recombinant leptin on food intake, body weight, hepatic and plasma lipids and lipoproteins in alcohol-induced liver injury.. Male Swiss mice weighing 28-32 g were administered ethanol (6.32 g x kg(-1) body weight, p.o.) for the first 30 days. Subsequently, ethanol-fed mice were given intraperitoneal injections of exogenous leptin (230 microg x kg(-1) body weight, i.p.) every alternate day for 15 days. At the end of the total experimental period of 45 days, plasma concentrations of total cholesterol, free fatty acids, triglycerides, lipoprotein lipase and lipoproteins were measured.. Exogenous leptin injections to alcohol-fed mice significantly (P<0.05) inhibited the rise in hepatic and plasma lipid and lipoprotein concentrations as compared with those of the unsupplemented ethanol fed mice. Food intake and average body weight at the end of the experimental period was significantly decreased on leptin administration.. Chronic administration of exogenous mouse recombinant leptin prevents the rise in lipids and lipoprotein concentrations significantly in an animal model of alcohol-induced hyperlipidemia.

Topics: Administration, Oral; Alcohol-Induced Disorders; Animals; Body Weight; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cholesterol, VLDL; Disease Models, Animal; Eating; Ethanol; Fatty Acids, Nonesterified; Hyperlipidemias; Injections, Intraperitoneal; Leptin; Lipoprotein Lipase; Liver; Male; Mice; Triglycerides

Obesity is associated with many comorbid conditions including diabetes, hyperlipidemia, and gallstones. However, the interaction among these modalities remains unclear. We recently demonstrated that both leptin-deficient and leptin-resistant obese mice have impaired biliary motility. These obese mice also are diabetic and hyperlipidemic. Therefore, we tested the hypothesis that serum glucose, insulin, cholesterol, and triglyceride levels would correlate with gallbladder contractility. Thirty-four lean control, 10 lean heterozygous leptin-deficient, 18 obese homozygous leptin-deficient, and 12 obese homozygous leptin-resistant mice were fed a nonlithogenic chow diet while nine lean control and nine obese homozygous leptin-deficient mice were fed a high-cholesterol diet for 4 weeks. In vitro gallbladder responses to cholecystokinin (CCK; 10(-8) mol/L), acetylcholine (ACh; 10(-5) mol/L), and neuropeptide Y (NPY; 10(-6) mol/L) were measured. Serum glucose, insulin, cholesterol, and triglyceride levels were measured from pooled serum from an additional 704 animals. Gallbladder responses were greatest for CCK, intermediate for ACh, and least for NPY. Serum glucose, insulin, cholesterol, and triglyceride levels and body weight all correlated similarly, negatively, and significantly (P<0.001) with gallbladder contractility. Hyperglycemia, insulin-resistance, hyperlipidemia, and body weight in obese mice with leptin dysfunction are associated with poor gallbladder contractility, which in turn may contribute to the association between obesity and gallstone formation.

Topics: Animals; Blood Glucose; Cholesterol; Diabetes Complications; Diabetes Mellitus; Gallbladder Emptying; Humans; Hyperlipidemias; Insulin; Leptin; Mice; Obesity; Triglycerides

The highly effective antibody has been obtained by immunizing rabbits with recombinant leptin many times. The leptin is iodinated with the chloramine-T method and purified with a Sephadex-G25 chromatography column. The reaction between antigen and antibody is carried out by a one-step balance method and cultured at 4 degrees C for 24 h; the binding and free antigen was then separated by PR reagent. The determining range of this method is about 0.5-24 ng/mL; limited detection level is 0.45 ng/mL, relative standard deviation in a group, and among groups, are less than 5.4% and 8%, respectively. The level of blood leptin in 277 samples of normal persons, in 112 samples of overweight persons (weight/hieght m2 > or = 25) and 224 samples of hyperlipidemic patients have been measured by this method. It is demonstrated that the level of blood leptin in males is much lower than that of the females, and becomes elevated with increased age. Serum leptin level in overweight persons and hyperlipidemic patients is also much higher than that of normal groups (P < 0.01). Serum leptin of 21 workers in our lab at 8:00 AM and 4:00 PM has been tested. It was found that there are no differences between the two time points. The same results are obtained within age groups. Leptin levels of pregnant women's serum is higher than those of the control group (P < 0.001). Leptin in newborn's serum is significantly lower than those of mothers (P < 0.01). There is no obvious correlation between leptin level of mother and newborns by correlation analysis (r = 0.19, P > 0.05). The body weight and body weight index of pregnant women are well correlated with their serum leptin levels (r = 0.33 and 0.35, P < 0.05). The body weight and body weight index of newborns are well correlated with their serum leptin levels (r = 0.54 and 0.49, P < 0.001). The serum leptin level of pregnant women is not correlated with newborn's body weight (r = 0.10). These results have shown that the proposed method is stable, simple, and specific, being sensitive enough to determine leptin levels in human serum or plasma.

Topics: Adolescent; Adult; Age Factors; Aged; Animals; Body Weight; Case-Control Studies; Circadian Rhythm; Female; Humans; Hyperlipidemias; Immune Sera; Infant, Newborn; Leptin; Male; Middle Aged; Obesity; Pregnancy; Rabbits; Radioimmunoassay; Reproducibility of Results; Sensitivity and Specificity

Topics: Alcohols; Animals; Apolipoproteins E; Arteriosclerosis; Biomarkers; Carbohydrate Metabolism; Cardiovascular Diseases; Dietary Fats, Unsaturated; Fatty Acids, Omega-3; Feeding Behavior; Fish Oils; Flavonoids; Garlic; Genes; Glycine max; Health Education; Homocysteine; Humans; Hyperlipidemias; Insulin Resistance; Leptin; Life Style; Lipid Metabolism; Nutritional Physiological Phenomena; Obesity; Phenols; Polymers; Polyphenols; Probiotics

:We present a novel method of scanning for intra-abdominal fat volume by helical computed tomography (CT), and describe the clinical significance of measuring the volumes of intra-abdominal visceral fat (V(vol)) and subcutaneous fat (S(vol)) vs these respective areas determined by conventional slice-by-slice CT at the umbilical level.. Subjects with obesity or hyperlipidemia (79 men, 74 women) were recruited for this study. We obtained helical CT scans with a tube current of 150 mA, voltage of 120 kV and 2:1 pitch (table speed in relation to slice thickness), starting at the upper edge of the liver and continuing until the pelvis. The intra-abdominal visceral fat volume was measured by drawing a line within the muscle wall surrounding the abdominal cavity. The abdominal subcutaneous fat volume was calculated by subtracting the visceral fat volume from the total abdominal fat volume. By comparison, the intra-abdominal visceral and subcutaneous fat areas were determined at the umbilical level by the established slice-by-slice CT scanning technique.. V(vol) was correlated positively with visceral fat area (V(area)) measured by conventional CT in both genders (in men (n=79) V(vol) vs V(area), r=0.81 P<0.0001; in women (n=74) V(vol) vs V(area), r=0.85, P<0.0001). S(vol) also showed a positive correlation with subcutaneous fat area (S(area)) in both genders (in men (n=78) S(vol) vs S(area), r=0.95, P<0.0001; in women (n=74) S(vol) vs S(area), r=0.92, P<0.0001).. We have reported a novel method for measuring intra-abdominal fat volume by the use of helical CT.

Topics: Abdomen; Adipose Tissue; Adult; Aged; Body Composition; Body Mass Index; Cholesterol, HDL; Female; Humans; Hyperlipidemias; Leptin; Lipids; Male; Middle Aged; Obesity; Sensitivity and Specificity; Sex Characteristics; Tomography, X-Ray Computed; Triglycerides; Viscera

Topics: Alanine Transaminase; Aspartate Aminotransferases; Body Mass Index; Child; Child Welfare; Child, Preschool; Cholesterol, LDL; Dermatitis, Atopic; Fatty Liver; Humans; Hyperlipidemias; Immunoglobulin E; Immunoglobulin G; Infant; Infant Welfare; Leptin; Male

The spontaneously hypertensive/NIH-corpulent (SHR/N-cp) rat is a genetic animal model that exhibits obesity, metabolic features of hyperinsulinemia, hyperglycemia, and hyperlipidemia, which are characteristic of type II diabetes and mild hypertension. To determine the role of leptin, the protein product of the ob gene, in the development of obesity and diabetes in this model, we measured steady-state circulating levels of leptin in obese and lean SHR/N-cp rats and examined the relation between plasma leptin levels and metabolic variables at the stage of established obesity in these animals. Mean fasting plasma leptin concentration was 8-fold higher in obese than in lean rats (p < 0.01). This was associated with a 6-fold elevation in plasma insulin in the obese group. Fasting levels of plasma glucose, cholesterol, and triglyceride were all significantly higher in obese rats than in lean controls. Spearman correlation analysis showed a significant positive correlation between plasma leptin concentration and body weight among the animals (r = 0.73, p < 0.01). Similarly, plasma insulin concentration was significantly correlated with BW in all animals (r = 0.54, p < 0.05). There was also a significant positive correlation between plasma leptin and plasma insulin in the entire group (r = 0.70, p < 0.01). However, this relationship was significant only for lean rats but not for obese rats (r = 10.59, p < 0.05 for lean rats, and r = 0.23, p = NS, for obese rats). Plasma leptin also correlated positively with fasting plasma glucose (r = 0.75, p < 0.05), total cholesterol (r = 0.63, p < 0.05), and triglyceride (r = 0.67, p < 0.05). The marked elevation of plasma leptin in obese SHR/N-cp rats suggests that obesity in this animal model is related to up-regulation of the ob gene. Circulating leptin appears to be one of the best biological markers of obesity and that hyperleptinemia is closely associated with several metabolic risk factors related to insulin resistance in the diabesity syndrome.

Topics: Analysis of Variance; Animals; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Type 2; Disease Models, Animal; Hyperinsulinism; Hyperlipidemias; Insulin; Leptin; Male; Obesity; Rats; Rats, Inbred SHR; Reference Values

Obesity, type II diabetes, hypertension, and dyslipidemia are major causes of morbidity and mortality throughout the world. Though these disorders often cluster in individuals and families and are collectively known as syndrome X, the basis for this aggregation is not well understood. To further understand the pathogenesis of syndrome X, a comprehensive epidemiological study was undertaken on the Pacific Island of Kosrae, Federated States of Micronesia (FSM).. The entire adult (>20 years of age) population of Kosrae underwent a clinical evaluation that included a questionnaire that noted the participants' sex, family data including listing of biological parents, siblings, and children, smoking status, village of residence, age and health status. The medical evaluation included: anthropometric measures (weight, height, waist, hip), serum chemistries (leptin, fasting blood sugar (FBS), insulin, total cholesterol (TC), triglycerides (TG), and apolipoproteins B and A-I (apo B and apo A-I) and blood pressure (BP) measurements.. Obesity (BMI >/=35) was found in 24%, diabetes (FBS >/=126 or 2-hour oral glucose tolerance test >/=200) in 12%, hypertension (SBP >/=140 or DBP >/=90) in 17%, and dyslipidemia (TC >/=240 or TG >/=200 or apo B >/=120 or apo A-I

Topics: Adult; Apolipoprotein A-I; Apolipoproteins B; Blood Glucose; Blood Pressure; Cholesterol; Diabetes Mellitus, Type 2; Factor Analysis, Statistical; Female; Humans; Hyperlipidemias; Hypertension; Insulin; Insulin Resistance; Leptin; Male; Micronesia; Middle Aged; Obesity; Risk Factors; Triglycerides

Topics: Animals; Chemical and Drug Induced Liver Injury; Diabetes Mellitus; Hyperlipidemias; Hypoglycemic Agents; Insulin Resistance; Leptin; Lipids; Obesity; Societies, Medical; Thiazoles

This study investigated the relationship of plasma leptin to obesity, diabetes and hyperlipidaemia in Asian Northern Indian subjects, considered to have a predisposition to abdominal obesity and metabolic syndrome. A total of 72 subjects, subcategorised into lean and obese healthy subjects, lean and obese Type 2 diabetic and lean and obese non-diabetic hyperlipidaemic subjects were recruited. High leptin values were observed in all obese groups, and obese diabetic patients showed the highest levels. In lean and obese diabetic subjects, plasma leptin did not show any correlation to any index of glycaemia. When all lean and all obese subjects were analysed in two separate groups, body mass index (BMI), percent total body fat, and body density significantly correlated with the plasma leptin levels (p<0.05). Leptin values, when correlated to all variables in all patients taken together, showed the greatest magnitude of correlation with BMI (r=0.64), percent total body fat (r=0.67), and waist circumference (r=0.51). Strong inverse correlation was seen with body density (r=-0.67). Levels of serum insulin did not show any correlation with leptin levels in all subjects combined, and separately in various groups. Multiple linear regression analysis performed in obese, non-diabetic and normolipidaemic subjects, all Type 2 diabetic and all non-diabetic hyperlipidaemic subjects separately showed that percent total body fat is the only significant predictor of plasma leptin concentration in all the 3 groups. The present study suggests that plasma leptin has a strong positive correlation with percent total body fat in Asian Northern Indian subjects. Among other components of metabolic syndrome, only abdominal obesity is weakly correlated to serum leptin levels.

Topics: Adipose Tissue; Adult; Anthropometry; Asia; Body Composition; Body Mass Index; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Genetic Predisposition to Disease; Humans; Hyperlipidemias; India; Leptin; Male; Middle Aged; Obesity

In order to examine a possible detrimental effect of hyperleptinemia on the reproductive system, we examined whether a decrease in circulating leptin levels by fasting affects the estradiol/progesterone-induced luteinizing hormone (LH) and prolactin (PRL) surges in genetically obese OLETF (Otsuka-Long-Evans-Tokushima-Fatty) rats. Experiments were performed on both normally fed and 3-day starved groups from ovariectomized OLETF rats and their controls LETO (Long-Evans-Tokushima-Otsuka). Starved LETO rats, whose leptin levels were less than 0.5 ng/ml, did not show a significant surge of either LH or PRL. Normally fed OLETF rats, whose leptin levels were 9.7 +/- 1.8 ng/ml, showed a significant but small surge for both LH and PRL. Interestingly, starved OLETF rats, whose leptin levels (4.1 +/- 0.7 ng/ml) were similar to those in normally fed LETO rats (3.3 +/- 0.4 ng/ml), had significantly greater surges of both hormones than normally fed OLETF group. This study demonstrates for the first time that the normalization of circulating leptin levels in female OLETF rats augments the steroid-induced LH and PRL surges, and also suggests a deleterious effect of hyperleptinemia on the reproductive axis.

Topics: Animals; Eating; Fasting; Female; Hyperlipidemias; Leptin; Luteinizing Hormone; Obesity; Ovariectomy; Prolactin; Rats; Rats, Inbred OLETF; Rats, Long-Evans; Reproduction

Because female sex protects against dyslipidaemia and atherosclerosis in normal subjects, we aimed to reveal potential sex differences in metabolic side-effects of a newly initiated highly active antiretroviral therapy (HAART) regimen, and to relate these changes to endothelial cell activation as measured by levels of circulating E-selectin (cE-selectin).. Prospective longitudinal cohort study.. Tertiary care centre at a University Hospital.. HIV-seropositive male (n = 27) and female patients (n = 13) with a plasma viral load of > or = 10 000 copies/ml and 35 healthy controls were enrolled in the study. All participants were weight stable, free of acute opportunistic infections, and had not taken any protease inhibitors before. Serum levels of lipids, insulin, leptin, and cE-selectin were measured before initiation of HAART, and at 3 and 6 months thereafter.. HAART increased serum levels of triglycerides, leptin, and low-density lipoprotein (LDL) cholesterol; these effects were more distinct in women. Fasting insulin levels and the LDL : high density lipoprotein (HDL) ratio increased only in female HIV-infected patients (P < 0.02 versus men). In contrast, endothelial activation, as measured by cE-selectin, decreased more in men (P < 0.02) than in women. As a consequence, women had higher triglycerides and leptin levels after therapy than did men, and the LDL : HDL ratio and cE-selectin levels, which were initially higher in men, were no longer different between the sexes.. Metabolic adverse effects during HAART are more pronounced in women than in men. Hence, female HIV-infected patients seem to loose part of their natural protection from atherosclerosis during antiretroviral therapy.

Topics: Adult; Antiretroviral Therapy, Highly Active; Body Composition; Body Weight; CD4 Lymphocyte Count; E-Selectin; Endothelium, Vascular; Female; HIV Infections; Humans; Hyperlipidemias; Insulin; Leptin; Lipids; Male; Middle Aged; Prospective Studies; Sex Factors; Viral Load

In males, aging, health and disease are processes that occur over physiologic time and involve a cascade of hormonal, biochemical and physiological changes that accompany the down-regulation of the hypothalamic-anterior pituitary-testicular axis. As aging progresses there are relative increases of body fat and decreases in muscle mass. The increased adipose tissue mass is associated with the production of a number of newly generated factors. These include aromatase, leptin, PAI-1, insulin resistance, and the dyslipidemias, all of which can lead to tissue damage. Fatty tissue becomes the focal point for study as it represents the intersection between energy storage and mobilization. The increase in adipose tissue is associated with an increase in the enzyme aromatase that converts testosterone to estradiol and leads to diminished testosterone levels that favor the preferential deposition of visceral fat. As the total body fat mass increases, hormone resistance develops for leptin and insulin. Increasing leptin fails to prevent weight gain and the hypogonadal-obesity cycle ensues causing further visceral obesity and insulin resistance. The progressive insulin resistance leads to a high triglyceride-low HDL pattern of dyslipidemia and increased cardiovascular risk. All of these factors eventually contribute to the CHAOS Complex: coronary disease, hypertension, adult-onset diabetes mellitus, obesity and/or stroke as permanent changes unfold. Other consequences of the chronic hypogonadal state include osteopenia, extreme fatigue, depression, insomnia, loss of aggressiveness and erectile dysfunction all of which develop over variable periods of time.

Topics: Adipose Tissue; Aging; Aromatase; Body Composition; Bone Diseases, Metabolic; Estradiol; Humans; Hyperlipidemias; Insulin; Leptin; Male; Muscles; Obesity; Testosterone

Topics: Adipocytes; Adiponectin; Animals; Blood Coagulation Disorders; Complement Factor D; Diabetes Mellitus, Type 2; Hormones, Ectopic; Humans; Hyperlipidemias; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Obesity; Proteins; Resistin; Serine Endopeptidases; Triglycerides; Tumor Necrosis Factor-alpha

To investigate how extracorporal cholesterol lowering therapy affects circulating leptin levels in patients with ravenous hunger after treatment and permanent weight gain.. A case report.. 51 y old caucasian male patient with moderate chronic renal failure.. Serum Leptin concentration (RIA, Linco Research Inc, St. Louis, MO, USA), total cholesterol, low density lipoprotein cholesterol, blood glucose levels, calorie intake by food records.. During treatment total cholesterol was reduced by 50%. Serum Leptin levels showed a 42% reduction at the end of treatment, that by far exceeds the physiological diurnal variation. Calorie intake was significantly increased on days of treatment.. We conclude that this artificial reduction in circulating leptin plays an important role in the pathogenesis of ravenous hunger and weight gain under extracorporal cholesterol lowering therapy in this case.

Topics: Blood Glucose; Cholesterol; Cholesterol, LDL; Energy Intake; Humans; Hunger; Hyperlipidemias; Leptin; Male; Middle Aged; Plasmapheresis; Weight Gain

In 1988, Reaven used the term syndrome X to describe a relation between several disorders including hypertension, dyslipidemia, impaired glucose tolerance, obesity, and coronary heart disease. Despite a number of studies dealing with syndrome X, its genetic basis remains poorly understood. Regarding the complexity of this syndrome, it is important to use animal models developing the traits of the disease. Here we show a genetic dissection of syndrome X in the WOKW rat, an animal model of genetically determined syndrome X. We found a major quantitative trait locus (QTL) for glucose metabolism on chromosome 3 and further QTLs influencing obesity and body weight on chromosomes 1 and 5. Genetic determinants of dyslipidemia were mapped to chromosomes 4 and 17. In addition, suggestive linkage for serum insulin was found on chromosome 1 to the region previously shown to be associated with type-1 diabetes mellitus. This is the first study demonstrating independent genetic factors influencing traits of the syndrome X in the rat as well as a possible genetic relationships between syndrome X and diabetes mellitus. Moreover, regarding the close similarities between WOKW rat and human syndrome X, the study could help in a search of genetic factors involved in this complex metabolic disorder in human.

Topics: Animals; Body Mass Index; Body Weight; Cholesterol; Cholesterol, HDL; Chromosome Mapping; Crosses, Genetic; Female; Glucose; Humans; Hyperlipidemias; Insulin Resistance; Leptin; Male; Obesity; Quantitative Trait, Heritable; Rats; Rats, Inbred Strains; Rats, Mutant Strains; Triglycerides

Leptin is a protein hormone produced by adipocytes that reflects the body fat content. The aim of our study was to compare serum leptin levels in randomly selected untreated males and females with hypercholesterolemia and combined hyperlipidemia and in healthy control subjects matched for age and body mass index and to study the relations between leptin and serum lipids and lipoproteins. No statistically significant differences in serum leptin levels were found between the male control group (5.26 +/- 2.81 ng/mL(-1)) and the male group with hypercholesterolemia (8.16 +/- 3.85 ng/mL(-1)) or combined hyperlipidemia (7.51 +/- 4.83 ng/mL(-1)) and between the female control group (13.0 +/- 8.12 ng/mL(-1)) and the female group with hypercholesterolemia (15.36 +/- 8.89 ng/mL(-1)) or combined hyperlipidemia (18.63 +/- 10.15 ng/mL(-1)). Leptin concentration in male group with hypercholesterolemia did not differ significantly from the female control group; in the other male groups, leptin levels were significantly lower than those of the other female groups. Serum leptin levels in all studied groups except for the male group with hypercholesterolemia positively correlated with body mass index. Serum leptin levels correlated negatively with high-density lipoprotein cholesterol in the female group with hypercholesterolemia (r = -0.67, P < 0.01) and the male group with combined hyperlipidemia (r = -0.56, P < 0.01). A positive correlation between serum leptin and high-density lipoprotein cholesterol (r = 0.67, P < 0.01) and between leptin and lipoprotein (a) (r = 0.71, P < 005) was found in female group with combined hyperlipidemia. No other significant relationships between leptin and serum lipids or lipoproteins were found. We conclude that serum leptin levels in patients with hyperlipidemias do not significantly differ from those healthy control subjects matched by age and body mass index.

Topics: Adult; Apolipoproteins E; Body Mass Index; Cholesterol, HDL; Female; Humans; Hypercholesterolemia; Hyperlipidemias; Leptin; Male; Middle Aged; Regression Analysis

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

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

Postprandial hyperlipidemia is frequently accompanied with intra-abdominal visceral accumulation in human subjects. We have found that the decreased lipoprotein lipase (LPL) mass and activity is negatively associated with the amount of visceral fat accumulation. Here, we studied the postprandial hyperlipidemia using the OLETF rat, a model with visceral obesity, in order to clarify the molecular mechanism causing postprandial hyperlipidemia accompanied with visceral obesity. At the same age of 32 weeks, the OLETF rats showed obviously higher plasma leptin, total cholesterol, triglyceride, and HDL-cholesterol levels than the control LETO rats, although the plasma glucose level was not significantly different. Fat-loading test revealed the delayed metabolism of exogenous fat in the OLETF rats compared to the LETO rats, similar to human subjects with visceral obesity. In the obese rats, plasma levels of LPL mass and activities were 60 and 49% of control rats. The expression of LPL gene was decreased in subcutaneous adipose tissues and skeletal muscle of OLETF rats to 40 and 52% compared to those of LETO rats. In OLETF rats, plasma tumor necrosis factor-alpha (TNF-alpha) and insulin levels were increased to 2.0- and 2.3-folds compared to those in control rats. Furthermore, plasma insulin and TNF-alpha levels in OLETF rats were negatively correlated with the expression levels of LPL gene in subcutaneous fat and muscle. These results indicate that decreased LPL mass and activity in the animal model with visceral obesity is possibly caused by decreased expression of LPL gene in tissues mediated by the increased levels of insulin and TNF-alpha. The different expression of LPL gene in tissues associated with the increased levels of insulin and TNF-alpha possibly elucidate the underlying mechanisms involving the postprandial hyperlipidemia observed in visceral obesity.

Topics: Adipose Tissue; Animals; Blood Glucose; Blotting, Northern; Body Weight; Cholesterol; Cholesterol, HDL; Cloning, Molecular; Disease Models, Animal; Diterpenes; Humans; Hyperlipidemias; Insulin; Leptin; Lipoprotein Lipase; Male; Muscle, Skeletal; Obesity; Rats; Rats, Long-Evans; Retinyl Esters; RNA, Messenger; Time Factors; Tissue Distribution; Triglycerides; Tumor Necrosis Factor-alpha; Vitamin A

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

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

To search for novel genes contributing to adiposity in familial combined hyperlipidemia (FCH), a disorder characterized by abdominal obesity, hyperlipidemia and insulin resistance, using a 10cM genome-wide scan.. Plasma leptin and soluble tumor necrosis factor receptor superfamily members 1A and 1B (sTNFRSF1A and sTNFRSF1B, also known as sTNFR1 and sTNFR2) were analyzed as unadjusted and adjusted quantitative phenotypes of adiposity, in addition to body mass index (BMI), in multipoint and single-point analyses. In the second stage of analysis, an important chromosome 1 positional candidate gene, the leptin receptor (LEPR), was studied.. Eighteen Dutch pedigrees with familial combined hyperlipidemia (FCH) (n= 198) were analyzed to search for chromosomal regions harboring genes contributing to adiposity.. Multipoint analysis of the genome scan data identified linkage (log of odds, LOD, 3.4) of leptin levels to a chromosomal region defined by D1S3728 and D1S1665, flanking the leptin receptor (LEPR) gene by approximately 9 and 3 cM, respectively. The LOD score decreased to 1.8 with age- and gender-adjusted leptin levels. Notably, BMI also mapped to this region with an LOD score of 1.2 (adjusted BMI: LOD 0.5). Two polymorphic DNA markers in LEPR and their haplotypes revealed linkage to unadjusted and adjusted BMI and leptin, and an association with leptin levels was found as well. In addition, the marker D8S1110 showed linkage (LOD 2.8) with unadjusted plasma concentrations of soluble TNFRSF1A. BMI gave a LOD score of 0.6. Moreover, a chromosome 10 q-ter locus, AFM198ZB, showed linkage with adjusted BMI (LOD 3.3).. These data provide evidence that a human chromosome 1 locus, harboring the LEPR gene, contributes to plasma leptin concentrations, adiposity and body weight in humans affected with this insulin resistant dyslipidemic syndrome. Novel loci on chromosome 8 and 10 qter need further study.

Topics: Adult; Antigens, CD; Body Mass Index; Carrier Proteins; Chromosome Mapping; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 10; Chromosomes, Human, Pair 8; Female; Genetic Linkage; Genome, Human; Genotype; Humans; Hyperlipidemias; Insulin Resistance; Leptin; Lod Score; Male; Microsatellite Repeats; Middle Aged; Netherlands; Obesity; Phenotype; Receptors, Cell Surface; Receptors, Leptin; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Regression Analysis

Leptin is a peptide hormone that mainly regulates food intake and energy expenditure of human body. A close correlation between serum leptin levels and the percentage of body fat stores is well known. Nonalcoholic steatohepatitis (NASH) is a common disorder which causes serum liver enzyme elevation. In this study, the serum leptin levels were investigated in patients with NASH to determine a possible role in the pathogenesis and in patients with chronic viral hepatitis to ascertain the effect of hepatic inflammation on serum leptin level.. Forty-nine patients (38 men, 11 women) with NASH diagnosed by biopsy, 32 patients with biopsy-proven chronic viral hepatitis (21 men and 11 women), and 30 healthy adults (17 men, 13 women) enrolled in the study. Fasting blood samples were obtained, and serum leptin levels were measured by ELISA. Body mass index (BMI) was calculated for all subjects, and serum insulin, C-peptide, and lipoprotein levels were also detected.. The mean serum leptin levels (+/-SEM) were 6.62 +/- 0.71, 4.24 +/- 1.0, and 4.02 +/- 0.46 ng/ml in NASH, chronic hepatitis, and the control group, respectively. Mean serum leptin level in the NASH group was significantly higher than those in the other groups tested. BMI was also slightly higher in the NASH group when compared to the other groups (26.7 +/- 0.3, 23.7 +/- 0.6, and 24.6 +/- 0.3, respectively). There was a significant correlation between BMI and serum leptin levels when all the subjects were evaluated together (NASH, hepatitis, and control groups, r = 0.337, p = 0.012) but not in the NASH group when evaluated alone (r = 0.238, p = 0.1). Of the predisposing factors for NASH, obesity was observed in 24% of patients and hyperlipidemia in 67%. Serum cholesterol and triglyceride levels were significantly higher in the NASH group than those in controls (p < 0.05). It has been detected that most of these patients consumed high amounts of fat in their dietary habits.. The serum leptin levels were significantly higher in patients with NASH, while they were not affected by chronic hepatitis. This elevation is out of proportion to BMI of these patients and may be related to hyperlipidemia in most. Elevated serum leptin levels, therefore, may promote hepatic steatosis and steatohepatitis.

Topics: Adult; Body Composition; Body Mass Index; Case-Control Studies; Causality; Dietary Fats; Enzyme-Linked Immunosorbent Assay; Fatty Liver; Female; Hepatitis, Viral, Human; Humans; Hyperlipidemias; Leptin; Male; Obesity

The author exposes the present concept of metabolic syndrome X, which is a complex of Type II diabetes, obesity, hypertension and vascular problems. This syndrome has been known for many years, but it has been individualized as such only recently. This is due to the huge importance that obesity is reaching in developed countries, especially in the U.S.A. Today this is a very important health problem. In this work, in addition to the description of the syndrome, which is purely an internal medicine issue, its relation to some women-specific problems is also explained, especially to the so-called polycystic ovary.

Topics: Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Humans; Hyperlipidemias; Hypertension; Insulin Resistance; Leptin; Menopause; Myocardial Ischemia; Obesity; Phenotype; Polycystic Ovary Syndrome; Syndrome

This cross sectional study was undertaken to determine whether serum leptin levels were associated with multiple risk factor (MRF) clustering syndrome. We examined the relationship between serum leptin concentrations and blood pressure (BP), serum lipids levels, calculated insulin resistance (HOMA-ratio) and adiposity among 581 Japanese adult women. The serum leptin was increased in female subjects with systolic (> or =160 mmHg) and diastolic > or =90 mmHg) hypertension compared with the normotensive females (mean+/-SE; 9.3+/-0.5 vs 7.7+/-0.3; 10.2+/-0.6 vs 7.1+/-0.3 ng/ml, both p<0.001). Serum leptin was elevated in those with hyper-cholesterolemia (C; > or =220 mg/dl) and triglyceridemia (TG; > or =150 mg/dl) compared with the normolipidemia (9.4+/-0.4 vs 7.8+/-0.3; 11.7+/-0.6 vs 7.5+/-0.2 ng/ml, both p <0.001). Serum leptin was also elevated in those with adiposity (BMI > or =26.4 kg/m2) and insulin resistance (HOMA-ratio > or =2.5) compared with the normal females (14.8+/-0.7 vs 5.2+/-0.2; 11.3+/-1.1 vs 7.1+/-0.4ng/ml, both p<0.001). Even after adjusting for BMI or percent body fat mass (BFM), leptin levels remained to be elevated significantly in all these diseases. There was a positive correlation between serum leptin and systolic, diastolic BP, TC, TG, BMI, BFM, IRI and HOMA-ratio (r=0.12, p=0.005; r=0.24, p<0.0001; r=0.19, p<0.0001; r=0.35, p<0.0001; r=0.72, p<0.0001; r=0.73, p<0.0001; r=0.47, p< 0.0001; r=0.44, p<0.0001), and a negative correlation with HDL-C levels (r= -0.20, p< 0.0001). These correlations were also observed in leptin levels after adjusting for the BMI or BFM. Multiple regression analysis showed that BFM, HOMA-ratio and TG were significant determinants of leptin concentration before (t=12.6, p<0.0001; t=3.33, p=0.001; t=3.22, p=0.001) and after adjusting for BMI or BFM. These results suggest that because serum leptin levels were elevated in components of MRF clustering syndrome, leptin may have a pathophysiological role in MRF clustering syndrome.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Arteriosclerosis; Blood Pressure; Body Mass Index; Cholesterol; Cross-Sectional Studies; Female; Humans; Hyperlipidemias; Hypertension; Insulin Resistance; Japan; Leptin; Middle Aged; Obesity; Risk Factors; Syndrome; Triglycerides

Insulin resistance is associated with hypertriglyceridemia, low serum high-density lipoprotein cholesterol (HDL-C) concentrations and high serum total cholesterol (TC) to HDL-C ratios. Several reports have demonstrated that either lovastatin or gemfibrozil may favorably lower serum lipid concentrations. However, their effects on insulin sensitivity are unknown. The primary aim of this study was to compare the effects of lovastatin and gemfibrozil on insulin sensitivity and serum leptin concentrations in subjects with high TC/HDL-C ratios. We enrolled 25 nondiabetic patients, similar in terms of age and weight with TC/HDL-C ratios greater than 5. Thirteen subjects were treated with lovastatin 20 mg per day, and 12 received gemfibrozil 300 mg twice per day. Plasma lipids, glucose, and leptin were measured, and a 75-g oral glucose tolerance test (OGTT) and a modified insulin suppression test were performed before and after 3 months of treatment. The study showed the mean plasma TC, low-density lipoprotein cholesterol (LDL-C) concentrations, and TC/HDL-C ratio were significantly reduced in the lovastatin-treated group, but no obvious effects on plasma triglyceride (TG) and HDL-C were noted. In the gemfibrozil group, plasma TG and HDL-C were markedly lowered, but no significantly different effects in other plasma lipids were found. Gemfibrozil did not affect steady-state plasma glucose (SSPG) concentrations, whereas lovastatin significantly increased SSPG concentrations. Neither drug affected the serum leptin concentration during the OGTT. We conclude that lovastatin significantly lowers plasma TC and LDL-C ratio, and TC/HDL-C concentrations and adversely affects insulin sensitivity, while gemfibrozil markedly reduces plasma TG concentrations without altering insulin sensitivity in subjects with high TC/HDL-C ratios.

Topics: Adult; Aged; Anticholesteremic Agents; Blood Glucose; Cholesterol; Cholesterol, HDL; Female; Gemfibrozil; Humans; Hyperlipidemias; Hypolipidemic Agents; Insulin; Leptin; Lovastatin; Male; Middle Aged; Obesity; Proteins

The effects of a serotonin (5-HT) precursor 5-hydroxytryptophan (5-HTP) on serum leptin levels were investigated in mice. 5-HTP dose dependently increased serum leptin levels in mice. Pretreatment of the peripheral aromatic amino acid decarboxylase inhibitor carbidopa suppressed 5-HTP-induced hyperleptinemia. These results suggest that the secretion of leptin may be modified by serotonergic mechanisms.

Topics: 5-Hydroxytryptophan; Animals; Carboxy-Lyases; Drug Interactions; Enzyme Inhibitors; Hyperlipidemias; Leptin; Male; Mice; Time Factors

The SHROB rat is a unique strain with genetic obesity, hypertriglyceridemia, hyperinsulinemia, renal disease with proteinuria, and genetically determined hypertension, characteristics paralleling human Syndrome X. The obese phenotype results from a single homozygous recessive trait, designated faK, and is allelic with the Zucker fatty trait (fa), but of distinct origin. The faK mutation is a premature stop codon in the extracellular domain of the leptin receptor, resulting in a natural receptor knockout. The SHROB are glucose intolerant compared to heterozygous or wild-type SHR, but retain fasting euglycemia even on a high sucrose diet, suggesting that diabetes requires polygenic interaction with additional modifier genes. Insulin-stimulated phosphorylation of tyrosine residues on the insulin receptor and on the associated docking protein IRS-1 are reduced in skeletal muscle and liver compared to SHR, due mainly to diminished expression of insulin receptor and IRS-1 proteins. Despite multiple metabolic derangements and severe insulin resistance, hypertension is not exacerbated in SHROB compared to SHR. Thus, insulin resistance and hypertension are independent in this model. Increased activity of the sympathetic nervous system may be a common factor leading by separate pathways to hypertension and to insulin resistance. We studied the chronic effects of sympathetic inhibition with moxonidine on glucose metabolism in SHROB. Moxonidine (8 mg/kg/day), a selective I1-imidazoline receptor agonist, not only reduced blood pressure but also ameliorated glucose intolerance. Moxonidine reduced fasting insulin by 47% and plasma free fatty acids by 30%. Moxonidine enhanced expression and insulin-stimulated phosphorylation of IRS-1 in skeletal muscle by 74 and 27%, respectively. Thus, central sympatholytic therapy not only counters hypertension but also insulin resistance, glucose tolerance, and hyperlipidemia in the SHROB model of Syndrome X.

Topics: Animals; Anti-Obesity Agents; Carrier Proteins; Disease Models, Animal; Endocrine System; Female; Hyperinsulinism; Hyperlipidemias; Hypertension; Imidazoles; Insulin Receptor Substrate Proteins; Insulin Resistance; Kidney Diseases; Leptin; Male; Obesity; Phenotype; Phosphoproteins; Phosphorylation; Rats; Rats, Mutant Strains; Receptor, Insulin; Receptors, Cell Surface; Receptors, Leptin

Expression of the obese (ob) gene is augmented in the adipose tissue in several rodent models of genetic obesity. In the present study, we examined the ob gene expression in a rodent model of acquired obesity obtained by pure overfeeding of normal rats. Male Sprague-Dawley rats at 8 weeks of age were fed standard diet or high-fat diet. Rats fed high-fat diet developed moderate degree of obesity, hyperglycemia, and hyperlipidemia as compared with rats fed standard diet. Northern blot analysis revealed that the ob gene is expressed abundantly in the adipose tissue obtained from the epididymal, mesenteric, subcutaneous, retroperitoneal, and interscapular fat pads in rats fed standard diet. Expression of the ob gene was augmented in all the adipose tissue examined in rats fed high-fat diet. The present study demonstrates that the ob gene expression is augmented in the adipose tissue in diet-induced obesity, thereby suggesting the pathophysiologic roles of the ob gene in acquired obesity.

Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Body Weight; Dietary Fats; Gene Expression; Hyperglycemia; Hyperlipidemias; Leptin; Male; Obesity; Organ Size; Protein Biosynthesis; Proteins; Rats; Rats, Sprague-Dawley