leptin and Diabetes-Mellitus

Organismal energy balance is controlled by inter-tissue communication mediated by the nervous system and hormones, the disruption of which causes metabolic syndrome exemplified by diabetes and obesity. Fat-storing adipose tissue, especially those located in subcutaneous white adipose tissue, secretes leptin in a proportion of fat mass, inhibiting the accumulation of organismal fat by suppressing appetite and promoting energy expenditure. With a prevalence of obesity that exhibits hyperleptinemia, most of the investigation on leptin has been focused on how it works and how it does not, which is expected to be a clue for treating obesity. In contrast, how it is synthesized, transported, and excreted, all of which are relevant to the homeostasis of blood leptin concentration, are not much understood. Of note, acute leptin reduction after hyperleptinemia in the context of obesity exhibited a beneficial effect on obesity and insulin sensitivity, indicating that manipulation of circulating leptin level may provide a therapeutic strategy. Technological advances such as "omics" analysis combined with sophisticated gene-engineered mice studies in the past decade enabled a deeper understanding of leptin's action in more detail. Here, we summarize the updated understanding of the action as well as regulation of leptin and point out the emerging direction of research on leptin.

Topics: Adipokines; Adipose Tissue; Animals; Diabetes Mellitus; Leptin; Mice; Obesity

Diabetic retinopathy (DR) is a common complication of diabetes. The adipocytokines are closely associated with the occurrence and development of diabetes and its related complications. Literature confirms that the level of adiponectin in patients with DR is significantly higher; however, the relationship between other adipocytokines (leptin, chemerin, apelin, and omentin-1) and DR remains unclear.. This study aimed to systematically evaluate the association between adipocytokines (leptin, chemerin, apelin, and omentin-1) and DR.. The PubMed, Web of Science, Embase, EBSCO and Willy databases were used to search for potential studies with keywords such as "diabetic retinopathy" or "DR" in combination with the terms "leptin," "chemerin", "apelin" or "omentin-1" in the search titles or abstracts. Standardized mean differences (SMD) with corresponding 95% confidence intervals (CIs) were determined as the results of the meta-analysis.. After screening, 18 articles were included in the meta-analysis including 750 DR cases and 993 controls. Leptin and chemerin levels in patients with DR were significantly higher than those in the control group (SMD: 0.68, 95% CI [0.1, 1.26]; SMD: 0.79, 95% CI [0.35, 1.23]). The omentin-1 levels in patients with DR were significantly lower than those in the controls (SMD: -0.85, 95% CI [-1.08, -0.62]).. To the best of our knowledge, this is the first meta-analysis to evaluate the leptin, chemerin, apelin, and omentin-1 levels in patients with DR. Further high-quality studies are warranted to support the association between these adipocytokines and DR.. https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=443770, identifier CRD42023443770.

Topics: Adipokines; Adiponectin; Apelin; Diabetes Mellitus; Diabetic Retinopathy; Humans; Leptin

The central nervous system (CNS) receives information from afferent neurons, circulating hormones, and absorbed nutrients and integrates this information to orchestrate the actions of the neuroendocrine and autonomic nervous systems in maintaining systemic metabolic homeostasis. Particularly the arcuate nucleus of the hypothalamus (ARC) is of pivotal importance for primary sensing of adiposity signals, such as leptin and insulin, and circulating nutrients, such as glucose. Importantly, energy state-sensing neurons in the ARC not only regulate feeding but at the same time control multiple physiological functions, such as glucose homeostasis, blood pressure, and innate immune responses. These findings have defined them as master regulators, which adapt integrative physiology to the energy state of the organism. The disruption of this fine-tuned control leads to an imbalance between energy intake and expenditure as well as deregulation of peripheral metabolism. Improving our understanding of the cellular, molecular, and functional basis of this regulatory principle in the CNS could set the stage for developing novel therapeutic strategies for the treatment of obesity and metabolic syndrome. In this review, we summarize novel insights with a particular emphasis on ARC neurocircuitries regulating food intake and glucose homeostasis and sensing factors that inform the brain of the organismal energy status.

Topics: Arcuate Nucleus of Hypothalamus; Diabetes Mellitus; Energy Metabolism; Glucose; Humans; Hypothalamus; Leptin; Obesity

Whether diabetes and adipokine-driven inflammation explain the association of obesity to cognitive impairment is unknown.. Structural equation models estimated the total effects of waist circumference on cognitive outcomes among African American participants cross-sectionally (index exam) and longitudinally. Total effects were deconstructed into direct pathways of waist circumference to cognitive impairment and indirect mediation pathways through leptin, soluble tumor necrosis factor receptor 2 (sTNFR2), and diabetes. Waist circumference, leptin, and sTNFR2 were standardized. Cognitive impairment was defined as MMSE <21 or a z-score < -1.5 standard deviation (SD). Incident cognitive impairment was defined among those without cognitive impairment at the index exam as follow-up MMSE<21, z- score < -1.5, MMSE decline >1 point/year, or z-score decline of >0.1 SD/year.. Among 1008 participants (70% women, mean age 62.9 years, 14.5% with obesity, 26% with diabetes), 132 (13%) had baseline cognitive impairment. Each SD higher waist circumference was associated with higher odds of cognitive impairment, odds ratio (OR) = 1.63; (95% confidence interval: 1.17, 2.24), with mediating pathways explaining 65% of the total effect (58% from diabetes; 7% from inflammation). At follow-up (mean 6.8 years), 106 of 535 (19.8%) had developed cognitive impairment. Each SD higher waist circumference was associated with higher odds of developing cognitive impairment (OR = 1.87; 95%CI: 1.18, 2.74); the direct effect of waist circumference explained 37% of the total effect and mediating pathways explained 63% (61% from diabetes; 2% from inflammation), although individual pathways were not statistically supported in the smaller sample.. Diabetes, and to a lesser degree, adiposity-driven inflammation, appear to explain a substantial proportion of abdominal adiposity relationships with cognitive impairment. The impact of preventing and treating obesity on cognitive outcomes merits study.

Topics: Adipokines; Adiposity; Black or African American; Body Mass Index; Cognitive Dysfunction; Diabetes Mellitus; Female; Humans; Inflammation; Leptin; Male; Middle Aged; Obesity; Receptors, Tumor Necrosis Factor, Type II; Risk Factors; Waist Circumference

Abdominal aortic aneurysm(AAA) is a chronic dilated artery disease induced by atherosclerosis,infection,trauma and other related causes.The available studies about AAA mainly focus on the inflammatory response,senility,and microenvironmental changes,while the research on the metabolic changes such as glucose metabolism and lipid metabolism remains to be conducted.As a critical regulatory factor in endocrine,glucose,and lipid metabolisms,leptin is associated with a variety of signaling pathways such as adenosine monophosphate-activated protein kinase,Janus kinase/signal transducer and activator of transcription,and cytokine-cytokine receptor,as demonstrated by the KEGG pathway enrichment analysis.Moreover,these signaling pathways are generally involved in regulating the occurrence of AAA.In addition,leptin affects the occurrence of a variety of diseases such as obesity,diabetes,and hyperlipidemia,which contribute to the formation of AAA.Diabetes might be a protective factor for the formation of AAA,while the relationship of hyperlipidemia and obesity with the formation of AAA remains unclear.Therefore,leptin might play an essential role in the formation of AAA.Further studies about the effect of leptin on AAA may provide the potential research direction and facilitate the discovery of therapeutic targets.

Topics: Aorta, Abdominal; Aortic Aneurysm, Abdominal; Diabetes Mellitus; Humans; Leptin; Obesity; Signal Transduction

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

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In obesity, an elevated accumulation and dysregulation of adipose tissue, due to an imbalance between energy intake and energy expenditure, usually coexists with the loss of responsiveness to leptin in central nervous system, and subsequently with hyperleptinemia. Leptin, a peptide hormone mainly produced by white adipose tissue, regulates energy homeostasis by stimulating energy expenditure and inhibiting food intake. Human obesity is characterized by increased plasma leptin levels, which have been related with different obesity-associated complications, such as chronic inflammatory state (risk factor for diabetes, cardiovascular and autoimmune diseases), as well as infertility and different types of cancer. Besides, leptin is also produced by placenta, and high leptin levels during pregnancy may be related with some pathological conditions such as gestational diabetes. This review focuses on the current insights and emerging concepts on potentially valuable nutrients and food components that may modulate leptin metabolism. Notably, several dietary food components, such as phenols, peptides, and vitamins, are able to decrease inflammation and improve leptin sensitivity by up- or down-regulation of leptin signaling molecules. On the other hand, some food components, such as saturated fatty acids may worsen chronic inflammation increasing the risk for pathological complications. Future research into nutritional mechanisms that restore leptin metabolism and signals of energy homeostasis may inspire new treatment options for obesity-related disorders.

Topics: Adipose Tissue; Adipose Tissue, White; Animals; Autoimmune Diseases; Diabetes Mellitus; Energy Intake; Energy Metabolism; Fatty Acids; Female; Humans; Infertility; Inflammation; Leptin; Male; Neoplasms; Nutritional Physiological Phenomena; Obesity

Increasing adipose tissue mass in obesity directly correlates with elevated circulating leptin levels. Leptin is an adipokine known to play a role in numerous biological processes including regulation of energy homeostasis, inflammation, vascular function and angiogenesis. While physiological concentrations of leptin may exhibit multiple beneficial effects, chronically elevated pathophysiological levels or hyperleptinemia, characteristic of obesity and diabetes, is a major risk factor for development of atherosclerosis. Hyperleptinemia results in a state of selective leptin resistance such that while beneficial metabolic effects of leptin are dampened, deleterious vascular effects of leptin are conserved attributing to vascular dysfunction. Leptin exerts potent proatherogenic effects on multiple vascular cell types including macrophages, endothelial cells and smooth muscle cells; these effects are mediated via an interaction of leptin with the long form of leptin receptor, abundantly expressed in atherosclerotic plaques. This review provides a summary of recent in vivo and in vitro studies that highlight a role of leptin in the pathogenesis of atherosclerotic complications associated with obesity and diabetes.

Topics: Animals; Atherosclerosis; Diabetes Mellitus; Endothelial Cells; Humans; Leptin; Macrophages; Myocytes, Smooth Muscle; Obesity

Many approaches have been used in the effective management of type 2 diabetes mellitus. A recent paradigm shift has focused on the role of adipose tissues in the development and treatment of the disease. Brown adipose tissues (BAT) and white adipose tissues (WAT) are the two main types of adipose tissues with beige subsets more recently identified. They play key roles in communication and insulin sensitivity. However, WAT has been shown to contribute significantly to endocrine function. WAT produces hormones and cytokines, collectively called adipocytokines, such as leptin and adiponectin. These adipocytokines have been proven to vary in conditions, such as metabolic dysfunction, type 2 diabetes, or inflammation. The regulation of fat storage, energy metabolism, satiety, and insulin release are all features of adipose tissues. As such, they are indicators that may provide insights on the development of metabolic dysfunction or type 2 diabetes and can be considered routes for therapeutic considerations. The essential roles of adipocytokines vis-a-vis satiety, appetite, regulation of fat storage and energy, glucose tolerance, and insulin release, solidifies adipose tissue role in the development and pathogenesis of diabetes mellitus and the complications associated with the disease.

Topics: Adipokines; Adiponectin; Adipose Tissue; Adipose Tissue, Beige; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Diabetes Complications; Diabetes Mellitus; Energy Metabolism; Humans; Insulin; Insulin Resistance; Leptin; Obesity

Inositol, or myo-inositol, and associated analog molecules, including myo-inositol hexakisphosphate, are known to possess beneficial biomedical properties and are now being widely studied. The impact of these compounds in improving diabetic indices is significant, especially in light of the high cost of treating diabetes mellitus and associated disorders globally. It is theorized that, within ten years, the global population of people with the disease will reach 578 million individuals, with the cost of care projected to be approximately 2.5 trillion dollars. Natural alternatives to pharmaceuticals are being sought, and this has led to studies involving inositol, and myo-inositol-hexakisphosphate, also referred to as IP6. It has been reported that IP6 can improve diabetic indices and regulate the activities of some metabolic enzymes involved in lipid and carbohydrate metabolism. Current research activities have been focusing on the mechanisms of action of inositol and IP6 in the amelioration of the indices of diabetes mellitus. We demonstrated that an IP6 and inositol combination supplement may regulate insulin secretion, modulate serum leptin concentrations, food intake, and associated weight gain, which may be beneficial in both prediabetic and diabetic states. The supplement attenuates vascular damage by reducing red cell distribution width. Serum HDL is increased while serum triglycerides tend to decrease with consumption of the combination supplement, perhaps due to the modulation of lipogenesis involving reduced serum lipase activity. We also noted increased fecal lipid output following combination supplement consumption. Importantly, liver function was found to be preserved. Concurrently, serum reactive oxygen species production was reduced, indicating that inositol and IP6 supplement consumption may reduce free radical damage to tissues and organs as well as serum lipids and blood glucose by preserving liver function. This review provides an overview of the findings associated with inositol and IP6 supplementation in the effective treatment of diabetes with a view to proposing the potential mechanisms of action.

Topics: Animals; Biomarkers; Blood Cell Count; Carbohydrate Metabolism; Diabetes Mellitus; Dietary Supplements; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Inositol; Intestines; Leptin; Lipid Metabolism; Metabolic Networks and Pathways; Phytic Acid; Treatment Outcome

Cardiometabolic diseases are the main contributor of reduced life expectancy in patients with schizophrenia. It is now widely accepted that antipsychotic treatment plays an important role in the development of obesity and its consequences. However, some intrinsic mechanisms need to be taken into consideration. One of these mechanisms might be related to impaired hormonal regulation of appetite in this group of patients. In this narrative review, we aimed to dissect impairments of appetite-regulating hormones attributable to intrinsic mechanisms and those related to medication effects. Early hormonal alterations that might be associated with intrinsic mechanisms include low levels of leptin and glucagon-like peptide-1 (GLP-1) together with elevated insulin levels in first-episode psychosis (FEP) patients. However, evidence regarding low GLP-1 levels in FEP patients is based on one large study. In turn, multiple-episode schizophrenia patients show elevated levels of insulin, leptin and orexin A together with decreased levels of adiponectin. In addition, patients receiving olanzapine may present with low ghrelin levels. Post mortem studies have also demonstrated reduced number of neuropeptide Y neurons in the prefrontal cortex of patients with schizophrenia. Treatment with certain second-generation antipsychotics may also point to these alterations. Although our understanding of hormonal regulation of appetite in schizophrenia has largely been improved, several limitations and directions for future studies need to be addressed. This is of particular importance since several novel pharmacological interventions for obesity and diabetes have already been developed and translation of these developments to the treatment of cardiometabolic comorbidities in schizophrenia patients is needed.

Topics: Antipsychotic Agents; Appetite; Appetite Regulation; Diabetes Complications; Diabetes Mellitus; Ghrelin; Hormones; Humans; Insulin; Leptin; Schizophrenia; Schizophrenic Psychology

Protein tyrosine phosphatases are enzymes which help in the signal transduction in diabetes, obesity, cancer, liver diseases and neurodegenerative diseases. PTP1B is the main member of this enzyme from the protein extract of human placenta. In phosphate inhibitors development, significant progress has been made over the last 10 years. In early-stage clinical trials, few compounds have reached whereas in the later stage trials or registration, yet none have progressed. Many researchers investigate different ways to improve the pharmacological properties of PTP1B inhibitors.. In the present review, authors have summarized various aspects related to the involvement of PTP1B in various types of signal transduction mechanisms and its prominent role in various diseases like cancer, liver diseases and diabetes mellitus.. There are still certain challenges for the selection of PTP1B as a drug target. Therefore, continuous future efforts are required to explore this target for the development of PTP inhibitors to treat the prevailing diseases associated with it.

Topics: Animals; Antineoplastic Agents; Diabetes Mellitus; Drug Design; Drug Evaluation, Preclinical; Enzyme Inhibitors; Female; Forecasting; Humans; Hypoglycemic Agents; Insulin; Leptin; Mice; Models, Molecular; Molecular Targeted Therapy; Neoplasm Proteins; Neoplasms; Neurodegenerative Diseases; Neuroprotective Agents; Placenta; Pregnancy; Protein Conformation; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Signal Transduction

Insulin and leptin are critical metabolic hormones that play essential but distinct roles in regulating the physiologic switch between the fed and starved states. The discoveries of insulin and leptin, in 1922 and 1994, respectively, arose out of radically different scientific environments. Despite the dearth of scientific tools available in 1922, insulin's discovery rapidly launched a life-saving therapy for what we now know to be type I diabetes, and continually enhanced insulin therapeutics are now effectively applied to both major forms of this increasingly prevalent disease. In contrast, although the discovery of leptin provided deep insights into the regulation of central nervous system energy balance circuits, as well as an effective therapy for an extremely rare form of obesity, its therapeutic impact beyond that has been surprisingly limited. Despite an enormous accumulated body of information, many important questions remain unanswered about the mechanisms of action and role in disease of both hormones. Additionally, although many decades apart, both discoveries reveal the complexities inherent to scientific collaboration and the assignment of credit, even when the efforts are spectacularly successful.

Topics: Diabetes Mellitus; Endocrinology; History, 20th Century; Humans; Insulin; Leptin; Obesity

Leptin is an endogenous protein having 167 amino acids and is derived from adipocytes. It has tertiary structure that resembles with that of the pro-inflammatory cytokines family. The fundamental role of leptin is to maintain the energy homeostasis with the aid of its counter hormone called ghrelin, known as the "hunger hormone." Small quantities of leptin are also present in various tissues like ovary, placenta, pituitary gland, mammary gland, skeletal muscle, stomach, and lymphoid tissue. Expression of leptin is strongly associated with various inflammatory responses and immune system, and plays crucial role in the pathophysiology of obesity and development of diabetes mellitus (DM) and insulin resistance. The metabolic action of leptin is equally important as that of insulin in the pathophysiology of obesity and DM. Thereby, this review article tends to discuss the diverse and complicated role of leptin in the pathogenesis of DM. Furthermore, this article will highlight the signifying role of leptin as a therapeutic target by indicating the targeted treatment of DM through the appropriate understanding of advanced therapeutic approaches using leptin as a treatment strategy for DM.

Topics: Diabetes Mellitus; Ghrelin; Humans; Insulin Resistance; Leptin

The hormone leptin is an important regulator of metabolic homeostasis, able to inhibit food intake and increase energy expenditure. Leptin can also independently lower blood glucose levels, particularly in hyperglycemic models of leptin or insulin deficiency. Despite significant efforts and relevance to diabetes, the mechanisms by which leptin acts to regulate blood glucose levels are not fully understood.. Here we assess literature relevant to the glucose lowering effects of leptin. Leptin receptors are widely expressed in multiple cell types, and we describe both peripheral and central effects of leptin that may be involved in lowering blood glucose. In addition, we summarize the potential clinical application of leptin in regulating glucose homeostasis.. Leptin exerts a plethora of metabolic effects on various tissues including suppressing production of glucagon and corticosterone, increasing glucose uptake, and inhibiting hepatic glucose output. A more in-depth understanding of the mechanisms of the glucose-lowering actions of leptin may reveal new strategies to treat metabolic disorders.

Topics: Animals; Blood Glucose; Corticosterone; Diabetes Mellitus; Eating; Energy Metabolism; Glucagon; Glucose; Homeostasis; Humans; Insulin; Insulin Secretion; Leptin; Liver; Receptors, Leptin

Diabetes constitutes an increasing threat to human health, particularly in newly industrialized and densely populated countries. Type 1 and type 2 diabetes arise from different etiologies but lead to similar metabolic derangements constituted by an absolute or relative lack of insulin that results in elevated plasma glucose. In the last three decades, a set of new medicines built upon a deeper understanding of physiology and diabetic pathology have emerged to enhance the clinical management of the disease and related disorders. Recent insights into insulin-dependent and insulin-independent molecular events have accelerated the generation of a series of novel medicinal agents, which hold the promise for further advances in the management of diabetes. In this chapter, we provide a historical context for what has been accomplished to provide perspective for future research and novel emerging treatment options.

Topics: Anti-Obesity Agents; Bariatric Surgery; Diabetes Mellitus; Fibroblast Growth Factors; Glucose; Humans; Hypoglycemic Agents; Leptin; Pancreas Transplantation

Sleep is important for regulating many physiologic functions that relate to metabolism. Because of this, there is substantial evidence to suggest that sleep habits and sleep disorders are related to diabetes risk. In specific, insufficient sleep duration and/or sleep restriction in the laboratory, poor sleep quality, and sleep disorders such as insomnia and sleep apnea have all been associated with diabetes risk. This research spans epidemiologic and laboratory studies. Both physiologic mechanisms such as insulin resistance, decreased leptin, and increased ghrelin and inflammation and behavioral mechanisms such as increased food intake, impaired decision-making, and increased likelihood of other behavioral risk factors such as smoking, sedentary behavior, and alcohol use predispose to both diabetes and obesity, which itself is an important diabetes risk factor. This review describes the evidence linking sleep and diabetes risk at the population and laboratory levels.

Topics: Diabetes Mellitus; Energy Intake; Ghrelin; Humans; Insulin Resistance; Leptin; Obesity; Risk Factors; Sleep; Sleep Wake Disorders

Leptin is an adipose tissue hormone that functions as an afferent signal in a negative feedback loop that maintains homeostatic control of adipose tissue mass. This endocrine system thus serves a critical evolutionary function by protecting individuals from the risks associated with being too thin (starvation) or too obese (predation and temperature dysregulation). Mutations in leptin or its receptor cause massive obesity in mice and humans, and leptin can effectively treat obesity in leptin-deficient patients. Leptin acts on neurons in the hypothalamus and elsewhere to elicit its effects, and mutations that affect the function of this neural circuit cause Mendelian forms of obesity. Leptin levels fall during starvation and elicit adaptive responses in many other physiologic systems, the net effect of which is to reduce energy expenditure. These effects include cessation of menstruation, insulin resistance, alterations of immune function, and neuroendocrine dysfunction, among others. Some or all of these effects are also seen in patients with constitutively low leptin levels, such as occur in lipodystrophy. Leptin is an approved treatment for generalized lipodystrophy, a condition associated with severe metabolic disease, and has also shown potential for the treatment of other types of diabetes. In addition, leptin restores reproductive capacity and increases bone mineral density in patients with hypothalamic amenorrhea, an infertility syndrome in females. Most obese patients have high endogenous levels of leptin, in some instances as a result of mutations in the neural circuit on which leptin acts, though in most cases, the pathogenesis of leptin resistance is not known. Obese patients with leptin resistance show a variable response to exogenous leptin but may respond to a combination of leptin plus amylin. Overall, the identification of leptin has provided a framework for studying the pathogenesis of obesity in the general population, clarified the nature of the biologic response to starvation, and helped to advance our understanding of the neural mechanisms that control feeding.

Topics: Adipose Tissue; Animals; Diabetes Mellitus; Humans; Hypothalamus; Leptin; Lipodystrophy; Mice; Neurons; Obesity; Receptors, Leptin; Starvation

Topics: Acro-Osteolysis; Adipose Tissue; Aging, Premature; Body Composition; Cardiovascular System; Combined Modality Therapy; Diabetes Mellitus; Diet, Carbohydrate-Restricted; Diet, Fat-Restricted; Erythema Nodosum; Fingers; Genes, Dominant; Humans; Hypoglycemic Agents; Insulin; Leptin; Lipodystrophy; Lipodystrophy, Familial Partial; Mandible; Metformin; Musculoskeletal Diseases; Phenotype; Recombinant Proteins; Surgery, Plastic; Werner Syndrome

A variety of leptin actions require a re-examination of classic concepts of metabolic diseases. Here we present evidence for two physiologic pathways: a pathway that protects nonadipose tissues from overaccumulation of potentially toxic lipids and unrecognized paracrine interactions between α and β cells revealed by leptin's ability to suppress diabetic hyperglucagonemia. These observations strongly point to new therapeutic possibilities for both type 1 and type 2 diabetes.

Topics: Animals; Ceramides; Diabetes Mellitus; Glucose; Humans; Leptin; Lipids; Serine C-Palmitoyltransferase

Diabetes and obesity are worldwide health problems. White fat dynamically participates in hormonal and inflammatory regulation. White adipose tissue is recognized as a multifactorial organ that secretes several adipose-derived factors that have been collectively termed "adipokines." Adipokines are pleiotropic molecules that gather factors such as leptin, adiponectin, visfatin, apelin, vaspin, hepcidin, RBP4, and inflammatory cytokines, including TNF and IL-1β, among others. Multiple roles in metabolic and inflammatory responses have been assigned to these molecules. Several adipokines contribute to the self-styled "low-grade inflammatory state" of obese and insulin-resistant subjects, inducing the accumulation of metabolic anomalies within these individuals, including autoimmune and inflammatory diseases. Thus, adipokines are an interesting drug target to treat autoimmune diseases, obesity, insulin resistance, and adipose tissue inflammation. The aim of this review is to present an overview of the roles of adipokines in different immune and nonimmune cells, which will contribute to diabetes as well as to adipose tissue inflammation and insulin resistance development. We describe how adipokines regulate inflammation in these diseases and their therapeutic implications. We also survey current attempts to exploit adipokines for clinical applications, which hold potential as novel approaches to drug development in several immune-mediated diseases.

Topics: Adipokines; Adiponectin; Adipose Tissue; Animals; Diabetes Mellitus; Humans; Inflammation; Interleukin-1beta; Leptin; Mice; Nicotinamide Phosphoribosyltransferase; Obesity; Retinol-Binding Proteins, Plasma; Tumor Necrosis Factor-alpha

This review focuses on seven aspects of physiology and pathophysiology of the exocrine pancreas that have been intensively discussed and studied within the past few years: (1) the role of neurohormonal mechanisms like melatonin, leptin, or ghrelin in the stimulation of pancreatic enzyme secretion; (2) the initiation processes of acute pancreatitis, like fusion of zymogen granules with lysosomes leading to intracellular activation of trypsinogen by the lysosomal enzyme cathepsin B, or autoactivation of trypsinogen; (3) the role of genes in the pathogenesis of acute pancreatitis; (4) the role of alcohol and constituents of alcoholic beverages in the pathogenesis of acute pancreatitis; (5) the role of pancreatic hypertension, neuropathy, and central mechanisms for the pathogenesis of pain in chronic pancreatitis; (6) the relation between exocrine pancreatic function and diabetes mellitus; and (7) pathophysiology, diagnosis and treatment of pancreatic steatorrhea.

Topics: Cathepsin B; Diabetes Mellitus; DNA Mutational Analysis; Ghrelin; Leptin; Melatonin; Pancreas; Pancreatic Juice; Pancreatitis, Acute Necrotizing; Pancreatitis, Alcoholic; Pancreatitis, Chronic; Trypsinogen

Enhancing β-cell proliferation is a major goal for type 1 and type 2 diabetes research. Unraveling the network of β-cell intracellular signaling pathways that promote β-cell replication can provide the tools to address this important task. In a previous Perspectives in Diabetes article, we discussed what was known regarding several important intracellular signaling pathways in rodent β-cells, including the insulin receptor substrate/phosphatidylinositol-3 kinase/Akt (IRS-PI3K-Akt) pathways, glycogen synthase kinase-3 (GSK3) and mammalian target of rapamycin (mTOR) S6 kinase pathways, protein kinase Cζ (PKCζ) pathways, and their downstream cell-cycle molecular targets, and contrasted that ample knowledge to the small amount of complementary data on human β-cell intracellular signaling pathways. In this Perspectives, we summarize additional important information on signaling pathways activated by nutrients, such as glucose; growth factors, such as epidermal growth factor, platelet-derived growth factor, and Wnt; and hormones, such as leptin, estrogen, and progesterone, that are linked to rodent and human β-cell proliferation. With these two Perspectives, we attempt to construct a brief summary of knowledge for β-cell researchers on mitogenic signaling pathways and to emphasize how little is known regarding intracellular events linked to human β-cell replication. This is a critical aspect in the long-term goal of expanding human β-cells for the prevention and/or cure of type 1 and type 2 diabetes.

Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Cell Proliferation; Diabetes Mellitus; ErbB Receptors; Estrogens; Glucose; Humans; Insulin-Secreting Cells; Leptin; NFATC Transcription Factors; Progesterone; Protein Serine-Threonine Kinases; Signal Transduction; Wnt Signaling Pathway

Diabetes afflicts hundreds of millions worldwide. People affected by type 1 diabetes mellitus (T1DM; the insulin-deficient form of diabetes) or type 2 diabetes mellitus (T2DM; the insulin-resistant form of diabetes) have significantly reduced life expectancy compared to normal individuals. This is due in part to the fact that (despite improvements) current anti-diabetic approaches are suboptimal. Indeed, severe morbidities (e.g.: cardiovascular disease, hypertension) are still too often associated with diabetes. Recent preclinical results indicate that different types of hypothalamic neurons are endowed with the ability to mediate the hyperglycemia-lowering action of the adipocyte-derived hormone leptin in an insulin-dependent and insulin-independent fashion. These results may pave the way for better anti-diabetic approaches and therefore positively impact on life expectancy of diabetic subjects.

Topics: Aging; Animals; Diabetes Mellitus; Glucose; Humans; Hypothalamus; Insulin; Leptin

New-onset diabetes has been observed in clinical trials and meta-analyses involving statin therapy. To explain this association, three major mechanisms have been proposed and discussed in the literature. First, certain statins affect insulin secretion through direct, indirect or combined effects on calcium channels in pancreatic β-cells. Second, reduced translocation of glucose transporter 4 in response to treatment results in hyperglycemia and hyperinsulinemia. Third, statin therapy decreases other important downstream products, such as coenzyme Q10, farnesyl pyrophosphate, geranylgeranyl pyrophosphate, and dolichol; their depletion leads to reduced intracellular signaling. Other possible mechanisms implicated in the effect of statins on new-onset diabetes are: statin interference with intracellular insulin signal transduction pathways via inhibition of necessary phosphorylation events and reduction of small GTPase action; inhibition of adipocyte differentiation leading to decreased peroxisome proliferator activated receptor gamma and CCAAT/enhancer-binding protein which are important pathways for glucose homeostasis; decreased leptin causing inhibition of β-cells proliferation and insulin secretion; and diminished adiponectin levels. Given that the magnitude of the risk of new-onset diabetes following statin use remains to be fully clarified and the well-established beneficial effect of statins in reducing cardiovascular risk, statins remain the first-choice treatment for prevention of CVD. Elucidation of the mechanisms underlying the development of diabetes in association with statin use may help identify novel preventative or therapeutic approaches to this problem and/or help design a new generation statin without such side-effects.

Topics: Adipocytes; Adiponectin; Animals; Calcium Channels; Caveolins; Cell Differentiation; Diabetes Mellitus; Dolichols; Glucose Transporter Type 4; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperglycemia; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Ion Channels; Leptin; MicroRNAs; Mitochondrial Proteins; Terpenes; Ubiquinone; Uncoupling Protein 3

Resistant hypertension in diabetes is associated with poor cardiovascular and renal outcomes. This brief review will examine the definitions and epidemiology of resistant hypertension and consider the differences between apparent resistant hypertension and truly resistant or refractory hypertension. It will review the role of the sympathetic nervous system in resistant hypertension. It will consider the relationship between obesity and leptin resistance and sympathetic signaling; the role of obstructive sleep apnea in resistant hypertension; and the role of aldosterone in resistant hypertension. It will conclude by mentioning briefly renal nerve ablation.

Topics: Aldosterone; Diabetes Mellitus; Humans; Hypertension; Leptin; Obesity; Sympathetic Nervous System

Leptin is an adipocyte-secreted hormone that has been proposed to regulate energy homeostasis as well as metabolic, reproductive, neuroendocrine, and immune functions. In the context of open-label uncontrolled studies, leptin administration has demonstrated insulin-sensitizing effects in patients with congenital lipodystrophy associated with relative leptin deficiency. Leptin administration has also been shown to decrease central fat mass and improve insulin sensitivity and fasting insulin and glucose levels in HIV-infected patients with highly active antiretroviral therapy (HAART)-induced lipodystrophy, insulin resistance, and leptin deficiency. On the contrary, the effects of leptin treatment in leptin-replete or hyperleptinemic obese individuals with glucose intolerance and diabetes mellitus have been minimal or null, presumably due to leptin tolerance or resistance that impairs leptin action. Similarly, experimental evidence suggests a null or a possibly adverse role of leptin treatment in nonlipodystrophic patients with nonalcoholic fatty liver disease. In this review, we present a description of leptin biology and signaling; we summarize leptin's contribution to glucose metabolism in animals and humans in vitro, ex vivo, and in vivo; and we provide insights into the emerging clinical applications and therapeutic uses of leptin in humans with lipodystrophy and/or diabetes.

Topics: Animals; Diabetes Mellitus; HIV-Associated Lipodystrophy Syndrome; Humans; Hypoglycemic Agents; Insulin Resistance; Leptin; Lipodystrophy, Congenital Generalized; Receptors, Leptin; Signal Transduction

Lipodystrophy is a congenital or acquired disorder characterized by complete or partial absence of subcutaneous fat tissue, often accompanied by insulin resistance, diabetes mellitus (DM), hypertriglyceridemia and hepatic steatosis. A decrease in both number and function of adipocytes leads to ectopic fat depositions and decreased production of adipokines such as leptin. We present 2 patients with inadequately regulated DM, hypertriglyceridemia and hepatic steatosis who were eventually diagnosed with lipodystrophy: 1 with congenital generalized lipodystrophy (Berardinelli-Seip syndrome) and 1 with congenital partial lipodystrophy (Dunnigan syndrome). Both received recombinant human leptin therapy (methionylleptin, available on a compassionate-use basis). This resulted in improved plasma levels of triglyceride, glucose and HbA1c and a decrease in liver size. In addition, hepatic triglyceride content decreased from 19.3% to 1.3% in the first patient and from 20.6% to 12.4% in the second. Leptin therapy is an effective and safe treatment for therapy-resistant diabetes and hypertriglyceridemia in patients with congenital lipodystrophy.

Topics: Adolescent; Adult; Blood Glucose; Compassionate Use Trials; Diabetes Mellitus; Fatty Liver; Female; Glycated Hemoglobin; Humans; Hypertriglyceridemia; Insulin Resistance; Leptin; Lipodystrophy; Lipodystrophy, Congenital Generalized; Triglycerides

Recombinant methionyl human leptin (r-metHuLeptin) was first used as a replacement therapy in patients bearing inactivating mutations in the leptin gene. In this indication, it was shown since 1999 to be very efficient in inducing a dramatic weight loss in rare children and adults with severe obesity due to the lack of leptin. These first clinical trials clearly showed that r-metHuLeptin acted centrally to reduce food intake, inducing loss of fat mass, and to correct metabolic alterations, immune and neuroendocrine defects. A few years later, r-metHuLeptin was also shown to reverse the metabolic complications associated with lipodystrophic syndromes, due to primary defects in fat storage, which induce leptin deficiency. The beneficial effects, which could be mediated by central and/or peripheral mechanisms, are thought to mainly involve the lowering effects of leptin on ectopic lipid storage, in particular in liver and muscles, reducing insulin resistance. Interestingly, r-metHuLeptin therapy also reversed the hypothalamic-pituitary-gonadal axis dysfunctions associated with hypothalamic amenorrhea. However, if r-metHuLeptin treatment has been shown to be dramatically efficient in leptin-deficient states, its very limited effect in inducing weight loss in common obese patients revealed that, in patients with adequate leptin secretion, mechanisms of leptin resistance and leptin tolerance prevent r-metHuLeptin from inducing any additional effects. This review will present the current data about the effects of r-metHuLeptin therapy in humans, and discuss the recent perspectives of this therapy in new indications.

Topics: Animals; Diabetes Mellitus; Humans; Leptin; Mutation; Obesity

Growing evidence links the stress at the endoplasmic reticulum (ER) to pathologies such as diabetes mellitus, obesity, liver, heart, renal and neurodegenerative diseases, endothelial dysfunction, atherosclerosis, and cancer. Therefore, identification of molecular pathways beyond ER stress and their appropriate modulation might alleviate the stress, and direct toward novel tools to fight this disturbance. An interesting resident of the ER membrane is protein tyrosine phosphatase 1B (PTP1B), an enzyme that negatively regulates insulin and leptin signaling, contributing to insulin and leptin resistance. Recently, new functions of PTP1B have been established linked to ER stress response. This review evaluates the novel data on ER stressors, discusses the mechanisms beyond PTP1B function in the ER stress response, and emphasizes the potential therapeutic exploitation of PTP1B to relieve ER stress.

Topics: Diabetes Mellitus; Dyslipidemias; Endoplasmic Reticulum Stress; Fatty Liver; Heart Diseases; Humans; Insulin; Kidney Diseases; Leptin; Obesity; Protein Tyrosine Phosphatase, Non-Receptor Type 1

In the last 50 years, the average self-reported sleep duration in the United States has decreased by 1.5-2 hours in parallel with an increasing prevalence of obesity and diabetes. Epidemiological studies and meta-analyses report a strong relationship between short or disturbed sleep, obesity, and abnormalities in glucose metabolism. This relationship is likely to be bidirectional and causal in nature, but many aspects remain to be elucidated. Sleep and the internal circadian clock influence a host of endocrine parameters. Sleep curtailment in humans alters multiple metabolic pathways, leading to more insulin resistance, possibly decreased energy expenditure, increased appetite, and immunological changes. On the other hand, psychological, endocrine, and anatomical abnormalities in individuals with obesity and/or diabetes can interfere with sleep duration and quality, thus creating a vicious cycle. In this review, we address mechanisms linking sleep with metabolism, highlight the need for studies conducted in real-life settings, and explore therapeutic interventions to improve sleep, with a potential beneficial effect on obesity and its comorbidities.

Topics: Adiponectin; Appetite; Diabetes Mellitus; Energy Metabolism; Female; Ghrelin; Glucose; Humans; Insulin Resistance; Leptin; Male; Melatonin; Obesity; Risk Factors; Sleep Deprivation; Sleep Wake Disorders

The study of how different intracellular metabolic signaling pathways impact the control of self-immune tolerance and how metabolic dysregulation in overweight, obesity, and diabetes is able to alter self-immune tolerance are topics of intensive investigation. Recent evidence suggests that metabolic and autoimmune diseases, both characterized by chronic inflammation and an altered self-immune tolerance, are more common in affluent countries. The reasons for such phenomena are still not completely understood, but the 'metabolic pressure' induced by nutritional overload, typical of more developed countries, seems to play a role. In this context, the discovery of the adipose tissue-derived hormone leptin has shed fundamental insights on how these processes might occur. We believe that there is a strong relationship among leptin, metabolic state, and immunological self-tolerance. We hypothesize that the leptin-induced metabolic pressure sets the basis for an exaggerated immuno-inflammatory response to altered self or non-self, leading to chronic inflammation, metabolic dysregulation, and autoimmunity in subjects with risk factors (i.e. genetic predisposition, environment, sex, infectious agents, etc). Capitalizing on our joint effort and trans-disciplinary expertise in metabolism, self-tolerance, and autoimmune diseases, this review highlights key questions on the basic mechanisms governing immune tolerance in the context of metabolic and autoimmune disease susceptibility.

Topics: Adipose Tissue; Animals; Autoimmune Diseases; Body Weight; Diabetes Mellitus; Energy Metabolism; Humans; Immune Tolerance; Inflammation; Leptin; Self Tolerance; Signal Transduction; T-Lymphocytes

Since the discovery of leptin in 1994, we now have a better understanding of the cellular and molecular mechanisms underlying its biological effects. In addition to its established anti-obesity effects, leptin exerts antidiabetic actions that are independent of its regulation of body weight and food intake. In particular, leptin can correct diabetes in animal models of type 1 and type 2 diabetes. In addition, long-term leptin replacement therapy improves glycaemic control, insulin sensitivity and plasma triglycerides in patients with severe insulin resistance due to lipodystrophy. These results have spurred enthusiasm for the use of leptin therapy to treat diabetes. Here, we review the current understanding of the glucoregulatory functions of leptin, emphasizing its central mechanisms of action and lessons learned from clinical studies, and discuss possible therapeutic applications of leptin in the treatment of type 1 and type 2 diabetes.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Humans; Leptin; Pro-Opiomelanocortin; Treatment Outcome

The serine/threonine kinase Akt, also known as protein kinase B, has been the focus of substantial attention, largely because it is frequently activated in human cancers. However, relatively little is known about the roles of Akt, particularly the individual isoforms of Akt, in glucose homeostasis in vivo. This review summarizes data on the role of Akt isoforms in glucose homeostasis and diabetes. Emphasis is given to the observation that certain combinations of whole-body Akt1 and Akt2 deficiencies reduce circulating levels of leptin and that restoration of leptin levels restores normal glucose homeostasis in diabetic Akt-deficient mice. The significance of these findings, together with recent observations suggesting that leptin emulates insulin action, is also discussed.

Topics: Animals; Diabetes Mellitus; Glucose; Homeostasis; Insulin; Insulin Resistance; Isoenzymes; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Proto-Oncogene Proteins c-akt

The incidence of diabetes mellitus has soared to epidemic proportion worldwide. The debilitating chronic hyperglycemia is caused by either lack of insulin as in diabetes type 1 or its ineffectiveness as in diabetes type 2. Frequent replacement of insulin with or without insulin analogs for optimum glycemic control are the conventional cumbersome therapies. Recent application of leptin gene transfer technology has uncovered the participation of adipocytes-derived leptin-dependent hypothalamic neural signaling in glucose homeostasis and demonstrated that a breakdown in this communication due to leptin insufficiency in the hypothalamus underlies the etiology of chronic hyperglycemia. Reinstatement of central leptin sufficiency by hyperleptinemia produced either by intravenous leptin infusion or a single systemic injection of recombinant adenovirus vector encoding leptin gene suppressed hyperglycemia and evoked euglycemia only transiently in rodent models of diabetes type 1. In contrast, stable restoration of leptin sufficiency, solely in the hypothalamus, with biologically active leptin transduced by an intracerebroventicular injection of recombinant adeno-associated virus vector encoding leptin gene (rAAV-lep) abolished hyperglycemia and imposed euglycemia through the extended duration of experiment by stimulating glucose disposal in the periphery in models of diabetes type 1. Further, similar hypothalamic leptin transgene expression abrogated chronic hyperglycemia and hyperinsulinemia, the predisposing risk factors of the age and environmentally acquired diabetes type 2, and instituted euglycemia by independently activating relays that stimulate glucose metabolism and repress hyperinsulinemia and improve insulin sensitivity in the periphery. Consequently, this durable antidiabetic efficacy of one time rAAV-lep neurotherapy offers a potential novel substitute for insulin therapy following preclinical trials in subhuman primates and humans.

Topics: Animals; Diabetes Mellitus; Genetic Therapy; Humans; Hyperglycemia; Hypothalamus; Leptin; Rats; Signal Transduction; Transgenes

The regulation of body fat stores and blood glucose levels is critical for survival. This review highlights growing evidence that leptin action in the central nervous system plays a key role in both processes. Investigation into underlying mechanisms has begun to clarify the physiological role of leptin in the control of glucose metabolism and raises interesting new possibilities for the treatment of diabetes and related disorders.

Topics: Adipose Tissue; Adiposity; Animals; Central Nervous System; Diabetes Mellitus; Glucose; Homeostasis; Humans; Insulin; Janus Kinases; Leptin; Nerve Net; Nutritional Physiological Phenomena; Obesity; Phosphatidylinositol 3-Kinases; Signal Transduction

In the past decade several novel findings point to the critical role of the skeleton in several homeostatic processes, including energy balance. The connection begins in the bone marrow with lineage allocation of mesenchymal stem cells to adipocytes or osteoblasts. Osteoblasts and adipocytes produce factors affecting insulin homeostasis. The hormonally active adipose tissue can regulate bone metabolism. In this review authors discuss targets taking critical part in the bone-fat network: leptin, osteocalcin, PPAR γ2 and the Wnt/beta catenin pathway. Leptin regulates energy metabolism through controlling appetite. Mutation of the leptin gene resulting leptin resistance leads to high leptin levels, enormous appetite and pathologic obesity. Leptin also can influence the bone mass. The main effects of the thiazolidinedions - PPARγ agonists - are mediated through receptors located in adipocytes. However, beside their positive effects, they also suppress osteoblastogenesis and increase the risk for pathologic fractures. Osteocalcin, a known marker of bone formation, produced by osteoblasts decreases fat mass, promotes adiponectin production and insulin sensitivity, increases the number of pancreatic β-cells and increases insulin secretion. Thus, the skeletal system can regulate glucose metabolism and this substantially changed our view on this issue. Novel molecules can now be tested as targets in order to enhance bone formation and possibly prevent fractures.

Topics: Animals; Bone and Bones; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Leptin; Lipid Peroxidation; Osteocalcin; Osteogenesis; Oxidative Stress; PPAR gamma; Signal Transduction; Wnt1 Protein

Body weight is tightly controlled in a species-specific range from insects to vertebrates and organisms have developed a complex regulatory network in order to avoid either excessive weight gain or chronic weight loss. Energy homeostasis, a term comprising all processes that aim to maintain stability of the metabolic state, requires a constant communication of the different organs involved; i.e. adipose tissue, skeletal muscle, liver, pancreas and the central nervous system (CNS). A tight hormonal network ensures rapid communication to control initiation and cessation of eating, nutrient processing and partitioning of the available energy within different organs and metabolic pathways. Moreover, recent experiments indicate that many of these homeostatic signals modulate the neural circuitry of food reward and motivation. Disturbances in each individual system can affect the maintenance and regulation of the others, making the analysis of energy homeostasis and its dysregulation highly complex. Though this cross-talk has been intensively studied for many years now, we are far from a complete understanding of how energy balance is maintained and multiple key questions remain unanswered. This review summarizes some of the latest developments in the field and focuses on the effects of leptin, insulin, and nutrient-related signals in the central regulation of feeding behavior. The integrated view, how these signals interact and the definition of functional neurocircuits in control of energy homeostasis, will ultimately help to develop new therapeutic interventions within the current obesity epidemic.

Topics: Animals; Body Weight; Brain; Diabetes Mellitus; Eating; Energy Metabolism; Glucose; Homeostasis; Humans; Hypothalamus; Insulin; Leptin; Neurosecretory Systems; Nutritional Physiological Phenomena; Obesity; Signal Transduction

Obesity is a universal health problem of increasing prevalence and represents a major public health concern. Obesity is associated with a high risk of developing cardiovascular and metabolic diseases such as hypertension, coronary atherosclerosis, myocardial hypertrophy, diabetes, dyslipidemia, and increased cardiovascular morbidity and mortality. There has been an ongoing search for mediators between obesity and cardiovascular disease. Leptin is a novel and very promising molecule of research that may link these pathologic conditions. Since its discovery in 1994, major advances have been made in the understanding of neuroendocrine mechanisms regulating appetite, metabolism, adiposity, sympathetic tone and blood pressure. In this review, we discuss the physiological and pathophysiological roles of leptin in the causation of various cardiovascular diseases.

Topics: Cardiovascular Diseases; Diabetes Mellitus; Homeostasis; Humans; Hypertension; Leptin; Obesity; Risk Factors

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

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

To review the pathophysiology, pharmacology, and current or future therapies under study for use in treating diabetes mellitus, inflammation associated with diabetes mellitus, and/or obesity related to diabetes mellitus, through 1 of 4 investigational pathways: adiponectin, ghrelin, resveratrol, or leptin.. A literature search using MEDLINE (1966-December 12, 2009), PubMed (1950-December 12, 2009), Science Direct (1994-December 12, 2009), and International Pharmaceutical Abstracts (1970-December 12, 2009) was performed using the terms adiponectin, ghrelin, resveratrol, leptin, inflammation, obesity, and diabetes mellitus. English-language, original research, and review articles were examined, and citations from these articles were assessed as well.. Clinical studies and in vitro studies were included in addition to any Phase 1, 2, or 3 clinical trials.. Mechanistic pathways regarding adiponectin, ghrelin, resveratrol, and leptin are of interest as future treatment options for diabetes mellitus. Each of these pathways has produced significant in vitro and in vivo clinical data warranting further research as a possible treatment pathway for diabetes-related inflammation and/or obesity reduction. While research is still underway to determine the exact effects these pathways have on metabolic function, current data suggest that each of these compounds may be of interest for future therapies.. While several pathways under investigation may offer additional benefits in the treatment of diabetes mellitus and associated impairments, further investigation is necessary for both investigational and approved therapies to ensure that the impact in new pathways does not increase risks to patient safety and outcomes.

Topics: Adiponectin; Animals; Anti-Inflammatory Agents; Anti-Obesity Agents; Antioxidants; Diabetes Mellitus; Ghrelin; Humans; Hypoglycemic Agents; Inflammation; Leptin; Obesity; Resveratrol; Stilbenes

Melanocortin peptides, derived from POMC (pro-opiomelanocortin) are produced in the ARH (arcuate nucleus of the hypothalamus) neurons and the neurons in the commissural NTS (nucleus of the solitary tract) of the brainstem, in anterior and intermediate lobes of the pituitary, skin and a wide range of peripheral tissues, including reproductive organs. A hypothetical model for functional roles of melanocortin receptors in maintaining energy balance was proposed in 1997. Since this time, there has been an extraordinary amount of knowledge gained about POMC-derived peptides in relation to energy homoeostasis. Development of a Pomc-null mouse provided definitive proof that POMC-derived peptides are critical for the regulation of energy homoeostasis. The melanocortin system consists of endogenous agonists and antagonists, five melanocortin receptor subtypes and receptor accessory proteins. The melanocortin system, as is now known, is far more complex than most of us could have imagined in 1997, and, similarly, the importance of this system for regulating energy homoeostasis in the general human population is much greater than we would have predicted. Of the known factors that can cause human obesity, or protect against it, the melanocortin system is by far the most significant. The present review is a discussion of the current understanding of the roles and mechanism of action of POMC, melanocortin receptors and AgRP (agouti-related peptide) in obesity and Type 2 diabetes and how the central and/or peripheral melanocortin systems mediate nutrient, leptin, insulin, gut hormone and cytokine regulation of energy homoeostasis.

Topics: Animals; Diabetes Mellitus; Energy Metabolism; Homeostasis; Humans; Leptin; Mice; Obesity; Peptides; Pro-Opiomelanocortin; Receptors, Melanocortin

The incidence of diabetes is increasing worldwide, yet current treatments are not always effective for all patient or disease types.. Here, we summarize the biologic and clinical roles of leptin in diabetes, and discuss candidate viral vectors that may be employed in the clinical use of central leptin gene therapy for diabetes.. We discuss how studies on leptin, a regulator of the insulin-glucose axis, have significantly advanced our understanding of the roles of energy homeostasis and insulin resistance in the pathogeneses of metabolic syndrome and diabetes. Recent studies have demonstrated the long-term therapeutic effects of central leptin gene therapy in obesity and diabetes via decreased insulin resistance and increased glucose metabolism. Many of these studies have employed viral vectors, which afford high in vivo gene transduction efficiencies compared with non-viral vectors.. Adeno-associated viral vectors are particularly well suited for central leptin gene therapy owing to their low toxicity and ability to drive transgene expression for extended periods.

Topics: Animals; Blood Glucose; Dependovirus; Diabetes Mellitus; Genetic Therapy; Genetic Vectors; Humans; Insulin; Insulin Resistance; Leptin; Treatment Outcome

Regulation of energy metabolism is controlled by the brain, in which key central neuronal circuits process a variety of information reflecting nutritional state. Special sensory and gastrointestinal afferent neural signals, along with blood-borne metabolic signals, impinge on parallel central autonomic circuits located in the brainstem and hypothalamus to signal changes in metabolic balance. Specifically, neural and humoral signals converge on the brainstem vagal system and similar signals concentrate in the hypothalamus, with significant overlap between both sensory and motor components of each system and extensive cross-talk between the systems. This ultimately results in production of coordinated regulatory autonomic and neuroendocrine cues to maintain energy homeostasis. Therapeutic metabolic adjustments can be accomplished by modulating viscerosensory input or autonomic motor output, including altering parasympathetic circuitry related to GI, pancreas, and liver regulation. These alterations can include pharmacological manipulation, but surgical modification of neural signaling should also be considered. In addition, central control of visceral function is often compromised by diabetes mellitus, indicating that circuit modification should be studied in the context of its effect on neurons in the diabetic state. Diabetes has traditionally been handled as a peripheral metabolic disease, but the central nervous system plays a crucial role in regulating glucose homeostasis. This review focuses on key autonomic brain areas associated with management of energy homeostasis and functional changes in these areas associated with the development of diabetes.

Topics: Animals; Autonomic Pathways; Blood Glucose; Brain; Diabetes Mellitus; Ghrelin; Humans; Hypothalamus; Insulin; Leptin; Neuronal Plasticity; Neurons; Neurosecretory Systems; Potassium Channels

The prevalence of Diabetes Mellitus (DM) is becoming a serious public health problem. The use of atypical antipsychotics has been associated with disruption of the glucose metabolism and therefore with causing DM. The underlying mechanisms are unknown, but knowledge of the differences between the pharmacological features of various antipsychotics combined with their diabetogenic profile might help us to understand those mechanisms. This article describes how the binding of various essential receptors or transporters in essential body tissues, adipose tissue, pancreatic tissue and liver and skeletal muscle tissue can cause disruption of the glucose metabolism. With such knowledge in mind one can try to explain the differences between the diabetogenic propensities of various antipsychotics. It is well known that clozapine and olanzapine cause weight gain and DM, whereas aripiprazole and ziprasidone have much less disruptive clinical profiles. The most significant risk factor for adiposity seems to be strong blocking of histaminergic receptors. An agonistic activity on serotonergic-1a receptors, with a very low affinity for muscarinergic-3 receptors, might protect against the development of DM. More data will become available which may help to solve the puzzle.

Topics: Adiponectin; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Blood Glucose; Clozapine; Diabetes Mellitus; Humans; Leptin; Obesity; Olanzapine; Piperazines; Quinolones; Receptor, Muscarinic M3; Receptor, Serotonin, 5-HT1A; Receptors, Dopamine D2; Receptors, Histamine; Serotonin 5-HT1 Receptor Agonists; Thiazoles; Weight Gain

The adipocyte-derived hormone, leptin controls feeding behavior, augments fatty acid beta-oxidation in the skeletal muscle, attenuates insulin secretion but enhances whole body insulin sensitivity and glucose disposal, thereby serving as a promising therapeutic candidate for the treatment of insulin resistance and dyslipidemia. Along with other researchers, we demonstrated the clinical efficacy and safety of leptin in the treatment of diabetes and dyslipidemia for patients with generalized lipodystrophy. However, the clinical application of leptin has been hampered by the notion that leptin does not fully exert its metabolic effects in human obesity and diet-induced obese rodents. We found that the activity of skeletal muscle AMP-activated protein kinase (AMPK) parallels hypothalamic leptin sensitivity and metabolic phenotype in transgenic mice overexpressing leptin. Our data indicate that the activation of skeletal muscle AMPK is mediated by the hypothalamic melanocortin pathway. In fact, intracerebroventricular administration of melanocortin agonist, MT-II in mice robustly overcomes high-fat diet-induced leptin resistance and ameliorates fuel dyshomeostasis and hyperphagia, with a concomitant recovery of AMPK activity in skeletal muscle. Conversely, AMPK/ACC phosphorylation by leptin was abrogated by the co-administration of melanocortin antagonist, SHU9119 and in the KKA(y) mice, which centrally express endogenous melanocortin antagonist. Importantly, high-fat diet-induced attenuation of AMPK/ACC phosphorylation in leptin-overexpressing transgenic mice was not reversed by central leptin per se, but was markedly recovered by MT-II. Our data provide evidence for the critical role of the central melanocortin system in leptin-skeletal muscle AMPK axis, and highlight the system as a therapeutic target for leptin insuffciency in obese humans.

Topics: Animals; Diabetes Mellitus; Humans; Hypothalamus; Leptin; Obesity; Receptor, Melanocortin, Type 4; Signal Transduction

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

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

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Calcium Channel Blockers; Cardiovascular Diseases; Diabetes Mellitus; Drug Therapy, Combination; Humans; Hypertension; Insulin Resistance; Leptin; Obesity

Multidisciplinary research from my and my colleagues' laboratory has shown that disruption at various levels of leptin signaling to the interactive hypothalamic network of neuropeptide Y (NPY) and cohorts contributes to the antecedent pathophysiologic sequelae of the disease cluster of the metabolic syndrome. Disruptions in NPY signaling due to high or low abundance of NPY and cognate receptors dysregulate the homeostatic milieu to promote hyperinsulinemia, hyperglycemia, fat accrual, and overt diabetes. Hyperleptinemia induced by consumption of energy-rich diets inhibits leptin transport across the blood-brain barrier and thereby produces leptin insufficiency in the hypothalamus. Sustained leptin insufficiency results in loss of hypothalamic restraint on pancreatic insulin secretion and diminished glucose metabolism and energy expenditure. This chain of events culminates in hyperinsulinemia, hyperglycemia, and diabetes. Our recent studies have shown that increasing the supply of leptin centrally by gene therapy reinstates the restraint on hypothalamic NPY signaling and ameliorates diabetes and the attendant disease cluster of the metabolic syndrome. Thus, newer therapies that would enhance leptin transport across the blood-brain barrier in a timely manner or reinstate leptin restraint on NPY signaling through central leptin gene therapy or pharmacologically with leptin mimetics are likely to curtail the pathophysiologic sequelae of diabetes and related ailments of the metabolic syndrome.

Topics: Animals; Diabetes Mellitus; Hypothalamus; Leptin; Metabolic Syndrome; Mice; Neuropeptide Y; Rats

The incidence of carbohydrate intolerance and overt diabetes is increased in patients with schizophrenia treated with the newer atypical antipsychotic agents. The precise mechanism for these abnormalities remains obscure. This review examines the potential interaction between atypical antipsychotic medications and several hormones known to influence appetite regulation and carbohydrate metabolism.

Topics: Animals; Antipsychotic Agents; Cannabinoid Receptor Modulators; Diabetes Mellitus; Ghrelin; Glucagon; Glucose Metabolism Disorders; Humans; Insulin; Insulin Resistance; Leptin; Schizophrenia

The various hormones, proteins and other compounds related to developing obesity, insulin resistance and type 2 diabetes are analyzed in the paper. 1) Leptin, ciliary neurutrophic factor, adiponectin, glucagon-like peptide 1, peptide YY, neuromedin S, as well as the protein receptors of these hormones decrease the food consumption, increase the energy turnover, and prevent obesity, insulin resistance, and type 2 diabetes development. The mediators of these hormone and receptor actions are melanocyte stimulating hormone (MSH), corticotropin-releasing hormone (CRH), and the others. 2) Ghrelin, endogenose cannabinoides, galanin-like peptide and the mediators of their actions: neuropeptide Y (NPY) and Agouti gene related protein (AGRP) increase the appetite and food consumption. Peroxisome proliferation-activated receptor (PPAR) performs the similar action on food intake. The activation of the first group compound functioning decreases the obesity, increases the energy turnover, facilitates the insulin action and prevents the insulin resistance and type 2 diabetes. Increasing the activities of the second group, as well as, decreasing the actions of the first one of substances induce the opposite effects and facilitate obesity, insulin resistance, and type 2 diabetes developments. The interconnections of the molecular mechanisms of so many hormone actions make the very complicated tusk to study the various endocrine disorders including diabetes mellitus as well.

Topics: Adiponectin; Ciliary Neurotrophic Factor Receptor alpha Subunit; Diabetes Mellitus; Hormones; Humans; Hypothalamus; Insulin Resistance; Leptin; Obesity; Transcription Factors

Acquired disturbances of several aspects of cellular metabolism appear pathologically important in sporadic Alzheimer's disease (SAD). Among these, brain glucose utilization is reduced in the early stages of the disease. Hyperinsulinemia, which is a characteristic finding of insulin resistance, results in a central insulin deficit. Insufficient insulin signaling impairs the intricate balance of nitric oxide regulation of the central nervous system. Reduction in central insulin decreases neuronal nitric oxide synthase and increases inducible synthase activity. This, in turn, decreases astrocytic energy substrates and antioxidant supply of neurons. In addition, an increase in peroxynitrite formation impairs redox balance. Hyperleptinemia and glucose excess, which are the other parameters of insulin resistance, may worsen the reduced astrocytic energy supply and the ongoing inflammation via the inhibition of AMP-activated protein kinase (AMPK). Consequently, energy deficit and inflammation in neuronal tissue may cause neurodegeneration of SAD.

Topics: Alzheimer Disease; AMP-Activated Protein Kinases; Antioxidants; Astrocytes; Blood-Brain Barrier; Brain; Cerebral Amyloid Angiopathy; Diabetes Mellitus; Glucose; Humans; Inflammation; Insulin Resistance; Ketones; Leptin; Liver; Mitochondrial Diseases; Multienzyme Complexes; Nerve Degeneration; Oxidation-Reduction; Peroxynitrous Acid; Protein Serine-Threonine Kinases

In this brief review, we introduce some major themes in the regulation of energy, lipid, and glucose metabolism by the central nervous system (CNS). Rather than comprehensively discussing the field, we instead will discuss some of the key findings made regarding the interaction of the hormones ghrelin and leptin with the CNS.

Topics: Aged; Appetite; Arcuate Nucleus of Hypothalamus; Body Weight; Central Nervous System; Diabetes Mellitus; Energy Metabolism; Ghrelin; Glucose; Homeostasis; Humans; Hypothalamus; Leptin; Obesity

Type I diabetes mellitus (T1D) is due to a loss of immune tolerance to islet antigen and thus, there is intense interest in developing therapies that can re-establish it. Tolerance is maintained by complex mechanisms that include inhibitory molecules and several types of regulatory T cells (Tr). A major historical question is whether gene therapy can be employed to generate Tr cells. This review shows that gene transfer of immunoregulatory molecules can prevent T1D and other autoimmune diseases. In our studies, non-viral gene transfer is enhanced by in vivo electroporation (EP). This technique can be used to perform DNA vaccination against islet cell antigens and when combined with appropriate immune ligands results in the generation of Tr cells and protection against T1D. In vivo EP can also be applied for non-immune therapy of diabetes. It can be used to deliver protein drugs such as glucagon-like peptide 1 (GLP-1), leptin or transforming growth factor beta (TGF-beta). These act in T1D or type II diabetes (T2D) by restoring glucose homeostasis, promoting islet cell survival and growth or improving wound healing and other complications. Furthermore, we show that in large animals EP can deliver peptide hormones, such as growth hormone releasing hormone (GHRH). We conclude that the non-viral gene therapy and EP represent a safe and efficacious approach with clinical potential.

Topics: Animals; Autoantigens; Autoimmune Diseases; Cytokines; Diabetes Mellitus; Electroporation; Genetic Therapy; Humans; Leptin; Mice; Mice, Inbred NOD; Vaccines, DNA

Adipokines, in particular adiponectin, have been highlighted in the pathogenesis of obesity-related illnesses, including type 2 diabetes, because of their role in the regulation of insulin sensitivity as well as vascular endothelial function. Since cardiovascular disease accounts for an overwhelming proportion of the morbidity and mortality suffered by patients with diabetes, researchers are actively seeking a better understanding of the role that adipokines play in the vasculature with the hope that the use of these agents, or activation of their signaling pathways, might help prevent micro- and macrovascular complications. This brief review highlights recent work on the vascular effects of circulating adipokines, focusing on adiponectin, and includes some recent findings with leptin and resistin. This highly active area of investigation has identified novel hormonal mechanisms by which the adipose tissue mass can influence vascular function with important consequences for cardiovascular risk.

Topics: Adiponectin; Animals; Diabetes Mellitus; Humans; Leptin; Resistin; Signal Transduction; Vascular Diseases

Topics: Cytokines; Diabetes Mellitus; Humans; Inflammation; Insulin; Insulin Resistance; Leptin; Obesity; Signal Transduction; Suppressor of Cytokine Signaling Proteins

Topics: Animals; Comorbidity; Diabetes Mellitus; Global Health; HIV Infections; Humans; Infections; Leptin; Malaria; Malnutrition; Measles; Obesity; Protein-Energy Malnutrition; Risk Factors; T-Lymphocytes; Tuberculosis

Ghrelin, an acylated 28-amino-acid peptide, is an endogenous ligand of the growth hormone secretagogue type 1a (GHS-R1a). Ghrelin is best known for its hypothalamic actions on growth hormone-releasing hormone neurons and neuropeptide Y/agouti-related peptide neurons; however, ghrelin affects multiple organ systems and the complexity of its functions is only now being realized. Although ghrelin is mainly produced in the stomach, it is also produced in low levels by the hypothalamus and by most peripheral tissues. GHS-R1a is expressed predominantly in the anterior pituitary gland, at lower levels in the brain including hypothalamic neurons that regulate feeding behavior and glucose sensing, and at even lower levels in the pancreas. A reciprocal relationship exists between ghrelin and insulin, suggesting that ghrelin regulates glucose homeostasis. Ablation of ghrelin in mice increases glucose-induced insulin secretion, and improves peripheral insulin sensitivity. This review focuses on the newly emerging role of ghrelin in glucose homeostasis and exploration of whether ghrelin is a potential therapeutic target for diabetes.

Topics: Animals; Brain; Diabetes Mellitus; Energy Metabolism; Ghrelin; Glucose; Homeostasis; Humans; Insulin; Leptin; Neurosecretory Systems

Obesity is considered one of the risk factors for metabolic disorders such as diabetes mellitus. There is increasing evidence that obesity and diabetes are under the control of numerous cytokines and hormones, such as adiponectin and leptin. In addition, a number of studies have revealed that the brain functions play a role in the development of obesity and diabetes mellitus. Histamine and its receptors are classical inflammatory mediators in peripheral tissues and also function in the brain. The results of physiological and pharmacological studies revealed that brain histamine and its receptors are involved in the regulation of obesity and diabetes mellitus. Leptin has been shown to regulate obesity and diabetes partially via brain histamine and its receptors. In this review, we focused on the roles of brain histamine and its receptors in regulating obesity and diabetes mellitus.

Topics: Animals; Brain; Diabetes Mellitus; Glucose; Histamine; Homeostasis; Humans; Leptin; Models, Biological; Neurons; Obesity; Receptors, Histamine

Leptin is an adipocyte-derived hormone that primarily acts in the hypothalamus and plays a key role in the regulation of food intake, body weight, energy expenditure and neuroendocrine function. Leptin has direct peripheral effects on several tissues, and it may be independently involved in insulin secretion and action besides its effects on body weight regulation. Basal plasma leptin and insulin concentrations correlate with each other. Insulin and glucose appear to increase leptin secretion. In turn, leptin increases peripheral insulin sensitivity while decreasing insulin secretion from pancreatic beta cells. Leptin increases skeletal muscle glucose uptake and oxidation, and suppresses hepatic glucose output. Effects of leptin on lipid metabolism might reduce lipotoxicity and therefore contribute to the improvement of hepatic, skeletal and whole body insulin sensitivity. Leptin is the first adipokine used in the treatment of hypoleptinemic clinical disorders. Although leptin therapy has limited success in common obesity, it has impressive effects in congenital leptin deficiency, lipoatrophic diabetes and syndromes of severe insulin resistance. Leptin has been reported to ameliorate hyperinsulinemia and diabetes in the clinical setting of congenital leptin deficiency. It also improves hyperglycemia, insulin resistance, hyperinsulinemia, dyslipidemia and hepatic steatosis in lipoatrophic diabetes. These promising results warrant clinical trials to test the hypothesis that leptin alone or with classical antidiabetic agents may potentially be beneficial in the treatment of hypoleptinemic non-obese individuals with glucose intolerance and diabetes. This review summarizes the clinical applications of leptin, particularly emphasizing the effects of leptin on glucose homeostasis.

Topics: Animals; Diabetes Mellitus; Diabetes Mellitus, Lipoatrophic; Glucose; Homeostasis; Humans; Insulin; Insulin Secretion; Leptin; Liver; Muscle, Smooth

In addition to serving as an energy reservoir, the adipocyte has been characterized as an endocrine cell, secreting many bioactive factors which influence energy homeostasis. Being overweight, with excessive adipose tissue, is considered to be part of the pathogenesis of type 2 diabetes. Insulin resistance and beta-cell dysfunction are two major pathophysiological changes seen in type 2 diabetes. In addition to inducing insulin resistance in insulin-responsive tissues, adipocyte-derived factors play an important role in the pathogenesis of beta-cell dysfunction. Leptin, free fatty acids, adiponectin, tumor necrosis factor-alpha and interleukin-6 are all produced and secreted by adipocytes, and may directly influence aspects of beta-cell function, including insulin synthesis and secretion, insulin cell survival and apoptosis. During the progression from normal weight to obesity and on to overt diabetes, the adipocyte-derived factors contribute to the occurrence and development of beta-cell dysfunction and type 2 diabetes.

Topics: Adipocytes; Adiponectin; Animals; Diabetes Mellitus; Fatty Acids, Nonesterified; Humans; Insulin-Secreting Cells; Interleukin-6; Leptin; Tumor Necrosis Factor-alpha

Recent evidence highlights the important role of the brain in the control of glucose homeostasis. Hypothalamic centers sense the availability of peripheral nutrients via redundant and overlapping nutrient-induced peripheral signals such as leptin and insulin and via direct metabolic signaling. Responding to nutrient availability, these hypothalamic regions in turn exert a negative feedback not only on food intake but also on endogenous glucose production. Disruptions in the mechanisms of central nervous system nutrient sensing alter these homeostatic responses and contribute to the pathophysiology of obesity and type 2 diabetes. In this review, we discuss the neural and molecular pathways so far identified as possible targets for therapeutic intervention.

Topics: Animals; Brain; Diabetes Mellitus; Glucose; Homeostasis; Humans; Hypothalamus; Insulin; Leptin

Obesity and diabetes are major public health threats worldwide. Insulin resistance appears to be a significant factor in this global epidemic. In this present review, we have focused on a human model of insulin resistance which embodies many of the metabolic abnormalities that are associated with the morbidity of diabetes and obesity. Lipodystrophy in rodents and humans is a severe model of insulin resistance, and we use a novel therapeutic approach with the administration of the newly discovered leptin to ameliorate many of these metabolic abnormalities. The ability to study the administration of leptin in this setting of severe insulin resistance allows us perform a coveted look into a human condition where metabolic dysfunction can be reversed or controlled.

Topics: Adiponectin; Animals; Diabetes Mellitus; Humans; Insulin Resistance; Leptin; Lipodystrophy; Obesity; Treatment Outcome

Adipose tissue plays a crucial role in energy homeostasis not only in storing triglyceride, but also responding to nutrient, neural, and hormonal signals, and producing factors which control feeding, thermogenesis, immune and neuroendocrine function, and glucose and lipid metabolism. Adipose tissue secretes leptin, steroid hormones, adiponectin, inflammatory cytokines, resistin, complement factors, and vasoactive peptides. The endocrine function of adipose tissue is typified by leptin. An increase in leptin signals satiety to neuronal targets in the hypothalamus. Leptin activates Janus-activating kinase2 (Jak2) and STAT 3, resulting in stimulation of anorexigenic peptides, e.g., alpha-MSH and CART, and inhibition of orexigenic peptides, e.g., NPY and AGRP. The reduction in leptin levels during fasting stimulates appetite, decreases thermogenesis, thyroid and reproductive hormones, and increases glucocorticoids. Leptin also stimulates fatty acid oxidation, insulin release, and peripheral insulin action. These effects involve regulation of PI-3 kinase, PTP-1B, suppressor of cytokine signaling-3 (SOCS-3), and AMP-activated protein kinase in the brain and peripheral organs. There is emerging evidence that leptin, adiponectin, and resistin act through overlapping pathways. Understanding the signal transduction of adipocyte hormones will provide novel insights on the pathogenesis and treatment of obesity, diabetes, and various metabolic disorders.

Topics: Adipose Tissue; Animals; Diabetes Mellitus; Enzyme Activation; Humans; Hypothalamus; Janus Kinase 2; Leptin; Lipid Metabolism; Obesity; Signal Transduction; STAT2 Transcription Factor

Stroke is an important cause of morbidity and mortality, and is an economic burden. Diabetes and obesity are two important modifiable risk factors for stroke. Patients with diabetes have a higher incidence of stroke and a poorer prognosis after stroke. Risk-factor modification is the most important aspect of prevention of stroke in diabetes and obesity. This includes lifestyle modifications and different therapeutic modalities to control conditions, such as diabetes, hypertension, dyslipidemia and arrhythmia. Recent landmark studies have shown the beneficial effects of statins in diabetic patients even with close to normal or normal low-density lipoprotein cholesterol. Obesity, which is a risk factor for diabetes, hypertension and hyperlipidemia has been shown to be an independent risk factor for stroke. Increased leptin, dysregulation of adipocyte proteins, increased insulin resistance and C-reactive protein may be factors involved in the increased incidence of cardiovascular morbidity and mortality directly related to obesity. Visceral fat is a much bigger health risk than subcutaneous fat. Lifestyle interventions and pharmacotherapeutic agents have been used to manage obesity. In morbidly obese patients, surgical intervention seems to be the best method of treatment with a long-lasting favorable metabolic outcome. In the 21st Century, with the advanced medical knowledge and the therapeutic modalities available, it should be possible to reduce the incidence of stroke associated with diabetes and obesity.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Atrial Fibrillation; Blood Glucose; Cardiovascular Agents; Carotid Stenosis; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Retinopathy; Dyslipidemias; Humans; Hypertension; Insulin Resistance; Ischemic Attack, Transient; Leptin; Life Style; Lipoproteins; Obesity; Plasminogen Activator Inhibitor 1; Risk Factors; Smoking; Stroke

1. The current worldwide epidemic of obesity and its major complications, namely type 2 diabetes and hypertension, is well documented. The present mini-review develops the thesis that 'thrifty' metabolic traits, evolved in the setting of intermittent famine, contribute to the obesity pandemic. 2. These thrifty traits, namely a decreased capacity for dietary thermogenesis and an increased resistance to insulin-mediated glucose uptake in skeletal muscle, would prolong survival during famine but predispose to obesity and diabetes in the face of abundance. The regulation of dietary thermogenesis by the sympathetic nervous system also explains the well-established association between obesity and high blood pressure. 3. These observations provide a deep-seated rationale for the efficacy of lifestyle interventions in the treatment of obesity and its complications and may also provide a predicate for the development of new therapeutic strategies aimed at neutralizing the impact of these thrifty traits. Such strategies may entail, for example, therapeutic agents that enhance metabolic rate during low-energy diets, thereby reversing the physiological impediment imposed by suppression of the sympathetic nervous system.

Topics: Diabetes Mellitus; Diet; Eating; Energy Metabolism; Humans; Hypertension; Insulin; Insulin Resistance; Leptin; Models, Biological; Obesity; Overnutrition; Quantitative Trait, Heritable; Sympathetic Nervous System; Thermogenesis

In this review, we would like to consider several aspects of the discovery of leptin and its evolution as a therapeutic agent. It has been shown that the administration of leptin in congenital leptin deficiency that there was improvement in satiety and weight loss. In hypoleptinemic patients with lipodystrophy, there is a dramatic improvement in glucose metabolism, dyslipidemia and hepatic steatosis. Leptin is the first and only adipokine administered to humans long term to produce such an effect.

Topics: Diabetes Mellitus; Dyslipidemias; Fatty Liver; Glucose; Humans; Insulin Resistance; Leptin; Lipodystrophy; Obesity; Satiation; Weight Loss

Topics: Animals; Cardiovascular Diseases; Clinical Trials as Topic; CREB-Binding Protein; Diabetes Mellitus; Dietary Fats; Energy Metabolism; Fatty Acids, Nonesterified; Glucose Transporter Type 4; Humans; Insulin Resistance; Leptin; Metabolic Syndrome; PPAR gamma; Receptors, Adiponectin; Receptors, Cell Surface; Resistin; Retinol-Binding Proteins; Retinol-Binding Proteins, Plasma; Tumor Necrosis Factor-alpha

Topics: Abnormalities, Multiple; Diabetes Mellitus; Diagnosis, Differential; Humans; Hypertrophy; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Mutation; Pineal Gland; Prognosis; Receptor, Insulin; Recombinant Proteins; Syndrome

Regulated energy homeostasis is fundamental for maintaining life. Unfortunately, this critical process is affected in a high number of mentally ill patients. Eating disorders such as anorexia nervosa are prevalent in modern societies. Impaired appetite and weight loss are common in patients with depression. In addition, the use of neuroleptics frequently produces obesity and diabetes mellitus. However, the neural mechanisms underlying the pathophysiology of these behavioral and metabolic conditions are largely unknown. In this review, we first concentrate on the established brain machinery of food intake and body weight, especially on the melanocortin and neuropeptide Y (NPY) systems as illustration. These systems play a critical role in receiving and processing critical peripheral metabolic cues such as leptin and ghrelin. It is also notable that both systems modulate emotion and motivated behavior as well. Secondly, we discuss the significance and potential promise of multidisciplinary molecular and neuroanatomic techniques that will likely increase the understanding of brain circuitries coordinating energy homeostasis and emotion. Finally, we introduce several lines of evidence suggesting a link between the melanocortin/NPY systems and several neurotransmitter systems on which many of the psychotropic agents exert their influence.

Topics: alpha-MSH; Animals; Antipsychotic Agents; Appetite Regulation; Body Weight; Diabetes Mellitus; Emotions; Energy Metabolism; Feeding and Eating Disorders; Homeostasis; Humans; Leptin; Neuropeptide Y; Obesity; RNA, Messenger

Insulin and its signaling systems are implicated in both central and peripheral mechanisms governing the ingestion, distribution, metabolism, and storage of nutrients in organisms ranging from worms to humans. Input from the environment regarding the availability and type of nutrients is sensed and integrated with humoral information (provided in part by insulin) regarding the sufficiency of body fat stores. In response to these afferent inputs, neuronal pathways are activated that influence energy flux and nutrient metabolism in the body and ensure reproductive competency. Growing evidence supports the hypothesis that reduced central nervous system insulin signaling from either defective secretion or action contributes to the pathogenesis of common metabolic disorders, including diabetes and obesity, and may therefore help to explain the close association between these two disorders. These considerations implicate insulin action in the brain, an organ previously considered to be insulin independent, as a key determinant of both glucose and energy homeostasis.

Topics: Animals; Caenorhabditis elegans; Central Nervous System; Diabetes Mellitus; Energy Metabolism; Glucose; Homeostasis; Humans; Insulin; Insulin Secretion; Leptin; Liver; Signal Transduction

With the growing prevalence of obesity, scientific interest in the biology of adipose tissue has been extended to the secretory products of adipocytes, since they are increasingly shown to affect several aspects in the pathogenesis of obesity-related diseases. The cloning of the ob gene is consistent with this concept and suggests that body fat content in adult rodents is regulated by a negative feedback loop centred in the hypothalamus. In recent years, a number of additional signalling molecules secreted by adipose tissue have been discovered, commonly referred to as 'adipocytokines'. Among these, adiponectin is perhaps the most interesting and promising compound for the clinician since it has profound protective actions in the pathogenesis of diabetes and cardiovascular disease. Adiponectin is low in obese subjects and, in particular, insulin-resistant patients. In contrast, resistin seems to be of greater relevance in relation to the immune stress response than in the regulation of glucose homeostasis. However, inflammatory processes have recently been connected with the development of atherosclerosis. Finally, little is known regarding the clinical relevance of visfatin. Recent research has revealed many functions of adipocytokines extending far beyond metabolism, such as immunity, cancer and bone formation. This report aims to review some of the recent topics of adipocytokine research that may be of particular importance.

Topics: Adiponectin; Adipose Tissue; Animals; Cardiovascular Diseases; Cytokines; Diabetes Mellitus; Humans; Insulin Resistance; Leptin; Mice; Nicotinamide Phosphoribosyltransferase; Resistin

In this review article, the crucial roles of adipocytes in the development of so-called metabolic syndrome and vascular disease are reviewed, focusing on adipocyte-derived bioactive substances, adipocytokines. Recent progress in adipocyte biology shows that adipocytes are not merely energy-storing cells but that they secrete a variety of hormones cytokines, growth factors, and other bioactive substances. To search for novel adipocytokines by the large-scale random sequence analysis of expressed genes in adipocytes, we identified an adipose-specific collagen-like molecule, adiponectin. This novel adipocytokine has plural biofunctions, such as antidiabetic, antiatherosclerotic, and antiinflammatory functions. Adiponectin plasma levels decrease with the accumulation of visceral adipose tissue. In this review, we discuss the link of adiponectin to visceral adiposity, insulin resistance, and vascular diseases.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Animals; Arteriosclerosis; Diabetes Mellitus; Gene Expression Profiling; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Metabolic Syndrome; Mice; Mice, Knockout; Models, Biological; Obesity; Organ Specificity; Proteins; Subcutaneous Tissue; Viscera

Topics: Adrenal Glands; Adult; Androgens; Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus; Female; Humans; Hydrocortisone; Insulin Resistance; Leptin; Luteinizing Hormone; Ovary; Pituitary Gland; Polycystic Ovary Syndrome

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

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

Topics: Amyloid; Animals; Biomarkers; Bone and Bones; Bone Density; Diabetes Complications; Diabetes Mellitus; Diabetic Angiopathies; Humans; Insulin; Insulin-Like Growth Factor I; Islet Amyloid Polypeptide; Leptin; Osteoblasts; Osteoporosis; Rats

Obesity represents one of the most serious global health issues with approximately 310 million people presently affected. It develops because of a mismatch between energy intake and expenditure that results from behavior (feeding behavior and time spent active) and physiology (resting metabolism and expenditure when active). Both of these traits are affected by environmental and genetic factors. The dramatic increase in the numbers of obese people in Western societies reflects mostly changing environmental factors and is linked to reduced activity and perhaps also increased food intake. However, in all societies and subpopulations, there are both obese and nonobese subjects. These differences are primarily a consequence of genetic factors as is revealed by the high heritability for body mass index. Most researchers agree that energy balance and, hence, body weight are regulated phenomena. There is some disagreement about exactly how this regulation occurs. However, a common model is the "lipostatic" regulation system, whereby our energy stores generate signals that are compared with targets encoded in the brain, and differences between these drive our food intake levels, activity patterns, and resting and active metabolisms. Considerable advances were made in the last decade in understanding the molecular basis of this lipostatic system. Some obese people have high body weight because they have broken lipostats, but these are a rare minority. This suggests that for the majority of obese people, the lipostat is set at an inappropriately high level. When combined with exposure to an environment where there is ready availability of food at low energy costs to obtain it, obesity develops. The evolutionary background to how such a system might have evolved involves the evolution of social behavior, the harnessing of fire, and the development of weapons that effectively freed humans from the risks of predation. The lipostatic model not only explains why some people become obese whereas others do not, but also allows us to understand why energy-controlled diets do not work. Drug-based solutions to the obesity problem that work with the lipostat, rather than against it, are presently under development and will probably be in regular use within 5-10 y. However, several lines of evidence including genetic mapping studies of quantitative trait loci associated with obesity suggest that our present understanding of the regulatory system is still rudimentary. In partic

Topics: Adult; Animals; Body Mass Index; Child; Diabetes Mellitus; Energy Intake; Energy Metabolism; Environment; Female; Humans; Leptin; Male; Obesity; Prevalence

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

The adipocyte-derived hormone leptin and the pancreatic beta cell-derived hormone insulin each function as afferent signals to the hypothalamus in an endocrine feedback loop that regulates body adiposity. Although these two hormones, and the receptors on which they act, are unrelated and structurally distinct, they exert overlapping effects in the arcuate nucleus, a key hypothalamic area involved in energy homeostasis. Defects in either insulin or leptin signaling in the brain result in hyperphagia, disordered glucose homeostasis, and reproductive dysfunction. To explain this striking physiological overlap, we hypothesize that hypothalamic insulin and leptin signaling converge upon a single intracellular signal transduction pathway, known as the insulin-receptor-substrate phosphatidylinositol 3-kinase pathway. Here we synthesize data from a variety of model systems in which such "cross-talk" between insulin and leptin signal transduction has either been observed or can be inferred, discuss our own data demonstrating that insulin and leptin both activate hypothalamic phosphatidylinositol 3-kinase signaling, and discuss the significance of such convergence with respect to neuronal function in normal individuals and in pathological states such as obesity. Identification of the key early molecular events mediating the action of both insulin and leptin in hypothalamic neurons promises new insight into the regulation of these neurons in health and disease.

Topics: Animals; Diabetes Mellitus; Eating; Feeding Behavior; Hypoglycemic Agents; Hypothalamus; Insulin; Intracellular Fluid; Leptin; Mice; Mice, Knockout; Models, Biological; Neurons; Obesity; Phosphatidylinositol 3-Kinases; Receptor Cross-Talk; Signal Transduction

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

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

Leptin has been shown to have a wide repertoire of peripheral effects, some of which are mediated through the central nervous system and others that are induced through a direct action on target tissues. There is now evidence showing that leptin exerts some of its metabolic effects acting directly on peripheral tissues. The role of leptin has expanded from a narrow position in obesity to effects on biological processes, such as diabetes, appetite, thermogenesis, the immune system and reproduction. Here in a first part, we review preclinical evidence for direct effects on specific tissues (neurons, liver and muscle) and metabolic pathways. In a second part we review clinical evidence for leptin effects. In particular we review the effects of recombinant human leptin in lean, obese, diabetic subjects and in patients with congenital leptin deficiency or lipoatrophic diabetes. Additionally, while clinic leptin has not shown dramatic effects in obese/diabetic subjects with measurable serum leptin, in states of leptin deficiency treatment with leptin has been shown to have profound effects on body weight and appetite and insulin resistance.

Topics: Animals; Diabetes Mellitus; Humans; Leptin; Liver; Muscles; Neurons; Obesity

Early onset obesity and type II diabetes is rapidly becoming an epidemic, especially within the United States. This dramatic increase is likely due to many factors including both prenatal and postnatal environmental cues. The purpose of this review is to highlight some of the recent advances in our knowledge of the development of the hypothalamic circuits involved in the regulation of energy balance, with a focus on the neuropeptide Y (NPY) system. Unlike the adult rat, during the postnatal period NPY is transiently expressed in several hypothalamic regions, along with the expected expression within the arcuate nucleus (ARH). These transient populations of NPY neurons during the postnatal period may provide local NPY production to sustain the necessary energy intake during this critical growth phase. This may be physiologically important since ARH-NPY projections do not fully develop until the 3rd postnatal week. The significance of this ontogeny is that many peripheral metabolic signals have little effect of feeding prior to the development of the ARH projections. The essential questions now are whether prenatal and/or postnatal exposure to high levels of insulin or leptin during development can cause permanent changes in the function of hypothalamic circuits. It is vital to understand not only the natural development of the hypothalamic circuits that regulate energy homeostasis, but also their abnormal development caused by maternal and postnatal environmental cues. This will be pivotal for designing intervention and therapeutics to treat early onset obesity/type II diabetes, which may very well need to be different from those designed to prevent/treat adult onset obesity/type II diabetes.

Topics: alpha-MSH; Animals; Arcuate Nucleus of Hypothalamus; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Humans; Hypothalamus; Insulin; Leptin; Male; Nerve Net; Neuropeptide Y; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Inbred Strains

Both type 2 diabetes and hypertension are multifactorial diseases. Several lines of evidence suggested that common genetic factors contribute to both conditions. Genes responsible for obesity and insulin resistance are candidates for common genetic factors. Among candidate genes are genes encoding glycogen synthase, beta 3-adrenergic receptor, glycogen-associated regulatory subunit of protein phosphatase-1, peroxisome proliferator--activated receptor-gamma (PPAR gamma), leptin and adiponectin. In addition, recent genome scans mapped loci linked to type 2 diabetes, hypertension and/or metabolic syndrome. Identification of genes responsible for both type 2 diabetes and hypertension will increase our understanding of molecular mechanisms of these conditions and facilitate the development of effective methods for prevention and intervention of diabetes and hypertension as well as metabolic syndrome.

Topics: Adiponectin; Animals; Diabetes Complications; Diabetes Mellitus; Glycogen Synthase; Humans; Hypertension; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Obesity; Proteins; Receptors, Adrenergic, beta-3; Receptors, Cytoplasmic and Nuclear; Transcription Factors

There is an increasing epidemic of obesity in the Western and developing world that has not spared children and, hence, is of great concern. Obesity presents numerous physiological and psychosocial problems for the child. Childhood obesity not only increases the risk of obesity in adulthood, it is associated with type 2 diabetes mellitus; is the leading cause of pediatric hypertension; increases the risk of coronary heart disease; and increases stress on the weight-bearing joints. Social and psychological problems are also significant consequences of obesity in children, with lowering of self-esteem and its effects on relationships with peers. Obesity is clearly associated with increased levels of the recently discovered hormone, leptin. Leptin, secreted from adipocytes, is involved in the regulation of food intake, energy expenditure, and energy balance in humans. This review focuses on the hormone, leptin, in an effort to document some of its many local and systemic effects on the body and, specifically, its potential role in obesity-induced diabetes.

Topics: Adipose Tissue; Animals; Appetite; Diabetes Mellitus; Gluconeogenesis; Humans; Leptin; Obesity; Satiation

Obesity is commonly associated with the development of insulin resistance and diabetes in humans and rodents. Insulin resistance and diabetes are observed in lipoatrophic individuals or rodent models of lipoatrophy. Here we focus on the role of leptin, the product of the obesity (ob) gene, in the development of insulin resistance and diabetes associated with obesity and lipoatrophy. We review the reported effects of leptin on whole body glucose metabolism and compare and contrast these with direct effects on skeletal muscle, fat and liver. This summary of paradoxical observations on the effects of leptin on glucose homeostasis and the ability of leptin to induce or improve insulin resistance suggests that a complex interplay exists between direct peripheral and centrally mediated effects of the hormone. Evidence suggesting that leptin acts as a mediator of insulin release from pancreatic beta cells is reviewed. Finally, intracellular signaling mechanisms stimulated by both leptin and insulin are discussed, with potential points of cross-talk suggested.

Topics: Adipose Tissue; Animals; Diabetes Mellitus; Diabetes Mellitus, Experimental; Glucose; Humans; Insulin; Insulin Resistance; Insulin Secretion; Leptin; Lipodystrophy; Liver; Mice; Muscle, Skeletal; Obesity; Rats; Signal Transduction

Topics: Animals; Body Mass Index; Carbohydrate Metabolism; Diabetes Mellitus; Energy Metabolism; Humans; Hypoglycemic Agents; Insulin Resistance; Leptin; Mutation; Obesity; Receptors, Cell Surface; Receptors, Leptin

Topics: Animals; Apoptosis; Appetite; Diabetes Mellitus; Dietary Fats; Fatty Acids, Nonesterified; Glucose; Humans; Insulin; Insulin Resistance; Islets of Langerhans; Leptin; Liver; Muscle, Skeletal; Myocardium; Obesity

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: Adiponectin; Adipose Tissue; Animals; Diabetes Mellitus; Energy Metabolism; Exercise; Fatty Acids, Nonesterified; Glucose; Hormones, Ectopic; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Lipid Metabolism; Obesity; Proteins; Resistin; Tumor Necrosis Factor-alpha

Topics: Adipose Tissue; Diabetes Mellitus; Humans; Inflammation; Leptin; Life Style; Obesity

Protein tyrosine phosphatases (PTPs) control signal transduction pathways and have recently emerged as potential drug targets. Inhibition of individual PTPs can result in the activation of therapeutically relevant kinase cascades. This is particularly useful in cases where disease is associated with hormonal resistance, such as insensitivity to insulin or leptin. Currently, PTP1B is being investigated by a number of companies as a promising target for leptin/insulin mimetics and in the treatment of diabetes and obesity. Since all 90-100 PTPs have been identified in the human genome, the challenge now is to identify the function of these enzymes and the therapeutic indications that may exist for specific PTP inhibitors.

Topics: Capillary Permeability; Cyclin-Dependent Kinases; Diabetes Mellitus; Drug Design; Drug Evaluation, Preclinical; Genes, Tumor Suppressor; Humans; Immune System; Infections; Insulin; Leptin; Multigene Family; Neoplasm Proteins; Neoplasms; Obesity; Osteoporosis; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatases; Receptors, Antigen; Signal Transduction; src-Family Kinases

Long chain fatty acid uptake across the plasma membrane occurs, in part, via a protein-mediated process involving a number of fatty acid binding proteins known as fatty acid transporters. A critical step in furthering the understandings of fatty acid transport was the discovery that giant vesicles, prepared from tissues such as muscle and heart, provided a suitable system for measuring fatty acid uptake. These vesicles are large (10-15 microm diameter), are oriented fully right side out, and contain cytosolic FABP in the lumen, which acts as a fatty acid sink, while none of the fatty acid taken up is metabolized or associated with the plasma membrane. The key fatty acid transporters FAT/CD36 and FABPpm are expressed in muscle and heart and their plasma membrane content is positively correlated with rates of fatty acid transport. These transporters are regulated acutely (within minutes) and chronically (days). For instance, both muscle contraction and insulin can translocate FAT/CD36 from an intracellular pool to the plasma membrane, thereby increasing fatty acid transport. With obesity, fatty acid transport is increased along with a concomitant increase in plasmalemmal FAT/CD36 (heart, muscle) and FABPpm (heart only), but without change in the expression of these transporters. This latter observation suggests that some of the fatty acid transporters are permanently relocated to the plasma membrane. In other studies it also appears that fatty acid transport rates are altered in a reciprocal manner to glucose transport. Since disorders in lipid metabolism appear to be an important factor contributing to the etiology of a number of common human diseases such as diabetes and obesity, our evidence that protein-mediated fatty acid transport is a key step in lipid metabolism allows the speculation that malfunctioning of the fatty acid transport process could be a common critical factor in the pathogenesis of these diseases.

Topics: Animals; Biological Transport; Carrier Proteins; CD36 Antigens; Diabetes Mellitus; Fatty Acid-Binding Proteins; Fatty Acids; Heart; Leptin; Membrane Glycoproteins; Membrane Transport Proteins; Muscle, Skeletal; Neoplasm Proteins; Obesity; Organic Anion Transporters; Transport Vesicles

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; Glucose; Humans; Leptin; Obesity; Pregnancy

Topics: Animals; Crosses, Genetic; Diabetes Mellitus; Food Deprivation; Glucose; Humans; Hypertension; Insulin; Leptin; Male; Mice; Mice, Transgenic; Obesity

The metabolic processes that are responsible for the pathophysiology of the fetus of the diabetic mother have been elucidated in recent years and include maternal hyperglycinemia, fetal hyperglycinemia, fetal hyperinsulinemia, and increased levels of maternal, placental, and fetal insulin-like growth factors. Counter-regulatory mechanisms, such as insulin-like growth factors binding proteins and leptin also play a role. The fetal hypermetabolic state leads to increased somatic growth, obesity, and metabolic disturbances with short- and long-term consequences.

Topics: Diabetes Mellitus; Embryonic and Fetal Development; Female; Fetus; Humans; Hyperglycemia; Hyperinsulinism; Insulin-Like Growth Factor Binding Proteins; Leptin; Pregnancy; Pregnancy in Diabetics; Somatomedins

Leptin, the obese gene product, is an adipocyte-derived satiety factor which is involved in the regulation of food intake and energy expenditure. Obesity often accompanies insulin resistance and high levels of leptin. In in vitro studies, leptin has been reported to increase fatty acid oxidation and decrease fatty acid synthesis in adipocytes and hepatocytes. The direct effects of leptin on glucose metabolism and insulin signaling have not been clarified yet. In in vivo studies, however, leptin has been reported to improve insulin sensitivity and glucose metabolism in normal and obese rodents acting mainly through hypothalamus. Moreover leptin has been reported to have antidiabetic effects in insulin-deficient diabetes rats and lipoatrophic diabetes mice. It is suggested that leptin modulates insulin sensitivity and glucose disposal and that leptin may have a pathophysiological and therapeutic implications in diabetes.

Topics: Adipocytes; Animals; Carrier Proteins; Diabetes Mellitus; Glucose; Insulin; Insulin Resistance; Leptin; Liver; Mice; Obesity; Rats; Receptors, Cell Surface; Receptors, Leptin

The clustering of cardiovascular risk factors such as abdominal obesity, hypertension, dyslipidaemia and glucose intolerance in the same persons has been called the metabolic or insulin-resistance syndrome. In 1998 WHO proposed a unifying definition for the syndrome and chose to call it the metabolic syndrome rather than the insulin-resistance syndrome. Although insulin resistance has been considered as a common denominator for the different components of the syndrome, there is still debate as to whether it is pathogenically involved in all of the different components of the syndrome. Clustering of the syndrome in families suggests a genetic component. It is plausible that so-called thrifty genes, which have ensured optimal storage of energy during periods of fasting, could contribute to the phenotype of the metabolic syndrome. Common variants in a number of candidate genes influencing fat and glucose metabolism can probably, together with environmental triggers, increase susceptibility to the syndrome. Among these, the genes for beta 3-adrenergic receptor, hormone-sensitive lipase, lipoprotein lipase, IRS-1, PC-1, skeletal muscle glycogen synthase, etc. appear to increase the risk of the metabolic syndrome. In addition, novel genes may be identified by genome-wide searches.

Topics: Carrier Proteins; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Genetic Predisposition to Disease; Glycogen Synthase; Humans; Hypertension; Insulin Resistance; Leptin; Male; Obesity; Receptors, Adrenergic, beta; Receptors, Cell Surface; Receptors, Cytoplasmic and Nuclear; Receptors, Leptin; Transcription Factors

Both overnutrition and undernutrition affect energy metabolism, with overnutrition raising energy expenditure and undernutrition lowering it. Fever is a powerful stimulator of thermogenesis. In diseases such as cancer, AIDS, diabetes mellitus, and rheumatoid arthritis, whether energy expenditure is increased or decreased often depends on how advanced the disorder is. Early on, when the greater protein turnover characteristic of these conditions is paramount, energy expenditure is increased. In addition, in diseases such as cancer, AIDS, and rheumatoid arthritis in which cytokines are released, the cytokines' thermogenic effect initially increases the metabolic rate. However, as the disease becomes more advanced and leads to cachexia, energy expenditure drops below normal. Acute conditions such as burns and trauma significantly raise energy expenditure, primarily by increasing sympathetic response and the release of catecholamines, which are powerful stimulators of energy expenditure.

Topics: Acquired Immunodeficiency Syndrome; Adult; Age Factors; Aged; Arthritis, Rheumatoid; Basal Metabolism; Burns; Diabetes Mellitus; Eating; Energy Metabolism; Female; Humans; Leptin; Male; Middle Aged; Neoplasms; Obesity; Wounds and Injuries

Obesity is a complex disease resulting from the interaction between a variety of genetic and environmental factors. Research conducted over the past 20 years in the field of genetic epidemiology has contributed to increase our understanding of the genetic basis of obesity. It is now clearly established that overweight and obesity aggregate in families. Studies have shown that the prevalence of obesity is 2 to 8 times higher in families of obese individuals than in the population at large and that the familial risk increases with the severity of obesity. The heritability of the various obesity phenotypes varies considerably depending on the phenotype under study, the nature of familial data and the methods used to compute heritability estimates. Heritability estimates tend to be highest when derived from twin studies (50% à 80%) while they are the lowest when derived from adoption studies (10% à 30%). Several studies have reported the presence of major gene effects for body mass index, body fat and abdominal visceral fat. Finally, there is increasing evidence that shared genetic factors could play a role in determining the covariation between obesity and its major co-morbidities, including blood pressure, insulin resistance, diabetes and dyslipidemia. This genetic covariation is however moderate and accounts for a smaller percentage of the variance compared to the genetic effects reported for each of the phenotypes studied independently.

Topics: Adipose Tissue; Adoption; Biomarkers; Body Mass Index; Diabetes Mellitus; Diseases in Twins; Family Health; Genes, Dominant; Genetic Predisposition to Disease; Genetic Variation; Humans; Leptin; Obesity; Phenotype

Topics: Adipose Tissue; Anti-Obesity Agents; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diet, Reducing; Energy Metabolism; Glucose; Humans; Insulin; Insulin Resistance; Insulin Secretion; Leptin; Muscle, Skeletal; Obesity; Risk Factors; Weight Loss

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

The basic premise of the thrifty gene hypothesis is that certain populations may have genes that determine increased fat storage, which in times of famine represent a survival advantage, but in a modern environment result in obesity and type 2 diabetes. The concept finds support in a unique animal model (Psammomys obesus) as well as among high type 2 diabetes susceptibility populations, such as North American Indians and South Pacific islanders. However, in some developing communities (e.g., Black South Africans) the thrifty phenotype hypothesis of perinatal malnutrition causing beta-cell dysfunction seems a better explanation, but this remains a contentious issue. Several genes have already been identified as candidates for the thrifty genotype, including those encoding proteins of the insulin-signaling and leptin pathways, as well as intermediary fat metabolism. Particular interest lies in the peroxisome-proliferator activated receptors. An innovative approach might be to focus on the "mirror image" of the thrifty genotype-congenital lipoatrophic diabetes mellitus, whose molecular defect remains enigmatic. We conclude that the genetic basis of the thrifty genotype probably derives from the multiplicative effects of polymorphisms at several sites mentioned above, rather than a single regulatory abnormality.

Topics: Adipose Tissue; Animals; Diabetes Mellitus; Diabetes Mellitus, Type 2; Genotype; Humans; Insulin; Leptin; Obesity; Phenotype; Proteins; Signal Transduction

Topics: Animals; Diabetes Mellitus; Drug Resistance; Humans; Insulin Resistance; Leptin; Mice; Obesity; Proteins; Rats

Topics: Diabetes Mellitus; DNA-Binding Proteins; Glucokinase; Hepatocyte Nuclear Factor 1; Hepatocyte Nuclear Factor 1-alpha; Hepatocyte Nuclear Factor 1-beta; Humans; Leptin; Nuclear Proteins; Obesity; Pro-Opiomelanocortin; Proteins; Transcription Factors

Topics: Adipose Tissue; Adolescent; Adult; Animals; Brain; Carrier Proteins; Child; Child, Preschool; Diabetes Mellitus; Energy Metabolism; Fetus; Gene Expression Regulation; Humans; Infant; Infant, Newborn; Leptin; Mice; Obesity; Protein Isoforms; Proteins; Receptors, Cell Surface; Receptors, Leptin; Research

Topics: Adipose Tissue; Animals; Diabetes Mellitus; Dietary Carbohydrates; Dietary Fats; Eating; Energy Metabolism; Humans; Leptin; Nutritional Physiological Phenomena; Obesity; Proteins

Topics: Adipose Tissue; Animals; Body Mass Index; Central Nervous System; Diabetes Mellitus; Humans; Interleukin-6; Leptin; Melanocyte-Stimulating Hormones; Mutation; Neuropeptide Y; Obesity; Proteins; RNA, Messenger; Signal Transduction; Tumor Necrosis Factor-alpha

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

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

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

We compared the associations of circulating biomarkers of inflammation, endothelial and adipocyte dysfunction and coagulation with incident diabetes in the placebo, lifestyle and metformin intervention arms of the Diabetes Prevention Program, a randomised clinical trial, to determine whether reported associations in general populations are reproduced in individuals with impaired glucose tolerance, and whether these associations are independent of traditional diabetes risk factors. We further investigated whether biomarker-incident diabetes associations are influenced by interventions that alter pathophysiology, biomarker concentrations and rates of incident diabetes.. The Diabetes Prevention Program randomised 3234 individuals with impaired glucose tolerance into placebo, metformin (850 mg twice daily) and intensive lifestyle groups and showed that metformin and lifestyle reduced incident diabetes by 31% and 58%, respectively compared with placebo over an average follow-up period of 3.2 years. For this study, we measured adiponectin, leptin, tissue plasminogen activator (as a surrogate for plasminogen activator inhibitor 1), high-sensitivity C-reactive protein, IL-6, monocyte chemotactic protein 1, fibrinogen, E-selectin and intercellular adhesion molecule 1 at baseline and at 1 year by specific immunoassays. Traditional diabetes risk factors were defined as family history, HDL-cholesterol, triacylglycerol, BMI, fasting and 2 h glucose, HbA. E-selectin, (HR 1.19 [95% CI 1.06, 1.34]), adiponectin (0.84 [0.71, 0.99]) and tissue plasminogen activator (1.13 [1.03, 1.24]) were associated with incident diabetes in the placebo group, independent of diabetes risk factors. Only the association between adiponectin and diabetes was maintained in the lifestyle (0.69 [0.52, 0.92]) and metformin groups (0.79 [0.66, 0.94]). E-selectin was not related to diabetes development in either lifestyle or metformin groups. A novel association appeared for change in IL-6 in the metformin group (1.09 [1.021, 1.173]) and for baseline leptin in the lifestyle groups (1.31 [1.06, 1.63]).. These findings clarify associations between an extensive group of biomarkers and incident diabetes in a multi-ethnic cohort with impaired glucose tolerance, the effects of diabetes risk factors on these, and demonstrate differential modification of associations by interventions. They strengthen evidence linking adiponectin to diabetes development, and argue against a central role for endothelial dysfunction. The findings have implications for the pathophysiology of diabetes development and its prevention.

Topics: Adiponectin; Biomarkers; Chemokine CCL2; Diabetes Mellitus; E-Selectin; Fibrinogen; Hypoglycemic Agents; Intercellular Adhesion Molecule-1; Interleukin-6; Leptin; Life Style; Metformin; Tissue Plasminogen Activator

To analyze the effect of low level laser treatment combined with basic therapy periodontal on cytokines and lipopolysaccharide, leptin in gingival sulcus of patients with diabetes mellitus complicated with chronic periodontitis (DMCP).. From January 2016 to January 2017, 80 patients with DMCP were randomly divided into experimental group and control group. Patients in the control group received basic periodontal therapy, while patients in the experimental group received low dose laser combined with basic periodontal treatment. Before treatment and 3 months after treatment, oral PD, SBI and CAL levels were detected in all patients. Venous blood was collected, HbA1c and FPG levels in blood serum were detected. TNF-α, IL-1, hs-CRP, LPS, leptin in gingival crevicular fluid were detected. Statistical analyses were performed using SPSS19.0 software package.. After treatment, CAL, PD, SBI, FBG, HbA1c, TNF-α, IL-1, hs-CRP, LPS levels were significantly decreased, Leptin level increased in both group, and the difference was significant (P<0.05). After treatment, CAL, PD, SBI, FBG, HbA1c, TNF-α, hs-CRP, IL-1 and the level of LPS in the experimental group was significantly lower than the control group (P<0.05), and the level of leptin was significantly higher than that of the control group (P<0.05).. Low level laser combined with basic periodontal treatment can effectively reduce LPS level of DMCP patients in gingival sulcus, and improve the level of Leptin, significantly improve the inflammatory reaction and clinical efficacy.

Topics: Chronic Periodontitis; Cytokines; Diabetes Complications; Diabetes Mellitus; Gingival Crevicular Fluid; Humans; Laser Therapy; Leptin; Lipopolysaccharides; Periodontal Index

To examine prospective changes in cardiovascular disease (CVD) and type-2 diabetes risk factors in young adult first episode psychotic (FEP) patients treated with second generation antipsychotic medications.. At baseline, fasting serum and anthropometric measures were obtained from 45 FEP patients and 41 healthy adults (controls) of similar age, ethnicity and sex; sixteen of the FEP patients remained on the same antipsychotic medication and were available for a second blood draw at 24 weeks of treatment. Serum was assayed for glucose, insulin, triglycerides, total cholesterol and high and low density lipoproteins (HDL, LDL), adiponectin, leptin, interleukin 6, E-selectin and VCAM-1. Wilcoxon nonparametric tests were used to compare risk markers between the FEP and control group at baseline and to evaluate pre-post treatment changes within the FEP group.. At baseline, the distributions of risk marker values were similar between the two groups and the percentages of FEP patients and healthy controls who were overweight/obese, dyslipidemic, hyperglycemic, and hyperinsulinemic did not differ. At 24 weeks, compared to baseline, FEP patients showed significant increases in BMI (p=0.0002), glucose (p=0.0449), insulin (p=0.0161), cholesterol (p=0.0129), leptin (p=0.0215), and E-selectin (p=0.0195), and a decrease in adiponectin (p=0.0371).. Among patients with first episode psychosis, 6-month treatment with second generation antipsychotics is associated with the exacerbation of pre-existing and emergence of new CVD and diabetes risk factors.

Topics: Adolescent; Adult; Antipsychotic Agents; Blood Glucose; Body Mass Index; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus; Female; Follow-Up Studies; Humans; Insulin; Leptin; Male; Psychotic Disorders; Retrospective Studies; Risk Factors; Statistics, Nonparametric; Triglycerides

The effect of statins on insulin resistance is controversial and poorly studied in nondiabetic subjects. In addition, the effect of statins on leptin and adiponectin has never been studied.. Forty healthy nondiabetic volunteers (22 men and 18 women) aged 28 to 72 were randomized either to placebo or pravastatin 40 mg daily for a 12-week period. Insulin resistance, assessed using the Quantitative Insulin Sensitivity Check Index (QUICKI), as well as serum leptin and adiponectin levels, was measured at baseline and at the end of therapy.. Pravastatin treatment decreased total cholesterol, low-density lipoprotein cholesterol, and triglycerides levels by 24%, 32%, and 14%, respectively ( P < .05 for all), but did not affect glucose and insulin levels, the (QUICKI) index, and adiponectin and leptin levels. When stratification was performed according to QUICKI index or sex, no significant differences were observed in the prevalues and postvalues of leptin, adiponectin, or QUICKI index in the pravastatin group. Adiponectin, leptin, and QUICKI index were statistically higher in women than in men ( P < .001 for both variables). Adiponectin was negatively correlated with body mass index (BMI; r = -0.39, P < .05) and positively correlated with the QUICKI index ( r = 0.54, P < .001) and with high-density lipoprotein cholesterol ( r = 0.50, P < .01). The relation between adiponectin and QUICKI index remained significant after adjustment for sex and BMI ( P = .005 and P = .007, respectively). Leptin was only related to BMI ( r = 0.57, P < .001) and to sex ( P < .001) with no significant correlations with lipid parameters or QUICKI index. Both sex and BMI are independent predictors of leptin ( P < .001 and P < .001).. A 12-week treatment with pravastatin 40 mg/d does not change the QUICKI index and leptin and adiponectin levels in healthy volunteers. In addition, our results emphasize the importance of sex and BMI in the determination of both adiponectin and leptin. Adiponectin was also related to QUICKI index, whereas this relation was not found with leptin.

Topics: Adiponectin; Adult; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus; Double-Blind Method; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Male; Middle Aged; Placebos; Pravastatin; Reference Values

Nonalcoholic steatohepatitis (NASH) is a metabolic disorder of the liver, which, although usually relatively mild, may in some cause fibrosis, cirrhosis, and premature death resulting from liver failure. Its prevalence is increasing, and it is probably underestimated as a cause for cirrhosis. The need for an effective treatment is clear and urgent. Although several small, pilot, and randomized studies have been reported, large-scale studies are yet to be performed in patients with NASH. The aim of therapy is to intervene early in patients at risk of progression of liver disease. In this review, we summarize the extant literature on the management of NASH and discuss the potential future therapies and prophylactic recommendations in patients with NASH.

Topics: Diabetes Mellitus; Fatty Liver; Hepatitis; Humans; Hyperinsulinism; Iron; Leptin; Liver Transplantation; Risk Factors; Silymarin; Triglycerides; Tumor Necrosis Factor-alpha; Ursodeoxycholic Acid; Vitamin E

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 discovery of leptin (LEP) shed new light on mechanisms regulating body fat mass (BFM). In this aspect, interactions between LEP and glucocorticoids at hypothalamic level may be of great importance. Factors that influence plasma LEP levels have not been fully recognized and available data on LEP levels are often inconsistent. The aim of this study was to evaluate absolute and BFM-corrected plasma LEP levels and their diurnal variation, as well as to assess the relationship between LEP levels, body fat distribution, and hormones influencing body fat in subjects with various levels of endogenous cortisol and different nutritional status. Group I was composed of 14 women aged 14-58 yrs, BMI of 23.9-37.1 kg/m2, with hypercortisolism due to ACTH-dependent and ACTH-independent Cushing's syndrome (CUS). 17 women with visceral obesity (OTY) and normal or disturbed carbohydrate metabolism, i.e. impaired glucose tolerance (IGT) and diabetes mellitus (DM), aged 24 do 50 yrs, BMI 30.0-46.1 kg/m2, were included in group II. Group III consisted of 14 women with Addison's disease (AD), aged 18 do 63 yrs, BMI 15.4-31.6 kg/m2. The control group IV (KON) included 17 healthy women with normal BMI. BMI, WHR, body composition, and body fat distribution (DEXA method) were assessed in all subjects. Basal plasma levels of LEP, beta-endorphin (B-EP), cortisol (F), insulin-like growth factor-1 (IGF-1) were measured with RIA test kits. Plasma adrenocorticotrophin (ACTH) levels, serum levels of insulin (IRI) and growth hormone (GH) were measured with IRMA test kits. Blood glucose (G) concentration was determined with an enzymatic method. Adiposity-corrected LEP levels were expressed as LEP/BFM and LEP/%BF indices. Fasting insulin resistance index (FIRI) was also calculated. Higher BFM and %BF values were found in the OTY group as compared with CUS KON and AD groups. BFM distribution did not differ in KON and AD groups whereas CUS subjects exhibited a higher accumulation of fat in the trunk when compared to OTY subjects. Absolute LEP levels were correlated with trunk BF in CUS patients whereas in KON and AD groups these levels were correlated only with limb fat. Absolute LEP levels in CUS and OTY groups were comparable, whereas LEP/BFM and LEP/%BF indices were higher in the CUS group (Table 1) reflecting upregulation of LEP levels (Figs. 1, 2). BFM-corrected LEP levels were comparable in groups with normal cortisolemia, i.e. in OTY and KON groups, whereas in the AD group both abso

Topics: Addison Disease; Adipose Tissue; Adolescent; Adult; Blood Glucose; Body Mass Index; Circadian Rhythm; Cushing Syndrome; Diabetes Mellitus; Down-Regulation; Female; Glucocorticoids; Hormones; Humans; Hydrocortisone; Insulin Resistance; Leptin; Middle Aged; Nutritional Status; Obesity; Tissue Distribution; Up-Regulation

The adipocyte hormone leptin is important in regulating energy homeostasis. Since severe lipodystrophy is associated with leptin deficiency, insulin resistance, hypertriglyceridemia, and hepatic steatosis, we assessed whether leptin replacement would ameliorate this condition.. Nine female patients (age range, 15 to 42 years; eight with diabetes mellitus) who had lipodystrophy and serum leptin levels of less than 4 ng per milliliter (0.32 nmol per milliliter) received recombinant methionyl human leptin (recombinant leptin). Recombinant leptin was administered subcutaneously twice a day for four months at escalating doses to achieve low, intermediate, and high physiologic replacement levels of leptin.. During treatment with recombinant leptin, the serum leptin level increased from a mean (+/- SE) of 1.3 +/- 0.3 ng per milliliter to 11.1 +/- 2.5 ng per milliliter (0.1 +/- 0.02 to 0.9 +/- 0.2 nmol per milliliter). The absolute decrease in the glycosylated hemoglobin value was 1.9 percent (95 percent confidence interval, 1.1 to 2.7 percent; P=0.001) in the eight patients with diabetes. Four months of therapy decreased average triglyceride levels by 60 percent (95 percent confidence interval, 43 to 77 percent; P<0.001) and liver volume by an average of 28 percent (95 percent confidence interval, 20 to 36 percent; P=0.002) in all nine patients and led to the discontinuation of or a large reduction in antidiabetes therapy. Self-reported daily caloric intake and the measured resting metabolic rate also decreased significantly with therapy. Overall, recombinant leptin therapy was well tolerated.. Leptin-replacement therapy improved glycemic control and decreased triglyceride levels in patients with lipodystrophy and leptin deficiency. Leptin deficiency contributes to the insulin resistance and other metabolic abnormalities associated with severe lipodystrophy.

Topics: Adolescent; Adult; Basal Metabolism; Blood Glucose; Diabetes Complications; Diabetes Mellitus; Energy Intake; Female; Glycated Hemoglobin; Humans; Injections, Subcutaneous; Insulin Resistance; Leptin; Lipodystrophy; Liver; Liver Function Tests; Prospective Studies; Triglycerides

A weight-reducing effect of metformin has been demonstrated in obese subjects with and without diabetes. The mechanisms of this action are unclear, which may be partly due to the fact that in obese and diabetic patients the substance's effects result from a complex interaction with the distinct endocrine and metabolic disturbances in these patients. To dissociate primary from secondary action of metformin, we examined effects of the substance in normal-weight healthy subjects. Fifteen normal-weight men were treated with metformin (850 mg twice daily) or placebo for a 15-day period in a double-blind, placebo-controlled, cross-over study. Anthropometric, psychologic, cardiovascular, endocrine, and metabolic parameters were assessed before and at the end of the treatment period. Metformin did not affect body weight (P =.838) and body fat mass (P =.916). Yet, serum leptin concentration was distinctly reduced after metformin (P <.001). Also, metformin reduced the concentration of plasma glucose (P =.011), serum insulin (P=.044), and serum insulin-like growth factor -1 (IGF-1) (P=.013), while it increased serum glucagon concentration (P <.001). There were no effects of metformin on feelings of hunger, blood pressure, heart rate, resting energy expenditure, the respiratory quotient, free fatty acids, beta-hydroxybutyrate, glycerol, triglycerides, cholesterol, and uric acid (all P >.1). Data indicate that metformin decreases the serum leptin concentration even without affecting body weight and body composition in normal-weight men.

Topics: Adipose Tissue; Adult; Blood Pressure; Body Weight; C-Peptide; Diabetes Mellitus; Glucagon; Humans; Hydrocortisone; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Male; Metformin; Obesity; Reference Values

The prevalence of type 2 diabetes in American adolescents has increased markedly during the past generation. Although the factors that contribute to the development of type 2 diabetes are complex and not wholly elucidated, the triad of severe obesity, hyperinsulinemia, and a family history of type 2 diabetes places a child at an increased risk for development of the disease. Current approaches to the prevention of type 2 diabetes, including dietary counseling and exercise, have had limited success. We reasoned that drugs that increase glucose tolerance in diabetic patients might prove useful in preventing the progression to glucose intolerance in high-risk patients. To that end, we conducted a double-blind, placebo-controlled study of the effects of metformin on body mass index (BMI), serum leptin, glucose tolerance, and serum lipids in obese adolescents with fasting hyperinsulinemia and a family history of type 2 diabetes.. The study population consisted of 29 white and black adolescents aged 12 to 19 years. All had BMIs exceeding 30 kg/m(2). Criteria for enrollment included: 1) a fasting insulin concentration exceeding 15 microU/mL; and 2) at least 1 first- or second-degree relative with type 2 diabetes. All patients had fasting plasma glucose concentrations <110 mg% and hemoglobin A1c concentrations

Topics: Adolescent; Blood Glucose; Body Mass Index; Body Weight; Child; Comorbidity; Diabetes Mellitus; Diabetes Mellitus, Type 2; Family; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Hypoglycemic Agents; Insulin; Leptin; Male; Metformin; Obesity; Pilot Projects

Acylation-stimulating protein is an adipocyte-derived protein that has recently been suggested to play an important role in the regulation of triglyceride storage. To date, little information has been reported with regard to fasting acylation-stimulating protein levels and its relation to metabolic control, leptin, and/or lipids in subjects with diabetes mellitus. We therefore evaluated fasting acylation-stimulating protein, leptin, and lipid levels before and 4 months after improving glycemic control with sulfonylurea treatment in a group of poorly controlled obese women with type 2 diabetes and in age- and body mass index-matched nondiabetic obese women. Fasting plasma acylation-stimulating protein (49.67 +/- 19.73 vs. 48.49 +/- 20.70 nmol/liter) and leptin concentrations (33.7 +/- 23.2 vs. 26.2 +/- 10.6 ng/ml) were not significantly different between the groups. Improvement of glycemic control produced parallel falls in fasting blood glucose and hemoglobin A1c. Plasma leptin concentrations were also significantly reduced (33.69 +/- 23.2 vs. 22.73 +/- 11.26 ng/ml; P = 0.036), whereas fasting acylation-stimulating protein concentrations were significantly increased after treatment (48.49 +/- 20.70 vs. 72,82 +/- 29,72 nmol/liter; P = 0.004). Nevertheless, lipids and apolipoprotein B did not significantly improve. We could not find any correlation between elevated acylation-stimulating protein levels and changes in body mass index, glucose, insulin, hemoglobin A1c, leptin, or lipid levels. Similarly, the decrement in circulating leptin levels observed after treatment did not correlate with changes in the levels of glucose, insulin, hemoglobin A1c, or any lipid parameters. We conclude that improved glycemic control increases fasting acylation-stimulating protein and decreases leptin concentrations, but not corrects critical lipid abnormalities in type 2 obese diabetic subjects. Moreover, altered plasma acylation-stimulating protein levels are not associated with changes in body mass index or lipid, leptin, insulin, or glucose levels. Thus, our findings suggest that improved glycemic control or insulin resistance is not responsible for abnormal fatty acid trapping, and failure of lipids to improve after treatment in our patients is consistent with the acylation-stimulating protein resistance concept.

Topics: Apolipoprotein A-I; Apolipoproteins B; Biomarkers; Blood Glucose; Blood Pressure; Blood Proteins; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cholesterol, VLDL; Complement C3a; Diabetes Mellitus; Diabetes Mellitus, Type 2; Fasting; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Leptin; Middle Aged; Obesity; Sulfonylurea Compounds; Triglycerides

The aim of the study was to examine the effects of weight reduction by exercise and diet on metabolic control in obese subjects with insulin resistance, particularly investigating if changes in serum leptin concentrations were directly associated with improvements in metabolic control. Twenty obese men (48 +/- 8 yr; body mass index 32. 1 +/- 3.9 kg/m(2)) with previously diagnosed type II diabetes mellitus were assigned to a 4-wk intervention program of exercise (2, 200 kcal/wk) and diet (1,000 kcal/day; 50% carbohydrates, 25% protein, 25% fat; polyunsaturated-to-saturated fatty acid ratio 1.0). Intervention induced significant reductions in body weight and serum leptin levels, and improvements in lipoprotein profile and glucose control. Reductions in leptin levels were directly associated with reductions in serum triglycerides and cholesterol, a finding that was independent of improvements in glucose control. These data show that serum leptin concentrations can be reduced with caloric restriction and exercise in male patients with type II diabetes, and they suggest a direct relationship between leptin and lipoprotein metabolism that is not solely due to weight reduction.

Topics: Adult; Blood Glucose; Cholesterol; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diet, Reducing; Exercise Therapy; Humans; Leptin; Lipids; Lipoproteins; Longitudinal Studies; Male; Middle Aged; Obesity; Prospective Studies; Proteins; Triglycerides; Weight Loss

To investigate the effect of physical training on leptin levels in elderly, obese patients with type 2 diabetes mellitus.. Twenty men and 38 women with type 2 diabetes mellitus with a body mass index (BMI) of > 25 kg/m2 participated in a prospective randomized study. Patients were either on oral glucose lowering drugs (n = 39) or insulin therapy (n = 19). Physical training consisted of a guided, standardized, 6-week training programme performed in the hospital on a cyclo ergometer followed by a 6-week period of guided training at home and ended in a 12-week period of training at home without supervision. Clinical data and laboratory samples including fasting insulin and leptin levels and maximal aerobic capacity were assessed at the start of the study and at 6 and 26 weeks thereafter.. Physical training resulted in significantly positive changes in maximal aerobic capacity (VO2max) and maximum work load. No effects of physical training on serum leptin levels and insulin concentrations were detected. Leptin levels were strongly correlated with body mass index (r = 0.63), body fat content (r = 0.61), and fasting insulin concentrations (r = 0.38). Women had threefold higher leptin levels than men. No differences in leptin levels between patients on insulin therapy and patients on oral glucose lowering drugs were found.. No effect of physical training on leptin levels was detectable in elderly, obese type 2 diabetes mellitus patients.

Topics: Aged; Diabetes Mellitus; Diabetes Mellitus, Type 2; Fasting; Female; Humans; Hypoglycemic Agents; Insulin; Leptin; Male; Middle Aged; Obesity; Oxygen Consumption; Physical Education and Training; Prospective Studies; Sex Characteristics

Leptin, a hormone produced by adipose tissue, is potentially involved in the regulation of adiposity. The effects of insulin and body fat distribution on human plasma leptin have not yet been clearly defined. The present study investigated the relationships between plasma leptin and total and regional body fat parameters measured by anthropometry and bienergetic absorptiometry associated or not with computed tomography, taking glucose metabolism into account. A cohort of 51 obese Caucasian women (23 with normal glucose tolerance, 11 with impaired glucose tolerance, and 17 with Type 2 diabetes) was analysed. All non-diabetic subjects had an oral glucose tolerance test together with plasma glucose and insulin measurements. Moreover, a subgroup of 7 diabetic subjects with failure to oral antidiabetic treatment was submitted to about 12 days of intensive subcutaneous insulin therapy. Plasma leptin was essentially dependent on total body fat mass (r = 0.83, p < 0.0001, for the whole population), but not related to adipose tissue distribution. An independent correlation between leptin adjusted on body fat mass and fasting insulinaemia (R = 0.72, p < 0.02) or C-peptide (R = 0.62, p < 0.03) was found significant only in the diabetic group. Insulin treatment was associated with a moderate and transient increase of plasma leptin. The relative variations of plasma leptin levels were strongly negatively correlated with those of free fatty acids. The present data confirm that plasma leptin is not dependent on body fat distribution and suggest an indirect effect of insulin on leptin secretion in clinical conditions.

Topics: Adipose Tissue; Adult; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Leptin; Linear Models; Middle Aged; Obesity; Proteins; White People

A diabetogenic high fat diet (HFD) can be used to induce insulin resistance and obesity in animal models; however, its effects on bone are unknown. We investigated the effects of long term HFD on bone in ovariectomized (OVX) female rats. We used 12-week-old female rats divided randomly into four groups: sham operation (sham), sham operation with HFD (SHFD), OVX and OVX with HFD (OVX + HFD). Ovaries were removed in the OVX and OVX + HFD groups and the SHFD and OVX + HFD groups were fed a HFD for 28 weeks. Serum estrogen, testosterone, lipid, adiponectin, leptin, tartrate-resistant acid phosphatase (TRAP) and

Topics: Adiponectin; Animals; Diabetes Mellitus; Diet, High-Fat; Estrogens; Female; Humans; Leptin; Osteocalcin; Ovariectomy; Rats; Testosterone

Obesity is a dramatically increasing disease, accompanied with comorbidities such as cardiovascular disease and obstructive sleep apnea syndrome (OSAS). Both obesity and OSAS per se are associated with systemic inflammation. However, the multifactorial impact of obesity, OSAS, and its concomitant diseases on the immunological characteristics of circulating monocytes has not yet been fully resolved. Monocyte subsets of 82 patients with obesity were analyzed in whole blood measurements in terms of the CD14/CD16 cell surface expression patterns and different monocytic adhesion molecules using flow cytometry. Plasma levels of adipokines adiponectin and leptin of all patients were evaluated and correlated with accompanying cellular and clinical values. Whole blood measurements revealed a significant overall redistribution of CD14/CD16 monocyte subsets in patients with obesity. Monocytic adhesion molecules CD11a, CD11b, and CX3CR1 were significantly elevated. The observed alterations significantly correlated with plasma leptin levels and diabetes status as crucial amplifying factors. The additive impact of obesity, diabetes, and OSAS on the immunological balance of peripheral blood monocytes requires a coordinated regimen in terms of therapeutic treatment, respiratory support, and weight loss to improve the systemic immunity in these patients.

Topics: Diabetes Mellitus; Humans; Leptin; Monocytes; Obesity; Sleep Apnea, Obstructive

Diabetes mellitus (DM) is one of the most common diseases worldwide. DM may disrupt hormone regulation. Metabolic hormones, leptin, ghrelin, glucagon, and glucagon-like peptide 1, are produced by the salivary glands and taste cells. These salivary hormones are expressed at different levels in diabetic patients compared to control group and may cause differences in the perception of sweetness. This study is aimed at assessing the concentrations of salivary hormones leptin, ghrelin, glucagon, and GLP-1 and their correlations with sweet taste perception (including thresholds and preferences) in patients with DM. A total of 155 participants were divided into three groups: controlled DM, uncontrolled DM, and control groups. Saliva samples were collected to determine salivary hormone concentrations by ELISA kits. Varying sucrose concentrations (0.015, 0.03, 0.06, 0.12, 0.25, 0.5, and 1 mol/l) were used to assess sweetness thresholds and preferences. Results showed a significant increase in salivary leptin concentrations in the controlled DM and uncontrolled DM compared to the control group. In contrast, salivary ghrelin and GLP-1 concentrations were significantly lower in the uncontrolled DM group than in the control group. In general, HbA1c was positively correlated with salivary leptin concentrations and negatively correlated with salivary ghrelin concentrations. Additionally, in both the controlled and uncontrolled DM groups, salivary leptin was negatively correlated with the perception of sweetness. Salivary glucagon concentrations were negatively correlated with sweet taste preferences in both controlled and uncontrolled DM. In conclusion, the salivary hormones leptin, ghrelin, and GLP-1 are produced either higher or lower in patients with diabetes compared to the control group. In addition, salivary leptin and glucagon are inversely associated with sweet taste preference in diabetic patients.

Topics: Diabetes Mellitus; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Humans; Leptin; Taste; Taste Perception; Transcription Factors

Post-transplant diabetes mellitus (PTDM) is a metabolic complication that often occurs after kidney transplantation. Factors that increase the risk of this complication are currently being researched, including polymorphisms in genes affecting carbohydrate-lipid metabolism. Leptin is a hormone that affects appetite and adipose tissue and plays an important role in regulating insulin secretion as well as glucose and lipid metabolism. The aim of this study was to examine the association between leptin receptor gene polymorphisms and the development of post-transplant diabetes mellitus in patients treated with tacrolimus. The study was carried out in a group of 201 patients who underwent kidney transplantation. The follow-up period was 12 months. PTDM was diagnosed in 35 patients. Analysing the LEPR gene rs1137101 polymorphism, we observed in patients with PTDM an increased frequency of GG genotype carriers (GG vs AA, OR 3.36; 95 % CI 0.99-11.46; p = 0.04). There were no statistically significant differences in the distribution of the LEPR rs1137100 and LEPR rs1805094 polymorphisms between patients with and without PTDM. Multivariate regression analysis confirmed that female sex, advanced age, increased BMI and a higher number of LEPR rs1137101 G alleles were independent risk factors for PTDM development. The risk of PTDM development was almost 3.5 times greater in LEPR rs1137101 G allele carriers than in AA homozygotes (GG + AG vs AA; OR 3.48; 95 %CI (1.09-11.18), p = 0.035). The results suggest that patients after kidney transplantation with the LEPR gene rs1137101 G allele may have an increased risk of post-transplant diabetes development.

Topics: Diabetes Mellitus; Female; Humans; Kidney Transplantation; Leptin; Polymorphism, Genetic; Receptors, Leptin; Risk Factors; Tacrolimus

Diabetic kidney disease (DKD) is a major health burden closely related to lipid metabolism disorders. Leptin has lipid-lowering efficacy, but the specific mechanism of its local effects on kidney is still unclear. This study aims to investigate the role of ectopic lipid deposition (ELD) in DKD and evaluate the lipid-lowering efficacy of leptin in the palmitic acid (PA)-induced renal tubular epithelial cells (NRK-52E). DKD model was established in Sprague-Dawley (SD) rats by giving single intraperitoneal injection of streptozotocin (STZ, 30 mg/kg) after high-fat diet for 8 weeks. Then, the expression changes of lipid metabolism-related markers were observed. At week 12, the protein expression level of lipid-deposited marker adipose differentiation-related protein (ADRP) was significantly increased. Besides, the lipid synthesis marker sterol regulatory element-binding protein 1c (SREBP 1c) was highly expressed while the expression of insulin-induced gene 1 (Insig-1), a key molecular of inhibiting SREBP 1c, was decreased. Leptin and compound c were incubated with the PA-induced NRK-52E cells to investigate the lipid-lowering effects and whether this effect was mediated by the AMPK/Insig-1/SREBP 1c signaling pathways. mRNA and protein of ADRP and SREBP 1c were reduced after leptin treatment, while Insig-1 and phosphorylated AMP-activated protein kinase (AMPK) were increased. Conversely, inhibition of AMPK phosphorylation by compound c mostly eliminated lipid-lowering efficacy of leptin in PA-induced cells. Collectively, these results suggested that there was ELD of renal tubular epithelial cells in DKD rats. Leptin upregulated the expression level of Insig-1 by activating AMPK to attenuate ELD in PA-induced NRK-52E cells.

Topics: AMP-Activated Protein Kinases; Animals; Diabetes Mellitus; Diabetic Nephropathies; Leptin; Lipid Metabolism; Palmitic Acid; Rats; Rats, Sprague-Dawley; Sterol Regulatory Element Binding Protein 1; Streptozocin

Current molecular characterization of pancreatic ductal adenocarcinoma (PDAC) does not incorporate the host reaction to cancer cells and cannot predict the response to chemo- or immunotherapy. Leptin is an adipokine involved in regulating energy balance with a possible role in the development of obesity-associated cancers, but its relationship with other pathways in pancreatic carcinogenesis has not been established yet. The aim of this prospective study was to assess the involvement of leptin and phosphoinositide 3-kinase (PI3K) in the survival of overweight and/or diabetic patients with PDAC.. A total of 112 patients were included, 56 diagnosed with PDAC and 56 age and sex-matched healthy controls, with a maximum follow-up of 24-months. The circulating leptin, interleukin 1-beta, tumor factor necrosis-alpha, and PI3K were measured by enzyme-linked immunosorbent assay (ELISA). A multivariate Cox regression model was used to determine the factors influencing survival.. The serum levels of leptin [38.5 (31.6-47.0) pg/ml] and other cytokines in PDAC patients were similar to controls, irrespective of the presence of diabetes. No significant correlation between the biomarkers was found. In obese and overweight patients, the leptin level and survival rate were lower than in non-obese patients.. The leptin level was not associated with the presence of PDAC, although it was lower in obese and overweight patients who had lower survival. No association with inflammatory biomarkers or PI3K was noted. Furthermore, leptin levels had no independent role in survival, suggesting that the prognostic role of obesity in PDAC is based on a different pathway.

Topics: Adenocarcinoma; Biomarkers; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Diabetes Mellitus; Humans; Leptin; Obesity; Overweight; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Prognosis; Prospective Studies

The role of BDNF in adipose tissue metabolism is poorly understood. We investigated the effects of decreased levels of BDNF on the expression of major adipokines in different fat depots (e.g., subcutaneous and epididymal) of mouse groups fed three different diet protocols.. BDNF heterozygous (+ / -) mice were used to evaluate the effect of reduced BDNF levels. Six groups of C57BL/6 J breed wild type (WT) and BDNF (+ / -) mice were formed. These groups were fed, respectively, a control diet (CD), a high-fat diet (HFD), and a high-sucrose diet (HSD) for 4 months. Serum samples and adipose tissues were used for biochemical assays. The serum concentrations and tissue expression levels of leptin, adiponectin, and resistin were measured.. Compared to the CD-fed WT group (control group), serum leptin and leptin expression levels were found to be higher in all experimental groups. Serum adiponectin levels were lower in the BDNF (+ / -) groups and HFD-fed WT group than in the control group. Epididymal adiponectin expression was found to be lower in the HFD-fed BDNF (+ / -) group and higher in HSD-fed groups than in the control group. Compared to the control group, adiponectin expression increased in the WT groups in subcutaneous adipose tissue. Serum resistin levels were elevated in the HFD-fed groups. Resistin expression in epididymal adipose tissue was lower in the CD-fed and HFD-fed groups than in the control group.. BDNF levels and diet differentially affect the expression of adipokines in different fat tissues in the body. BDNF may play a protective role in obesity and diabetes.

Topics: Adipokines; Adiponectin; Adipose Tissue; Animals; Brain-Derived Neurotrophic Factor; Diabetes Mellitus; Diet, High-Fat; Humans; Leptin; Mice; Mice, Inbred C57BL; Obesity; Resistin

Obesity leads to insulin resistance and is a major risk factor for the development of diabetes mellitus in cats. Prevention of obesity and obesity-induced insulin resistance is difficult, and reliable long-term strategies are currently lacking. Retinoid-related orphan receptor gamma (RORγ) was recently identified as an important transcription factor in the development of large insulin-resistant adipocytes in mice and humans. RORγ negatively affects adipocyte differentiation through expression of its target gene matrix metalloproteinase 3 (MMP3) and promotes the development of large insulin-resistant adipocytes. Preliminary studies in mice showed that RORγ can be inhibited by its ligand tetra-hydroxylated bile acid (THBA). In the present study, serum THBA levels were determined in healthy and diabetic cats. Moreover, potential side effects and the effects of THBA supplementation on adipocyte size, mRNA expression of RORγ, MMP3, interleukin 6, tumor necrosis factor α, adiponectin and leptin in feline subcutaneous adipocytes and insulin sensitivity were investigated in healthy normal weight cats. Thirteen healthy and 13 diabetic cats were used for determination of serum THBA level, and six healthy normal-weight cats were included in a feeding trial. Similar THBA levels were determined in serum of healthy and diabetic cats. Supplementation of 5 mg/kg THBA for 8 wk did not cause any negative effect on feeding behavior, general condition and blood parameters of tested cats. It significantly reduced adipocyte size and mRNA expression of MMP3, interleukin 6, and tumor necrosis factor α in adipocytes, while mRNA expression of adiponectin significantly increased and mRNA expression of RORγ and leptin remained unchanged. Administration of THBA did not influence fasting blood glucose levels or the response of cats to acute insulin administration. Based on these results, THBA is palatable and is considered safe for use in cats. It reduces expression of MMP3 and promotes the development of small adipocytes with increased expression of adiponectin and reduced expression of interleukin 6 and tumor necrosis factor α. Further studies are recommended to evaluate the effect of THBA on adipocyte size and insulin sensitivity in obese cats.

Topics: Adipocytes; Adiponectin; Animals; Bile Acids and Salts; Cat Diseases; Cats; Diabetes Mellitus; Insulin; Insulin Resistance; Interleukin-6; Leptin; Matrix Metalloproteinase 3; Mice; Obesity; RNA, Messenger; Rodent Diseases; Tumor Necrosis Factor-alpha

Adipose tissue is involved in the synthesis of hormones that have an impact on food intake regulation, control of insulin sensitivity or regulation of inflammatory processes. The aim of this study was to determine the importance of adipocytokines and interleukins levels for the development of post-transplant diabetes mellitus (PTDM) after kidney transplantation (KT).. In the prospective analysis, the studied sample (n = 104) was divided into the control group, prediabetes group and PTDM group. Prior to transplantation, and subsequently, at 3, 6 and 12 months after KT, we recorded the basic characteristics of the donor and recipient, including parameters reflecting graft function, metabolic and anthropometric parameters. At the same time, we monitored the levels of adiponectin, leptin and interleukins during the monitored period.. Using multivariate logistic regression, we identified hyperleptinemia 12 months after KT as an independent risk factor for PTDM development 1 year after KT [OR 1.0320; 95% Cl 0.9785-1.0884 (p=0.0038)]. At the same time, we confirmed that age at the time of KT is also an independent risk factor for PTDM [OR 1.0903; 95% Cl 1.0149-1.1714 (p=0.0180)].. We confirmed that elevated leptin level 12 months after KT is associated with the development of PTDM (Tab. 3, Fig. 4, Ref. 22). Text in PDF www.elis.sk Keywords: adipocytokines, interleukins, post-transplant diabetes mellitus, kidney transplantation, leptin.

Topics: Diabetes Mellitus; Humans; Kidney Transplantation; Leptin; Postoperative Complications; Risk Factors

Topics: Angiopoietin-1; Biomarkers; Cardiovascular Diseases; Cystatins; Diabetes Mellitus; E-Selectin; Endoglin; Endothelium; Humans; Interleukin-8; Leptin; Lipocalin-2; P-Selectin; Vascular Endothelial Growth Factor A; von Willebrand Factor

Background and Objectives: It has been confirmed that adiponectin/leptin (A/L) ratio correlates better with cardiometabolic risk factors than hormone levels alone. The aim of our study was to determine the risk of developing post-transplant diabetes mellitus (PTDM) and other metabolic conditions depending on A/L ratio after kidney transplantation (KT). Material and Methods: In a prospective analysis, the studied samples were divided into three groups: control group, prediabetes and PTDM group. Pre-transplantation, at 3, 6 and 12 months after KT, we recorded basic characteristics of donor and recipient. We also monitored levels of adipocytokines and calculated A/L ratio. Results: During observed period, we recorded significant increase in A/L ratio in control group (p = 0.0013), on the contrary, a significant decrease in PTDM group (p = 0.0003). Using Cox regression Hazard model, we identified age at time of KT (HR 2.8226, p = 0.0225), triglycerides at 1 year (HR 3.5735, p = 0.0174) and A/L ratio < 0.5 as independent risk factors for prediabetes and PTDM 1-year post-transplant (HR 3.1724, p = 0.0114). Conclusions: This is the first study to evaluate the relationship between A/L and risk of PTDM and associated metabolic states after KT. We found out that A/L ratio <0.5 is independent risk factor for prediabetes and PTDM 1 year post-transplant.

Topics: Adiponectin; Diabetes Mellitus; Humans; Kidney Transplantation; Leptin; Postoperative Complications; Prediabetic State

Plasma leptin is considered a risk factor for obesity and cardio-metabolic disease, but the link between serum leptin and renal function is still under evaluation. In our study, we focused on the relationship between serum leptin and renal function, and we investigated the relationship in more detail.. The 396 middle-aged and elderly Taiwanese adults recruited for our health survey were the subject of our research. All participants agreed to participate and signed a consent form before they joined and completed our study. We divided the participants into three groups according to eGFR tertiles and analyzed the parameters between each group. Then, we used Pearson's correlation test to investigate the relationship between eGFR levels and cardio-metabolic risk factors with adjustment for age. The scatter plot indicates the trend between serum leptin levels and eGFR levels. Participants were reclassified into three subgroups according to their leptin levels and the bar chart reveals the prevalence of chronic kidney disease (CKD) in each group. Finally, we used multivariate linear regression to evaluate the relationship between serum leptin and eGFR levels with adjustment for age, sex, smoking status, drinking status, body mass index (BMI), uric acid levels, hypertension (HTN), diabetes mellitus (DM), and dyslipidemia.. In our study, we analyzed the data from 396 eligible participants. A total of 41.4% of the participants were male, and the average age of all participants was 64.81 years ( ± 8.78). The participants in the high eGFR group were more likely to have lower serum leptin levels. Furthermore, eGFR values were negatively correlated with serum leptin levels even after adjustment for age. The prevalence of CKD in the high serum leptin group was higher than that in the low serum leptin group. Serum leptin levels showed significant negative correlations with eGFR levels (β=-0.14, p<0.01) in the multivariate linear regression after adjusting for age, sex, smoking status, drinking status, BMI, uric acid levels, HTN, DM, and dyslipidemia.. According to our study, serum leptin levels show a negative relationship with eGFR levels in middle-aged and elderly people in Taiwan. In addition, high serum leptin levels could be an novel marker to survey kidney failure in clinical practices.

Topics: Adult; Aged; Cross-Sectional Studies; Diabetes Mellitus; Female; Humans; Hypertension; Kidney; Leptin; Male; Middle Aged; Renal Insufficiency, Chronic; Taiwan; Uric Acid

Background The prognostic value of anthropometric, adipokine, and computed tomography measures of adiposity to predict diabetes in Black, specifically by normoglycemia versus prediabetes, remains incompletely understood. Methods and Results Among Black participants without diabetes in the JHS (Jackson Heart Study), waist circumference [WC], body mass index, adiponectin, leptin, and leptin:adiponectin ratio were standardized in sample 1 (2422 participants at baseline [2000-2004]) and WC, body mass index, visceral adipose tissue (VAT), subcutaneous adipose tissue, and liver attenuation in 1537 participants at examination 2 (2005-2008) (sample 2). Hazard ratios (HRs) for diabetes were estimated using interval-censored Cox modeling adjusting for traditional risk factors and validated with the C index. Over 5 years, 300 and 122 incident diabetes cases occurred in sample 1 and sample 2, respectively. In sample 1 and sample 2, a 1-SD higher log-leptin:adiponectin ratio and VAT had the strongest associations (HR, 1.95 [95% CI, 1.67-2.27] and 1.76 [95% CI, 1.52-2.04]) and discriminatory power (C index 0.68 [95% CI, 0.64-0.71] and C index 0.67 [95% CI, 0.61-0.74]) with diabetes. The normoglycemic compared with the prediabetes group had a 1.3 to 1.9 times greater magnitude of associations with diabetes for WC, liver attenuation, and VAT (

Topics: Adiponectin; Adiposity; Adult; Body Mass Index; Diabetes Mellitus; Humans; Intra-Abdominal Fat; Leptin; Longitudinal Studies; Obesity; Prediabetic State; Risk Factors; Waist Circumference

Lipodystrophy syndromes are rare complex multisystem disorders caused by generalized or partial lack of adipose tissue. Adipose tissue dysfunction in lipodystrophy is associated with leptin deficiency. Lipodystrophy leads to severe metabolic problems. These abnormalities include, but are not limited to, insulin-resistant diabetes, severe hypertriglyceridemia, and lipid accumulation in ectopic organs such as the liver, and are associated with end-organ complications. Metabolic abnormalities can be present at the time of diagnosis or may develop over time as the disease progresses. In addition to metabolic abnormalities, subtype-specific presentations due to underlying molecular etiology in genetic forms and autoimmunity in acquired forms contribute to severe morbidity in lipodystrophy.

Topics: Autoimmune Diseases; Diabetes Mellitus; Heart Diseases; Humans; Hypertriglyceridemia; Insulin Resistance; Kidney Diseases; Leptin; Lipid Metabolism; Lipodystrophy; Liver; Metabolic Syndrome; Neuromuscular Diseases; Non-alcoholic Fatty Liver Disease; Pancreatitis; Syndrome

Leptin and adiponectin are thought to modulate insulin sensitivity and pancreatic β-cell function, but there is limited information regarding the adipokine status of hyperglycemic dogs with hyperadrenocorticism. This study aimed to determine whether alterations in the leptin/adiponectin ratio, insulin sensitivity, and/or pancreatic β-cell function are associated with diabetes mellitus (DM) in dogs with pituitary-dependent hyperadrenocorticism (PDH). A total of 48 client-owned dogs were included in this prospective observational study: 20 dogs with PDH (10 normoglycemic and 10 with DM), 15 dogs with DM, and 13 healthy dogs. The serum concentrations of leptin, adiponectin, resistin, interleukin (IL)-1β, IL-6, IL-10, IL-18, and tumor necrosis factor (TNF)-α were measured, and homeostatic model assessment indices (HOMAs) were calculated and compared among the groups. Serum leptin was significantly higher in PDH dogs with and without DM than in healthy and DM dogs, and it was lower in DM dogs than in PDH dogs without DM. Serum adiponectin was significantly lower in PDH dogs with DM than in healthy and PDH dogs, and it was significantly lower in DM dogs than in healthy dogs. Serum IL-10 was significantly higher in PDH dogs with DM than in healthy and PDH dogs without DM. The leptin/adiponectin ratio was significantly higher in PDH dogs with DM than in normoglycemic PDH dogs. Serum IL-6 concentrations were significantly higher in DM dogs than in healthy dogs. Serum IL-1β concentration was significantly higher in DM dogs than in healthy dogs and PDH dogs with DM and without DM. Serum TNF-α and IL-18 concentrations were not different among groups. The HOMA

Topics: Adiponectin; Adrenocortical Hyperfunction; Animals; Cytokines; Diabetes Complications; Diabetes Mellitus; Dog Diseases; Dogs; Female; Insulin-Secreting Cells; Leptin; Male; Pituitary Gland; Resistin

A 17-year-old woman with a history of childhood leukemia and hematopoietic stem cell transplantation (HSCT), preceded by total body irradiation, developed diabetes, dyslipidemia, fatty liver, and marked insulin resistance. Based on Dunnigan phenotype, HSCT-associated lipodystrophy was suspected. Because of rapid deterioration of diabetes control, metreleptin was introduced at 23 years of age upon receipt of her caregiver's documented consent. This trial was initially planned as a prospective 18 month-long study, with regular assessments of the patient's physical activity, food intake, and body composition analysis. However, because an abrupt and transient attenuation of the metreleptin effect occurred 16 months after the treatment initiation, the entire course of 28 months is reported here. Over the period, her HbA1c decreased from 10.9% to 6.7% despite no significant increase of physical activity and with a stable food intake. Decreased levels of triglyceride and non-HDL cholesterol were found. Her liver function improved, indicating the amelioration of fatty liver. In addition, a 25% reduction in the subcutaneous fat area at umbilical level was found, accompanied by a decrease in fat percentage of both total-body and trunk. The formation of neutralizing antibodies to metreleptin may be responsible for the transient loss of efficacy, considering a sudden elevation in her serum leptin level. In conclusion, metreleptin is useful for the management of HSCT-associated lipodystrophy, supporting the concept that adipose tissue dysfunction is responsible for diverse post-HSCT metabolic aberrations.

Topics: Adolescent; Body Composition; Body Weight; Carbohydrate Metabolism; Diabetes Mellitus; Female; Hematopoietic Stem Cell Transplantation; Humans; Leptin; Lipodystrophy; Treatment Outcome; Young Adult

Whether leptin and adiponectin are independently associated with regional body fat distribution was investigated in a prospective study of Japanese Americans.. Nondiabetic participants 39 to 79 years of age were followed for 5 years to assess change in body composition. Leptin and adiponectin concentrations were evaluated at baseline and by single-slice computed tomography measurements of intra-abdominal fat (IAF), abdominal subcutaneous fat (SCF), and thigh SCF cross-sectional areas at baseline and at 5 years.. In nondiabetic Japanese Americans, a higher concentration of leptin was associated with greater accumulation of IAF and a higher concentration of adiponectin with lesser accumulation of IAF over 5 years.

Topics: Adiponectin; Adult; Asian; Body Composition; Body Fat Distribution; Diabetes Mellitus; Female; Humans; Insulin Resistance; Intra-Abdominal Fat; Japan; Leptin; Male; Middle Aged; Prospective Studies; Thigh; United States

Beinaglutide has been approved for glucose lowering in type 2 diabetes mellitus (T2DM) in China. In addition to glycemic control, significant weight loss is observed from real world data. This study is designed to investigate the pharmacological and pharmacokinetic profiles of beinaglutide in different models.. The pharmacological efficacy of beinaglutide was evaluated in C57BL/6 and ob/ob mice after single administration. Pharmacokinetic profiles in mice were investigated after single or multiple administration. Sub-chronic pharmacological efficacy was investigated in ob/ob mice for two weeks treatment and diet-induced ob/ob mice model of nonalcoholic steatohepatitis (NASH) for four weeks treatment.. Beinaglutide could dose-dependently reduce the glucose levels and improve insulin secretion in glucose tolerance tests, inhibit food intake and gastric emptying after single administration. At higher doses, beinaglutide could inhibit food intake over 4 h, which results in weight loss in ob/ob mice after about two weeks treatment. No tachyphylaxis is observed for beinaglutide in food intake with repeated administration. In NASH model, beinaglutide could reduce liver weight and hepatic steatosis and improve insulin sensitivity. Signiant changes of gene levels were observed in fatty acid β-oxidation (Ppara, Acadl, Acox1), mitochondrial function (Mfn1, Mfn2), antioxidation (Sod2), Sirt1, and et al. SIGNIFICANCE: Our results characterize the pharmacological and pharmacokinetic profiles of beinaglutide in mice and supported that chronic use of beinaglutde could lead to weight loss and reduce hepatic steatosis, which suggest beinaglutide may be effective therapy for the treatment of obesity and NASH.

Topics: Animals; Antioxidants; Diabetes Complications; Diabetes Mellitus; Glucagon-Like Peptide 1; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Liraglutide; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Non-alcoholic Fatty Liver Disease; Obesity; Oxidation-Reduction; Peptide Fragments; PPAR alpha; Weight Loss

Obesity is defined as abnormal or excessive fat accumulation that presents a risk to health. The ability to exercise is affected by adiposity, and this mechanism involves low-grade chronic inflammation and homeostatic stress produced mainly in adipocytes, which can result in abnormal adipokine secretion. To date, the gold standard for cardiorespiratory fitness assessment is considered to be the maximum oxygen uptake (VO

Topics: Adiponectin; Adolescent; Blood Glucose; Cardiorespiratory Fitness; Case-Control Studies; Child; Cross-Sectional Studies; Diabetes Mellitus; Exercise Test; Female; Fibrinogen; Humans; Insulin; Leptin; Male; Obesity; Oxygen Consumption; Risk Factors; ROC Curve

Metabolic health depends on the brain's ability to control food intake and nutrient use versus storage, processes that require peripheral signals such as the adipocyte-derived hormone, leptin, to cross brain barriers and mobilize regulatory circuits. We have previously shown that hypothalamic tanycytes shuttle leptin into the brain to reach target neurons. Here, using multiple complementary models, we show that tanycytes express functional leptin receptor (LepR), respond to leptin by triggering Ca

Topics: Brain; Diabetes Mellitus; Energy Metabolism; Ependymoglial Cells; ErbB Receptors; Insulin-Secreting Cells; Leptin; Lipid Metabolism; Pancreas; Phosphorylation; Receptors, Leptin

Sex differences in heart failure with preserved ejection fraction (HFpEF) have been established, but insights into the mechanistic drivers of these differences are limited.. To examine sex differences in cardiometabolic profiles and exercise hemodynamic profiles among individuals with HFpEF.. This cross-sectional study was conducted at a single-center tertiary care referral hospital from December 2006 to June 2017 and included 295 participants who met hemodynamic criteria for HFpEF based on invasive cardiopulmonary exercise testing results. We examined sex differences in distinct components of oxygen transport and utilization during exercise using linear and logistic regression models. The data were analyzed from June 2018 to May 2019.. Resting and exercise gas exchange and hemodynamic parameters obtained during cardiopulmonary exercise testing.. Of 295 participants, 121 (41.0%) were men (mean [SD] age, 64 [12] years) and 174 (59.0%) were women (mean [SD] age, 61 [13] years). Compared with men, women with HFpEF in this tertiary referral cohort had fewer comorbidities, including diabetes, insulin resistance, and hypertension, and a more favorable adipokine profile. Exercise capacity was similar in men and women (percent predicted peak oxygen [O2] consumption: 66% in women vs 68% in men; P = .38), but women had distinct deficits in components of the O2 pathway, including worse biventricular systolic reserve (multivariable-adjusted analyses: ΔLVEF β = -1.70; SE, 0.86; P < .05; ΔRVEF β = -2.39, SE=0.80; P = .003), diastolic reserve (PCWP/CO: β = 0.63; SE, 0.31; P = .04), and peripheral O2 extraction (C(a-v)O2 β=-0.90, SE=0.22; P < .001)).. Despite a lower burden of cardiometabolic disease and a similar percent predicted exercise capacity, women with HFpEF demonstrated greater cardiac and extracardiac deficits, including systolic reserve, diastolic reserve, and peripheral O2 extraction. These sex differences in cardiac and skeletal muscle responses to exercise may illuminate the pathophysiology underlying the development of HFpEF and should be investigated further.

Topics: Adipokines; Adiponectin; Aged; C-Reactive Protein; Cardiometabolic Risk Factors; Diabetes Mellitus; Exercise Test; Exercise Tolerance; Female; Heart Failure; Humans; Hypertension; Insulin Resistance; Interleukin-6; Leptin; Linear Models; Logistic Models; Male; Middle Aged; Obesity; Oxygen Consumption; Pulmonary Gas Exchange; Sex Factors; Stroke Volume

Topics: Adult; Alanine Transaminase; Aspartate Aminotransferases; Blood Glucose; Diabetes Mellitus; Dyslipidemias; Fatty Liver; Glycated Hemoglobin; Humans; Hypogonadism; Lamin Type A; Leptin; Lipase; Lipodystrophy, Congenital Generalized; Male; Progeria; Treatment Outcome

Both obesity and malnutrition leading to cachexia and sarcopenia are relevant risk factors in the development of many diseases. They also increase mortality, also prolong hospitalisations and convalescence, and undoubtedly increase the cost of treatment, mostly in the elderly populations. The aim of the study was to assess the relationship between the levels of leptin and adiponectin with regard to insulin resistance and malnutrition status by studying a senior female population and to evaluate predictors of insulin resistance and malnutrition. A total of 88 elderly females were enrolled prospectively with a median age of 75 years. Anthropometric and biochemical parameters (fasting glucose, insulin, folic acid, vitamin B12 concentrations, lipid profile, complete blood count) were recorded along with a full geriatric assessment, have been made in all participants. A comprehensive nutritional phenotype has been established. Leptin and adiponectin concentrations were measured by applying immunoassay techniques. Lipid profile and other parameters were performed by biochemical methods. We observed significant decreases of albumin, alanine aminotransferase, insulin, and triglycerides concentrations with age. The risk of insulin resistance based on HOMA-IR index was decreased with age. Significantly higher concentrations of leptin, leptin-to-adiponectin ratio (LAR), hsCRP, fasting glucose, insulin in the insulin resistant subgroup in respect of normal sensitivity insulin cases were noted. The concentrations of albumin, aspartate aminotransferase, alanine aminotransferase and total cholesterol were significantly lower in those patients at risk of malnutrition than in the well-nourished subjects. LAR reached the most accurate AUC

Topics: Adiponectin; Aged; Aged, 80 and over; Biomarkers; Cross-Sectional Studies; Diabetes Mellitus; Female; Geriatric Assessment; Humans; Insulin Resistance; Leptin; Nutritional Status; Population Surveillance; Predictive Value of Tests; Prospective Studies

De novo lipogenesis (DNL) plays a role in the development of hepatic steatosis. In humans with lipodystrophy, reduced adipose tissue causes lower plasma leptin, insulin resistance, dyslipidemia, and ectopic triglyceride (TG) accumulation. We hypothesized that recombinant leptin (metreleptin) for 6 months in 11 patients with lipodystrophy would reduce DNL by decreasing insulin resistance and glycemia, thus reducing circulating TG and hepatic TG. The percentage of TG in TG-rich lipoprotein particle (TRLP-TG) derived from DNL (%DNL) was measured by deuterium incorporation from body water into palmitate. At baseline, DNL was elevated, similar to levels previously shown in obesity-associated nonalcoholic fatty liver disease (NAFLD). After metreleptin, DNL decreased into the normal range. Similarly, absolute DNL (TRLP-TG × %DNL) decreased by 88% to near-normal levels. Metreleptin improved peripheral insulin sensitivity (hyperinsulinemic-euglycemic clamp) and lowered hemoglobin A1c and hepatic TG. Both before and after metreleptin, DNL positively correlated with insulin resistance, insulin doses, and hepatic TG, supporting the hypothesis that hyperinsulinemia stimulates DNL and that elevated DNL is integral to the pathogenesis of lipodystrophy-associated NAFLD. These data suggest that leptin-mediated improvement in insulin sensitivity increases clearance of blood glucose by peripheral tissues, reduces hepatic carbohydrate flux, and lowers insulinemia, resulting in DNL reductions and improvements in hepatic steatosis and dyslipidemia.

Topics: Adult; Blood Glucose; Diabetes Mellitus; Fatty Liver; Female; Glycated Hemoglobin; Humans; Insulin; Insulin Resistance; Leptin; Lipodystrophy; Lipogenesis; Liver; Male; Middle Aged; Triglycerides

Topics: Adiponectin; Aged; Aged, 80 and over; Ankle Brachial Index; Aorta, Abdominal; Cardiovascular Diseases; Carotid Artery, Common; Carotid Intima-Media Thickness; Case-Control Studies; Comorbidity; Cross-Sectional Studies; Diabetes Mellitus; Female; Humans; Hypercholesterolemia; Leptin; Male; Middle Aged; Overweight; Peripheral Arterial Disease; Polymyalgia Rheumatica; Resistin; Risk Factors; Smoking; Ultrasonography, Doppler, Color; Vascular Stiffness

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

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

Topics: Adolescent; Adult; Blood Pressure; Body Mass Index; Diabetes Mellitus; Dyslipidemias; Female; Follow-Up Studies; Gastrectomy; Ghrelin; Humans; Hypertension; Laparoscopy; Leptin; Male; Middle Aged; Obesity, Morbid; Postoperative Period; Preoperative Period; Prospective Studies; Sleep Apnea, Obstructive; Time Factors; Treatment Outcome; Weight Loss; Young Adult

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

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

The phenomenon of a discrepancy between glycated hemoglobin levels and other indicators of average glycemia may be due to many factors but can be measured as the glycation gap (GGap). This GGap is associated with differences in complications in patients with diabetes and may possibly be explained by dissimilarities in deglycation in turn leading to altered production of advanced glycation end products (AGEs). We hypothesized that variations in the level of the deglycating enzyme fructosamine-3-kinase (FN3K) might be associated with the GGap. We measured erythrocyte FN3K concentrations and enzyme activity in a population dichotomized for a large positive or negative GGap. FN3K protein was higher and we found a striking threefold greater activity (323%) at any given FN3K protein level in the erythrocytes of the negative-GGap group compared with the positive-GGap group. This was associated with lower AGE levels in the negative-GGap group (79%), lower proinflammatory adipokines (leptin-to-adiponectin ratio) (73%), and much lower prothrombotic PAI-1 levels (19%). We conclude that FN3K may play a key role in the GGap and thus diabetes complications such that FN3K may be a potential predictor of the risk of diabetes complications. Pharmacological modifications of its activity may provide a novel approach to their prevention.

Topics: Adipokines; Adiponectin; Aged; Aged, 80 and over; Blood Glucose; Diabetes Mellitus; Female; Glycated Hemoglobin; Glycation End Products, Advanced; Glycosylation; Humans; Leptin; Male; Middle Aged; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Plasminogen Activator Inhibitor 1

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are used in the treatment of human diabetics. They increase glucose excretion and correct hyperglycemia. We examined the investigational SGLT2 inhibitor velagliflozin in two groups of six neutered adult obese cats (equal gender distribution). Placebo (Pl) or drug (D; 1 mg/kg) was administered for 35 days. Routine blood examinations, fructosamine, beta-hydroxybutyrate (BHB), nonesterified fatty acids (NEFA), glucagon, adiponectin, and leptin were measured before and after treatment, also water intake, and urinary electrolytes, glucose, and volume. Indirect calorimetry, an intravenous glucose tolerance test (IVGTT; 0.8 g/kg) and insulin tolerance test (IVITT) were conducted. All cats tolerated treatment well. Significant changes with D included a decrease in the respiratory exchange ratio, an increase in cholesterol, a small increase in albumin, and a rise in BHB and NEFA. Glucose clearance was unaltered, although less insulin was secreted during the IVGTT (p = .056) suggesting improved insulin sensitivity. IVITT was unchanged. Treatment did not affect glucagon, leptin, or adiponectin. Water intake, urine output, urinary glucose excretion, and the glucose/creatinine ratio but not urinary electrolytes were significantly higher post-D. We conclude that velagliflozin is a promising drug, which increases urinary glucose excretion in cats and could thereby be beneficial for the treatment of hyperglycemia.

Topics: 3-Hydroxybutyric Acid; Adiponectin; Animals; Cat Diseases; Cats; Diabetes Mellitus; Drinking; Electrolytes; Fatty Acids, Nonesterified; Female; Fructosamine; Glucagon; Glucose Tolerance Test; Glycosuria; Hypoglycemic Agents; Leptin; Male; Nitriles; Obesity; Sodium-Glucose Transporter 2 Inhibitors

BACKGROUND Insulin resistance (IR) and inflammation are associated with increased risk of complications in chronic kidney disease (CKD) patients. However, the relationship between IR and the important proinflammatory interleukin-1β (IL-1β) is unclear in CKD patients. MATERIAL AND METHODS We conducted a cross-sectional study including 79 non-diabetic patients who received hemodialysis after the exclusion process. Homeostasis model assessment (HOMA-IR) and leptin adiponectin ratio (LAR) were used to evaluate IR. Inflammation was assessed through C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and IL-1β evaluation. We tested associations of IR with IL-1β using logistic analysis and linear regression. RESULTS Patients were divided into a HOMA-IR-positive group and a HOMA-IR-negative group. Although there were no differences between the 2 groups in terms of etiological causes, age, sex, BMI, triglyceride, cholesterol, ferritin, uric acid, and inflammatory indicators such as CRP, we found that IL-6, TNF-α, and IL-1β were significantly increased in the HOMA-IR-positive group compared with the HOMA-IR-negative group. Moreover, IL-1β contributed to HOMA-IR positivity and was positively correlated with LAR after adjusting for possible confounding factors. CONCLUSIONS Insulin resistance correlates positively with IL-1β among non-diabetic hemodialysis patients, which suggests that IL-1β may be involved in the pathogenesis of IR in this setting.

Topics: Adiponectin; Adult; Aged; Diabetes Mellitus; Female; Homeostasis; Humans; Insulin Resistance; Interleukin-1beta; Leptin; Linear Models; Male; Middle Aged; Odds Ratio; Renal Dialysis

This study assessed short-term memory and biochemical indicators with the levels of ghrelin, leptin, and cortisol between cognitive impairment and normal older adults with or without diabetes.. We enrolled 286 older adults (aged 65-85 years) with or without diabetes from the local community. Short-term memory was assessed using pictures of common objects; cognitive functioning was assessed using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). The physiological indexes assessed were plasma levels of fasting ghrelin and leptin, ghrelin level at 2_h after breakfast, 24-h urinary cortisol value, body mass index, and plasma cortisol levels at 8:00 a.m., 4:00 p.m., and 12:00 p.m.. In both non-diabetic and diabetic subjects, short-term memory was significantly lower in the impaired cognition group (5.99 ± 2.90 in non-diabetic subjects and 4.71 ± 2.14 in diabetic subjects) than in the normal cognition group (8.14 ± 2.23 in non-diabetic subjects and 7.82 ± 3.37 in diabetic subjects). Baseline ghrelin level was significantly lower in the impaired cognition group (9.07 ± 1.13 ng/mL in non-diabetic subjects and 7.76 ± 1.34 ng/mL in diabetic subjects) than in the normal cognition group (10.94 ± 1.53 ng/mL in non-diabetic subjects and 9.93 ± 1.76 ng/mL in diabetic subjects); plasma cortisol levels at 8:00 a.m., 4:00 p.m., and 12:00 p.m. were significantly higher in the impaired cognition group than in the normal cognition group, while no significant difference was observed in plasma levels of fasting leptin between different groups.. Fasting plasma ghrelin and cortisol levels may be markers of cognitive decline and memory loss. It is possible that adjusting their levels may have a therapeutic effect, and this should be investigated in future studies.

Topics: Aged; Aged, 80 and over; Biomarkers; Body Mass Index; Case-Control Studies; Cognition; Cognitive Dysfunction; Diabetes Complications; Diabetes Mellitus; Fasting; Female; Ghrelin; Humans; Hydrocortisone; Leptin; Male; Memory Disorders; Memory, Short-Term

Dietary guidelines for obesity typically focus on three food groups (carbohydrates, fat, and protein) and caloric restriction. Intake of noncaloric nutrients, such as salt, are rarely discussed. However, recently high salt intake has been reported to predict the development of obesity and insulin resistance. The mechanism for this effect is unknown. Here we show that high intake of salt activates the aldose reductase-fructokinase pathway in the liver and hypothalamus, leading to endogenous fructose production with the development of leptin resistance and hyperphagia that cause obesity, insulin resistance, and fatty liver. A high-salt diet was also found to predict the development of diabetes and nonalcoholic fatty liver disease in a healthy population. These studies provide insights into the pathogenesis of obesity and diabetes and raise the potential for reduction in salt intake as an additional interventional approach for reducing the risk for developing obesity and metabolic syndrome.

Topics: Adult; Aged; Aged, 80 and over; Animals; Diabetes Mellitus; Fructokinases; Fructose; Humans; Leptin; Metabolic Syndrome; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Non-alcoholic Fatty Liver Disease; Obesity; Sodium Chloride, Dietary; Sucrose; Transcription Factors

We have developed a compact disc (CD)-shaped microfluidic device for multiple, rapid enzyme-linked immunosorbent assays (ELISA). The device has a versatile design that can be adapted for the detection of various proteins by selecting the push-in-type reaction parts and appropriate reagents for each target. In this paper, we report the rapid quantification of insulin, adiponectin, and leptin, which can be used for the early diagnosis of diabetes, in human serum in only 16 min with our device.

Topics: Adiponectin; Compact Disks; Diabetes Mellitus; Enzyme-Linked Immunosorbent Assay; Humans; Insulin; Lab-On-A-Chip Devices; Leptin; Time Factors

Leptin acts via its receptor (LepRb) to modulate gene expression in hypothalamic LepRb-expressing neurons, thereby controlling energy balance and glucose homeostasis. Despite the importance of the control of gene expression in hypothalamic LepRb neurons for leptin action, the transcriptional targets of LepRb signaling have remained undefined because LepRb cells contribute a small fraction to the aggregate transcriptome of the brain regions in which they reside. We thus employed translating ribosome affinity purification followed by RNA sequencing to isolate and analyze mRNA from the hypothalamic LepRb neurons of wild-type or leptin-deficient (

Topics: Activating Transcription Factor 3; Animals; Crosses, Genetic; Diabetes Mellitus; Energy Metabolism; Female; Gene Expression Profiling; Gene Expression Regulation; Hypoglycemic Agents; Hypothalamus; Leptin; Lipotropic Agents; Male; Mice, Knockout; Mice, Mutant Strains; Mice, Transgenic; Nerve Tissue Proteins; Neurons; Obesity; Receptors, Leptin; RNA, Messenger; Sequence Analysis, RNA; Signal Transduction

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

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

Obese patients have increased leptin production and selective resistance to its central anti-adipogenic effects, yet its pro-inflammatory immunostimulating effects persist.. In a group of 70 patients who underwent primary kidney transplantation (KT) we examined adiponectin and leptin levels at the time of KT and 6 months post-transplantation. Patients with diabetes mellitus type 1 or type 2 at the time of KT were excluded from the study.. We found that leptin levels significantly increased during the post-transplant period (P = 0.0065). Overall, leptin levels were positively correlated with the level of triacylglycerols, post-transplant diabetes mellitus (PTDM) development and acute rejection (AR). We discovered that, in particular, high leptin levels were associated with AR [OR 2.1273; 95% CI 1.0130-4.4671 (P = 0.0461)] and PTDM development [OR 7.200; 95% CI 1.0310-50.2836 (P = 0.0465)], whereas, low adiponectin levels represent a risk factor for the development of insulin resistance [HR 38.6135; 95% CI 13.3844-67.7699 (P < 0.0001)] and obesity [HR 3.0821; 95% CI 0.8700-10.9192 (P = 0.0053)].. We found that a high serum concentration of leptin before KT is associated with both PTDM development and AR and merits further investigation in relation to KT.

Topics: Acute Disease; Adiponectin; Adult; Biomarkers; Diabetes Mellitus; Female; Follow-Up Studies; Graft Rejection; Humans; Insulin Resistance; Kidney Transplantation; Leptin; Male; Middle Aged; Postoperative Complications; Predictive Value of Tests; Sensitivity and Specificity

BACKGROUND Low physical activity is considered to be a risk factor for type 2 diabetes mellitus (T2DM). One theory suggest that leptin resistance is involved in the pathophysiology of impaired glucose metabolism. In this study we aimed to assess the correlation of physical fitness scores (PFS) with serum total leptin (TL), serum leptin soluble receptor (LSR), and free leptin index (FLI) in a group of Saudi patients with T2DM. MATERIAL AND METHODS This cross-sectional study involved 115 subjects: 52 healthy control subjects and 63 patients with T2DM. All subjects underwent body composition analysis. Blood samples were analyzed for fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), serum total leptin (TL), and serum leptin soluble receptor (LSR). Based on ideal body composition and our previous studies, physical fitness scores (PFS) were recorded for each subject. RESULTS In patients with T2DM, levels of LSR were positively correlated with PFS (r=0.281, p=0.025), while the levels of TL (r=-0.425, p=0.001) and FLI (r=-0.439, p=0.001) were negatively correlated with PFS. In control subjects, TL and FLI levels were negatively correlated (r=-0.612, p=0.001and r=-0.543, p=0.001 respectively) with PFS. In linear regression analysis, after adjustment for age and BMI, TL and FLI were independent predictors of PFS. CONCLUSIONS Serum TL and FLI were negatively correlated while LSR was positively correlated with PFS in patients with T2DM. Therefore, they may be important biomarkers for predicting the outcomes of physical fitness and exercise programs.

Topics: Adult; Blood Glucose; Body Mass Index; Cross-Sectional Studies; Diabetes Mellitus; Female; Glucose; Humans; Leptin; Male; Middle Aged; Obesity; Physical Fitness; Receptors, Leptin; Saudi Arabia

Gain-of-function (GOF) mutations in the ATP-sensitive potassium (K

Topics: Animals; Blood Glucose; Cytokines; Diabetes Mellitus; Glucagon; Glucagon-Like Peptide 1; Glyburide; Inflammation; Insulin; Insulin Resistance; Leptin; Mice; Mice, Transgenic; Mutation; Potassium Channels, Inwardly Rectifying

Mutations in the genes encoding leptin (LEP), the leptin receptor (LEPR), and the melanocortin 4 receptor (MC4R) are known to cause severe early-onset childhood obesity. The aim of the current study was to examine the prevalence of damaging LEP, LEPR, and MC4R mutations in Pakistani families having a recessive heritance of early-onset obesity.. Using targeted resequencing, the presence of rare mutations in LEP, LEPR, and MC4R, was investigated in individuals from 25 families suspected of having autosomal recessive early-onset obesity. Segregation patterns of variants were assessed based on chip-based genotyping.. Homozygous LEPR variants were identified in two probands. One carried a deletion (c.3260AG) resulting in the frameshift mutation p.Ser1090Trpfs*6, and the second carried a substitution (c.2675C > G) resulting in the missense mutation p.Pro892Arg. Both mutations were located within regions of homozygosity shared only among affected individuals. Both probands displayed early-onset obesity, hyperphagia and diabetes. No mutations were found in LEP and MC4R.. The current study highlights the implication of LEPR mutations in cases of severe early-onset obesity in consanguineous Pakistani families. Through targeted resequencing, we identified novel damaging mutations, and our approach may therefore be utilized in clinical testing or diagnosis of known forms of monogenic obesity with the aim of optimizing obesity treatment.

Topics: Age of Onset; Child; Consanguinity; Diabetes Mellitus; DNA Mutational Analysis; Female; Gene Expression; Genes, Recessive; Genetic Predisposition to Disease; Humans; Hyperphagia; Infant; Infant, Newborn; Leptin; Male; Mutation; Obesity, Morbid; Pakistan; Pediatric Obesity; Pedigree; Receptor, Melanocortin, Type 4; Receptors, Leptin

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

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

Both the consumption of high-fat diets and exercise are known to produce alterations in metabolism and behavior. This study focuses on the effects of a change to a low-fat diet from a high-fat diet and voluntary exercise on obesity, type-2 diabetic-like symptoms, and locomotor behavior in male C57BL/6J mice.. Mice were initially given either a high-fat diet or regular chow, along with a cage with a running-wheel to mimic exercise, or one without, to determine to what extend exercise affects these symptoms. Then half of the mice given a high-fat diet were switched to regular chow to ascertain if the switch in diet would improve type-2 diabetic-like and obesity symptoms.. Wheel-running alone produced an improvement in insulin in mice continuously fed a high-fat diet (p=0.006), but running-wheels did not produce any further improvements in mice with regular chow replacement (p=0.999) or in controls (p=0.996). Replacement of a high-fat diet with regular chow led to physiological improvements in insulin (p=0.012) and leptin (p <0.001), glucose tolerance (p <0.001), and obesity (p <0.001), more so than exercise alone. Mice consuming a high-fat diet without a wheel exhibited reduced home-cage activity compared to controls after the diet switch (p=0.030), while no reduction was found in running-wheel activity between high-fat diet and regular chow consuming mice after switching diets (p=0.516).. These results suggest that exercise is only partially beneficial to improving health outcomes in mice consuming a high-fat diet, whereas incorporating a better diet, even without exercise, improves quality of health and can suppress T2DM symptoms and related conditions more so than exercise alone.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Dietary Fats; Glucose Tolerance Test; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Motor Activity; Obesity; Triglycerides

Adipokines are implicated in the development of obesity-related traits. We hypothesized that nonobese participants without diabetes mellitus (DM) whose parents were obese or had DM would have altered circulating adipokines compared with those without parental history of these conditions.. Participants in the community-based Framingham Third Generation cohort who were not obese (body mass index <30) and not diabetic with both parents in the Framingham Offspring cohort were included in this analysis (n=2034, mean age 40 years, 54% women). Circulating concentrations of fetuin A, RBP4 (retinol binding protein 4), FABP4 (fatty acid binding protein 4), leptin, LEP-R (leptin receptor), and adiponectin were assayed. Parental DM was defined as occurring before age 60 years, and obesity was defined as body mass index ≥30 before age 60 years. General estimating equations were used to compare concentrations of adipokines among participants with 0, 1, or 2 parents affected by obesity or DM (separate analyses for each), adjusting for known correlates of adipokines. Overall, 44% had at least 1 parent who was obese and 15% had parents with DM. Parental obesity was associated with higher serum levels of FABP4 and LEP-R in their offspring (. In our community-based sample, a parental history of DM or obesity was associated with an altered adipokine profile in nonobese nondiabetic offspring. Additional studies are warranted to evaluate whether such preclinical biomarker alterations presage future risk of disease.

Topics: Adipokines; Adiponectin; Adult; alpha-2-HS-Glycoprotein; Biomarkers; Body Mass Index; Child of Impaired Parents; Cross-Sectional Studies; Diabetes Mellitus; Fatty Acid-Binding Proteins; Female; Genetic Predisposition to Disease; Heredity; Humans; Leptin; Male; Middle Aged; Obesity; Pedigree; Receptors, Leptin; Retinol-Binding Proteins, Plasma; Risk Factors

There are millions of chronic hepatitis C (CHC) virus-infected patients who have been treated with a combination therapy (interferon and ribavirin) and have achieved a virological response (SVR) worldwide. The aim of this study is to evaluate the risk factors for de-novo diabetes mellitus in CHC patients treated with combination therapy (interferon and ribavirin) and have achieved an SVR.. A total of 214 nondiabetic CHC patients with SVR and baseline homeostasis model assessment (HOMA) less than or equal to 2 were divided into group A, which included 108 patients with a BMI less than 25, and group B, which included 106 patients with a BMI of at least 25 and less than 30. HOMA insulin resistance (IR) and BMI were measured at the baseline, at achievement of an SVR, and 1 year after achievement of an SVR. Leptin levels were assessed at baseline and 1 year after achievement of an SVR in patients with increased BMI.. One year after SVR, 36 (33.33%) patients from group A developed increasing BMI with no significant changes in HOMA versus that at SVR (P=0.53), but showed a significant reduction versus baseline HOMA (P=0.02). In group B, 68 (64.1%) patients showed increased BMI of at least 25, with a significant increase in HOMA versus that at SVR (P=0.02), and with no significant reduction versus baseline HOMA (P=0.44). In group B, serum leptin showed a significant reduction 12 months after achievement of an SVR versus baseline in patients with increased BMI. Six patients from group B with increased BMI after 1 year developed de-novo IR and type two diabetes mellitus.. In nondiabetic CHC patients with SVR and baseline BMI of at least 25, the post-SVR increase in BMI predisposed to an increase in HOMA-IR and could be considered a predisposing factor for diabetes mellitus.

Topics: Adult; Antiviral Agents; Biomarkers; Blood Glucose; Body Mass Index; Diabetes Mellitus; Drug Therapy, Combination; Female; Hepatitis C, Chronic; Humans; Insulin; Insulin Resistance; Interferon alpha-2; Interferon-alpha; Leptin; Male; Middle Aged; Polyethylene Glycols; Predictive Value of Tests; Prospective Studies; Recombinant Proteins; Ribavirin; Risk Factors; Sustained Virologic Response; Time Factors; Treatment Outcome

Topics: Adipose Tissue, White; Body Composition; Cardiovascular Diseases; Diabetes Mellitus; Humans; Leptin; Lipolysis; Metabolic Syndrome; Obesity

The relationship between loss of hypothalamic function and onset of diabetes mellitus remains elusive. Therefore, we generated a targeted oxidative-stress murine model utilizing conditional knockout (KO) of selenocysteine-tRNA (Trsp) using rat-insulin-promoter-driven-Cre (RIP-Cre). These Trsp-KO (Trsp

Topics: Animals; Antioxidants; Diabetes Mellitus; Hypothalamus; Insulin; Insulin Resistance; Insulin-Secreting Cells; Leptin; Mice; Mice, Knockout; NF-E2-Related Factor 2; Oxidative Stress; Promoter Regions, Genetic; RNA, Transfer, Amino Acid-Specific; Signal Transduction

The SNP 3'UTR C/T (rs10401670), it is a polymorphism that has been associated with diabetes mellitus and it has been scarcely studied before. As far as we know, no studies on interaction among diet intervention, rs10401670 variant of RETN and metabolic response has been realized.. Our aim was to analyze the effects of the rs10401670 RETN gene polymorphism on insulin resistance response and metabolic changes secondary to weight loss after 3 months of a hypocaloric diet in adults obese patients without diabetes mellitus.. A Caucasian population of 135 obese patients without diabetes mellitus was analyzed. Before and after 3 months on a low fat hypocaloric diet, an anthropometric evaluation, an assessment of nutritional intake and a biochemical analysis were performed. The statistical analysis was performed for the combined CT and TT as a group (minor allele group) and wild type CC as second group (major allele group) (dominant model).. Forty nine patients (36.3%) had the genotype CC (major allele group) and 86 (63.7%) patients had the next genotypes; CT (67 patients, 49.6%) or TT (19 patients, 14.1%) (minor allele group). After dietary treatment and in major allele group, weight, BMI, fat mass, systolic blood pressure and waist circumference decreases were similar than minor allele group. In T allele carriers, fasting plasma glucose, insulin, HOMA-IR, total cholesterol and LDL cholesterol levels decreased significantly. In non T allele carriers and after dietary treatment, only LDL cholesterol and total cholesterol decreased. In non T Allele carriers, the decrease in total cholesterol was -15.1 ± 18.3 mg/dl (decrease in T Allele carriers -18.3 ± 15.7 mg/dl: p > 0.05), LDL-cholesterol was -14.3 ± 18.5 mg/dl (decrease in T Allele carriers -17.3 ± 10.1 mg/dl:p > 0.05), fasting glucose plasma -2.2 ± 1.5 mg/dL (decrease in T Allele carriers -4.8 ± 1.2 mg/dL: p = 0.02), insulin -1.1 ± 2.0 mUI/L (decrease in T Allele carriers -6.3 ± 1.9 mUI/L: p = 0.001) and HOMA-IR -0.2 ± 1.0 (decrease in T Allele carriers -1.8 ± 1.4: p = 0.005). Leptin levels decrease in both genotypes after dietary treatment (-21.1 ± 8.5 ng/dL in nonT Allele carriers vs -16.2 ± 10.2 ng/dL in T Allele carriers:p > 0.05). Resistin remained unchanged in both groups.. In our study in non-diabetic obese subjects, we describe an association of rs10401670T allele with a better metabolic response (glucose, insulin and HOMA-IR) secondary to weight loss with a hypocaloric diet.

Topics: Adult; Alleles; Anthropometry; Blood Pressure; Body Mass Index; Body Weight; Cholesterol; Diabetes Complications; Diabetes Mellitus; Diet, Reducing; Female; Genotype; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Polymorphism, Single Nucleotide; Resistin; Waist Circumference; Weight Loss

Obesity and metabolic syndrome are the major risk factors for cardiovascular disease. Obesity is caused by increased food intake and/or decreased energy expenditure. Leptin potently inhibits food intake and promotes energy expenditure. These effects of leptin involve the activation of proopiomelanocortin (POMC) neurons in the hypothalamus arcuate nucleus (ARC). Disruption of leptin signaling in POMC neuron is considered one of the major causes for obesity.. The present study aimed to examine whether overexpression of interleukin-10 (IL-10) could substitute for the leptin action and ameliorate obesity in leptin-deficient Lep(ob/ob) mice.. Adeno-associated virus (AAV) expressing murine IL-10 (AAV-mIL-10) was injected into the skeletal muscle to overexpress IL-10 in mice. These mice were subsequently subjected to analysis of body weight, food intake, glucose metabolism and underlying mechanisms.. In Lep(ob/ob) mice, AAV-IL-10 ameliorated hyperphagia, obesity, glucose intolerance and insulin resistance, as well as attenuated tumor necrosis factor-α expression. The IL-10 treatment also improved glucose-induced insulin release. Furthermore, IL-10 treatment increased POMC mRNA expression in ARC and phosphorylation of signal transducer and activator of transcription-3 (STAT3) in ARC and white adipose tissue (WAT). In neuron-specific STAT3-null mice that exhibited obesity and hyperphagia, AAV-mIL-10 administration failed to affect food intake, body weight and phosphorylation of STAT3 in WAT.. These results demonstrate that peripheral overexpression of IL-10 induces STAT3 phosphorylation in ARC POMC neurons, and thereby ameliorates hyperphagia and obesity caused by leptin deficiency. IL-10 gene transfer may provide an effective approach for preventing progression of metabolic syndrome due to leptin resistance.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Diabetes Mellitus; Disease Models, Animal; Energy Metabolism; Gene Transfer Techniques; Hyperphagia; Interleukin-10; Leptin; Male; Mice; Obesity; Pro-Opiomelanocortin; Up-Regulation

Epidemiological studies suggest that diabetics may be more susceptible to the adverse health effects from exposure to high ambient concentrations of ozone, the primary oxidant gas in photochemical smog. While increased morbidity and mortality from ozone inhalation has been linked to disruption of normal cardiovascular and airway functions, potential effects on glucose and insulin homeostasis are not understood. We tested the hypothesis that ozone exposure would worsen metabolic homeostasis in KKAy mice, a genetic diabetic animal model. Male KKAy mice were exposed to 0.5 ppm ozone for 13 consecutive weekdays, and then assessed for airway, adipose and systemic inflammation, glucose homeostasis, and insulin signaling. Ozone exposure increased plasma TNFα, as well as expression of VCAM-1, iNOS and IL-6 in both pulmonary and adipose tissues. Pro-inflammatory CD11b(+)Gr-1(lo)7/4(hi) macrophages were increased by 200% in adipose tissue, but unchanged in blood. Interestingly, glucose levels were not significantly different in the insulin tolerance test between air- and ozone-exposed mice, whereas fasting insulin levels and HOMA-IR in ozone-exposed animals were significantly reduced. These changes were accompanied by increased insulin signaling in skeletal muscle and liver, but not adipose tissues. Ozone also caused decrease in body weight and plasma leptin. Our results show that in addition to marked local and systemic inflammation, ozone increases insulin sensitivity that may be related to weight loss/leptin sensitization-dependent mechanisms in KKAy mice, warranting further study on the role of hyperglycemia in mediating cardiometabolic effects of ozone inhalation.

Topics: Adiponectin; Adipose Tissue; Administration, Inhalation; Animals; Blood Glucose; Diabetes Mellitus; Disease Models, Animal; Inflammation; Insulin; Insulin Resistance; Leptin; Liver; Male; Mice; Muscle, Skeletal; Sulfuric Acids

We discuss the case of a 56-year-old woman who presented with diabetes from the age of 24. The diagnosis of familial partial lipodystrophy was made after the discovery of the lamin A/C gene 20 years later. The diagnosis enabled the detection of a severe cardiac rhythm disorder with the need for an implantable defibrillator. This disease is a rare disorder characterized by an altered body fat repartition, cardiac rhythm anomalies and muscular dystrophy.

Topics: Body Fat Distribution; Diabetes Complications; Diabetes Mellitus; Diagnosis, Differential; Female; Humans; Lamin Type A; Leptin; Lipodystrophy, Familial Partial; Middle Aged; Mutation; Myotonic Dystrophy

Low birth weight is associated with increased rates of obesity, insulin resistance and type 2 diabetes, but the precise mechanisms for this association remain unclear. We aimed to assess the relationships between birth weight and markers of glucose homeostasis or obesity in adults.. Cross-sectional population-based study on 1458 women and 1088 men aged 35-75 years living in Lausanne, Switzerland. Birth weight was self-reported and categorized into ≤ 2.5, 2.6-3.5, 3.6-4.0 and >4.0 kg. Body composition was assessed by bioimpedance. Leptin and adiponectin levels were measured by ELISA.. Women with low birth weight (≤ 2.5 kg) had higher levels of fasting plasma glucose, insulin, HOMA, diabetes and metabolic syndrome; a non significant similar trend was seen in men. In both genders, height increased with birth weight, whereas a U-shaped association was found between birth weight and body mass index, waist circumference and body fat percentage. After adjusting for age, smoking status, physical activity and fat mass, an inverse association was found between leptin and birth weight categories: adjusted mean ± standard error 17.3 ± 0.7, 16.2 ± 0.3, 15.6 ± 0.5 and 14.0 ± 0.8 ng/dL for birth weight categories ≤ 2.5, 2.6-3.5, 3.6-4.0 and >4.0 kg, respectively, in women (p < 0.05) and 9.8 ± 0.8, 9.1 ± 03, 7.8 ± 0.4 and 7.7 ± 0.5 ng/dL in men (p < 0.05). An inverse association was also found between reported birth weight and leptin to fat mass ratio: mean ± standard error 0.77 ± 0.04, 0.73 ± 0.02, 0.69 ± 0.03 and 0.62 ± 0.04 in women (p < 0.05); 0.46 ± 0.05, 0.45 ± 0.02, 0.39 ± 0.02 and 0.38 ± 0.03 in men (p < 0.05). No differences in adiponectin levels were found between birth weight groups.. Middle-aged adults born with a low weight present a higher prevalence of diabetes and obesity and also higher leptin levels and leptin to fat mass ratio than adults born with a normal weight. The higher leptin levels and leptin to fat mass ratio among adults born with a low weight might be related to nutritional factors during childhood or to the development of leptin resistance and/or higher leptin production by body fat unit. Subjects born with a low weight should be counselled regarding the risks of developing diabetes and/or cardiovascular disease.

Topics: Adult; Aged; Body Composition; Cross-Sectional Studies; Diabetes Mellitus; Exercise; Female; Humans; Infant, Low Birth Weight; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Middle Aged; Obesity; Switzerland

Leptin (LEP) deficiency results in major metabolic perturbations, including obesity, dyslipidemia, and diabetes. Although LEP deficiency can be treated with daily injections of a recombinant LEP, generation of an antibody activating the LEP receptor (LEPR) that has both an intrinsically long half-life and low immunogenicity could be useful in the treatment of this condition.. Phage display technology coupled with flow cytometry and cell-based in vitro assays were employed to identify an allosteric agonist of the mouse LEPR. LEP-deficient Lep(ob) /Lep(ob) mice were used to compare in vivo effects of LEP to antibody administration. To evaluate hypothalamic effects of treatment, changes in mRNA levels of neuropeptide Y and proopiomelanocortin were measured.. XPA.80.037 is a monoclonal antibody that demonstrates allosteric agonism of the mouse LEPR. Treatment of Lep(ob) /Lep(ob) mice with XPA.80.037 markedly reduced hyperphagia and body weight, normalized blood glucose and plasma insulin levels, and corrected dyslipidemia. These metabolic alterations correlated with changes in mRNA levels of neuropeptide Y and proopiomelanocortin, suggesting that XPA.80.037 had hypothalamic effects.. Agonist allosteric monoclonal antibodies to the LEPR can correct metabolic effects associated with LEP deficiency in vivo and thereby have the potential to treat conditions of LEP deficiency.

Topics: Allosteric Regulation; Animals; Blood Glucose; Body Weight; Diabetes Mellitus; Half-Life; Hypothalamus; Insulin Resistance; Leptin; Mice; Mice, Inbred C57BL; Obesity; Phenotype; Pro-Opiomelanocortin; Receptors, Leptin

We aimed to selectively breed a spontaneous diabetic gerbil when a sub-line of inbred gerbil showed increased blood glucose levels was found recently. Then we investigated the characteristics including the serum insulin, triglyceride, cholesterol, leptin, adiponectin and explored the underlying molecular mechanism for the diabetic phenotype.. The spontaneous diabetic line of gerbils was selectively inbreed the sub-line of gerbil by monitoring blood glucose of each animal. The serum insulin, adiponectin, and leptin levels were tested using an ELISA kit. The expression levels of GLUT4, Akt, leptin, adiponectin, and calpain 10 (CAPN10) were tested by western blot and Quantitative Real-time PCR (qPCR) in liver, skeletal muscle, and white adipose.. Our results show that the percentages of animals with FPG≥5.2 (mmol/l), PG2h≥6.8 (mmol/l) and both FPG≥5.2 and PG2h≥6.8 (mmol/l) were increased with the number of breeding generations from F0 (21.33%) to F6 (38.46%). These diabetic gerbils exhibited insulin resistance and leptin resistance as well as decreased adiponectin level in the serum. We also observed decreased expression of adiponectin and increased expression of leptin in the skeletal muscle, respectively.. These results indicate that we have primarily established a spontaneous diabetic gerbil line, and the diabetic phenotypes may have been accounted for by altered expression of leptin and adiponectin.

Topics: Adiponectin; Adipose Tissue, White; Animals; Blood Glucose; Breeding; Calpain; Cholesterol; Diabetes Mellitus; Female; Founder Effect; Gene Expression Regulation; Gerbillinae; Glucose Transporter Type 4; Insulin; Insulin Resistance; Leptin; Liver; Male; Muscle, Skeletal; Phenotype; Proto-Oncogene Proteins c-akt; Triglycerides

Hyperinsulinemia is commonly associated with obesity. Mice deficient in the adipose-derived hormone leptin (. Leptin expressing (. We found that in young. Taken together, our findings indicate that hyperinsulinemia is required for excess adiposity in

Topics: Animals; Diabetes Mellitus; Hyperinsulinism; Insulin; Leptin; Mice; Obesity

Many epidemiological studies find an inverse correlation between carotenoids intake or carotenoids plasma concentrations and body mass index (BMI), insulin resistance or metabolic syndrome in the general population. However, it is not clear whether these relationships occur in obese population.. We conducted a cross-sectional study in 108 obese non-diabetic patients.. There was an inverse correlation between plasma levels of pro-vitamin A carotenoids (α-carotene, β-carotene and β-cryptoxanthin) and both BMI and insulin resistance (estimated by the HOMA-IR). No correlation between plasma concentrations of lycopene or lutein/zeaxanthin and BMI or insulin resistance was found. The inverse association between the three pro-vitamin A carotenoids and HOMA-IR disappeared after adjustment for BMI and waist circumference. Interestingly, we identified a positive association between concentrations of β-carotene and adiponectin in plasma that was independent of sex, age, smoking status, BMI and waist circumference. To our knowledge, such association has never been described in obese patients.. These results suggest the existence of a favourable effect of β-carotene on insulin sensitivity in obese individuals that could involve a positive regulation of adiponectin, either directly or via its pro-vitamin A activity. The demonstration of the potential benefits of β-carotene towards insulin sensitivity would open the way to dietary strategies to prevent metabolic syndrome.

Topics: Adiponectin; Adolescent; Adult; Aged; beta Carotene; Body Mass Index; Carotenoids; Cholesterol, HDL; Cholesterol, LDL; Cross-Sectional Studies; Diabetes Mellitus; Diet; Female; Humans; Insulin Resistance; Interleukin-1; Leptin; Linear Models; Lutein; Lycopene; Male; Metabolic Syndrome; Middle Aged; Multivariate Analysis; Obesity; Plasminogen Activator Inhibitor 1; Triglycerides; Tumor Necrosis Factor-alpha; Young Adult; Zeaxanthins

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

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

Fibrosis of adipose tissue (AT) increases AT rigidity, reduces its expandability, and contributes to metabolic dysfunction. Collagen type VI, α3 (COL6A3) encodes 1 subunit of a fibrotic extracellular matrix protein highly expressed in rodent AT. Knockout of collagen VI in rodent AT led to a significant improvement in metabolic health in obese, diabetic ob/ob mice. However, it is unknown whether this collagen has the same metabolic significance in human AT. We therefore aimed to undertake a comprehensive assessment of COL6A3 in relation to human AT and obesity. Characterization of COL6A3 in human AT showed 5-fold higher expression in the stromalvascular fraction compared with adipocyte expression and significantly higher expression in subcutaneous AT (SCAT) than omental AT. In both depots, COL6A3 expression appeared to be lowered in obesity, whereas diet- and surgery-induced weight loss increased COL6A3 expression in SCAT. Leptin treatment caused a dose-dependent decrease in COL6A3 expression, although no effect was seen with insulin or glucose treatment and no difference observed in subjects with diabetes. In addition, we found that the collagen expression profile in humans differs significantly from rodents, because COL6A3 does not appear to be the predominant collagen in adipose, muscle, or liver. Our findings oppose those initially seen in rodent studies and, most importantly, demonstrate a direct regulation of COL6A3 by leptin. This highlights the importance of a paracrine leptin signaling pathway in human AT and suggests an additional mechanism by which leptin can regulate extracellular matrix composition and, with it, AT expandability.

Topics: Adipose Tissue; Adult; Caloric Restriction; Case-Control Studies; Collagen Type VI; Diabetes Mellitus; Female; Humans; Leptin; Middle Aged; Obesity

Obesity is a risk factor for decline in glomerular filtration rate (GFR). One proposed mechanism leading to glomerulopathy is an increase in leptin levels. However, the association between leptin and GFR has never been demonstrated. The aim of this study is to verify whether higher levels of leptin are associated with longitudinal changes of estimated GFR (eGFR).. We selected 744 participants in the InCHIANTI study (416 women). The association between eGFR and leptin changes over a 6-years follow-up was assessed using random effect models including leptin as a time-varying covariate and adjusted for potential confounders. We also compared the proportion of patients with rapid decline of renal function across tertiles of change in serum leptin between baseline and 6-years follow-up. Mean baseline eGFR was 82.2 ml/min/1.73 m, 78.7 ml/min/1.73 m, and 75.4 ml/min/1.73 m in the first, second and third tertile of baseline serum leptin concentration, respectively. After adjustment for potential confounders, leptin concentration was inversely associated with changes of eGFR over time (β for log-leptin: -1.288, 95% CI: -2.079 - -0.497). Relative to baseline levels, the estimated change in eGFR for unit-increase in log-leptin was -1.9% (95% CI: -2.977 - -0.761). After stratification by sex, the results were confirmed in women only. In women we also found an association between increasing leptin concentration over time and rapid decline of renal function.. In women, serum leptin may contribute to eGFR decline independently from obesity and diabetes mellitus, although a cause-effect relationship cannot be established due to the observational nature of our study. A better characterization of adipokine profile of obese individuals may shed light on the accelerated renal function decline reported in a proportion of high-risk obese individuals.

Topics: Aged; Aged, 80 and over; Diabetes Mellitus; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Kidney; Leptin; Longitudinal Studies; Male; Middle Aged; Obesity; Sex Factors

We previously demonstrated that leptin has powerful central nervous system (CNS)-mediated antidiabetic actions. In this study we tested the importance of melanocortin-4 receptors (MC4Rs) for leptin's ability to suppress food intake, increase blood pressure (BP) and heart rate (HR), and normalize glucose levels in insulin-dependent diabetes. MC4R knockout (MC4R-KO) and control wild-type (WT) rats were implanted with intracerebroventricular (ICV) cannula and BP and HR were measured 24 h/day by telemetry. After 5-day control period, an injection of streptozotocin (50 mg/kg, ip) was used to induce diabetes. Eight days after injection, an osmotic pump was implanted subcutaneously and connected to the ICV cannula to deliver leptin (15 μg/day) for 7 days. At baseline, MC4R-KO rats were hyperphagic and 40% heavier than WT rats. Despite obesity, BP was similar (112 ± 2 vs. 111 ± 2 mmHg) and HR was lower in MC4R-KO rats (320 ± 6 vs. 347 ± 5 beats/min). Induction of diabetes increased food intake (30%) and reduced BP (∼17 mmHg) and HR (∼61 beats/min) in WT rats, while food intake, BP, and HR were reduced by ∼10%, 7 mmHg, and 33 beats/min, respectively, in MC4R-KO rats. Leptin treatment normalized blood glucose (437 ± 10 to 136 ± 18 mg/dl), reduced food intake (40%), and increased HR (+60 beats/min) and BP (+9 mmHg) in WT rats. Only modest changes in blood glucose (367 ± 16 to 326 ± 23 mg/dl), food intake (5%), HR (+16 beats/min) and BP (+4 mmHg) were observed in MC4R-KO rats. These results indicate that intact CNS MC4R signaling is necessary for leptin to exert its chronic antidiabetic, anorexic, and cardiovascular actions.

Topics: Animals; Anorexia; Blood Pressure; Brain; Diabetes Mellitus; Eating; Glucose; Heart Rate; Leptin; Male; Mice; Mice, Knockout; Rats, Wistar; Receptor, Melanocortin, Type 4

Small heterodimer partner (SHP, NR0B2) is involved in diverse metabolic pathways, including hepatic bile acid, lipid and glucose homeostasis, and has been implicated in effects on the peroxisome proliferator-activated receptor γ (PPARγ), a master regulator of adipogenesis and the receptor for antidiabetic drugs thiazolidinediones (TZDs). In this study, we aim to investigate the role of SHP in TZD response by comparing TZD-treated leptin-deficient (ob/ob) and leptin-, SHP-deficient (ob/ob;Shp(-/-)) double mutant mice.. Both ob/ob and double mutant ob/ob;Shp(-/-) mice developed hyperglycemia, insulin resistance, and hyperlipidemia, but hepatic fat accumulation was decreased in the double mutant ob/ob;Shp(-/-) mice. PPARγ2 mRNA levels were markedly lower in ob/ob;Shp(-/-) liver and decreased to a lesser extent in adipose tissue. The TZD troglitazone did not reduce glucose or circulating triglyceride levels in ob/ob;Shp(-/-) mice. Expression of the adipocytokines, such as adiponectin and resistin, was not stimulated by troglitazone treatment. Expression of hepatic lipogenic genes was also reduced in ob/ob;Shp(-/-) mice. Moreover, overexpression of SHP by adenovirus infection increased PPARγ2 mRNA levels in mouse primary hepatocytes.. Our results suggest that SHP is required for both antidiabetic and hypolipidemic effects of TZDs in ob/ob mice through regulation of PPARγ expression.

Topics: Animals; Bile Acids and Salts; Diabetes Mellitus; Gene Expression Regulation; Glucose; Hepatocytes; Humans; Insulin; Insulin Resistance; Leptin; Lipid Metabolism; Mice; Mice, Obese; PPAR gamma; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Thiazolidinediones

Increasing evidence links the widespread exposure to organophosphate (OP) pesticides to the global epidemics of type 2 diabetes and obesity. Our recent data highlighted gene×environment interactions: mice expressing the human apolipoprotein E3 (apoE3) isoform were more prone to develop obesity than those expressing apoE2 or apoE4 upon dietary challenge with chlorpyrifos (CPF), the most used OP worldwide. Thus, we aimed to further explore the contribution of the APOE3 genotype on the emergence of obesity and related metabolic dysfunctions upon subchronic exposure to CPF. Seven-month-old targeted replacement apoE3 and C57BL/6N male mice were orally exposed to CPF at 0 or 2mg/kg body weight/day for 8 consecutive weeks. We examined body weight status, food and water intake, lipid and glucose homeostasis, metabolic biomarkers concentrations, insulin levels and insulin resistance, and leptin and ghrelin profiles. CPF exposure generally increased food ingestion, glucose and total cholesterol concentrations, and tended to elevate acyl ghrelin levels. Nonetheless, excess weight gain and increased leptin levels were inherent to apoE3 mice. Moreover, the propensity towards a diabetic profile was markedly higher in these animals than in C57BL/6N, as they showed a higher homeostatic model assessment for insulin resistance index and higher insulin levels. Although both genotypes were metabolically affected by CPF, the results of the present investigation revealed that apoE3 mice were the most vulnerable to developing obesity and related disturbances following CPF administration through the diet. Since the APOE3 genotype is the most prevalent worldwide, current findings have particular implications for human health.

Topics: Animals; Apolipoprotein E3; Blood Glucose; Body Weight; Chlorpyrifos; Cholesterol; Cholinesterases; Diabetes Mellitus; Diet; Eating; Ghrelin; Insecticides; Insulin; Insulin Resistance; Leptin; Male; Mice, Inbred C57BL; Mice, Transgenic; Obesity; Phenotype; Triglycerides

Post-transplant diabetes mellitus (PTDM) is a common metabolic complication after organ transplantation and may be associated with the use of calcineurin inhibitors (tacrolimus and cyclosporine). Leptin and adiponectin are adipokines and play an important role in the regulation of insulin secretion as well as glucose and lipid metabolism.. The aim of this study was to examine the association between adiponectin and leptin gene polymorphisms and development of PTDM.. The study included 323 patients who received kidney transplants and were treated with calcineurin inhibitors (tacrolimus or cyclosporine).. The association between adiponectin and leptin gene polymorphisms and PTDM was studied in three models of Cox regression analysis--additive, dominant and recessive. In these three models, the LEP rs2167270 gene polymorphism was statistically significantly associated with increased risk of PTDM. The association between the LEP rs2167270 polymorphism and PTDM was confirmed by multivariate regression analysis.. The results of our study suggest an association between the leptin rs2167270 gene A allele and PTDM. Original submitted 27 February 2015; Revision submitted 22 May 2015.

Topics: Adiponectin; Adult; Alleles; Cyclosporine; Diabetes Mellitus; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Leptin; Male; Middle Aged; Polymorphism, Genetic; Postoperative Complications; Risk; Tacrolimus

Mast cells (MCs) contribute to the pathogenesis of obesity and diabetes. This study demonstrates that leptin deficiency slants MCs toward anti-inflammatory functions. MCs in the white adipose tissue (WAT) of lean humans and mice express negligible leptin. Adoptive transfer of leptin-deficient MCs expanded ex vivo mitigates diet-induced and pre-established obesity and diabetes in mice. Mechanistic studies show that leptin-deficient MCs polarize macrophages from M1 to M2 functions because of impaired cell signaling and an altered balance between pro- and anti-inflammatory cytokines, but do not affect T cell differentiation. Rampant body weight gain in ob/ob mice, a strain that lacks leptin, associates with reduced MC content in WAT. In ob/ob mice, genetic depletion of MCs exacerbates obesity and diabetes, and repopulation of ex vivo expanded ob/ob MCs ameliorates these diseases.

Topics: Animals; Diabetes Mellitus; Humans; Leptin; Macrophages; Mast Cells; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity

An increased frequency of atherosclerosis (ATH) in systemic lupus erythematosus (SLE) is well-documented but not fully explained by the presence of traditional cardiac risk factors. Several nontraditional biomarkers, including proinflammatory high-density lipoprotein (piHDL) and leptin, have been individually associated with subclinical ATH in SLE. The aim of this study was to examine whether these and other biomarkers can be combined into a risk profile, the Predictors of Risk for Elevated Flares, Damage Progression, and Increased Cardiovascular Disease in Patients with SLE (PREDICTS), that could be used to better predict future progression of ATH.. In total, 210 patients with SLE and 100 age-matched healthy control subjects (all women) participated in this prospective cohort study. The longitudinal presence of carotid plaque and intima-media thickness (IMT) were measured at baseline and followup (mean ± SD 29.6 ± 9.7 months).. At followup, carotid plaque was present in 29% of SLE patients. Factors significantly associated with plaque, determined using Salford Predictive Modeling and multivariate analysis, included age ≥48 years (odds ratio [OR] 4.1, P = 0.002), high piHDL function (OR 9.1, P < 0.001), leptin levels ≥34 ng/dl (OR 7.3, P = 0.001), plasma soluble TWEAK levels ≥373 pg/ml (OR 28.8, P = 0.004), and history of diabetes (OR 61.8, P < 0.001). Homocysteine levels ≥12 μmoles/liter were also a predictor. However, no single variable demonstrated an ideal combination of good negative predictive values (NPVs), positive predictive values (PPVs), sensitivity, and specificity. A high-risk PREDICTS profile was defined as ≥3 positive biomarkers or ≥1 positive biomarker plus a history of diabetes; for high-risk SLE patients, the PPV was 64%, NPV was 94%, sensitivity was 89%, and specificity was 79%. In multivariate analysis, SLE patients with the high-risk profile had 28-fold increased odds for the longitudinal presence of plaque (P < 0.001) and increased progression of IMT (P < 0.001).. A high-risk PREDICTS score confers 28-fold increased odds of the presence of any current, progressive, or acquired carotid plaque, both in patients with SLE and in control subjects, and is significantly associated with higher rates of IMT progression.

Topics: Adiponectin; Adult; Age Factors; Apolipoprotein A-I; Atherosclerosis; Biomarkers; Carotid Arteries; Carotid Artery Diseases; Carotid Intima-Media Thickness; Case-Control Studies; Cholesterol, HDL; Cholesterol, LDL; Cohort Studies; Cytokine TWEAK; Diabetes Complications; Diabetes Mellitus; Disease Progression; Female; Homocysteine; Humans; Leptin; Longitudinal Studies; Lupus Erythematosus, Systemic; Middle Aged; Multivariate Analysis; Odds Ratio; Plaque, Atherosclerotic; Predictive Value of Tests; Prospective Studies; Risk Assessment; Risk Factors; Sensitivity and Specificity; Tumor Necrosis Factors

Soy isoflavones have received great attention for their beneficial effects on health and disease, i.e., in patients with diabetes. Equol is a biologically active isoflavone-related metabolite with interindividual differences in its production. The current study investigated the relationship between an equol-producing state and the levels of adipocytokine markers in a prediabetic and diabetic population.. A total of 79 subjects (34 males/45 females) in a prediabetic or diabetic state recruited from the general population were examined regarding their ability to produce equol using urine samples. Clinical data, such as age, smoking as well as anthropometric and biochemical variables, including body mass index (BMI), lipids, insulin, glucose, hemoglobin A1c, leptin and adiponectin, were recorded.. Equol producers exhibited lower leptin and leptin/BMI than non-producers among females. Simple correlation tests and stepwise multiple regression analyses revealed a significant inverse correlation between the leptin/BMI and equol-production. This relationship was not found in males.. Female equol producers can have favorable metabolic traits in relation to leptin metabolism in this population. Further studies are needed to confirm these results.

Topics: Adiponectin; Age Factors; Blood Glucose; Body Mass Index; Cross-Sectional Studies; Diabetes Mellitus; Equol; Female; Glycated Hemoglobin; Humans; Insulin; Intestinal Mucosa; Intestines; Isoflavones; Leptin; Lipids; Male; Prediabetic State; Sampling Studies; Sex Characteristics; Smoking; Soy Foods

Mid-life obesity and type 2 diabetes mellitus (T2DM) confer a modest, increased risk for Alzheimer's disease (AD), though the underlying mechanisms are unknown. We have created a novel mouse model that recapitulates features of T2DM and AD by crossing morbidly obese and diabetic db/db mice with APPΔNL/ΔNLx PS1P264L/P264L knock-in mice. These mice (db/AD) retain many features of the parental lines (e.g. extreme obesity, diabetes, and parenchymal deposition of β-amyloid (Aβ)). The combination of the two diseases led to additional pathologies-perhaps most striking of which was the presence of severe cerebrovascular pathology, including aneurysms and small strokes. Cortical Aβ deposition was not significantly increased in the diabetic mice, though overall expression of presenilin was elevated. Surprisingly, Aβ was not deposited in the vasculature or removed to the plasma, and there was no stimulation of activity or expression of major Aβ-clearing enzymes (neprilysin, insulin degrading enzyme, or endothelin-converting enzyme). The db/AD mice displayed marked cognitive impairment in the Morris Water Maze, compared to either db/db or APPΔNLx PS1P264L mice. We conclude that the diabetes and/or obesity in these mice leads to a destabilization of the vasculature, leading to strokes and that this, in turn, leads to a profound cognitive impairment and that this is unlikely to be directly dependent on Aβ deposition. This model of mixed or vascular dementia provides an exciting new avenue of research into the mechanisms underlying the obesity-related risk for age-related dementia, and will provide a useful tool for the future development of therapeutics.

Topics: Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Blood Pressure; Cognition Disorders; Dementia, Vascular; Diabetes Mellitus; Disease Models, Animal; Glucose Tolerance Test; Humans; Insulin; Leptin; Maze Learning; Mice; Mice, Transgenic; Mutation; Neprilysin; Obesity, Morbid; Presenilin-1; Receptors, Leptin

Leptin and C-reactive protein (CRP) have each been linked to adverse cardiovascular events, and prior cross-sectional research suggests that increased levels of both biomarkers pose an even greater risk. The effect of increased levels of both leptin and CRP on mortality has not, however, been previously assessed.. We used data from the third National Health and Nutrition Examination Survey (NHANES III) to estimate the mortality effect of high leptin and high CRP levels. Outcomes were compared with the use of inverse-probability-weighting adjustment. Among 6259 participants included in the analysis, 766 were in their sex-specific, population-weighted highest quartiles of both leptin and CRP. Median follow-up time was 14.3 years.. There was no significant difference in adjusted all-cause mortality between the groups (risk ratio 1.22, 95% confidence interval [CI], 0.97-1.54). Similar results were noted with the use of several different analytic methods and in many subgroups, though high leptin and CRP levels may increase all-cause mortality in males (hazard ratio, 1.80, 95% CI, 1.32-2.46; P for interaction, 0.011). A significant difference in cardiovascular mortality was also noted (risk ratio, 1.54, 95% CI, 1.08-2.18), though that finding was not confirmed in all sensitivity analyses... In this observational study, no significant difference in overall all-cause mortality rates in those with high leptin and high CRP levels was found, though high leptin and CRP levels appear associated with increased mortality in males. High leptin and CRP levels also likely increase risk for cardiovascular death..

Topics: Adult; Aged; Aged, 80 and over; C-Reactive Protein; Cardiovascular Diseases; Cause of Death; Comorbidity; Cross-Sectional Studies; Diabetes Mellitus; Dyslipidemias; Ethnicity; Female; Follow-Up Studies; Health Surveys; Humans; Inflammation; Kidney Diseases; Leptin; Lung Diseases; Male; Middle Aged; Mortality; Risk Factors; Sex Factors; Smoking; United States; Young Adult

Cachexia may occur in 40% of cancer patients, representing the major cause of death in more than 20% of them. The aim of this study was to investigate the role of leptin, ghrelin and obestatin as diagnostic and predictive markers of cachexia in oncologic patients. Their impact on patient survival was also evaluated.. 140 adults with different cancer diagnoses were recruited. Thirty healthy volunteers served as control. Serum ghrelin, obestatin and leptin were tested at baseline and after a follow-up period of 18 months.. Ghrelin levels were significantly higher in cancer patients than in healthy subjects (573.31 ± 130 vs 320.20 ± 66.48 ng/ml, p < 0.0001), while obestatin (17.42 ± 7.12 vs 24.89 ± 5.54 ng/ml, p < 0.0001) and leptin (38.4 ± 21.2 vs 76.28 ± 17.48 ng/ml, p < 0.0001) values were lower. At ROC analyses the diagnostic profile of ghrelin (AUC 0.962; sensitivity 83%; specificity 98%), obestatin (AUC 0.798; sensitivity 74.5%; specificity 81.5%) and leptin (AUC 0.828; sensitivity 79%; specificity 73%) was superior to that of albumin (AUC 0.547; sensitivity 63%, specificity 69.4%) for detecting cachexia among cancer patients. On Cox multivariate analyses ghrelin (HR 1.02; 95% CI 1.01 - 1.03; p < 0.0001) and leptin (HR 0.94; 95% CI 0.92 - 0.96; p < 0.0001) were significant predictors of death even after correction for other known risk factors such as presence of metastasis and chronic kidney disease.. Ghrelin and leptin are promising biomarkers to diagnose cachexia and to predict survival in cancer patients.

Topics: Aged; Area Under Curve; Biomarkers; Cachexia; Case-Control Studies; Cholesterol; Diabetes Mellitus; Female; Follow-Up Studies; Ghrelin; Heart Failure; Humans; Kaplan-Meier Estimate; Leptin; Male; Middle Aged; Neoplasm Metastasis; Neoplasms; Predictive Value of Tests; Proportional Hazards Models; ROC Curve; Serum Albumin; Survival Rate

We have previously described the pharmacokinetics of mouse [D-Leu-4]-OB3, a synthetic peptide amide with leptin-like activity, following delivery by subcutaneous (SC), intraperitoneal (IP), and intramuscular (IM) injection, and by oral gavage and intranasal instillation. These profiles suggested that the observed efficacy of [D-Leu-4]-OB3 on energy balance, glycemic control, and bone turnover in ob/ob and db/db mice might be improved by efforts directed toward improving its bioavailability, i.e., increasing maximum uptake (Cmax), extending serum half-life (t½), and reducing plasma clearance (CL). To address these issues, myristic (tetradecanoic) acid was conjugated to the N-terminal of [D-Leu-4]-OB3 (designated MA-[D-Leu-4]-OB3), and the pharmacokinetics of MA-[D-Leu-4]-OB3 in male Swiss Webster mice following SC, IP, and IM injection in PBS, and by oral and intranasal delivery in dodecyl maltoside (DDM, trade name Intravail®), a transmucosal absorption enhancing agent, were compared to those of [D-Leu-4]-OB. At a dose of MA-[D-Leu-4]-OB3 10-fold lower than that used previously for [D-Leu-4]-OB3 (0.1 mg vs.1.0 mg, respectively), Cmax of MA-[D-Leu-4]-OB3 was 11.1-, 7.5-, 1.9-, and 1.7-fold higher, t1/2 was 3.5-, 5.0-, 9.1-, and 86.7-fold longer, and CL was 17.0-, 11.6-, 5.7-, and 5.0-fold slower than [D-Leu-4]-OB3 following SC, IP, IM, and oral delivery, respectively. Furthermore, in leptin-resistant obese male db/db mice, oral delivery of MA-[D-Leu-4]-OB3 in DDM at concentrations up to 10-fold lower than those used with [D-Leu-4]-OB3 reduced fasting blood glucose levels in a dose-related manner.

Topics: Animals; Diabetes Mellitus; Humans; Leptin; Male; Mice; Mice, Inbred NOD; Mice, Obese; Myristic Acid; Obesity; Peptide Fragments; Peptides; Pharmacokinetics

Leptin resistance oriented hyperleptinaemia is a common problem in obese subjects in association with hypercholesterolaemia. The most common target for hypercholesterolaemia is impaired low density lipoprotein receptor (LDLR). This study was carried out to investigate whether any alteration in LDLR expression could explain the occurrence of hypercholesterolaemia in the event of hyperleptinaemia.. Expression of LDLR and SREBP2 (sterol regulatory element binding protein 2) were examined in HepG2 cells by RT-PCR and Western blotting. JAK2 inhibitor II was used to verify the effect of JAK-STAT (Janus Kinase-Signal Transducer and Activator of Transcription) pathway (common mediator for cytokine signaling). Co-localization of LDLR and insulin receptor (IR) was examined by confocal microscopy.. Leptin was found to reduce the expression of LDLR and its transcription factor SREBP2. On the other hand, a weak signal for stimulation of LDLR by leptin was noted to be mediated by JAK2 pathway. But the joint effect of the two signaling pathways kept LDLR only in depressed mode in presence of leptin. Confocal microscopy showed that LDLR made an intensively co-localized complex with insulin receptor in presence of leptin.. Our results show that though leptin stimulates LDLR expression very weakly through JAK-STAT signaling pathway, it mainly imposes inhibition on LDLR expression by inhibiting transcription factor SREBP2. The inter-association between LDLR and IR may be a reason to render LDLR functionally inactive in presence of leptin.

Topics: Diabetes Mellitus; Gene Expression Regulation; Hep G2 Cells; Humans; Hypercholesterolemia; Janus Kinase 2; Leptin; Obesity; Receptor, Insulin; Receptors, LDL; STAT Transcription Factors; Sterol Regulatory Element Binding Protein 2

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

Sixteen plasma markers of inflammation and oxidative stress were measured during OGTT in 54 subjects. Leptin, RBP4, CRP, OPN, ANG, MDC, and MCSF concentrations significantly decreased during OGTT (P<0.05). IL6, IL8, and MCP3 concentrations significantly increased during OGTT (P<0.05). These results provide evidence that glucose ingestion affects systemic inflammation and oxidative stress.

Topics: Aged; Biomarkers; Blood Glucose; C-Reactive Protein; Chemokine CCL2; Chemokine CCL22; Diabetes Mellitus; Female; Glucose; Glucose Tolerance Test; Humans; Inflammation; Interleukin-6; Leptin; Male; Middle Aged; Osteopontin; Oxidative Stress; Retinol-Binding Proteins, Plasma; Ribonuclease, Pancreatic

Much has been made of obesity's health impact, largely founded on data regarding patient weight and circulating adipose-derived mediator levels. Paradoxically, a "healthy obese" state exists, but substantial knowledge gaps also exist regarding human adipose-phenotype determinants. Surgical major amputation (AMP) patients are the "sickest-of-the-sick." Conversely, elective knee replacement (TKR) is reserved for patients who expect continued health and longevity. To delineate human adipose biology variability and clinical determinants, we studied fresh subcutaneous adipose from AMP patients, using TKR patients as controls. We hypothesized that AMP patients would display a pro-inflammatory adipokine signature, and that certain clinical conditions (diabetes, hypertension, hyperlipidemia, high BMI, uremia) would independently drive elevated adipose inflammation.. AMP (n = 29) and TKR (n = 20) adipose tissue samples and clinical data were collected prospectively, and protein was isolated and analyzed for 8 adipose-related mediators. Statistical analyses included Wilcoxon's rank sum test, Fisher's exact test, and multiple linear regression modeling of clinical parameter predictors of mediator expression.. Interleukin-(IL)-6, IL-8, leptin, resistin, and PAI-1 were differentially expressed (up to 200-fold) between AMP/TKR cohorts. Key clinical parameters that associated with protein levels of adipose phenotype included age, gender, hypertension, hyperlipidemia, congestive heart failure, cerebrovascular disease, renal disease, and warfarin, statin, and insulin use. BMI failed to be predictive.. AMP patients display adiposopathy with a pro-inflammatory adipose phenotypic signature compared with TKR controls. BMI fails to predict phenotype, yet other clinical conditions, such as age, hyperlipidemia, and renal insufficiency, do drive adipokine expression. Understanding human adipose phenotypic determinants stands as a fundamental priority when future studies dissect the interplay between adipose biology and surgical diseases/outcomes.

Topics: Age Factors; Aged; Amputation, Surgical; Arthroplasty, Replacement, Knee; Cardiovascular Diseases; Case-Control Studies; Chronic Disease; Comorbidity; Cytokines; Diabetes Mellitus; Elective Surgical Procedures; Female; Humans; Inflammation; Inflammation Mediators; Interleukin-6; Interleukin-8; Leptin; Linear Models; Male; Middle Aged; Obesity; Peripheral Vascular Diseases; Phenotype; Plasminogen Activator Inhibitor 1; Polypharmacy; Prospective Studies; Resistin; Sex Factors; Subcutaneous Fat

Peroxisome proliferator-activated receptor γ (PPARγ) is a unique target for insulin sensitizer agents. These drugs have been used for the clinical treatment of type 2 diabetes for almost twenty years. However, serious safety issues are associated with the PPARγ agonist thiazolidinediones (TZDs). Selective PPARγ modulators (SPPARMs) which retain insulin sensitization without TZDs-like side effects are emerging as a promising new generation of insulin sensitizers. C333H is a novel structure compound synthesized by our laboratory. In diabetic rodent models, C333H has insulin-sensitizing and glucose-lowering activity comparable to that of TZDs, and causes no significant increase in body weight or adipose tissue weight in db/db mice. In diabetic db/db mice, C333H elevated circulating high molecular weight adiponectin isoforms, decreased PPARγ 273 serine phosphorylation in brown adipose tissue and selectively modulated the expression of a subset of PPARγ target genes in adipose tissue. In vitro, C333H weakly recruited coactivator and weakly dissociated corepressor activity. These findings suggest that C333H has similar properties to SPPARMs and may be a potential therapeutic agent for the treatment of type 2 diabetes.

Topics: Adipose Tissue, Brown; Adipose Tissue, White; Animals; Blood Glucose; Cell Line, Tumor; Diabetes Mellitus; Furans; Gene Expression Regulation; Humans; Insulin; Insulin Resistance; Leptin; Male; Mice; Obesity; Organ Size; Oxazoles; PPAR gamma; Rats; Rats, Wistar; Sodium Glutamate

Non-alcoholic fatty liver disease (NAFLD) is associated with cardiovascular atherosclerosis independent of classical risk factors. This study investigated the influence of NAFLD on autonomic changes, which is currently unknown.. Subjects without an overt history of cardiovascular disease were enrolled during health checkups. The subjects diagnosed for NAFLD using ultrasonography underwent 5-min heart rate variability (HRV) measurements that was analyzed using the following indices: (1) the time domain with the standard deviation of N-N (SDNN) intervals and root mean square of successive differences between adjacent N-N intervals (rMSSD); (2) the frequency domain with low frequency (LF) and high frequency (HF) components; and (3) symbolic dynamics analysis. Routine blood biochemistry data and serum leptin levels were analyzed. Homeostasis model assessment of insulin resistance (HOMA-IR) was measured.. Of the 497 subjects (mean age, 46.2 years), 176 (35.4%) had NAFLD. The HRV indices (Ln SDNN, Ln rMSSD, Ln LF, and Ln HF) were significantly decreased in the NAFLD group (3.51 vs 3.62 ms, 3.06 vs 3.22 ms, 5.26 vs 5.49 ms(2), 4.49 vs 5.21 ms(2), respectively, all P<0.05). Ln SDNN was significantly lower in the NAFLD group after adjustment for age, sex, hypertension, dyslipidemia, metabolic syndrome, body mass index, smoking, estimated glomerular filtration rate, HOMA-IR, and leptin (P<0.05). In the symbolic dynamic analysis, 0 V percentage was significantly higher in the NAFLD group (33.8% vs 28.7%, P = 0.001) and significantly correlated with linear HRV indices (Ln SDNN, Ln rMSSD, and Ln HF).. NAFLD is associated with decreased Ln SDNN and increased 0 V percentage. The former association was independent of conventional cardiovascular risk factors and serum biomarkers (insulin resistance and leptin). Further risk stratification of autonomic dysfunction with falls or cardiovascular diseases by these HRV parameters is required in patients with NAFLD.

Topics: Adult; Age Factors; Atherosclerosis; Body Mass Index; Diabetes Mellitus; Fatty Liver; Female; Glomerular Filtration Rate; Heart Rate; Humans; Hypertension; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Middle Aged; Non-alcoholic Fatty Liver Disease; Risk Factors; Sex Factors; Ultrasonography

The agaricoglyceride is a new fungal secondary metabolite that constitutes esters of chlorinated 4-hydroxy benzoic acid and glycerol. The objective of this study was to explore whether the administration of agaricoglyceride could correct hepatic glycemic metabolism dysfunction by attenuating inflammation in the liver. The effects of agaricoglycerides on tumor necrosis factor-α, interleukin-1β, vascular endothelial growth factor-α, interleukin-17, insulin secretion, adiponectin, leptin, hepatic glycogen, nuclear factor-κB activation, and total antioxidant activity were studied respectively. We demonstrated that administration of agaricoglycerides alleviated glycemic metabolism dysfunction, inflammation, and oxidative stress in mice. These data indicate that agaricoglyceride supplementation could restrain metabolic dysfunction through suppressing the nuclear factor-κB pathway as well as decreasing the levels of inflammatory cytokines and total antioxidant activities.

Topics: Adiponectin; Agaricus; Animals; Anti-Inflammatory Agents; Benzoates; Blood Glucose; Diabetes Mellitus; Female; Glycerides; Insulin; Leptin; Liver; Liver Glycogen; Mice; Random Allocation

This study tested whether chronic systemic administration of 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) could attenuate hyperphagia, reduce lean and fat mass losses, and improve whole-body energy homeostasis in insulin-deficient rats. Male Wistar rats were first rendered diabetic through streptozotocin (STZ) administration and then intraperitoneally injected with AICAR for 7 consecutive days. Food and water intake, ambulatory activity, and energy expenditure were assessed at the end of the AICAR-treatment period. Blood was collected for circulating leptin measurement and the hypothalami were extracted for the determination of suppressor of cytokine signaling 3 (SOCS3) content, as well as the content and phosphorylation of AMP-kinase (AMPK), acetyl-CoA carboxylase (ACC), and the signal transducer and activator of transcription 3 (STAT3). Rats were thoroughly dissected for adiposity and lean body mass (LBM) determinations. In non-diabetic rats, despite reducing adiposity, AICAR increased (∼1.7-fold) circulating leptin and reduced hypothalamic SOCS3 content and food intake by 67% and 25%, respectively. The anorexic effect of AICAR was lost in diabetic rats, even though hypothalamic AMPK and ACC phosphorylation markedly decreased in these animals. Importantly, hypothalamic SOCS3 and STAT3 levels remained elevated and reduced, respectively, after treatment of insulin-deficient rats with AICAR. Diabetic rats were lethargic and displayed marked losses of fat and LBM. AICAR treatment increased ambulatory activity and whole-body energy expenditure while also attenuating diabetes-induced fat and LBM losses. In conclusion, AICAR did not reverse hyperphagia, but it promoted anti-catabolic effects on skeletal muscle and fat, enhanced spontaneous physical activity, and improved the ability of rats to cope with the diabetes-induced dysfunctional alterations in glucose metabolism and whole-body energy homeostasis.

Topics: Acetyl-CoA Carboxylase; Adipose Tissue; Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Animals; Appetite Depressants; Body Composition; Body Weight; Diabetes Mellitus; Drinking; Energy Metabolism; Hypothalamus; Insulin; Leptin; Male; Muscle, Skeletal; Phosphorylation; Rats; Rats, Wistar; Ribonucleosides; Signal Transduction; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins

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

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

To evaluate clinical, biochemical, hormonal and genetic characteristics of relatives of two patients with familial partial lipodystrophy (FPLD) type 2.. Fifty subjects, members of two non-related Brazilian families from two different probands with FPLD phenotype, were evaluated. A mutation in exon 8 of LMNA gene was confirmed in 18 of them, and a heterozygous substitution at codon 482 was identified, predicting a p.R482W mutation. Based on the presence or absence of the mutation, subjects were classified in affected and unaffected, and compared in terms of clinical, biochemical and hormonal parameters.. Affected subjects were 2.8 times more likely to manifest diabetes and PCOS, higher HOMA-IR, insulin and triglyceride levels, and lower levels of leptin. These changes preceded the onset of diabetes, because they were observed in diabetic and non-diabetic affected patients. A phenotypic heterogeneity was found among mutation carriers.. A mutation in the LMNA gene is a determinant of clinical, biochemical and hormonal changes that imply in metabolic deterioration in mutation carriers.

Topics: Adolescent; Adult; Biomarkers; Blood Glucose; Diabetes Mellitus; Female; Humans; Insulin Resistance; Lamin Type A; Leptin; Lipodystrophy, Familial Partial; Middle Aged; Mutation; Pedigree; Polycystic Ovary Syndrome; Sequence Analysis, DNA; Young Adult

Chemerin is a potent chemoattractant for chemokine-like receptor 1 expressing cells and is involved in inflammatory and immune processes that play an important role in chronic pancreatitis.. To test the hypothesis that serum chemerin concentration may be affected in chronic pancreatitis patients and that chemerin can influence the course of chronic pancreatitis by increasing profibrotic cytokine production.. Serum concentrations of chemerin and the major cytokines involved in pancreatic fibrosis such as platelet-derived growth factor BB and transforming growth factor β-1 were determined by ELISA in samples from 40 nondiabetic and 28 diabetic male patients with chronic pancreatitis of alcoholic origin and 40 age-matched healthy controls.. Serum concentrations of chemerin were increased both in nondiabetic and diabetic chronic pancreatitis patients compared to controls. Moreover, in chronic pancreatitis patients a positive correlation was found between serum chemerin and platelet-derived growth factor BB as well as transforming growth factor β-1 concentrations.. The results indicate for the first time that: (a) chronic pancreatitis in humans is associated with an increased serum chemerin concentration and (b) serum chemerin concentration correlates with serum concentrations of the major profibrotic cytokines. Elevated level of chemerin, by stimulating macrophage infiltration of the pancreas, might lead to overproduction of platelet-derived growth factor BB and transforming growth factor β-1 and, consequently, to pancreatic fibrosis.

Topics: Adult; Aged; Becaplermin; Body Mass Index; C-Reactive Protein; Case-Control Studies; Chemokines; Diabetes Mellitus; Enzyme-Linked Immunosorbent Assay; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Leukocyte Count; Male; Middle Aged; Pancreatitis, Alcoholic; Proto-Oncogene Proteins c-sis; Resistin; Severity of Illness Index; Transforming Growth Factor beta1

Cystic fibrosis (CF)-related diabetes is an important complication of CF caused by a decrease in insulin secretion that is associated with weight loss, poor nutritional status and increased mortality. Leptin, a hormone secreted from white adipose tissue, has an important role in energy homoeostasis by inhibiting food intake and increasing energy expenditure. Leptin secretion can be increased by nutrient signals such as insulin.. Considering that leptin plays a role in energy homoeostasis and that CF is associated to poor weight gain and decreased insulin secretion, leptin levels in CF patients with different glucose tolerances were investigated and compared with those of healthy control subjects.. Two-hour oral glucose tolerance tests (OGTT) were performed in 82 patients with CF and various glucose tolerances as well as in 17 healthy control subjects during which blood was withdrawn every 30 min to measure glucose and insulin. Fasting leptin, fibrinogen and fat mass were also measured, and body mass index (kg/m(2)) calculated for all participants. Early and late insulin secretion was separated by calculating the area under the curve from time 0 to 30 min and 30 to 120 min of the OGTT (AUC(0-30) and AUC(30-120)).. Leptin levels were comparable between CF patients and healthy control subjects. Interestingly, correlations were observed between leptin levels and insulin (AUC(0-120) and AUC(30-120)) after adjusting for gender and fat mass (P<0.05).. This study suggests a potential role of insulin in regulating leptin levels in adults with stable CF.

Topics: Adult; Area Under Curve; Blood Glucose; Body Mass Index; Canada; Cohort Studies; Cystic Fibrosis; Diabetes Mellitus; Fasting; Female; Fibrinogen; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion; Leptin; Male; Prospective Studies

Insulin resistance and type 2 diabetes correlate with impaired leptin and insulin signaling. Insulin receptor substrate-2 deficient (IRS2(-/-)) mice are an accepted model for the exploration of alterations in these signaling pathways and their relationship with diabetes; however, disturbances in hypothalamic signaling and the effect on neuropeptides controlling food intake remain unclear. Our aim was to analyze how leptin and insulin signaling may differentially affect the expression of hypothalamic neuropeptides regulating food intake and hypothalamic inflammation in diabetic (D) and nondiabetic (ND) IRS2(-/-) mice. We analyzed the activation of leptin and insulin targets by Western blotting and their association by immunoprecipitation, as well as the mRNA levels of neuropeptide Y (NPY), proopiomelanocortin, and inflammatory markers by real-time PCR and colocalization of forkhead box protein O1 (FOXO1) and NPY by double immunohistochemistry in the hypothalamus. Serum leptin and insulin levels and hypothalamic Janus kinase 2 and signal transducer and activator of transcription factor 3 activation were increased in ND IRS2(-/-) mice. IRS1 levels and its association with Janus kinase 2 and p85 and protein kinase B activation were increased in ND IRS2(-/-). Increased FOXO1 positively correlated with NPY mRNA levels in D IRS2(-/-) mice, with FOXO1 showing mainly nuclear localization in D IRS2(-/-) and cytoplasmic in ND IRS2(-/-) mice. D IRS2(-/-) mice exhibited higher hypothalamic inflammation markers than ND IRS2(-/-) mice. In conclusion, differential activation of these pathways and changes in the expression of NPY and inflammation may exert a protective effect against hypothalamic deregulation of appetite, suggesting that manipulation of these targets could be of interest in the treatment of insulin resistance and type 2 diabetes.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Gene Expression Regulation; Hypothalamus; Immunohistochemistry; Inflammation; Insulin Receptor Substrate Proteins; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Models, Biological; Neuropeptide Y; Pro-Opiomelanocortin

In peritoneal dialysis (PD), the peritoneal membrane exhibits structural and functional changes following continuous exposure to the non-physiological peritoneal dialysis fluid (PDF). In this study, we examined the effect of PDF on peritoneal adipose tissue in a diabetic milieu.. Six-week-old db/db mice and their non-diabetic littermates (db/m) were subjected to uninephrectomy. All animals then received intra-abdominal infusion of lactated Ringer's solution (Ringer) or 1.5% glucose-containing PDF (Dianeal) twice daily. Mice were sacrificed 4 weeks later. Parietal and visceral adipose tissues were harvested for examining gene and protein expression of adiponectin, leptin, monocyte chemotactic protein-1, vascular endothelial growth factor, tumor necrosis factor alpha (TNF-α), transforming growth factor beta and interleukin 6 (IL-6). Expression of TNF-α and F4/80+ macrophage accumulation in adipose tissues was assessed by immunohistochemical staining. Modulation of leptin synthesis and leptin receptors expression and the relevant signaling pathways were also determined by quantitative reverse transcription-polymerase chain reaction, immunoblotting or enzyme-linked immunosorbent assay.. Compared to Ringer infusion, Dianeal infusion significantly increased serum leptin but decreased adiponectin in db/db mice. Increased expression of leptin, TNF-α and IL-6 was observed in visceral but not in parietal adipose tissue. Dianeal infusion also increased F4/80+ macrophage accumulation and enhanced the expression of pro-inflammatory cytokines including IL-6 and TNF-α in the visceral adipose tissue. Compared to db/m mice, infusion with Dianeal exhibited a more deleterious effect on db/db mice, characterized by an upregulation of short-form leptin receptor ObRa and activation of the mitogen-activated protein kinase signaling pathway.. In conclusion, PD-induced hyperleptinemia amplifies the inflammatory response of adipose tissue through short-form leptin receptor when the long-form isotype is defective.

Topics: Adipocytes; Adipokines; Adipose Tissue; Animals; Base Sequence; Diabetes Mellitus; Dialysis Solutions; DNA Primers; Inflammation; Interleukin-6; Leptin; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Peritoneal Dialysis, Continuous Ambulatory; Receptors, Leptin; RNA, Messenger; Tumor Necrosis Factor-alpha

Ileal interposition (IT), in which the distal ileum is transposed isoperistaltically into the proximal jejunum, is considered as a procedure for metabolic or antidiabetes surgery. Our aim was to study the effects of IT on glycemic control, fat metabolism, and hormonal changes in obese rats with spontaneous diabetes.. Animals were divided into either an IT or a sham (SH) group. They underwent an oral glucose tolerance test (OGTT) before and 4 and 8 weeks after the operation. All animals were killed 10 weeks after operation for analyses of tissue weight (liver, pancreas, epididymal fat, brown fat), immunoblotting of uncoupling protein-1 (UCP1) protein in brown adipose tissue (BAT), and fasting plasma levels of glucose, insulin, glucagon-like peptide (GLP)-1, peptide YY (PYY), glucose-dependent insulinotropic polypeptide (GIP), and leptin.. Body weight increased postoperatively in both groups compared with preoperative weight, but it did not differ between the 2 groups. Eight weeks postoperatively, integrated blood glucose levels during the OGTT were decreased in IT compared with SH (P < .05). Fasting plasma levels of insulin, GLP-1, and GIP did not differ between the 2 groups, but PYY levels were higher in the IT animals (P < .01). The weight of epididymal and BATs, homeostasis model assessment insulin resistance, and fasting plasma leptin levels were decreased in the IT group (P < .05). Expression of UCP1 was higher in IT than SH animals (P < .05).. These results suggest that IT improves glucose and lipid metabolism by decreasing insulin resistance and epididymal fat, and increased expression of UCP1 in BAT might be among the mechanisms responsible.

Topics: Adipose Tissue, Brown; Animals; Body Weight; Comorbidity; Diabetes Mellitus; Disease Models, Animal; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Ileum; Insulin Resistance; Ion Channels; Jejunum; Leptin; Lipid Metabolism; Male; Mitochondrial Proteins; Obesity; Peptide YY; Rats, Inbred OLETF; Uncoupling Protein 1

To demonstrate whether leptin modulates reproduction by a direct effect within the ovary.. Animal model.. National Key Laboratory of Infertility.. Adult female db/db mice.. Adult littermate wild-type (WT) and diabetic (db) leptin receptor (LR) mutant female mice were matched for the allograft of the ovary to construct new genotypic models, respectively. WT mouse received only one ovary from a WT or a db/db mouse (WT Ov-WT, WT Ov-db), and db/db mouse received one ovary from a WT or a db/db mouse (db Ov-WT, db Ov-db). WT and db/db mice received one ovary from a WT mouse and another ovary from a db/db mouse (WT Ov-WT/db, db Ov-WT/db) or received two ovaries all from a WT mouse (db Ov-WT/WT).. Hormones, lipids, and reverse transcription polymerase chain reaction.. Both WT Ov-WT and WT Ov-db mice presented normal cycles, comparable serum E(2) and FSH levels, and ovarian expressions of the Star, Cyp17, and Cyp19 mRNA, even with different ovary genotypes. In WT Ov-WT/db with hMG stimulation, db ovaries with LR mutation expressed higher Star, Cyp17, Cyp19, Jak2, Stat3, and Pias3 mRNA than in the basal state, whereas WT ovaries with intact LR expressed higher Star, Cyp17, and Cyp19 but divergently lower Jak2, Stat3, and Pias3 levels.. We confirmed that impairment of reproduction in intact db/db mice is not mediated by intraovary intact/defective leptin signaling even in face of a divergent modulation by gonadotropins.

Topics: Animals; Aromatase; Diabetes Mellitus; Disease Models, Animal; Estradiol; Female; Follicle Stimulating Hormone; Genotype; Janus Kinase 2; Leptin; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Mutant Strains; Mutation; Ovary; Phenotype; Phosphoproteins; Protein Inhibitors of Activated STAT; Receptors, Leptin; Reproduction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Steroid 17-alpha-Hydroxylase; Time Factors; Transplantation, Homologous

Dissecting the genetics of complex traits such as obesity allows the identification of causal genes for disease. Here, we show that the BALB/c mouse strain carries genetic variants that confer resistance to obesity induced by leptin-deficiency or a high-fat diet (HFD). We set out to identify the physiological and genetic bases underlying this phenotype. When compared with C57BL6/J ob/ob mice (B6), BALB/c ob/ob mice exhibited decreased food intake, increased thermogenic capacity, and improved fat catabolism, each of which can potentially modify obesity. Interestingly, analysis of F1 ob/ob (progeny of B6 ob/+ × BALB/c ob+) mice revealed that obesity resistance in BALB/c ob/ob mice principally relied upon improved fat mobilization. This was mechanistically explained by increased adipose triglyceride lipase (ATGL) content in adipocytes, along with increased lipolysis and fatty acid oxidation. We conducted a genome-wide scan and defined a quantitative trait locus (QTL) on chromosome 2. BALB/c alleles on chromosome 2 not only associated with the obesity resistance phenotype but also supported increased ATGL content in adipose tissue. In summary, our study provides evidence that leptin-independent control of adipocyte lipolysis rates directly modifies the balance of macronutrient handling and is sufficient to regulate fat mass in the absence of alterations in food intake and energy expenditure.-Marcelin, G., S-M. Liu, X. Li, G. J. Schwartz, and S. Chua.

Topics: Adipocytes; Adipose Tissue; Animals; Basal Metabolism; Chromosomes, Mammalian; Diabetes Mellitus; Diet, High-Fat; Disease Resistance; Eating; Energy Metabolism; Fatty Acids; Female; Intracellular Space; Leptin; Lipase; Lipolysis; Male; Mice; Obesity; Oxidation-Reduction; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Species Specificity; Triglycerides

Although the flavonoid tangeretin (5, 6, 7, 8, 4'-pentamethoxyflavone) is known to possess beneficial health effects, the anti-diabetic effects and the mechanism of action have not been elucidated. Treatment with 100 μM tangeretin significantly increased the uptake of 2-NBDG in C2C12 myotubes. We also found that AMPK and AS160 were markedly phosphorylated by tangeretin treatment. In addition, pretreatment with an AMPK inhibitor significantly abrogated tangeretin-stimulated AS160 phosphorylation, glucose uptake, and Glut4 translocation from the cytosol to the plasma membrane. Furthermore, disruption of AMPK using siRNA transfection prevented the glucose uptake stimulated by tangeretin. We also examined the anti-diabetic properties of tangeretin in mice on HFD. Administration of HFD plus 200 mg/kg of tangeretin significantly altered weight gain, glucose tolerance, total cholesterol levels, and the secretion of adipocytokines, such as adiponectin, leptin, resistin, IL-6, and MCP-1. Moreover, AMPK was activated by 200 mg/kg of tangeretin in mouse muscle tissue, as expected from the cell system. These results suggest that tangeretin exerts anti-diabetic effects in both cell culture and mouse models, and these effects are necessary for activating AMPK.

Topics: 4-Chloro-7-nitrobenzofurazan; Adiponectin; AMP-Activated Protein Kinases; Animals; Blood Glucose; Cell Line; Chemokine CCL2; Deoxyglucose; Diabetes Mellitus; Diet, High-Fat; DNA-Binding Proteins; Flavones; Glucose; GTPase-Activating Proteins; HEK293 Cells; Humans; Interleukin-6; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Muscle Fibers, Skeletal; Phosphorylation; PPAR gamma; Resistin; Retinoid X Receptor alpha; RNA Interference; RNA, Small Interfering; Transcription Factors

Serum C-reactive protein (CRP) and leptin levels have been independently associated with the cardiovascular risk factors. The aim of the present study was to determine if their serum levels were associated with cardiovascular risk factors or metabolic syndrome as well as their correlation in the Taiwanese population.. This retrospective study included 999 subjects (> 18 y), who underwent a physical examination in Chang-Gung Memorial Hospital-Linkou and Chiayi in Taiwan. The associations between CRP and/or leptin levels and cardiovascular risk factors and metabolic syndrome were determined using independent two sample t-tests to detect gender differences and chi-square tests to evaluate differences in frequencies. To compare the means of the variables measured among the four groups (high and low leptin and high and low CRP), analysis of variance (ANOVA) was used.. Both CRP and leptin levels were independently associated with several cardiovascular risk factors, including diabetes, hypercholesterolemia and metabolic syndrome in both men and women (P < 0.05). In addition, a positive correlation between leptin and CRP levels was observed in both genders. Both high-CRP and high-leptin were associated with high blood glucose, waist circumference and serum triglyceride. Whereas increased metabolic syndrome incidence was observed in males with elevated leptin regardless of CRP levels, females with elevated CRP or leptin had increased incidence of metabolic syndrome.. Both leptin and CRP levels were associated with cardiovascular risk factors as well as metabolic syndrome score in both men and women although gender-specific differences were observed. Thus, CRP and leptin may represent useful biomarkers for predicting the onset of cardiovascular disease or metabolic syndrome in Taiwanese adults.. IRB/CGMH 100-3514B.

Topics: Adult; Age Factors; Analysis of Variance; Asian People; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Chi-Square Distribution; Cross-Sectional Studies; Diabetes Mellitus; Female; Humans; Hypercholesterolemia; Incidence; Leptin; Male; Metabolic Syndrome; Middle Aged; Retrospective Studies; Risk Assessment; Risk Factors; Sex Factors; Taiwan

To study the relationship between adipokines and metabolic syndrome (MS), and the predictive value of adipokines on diagnosis of MS.. According to the IDF consensus worldwide definition on MS in 2005, we divided the subjects into 4 groups: 115 in MS0 (with none of MS component); 118 in MS1 (with one MS component); 77 in MS2 (with two MS components) and 104 in MS3 (with none of MS component). Serum levels of leptin, visfatin adiponectin and resistin were measured in these groups, using the enzyme linked immunosorbent assay (ELISA) method. Retinol-binding protein 4 (RBP-4) was assessed by radioimmunoassay (RIA).. (1) Serum adiponectin level decreased while the serum level of leptin and RBP-4 increased in women with the number of MS components gathered. However, the level of visfatin obviously decreased only in the MS3 phase. The level of resistin showed no changes with MS components gathered. (2) Detection rates of the MS components such as high blood pressure, hyperglycemia, dyslipidemia, insulin resistance and obesity were significantly higher in the Q4 group with high level of leptin when compared to the Q1 group with lower level (odd ratio: Q4/Q1 is 1.3, 1.8, 1.6, 5.2, 3.0 respectively). (3) The higher level of serum RBP-4 was not only associated with greater risk for impaired glucose regulation (odd ratio: Q4/Q1=2.6), but also significantly with the risks for hyperglycemia (odd ratio: Q4/Q1=1.6) dyslipidemia (odd ratio: Q4/Q1=1.9), obesity (odd ratio: Q4/Q1=1.5) and MS (odd ratio: Q4/Q1=2.7). In the Q4 group with higher levels of RBP-4, the positive rates of MS reached 50%. (4) The detection rates of MS components such as dyslipidemia, obesity, hyperglycemia, and insulin resistance were significantly higher in the Q1 group with the lowest level of adiponectin when compared to the Q4 group with the highest level.. The levels of adipokines, serum adiponectin, leptin and RBP-4 showed significant associations with MS. Our findings suggested that these adipokines might serve as the key factors that participating in MS and could be used as markers for early prediction of MS as well as the new targets for therapy.

Topics: Adipokines; Adiponectin; Adult; Aged; Diabetes Mellitus; Female; Humans; Leptin; Male; Metabolic Syndrome; Middle Aged; Retinol-Binding Proteins, Plasma

This an edited transcript of the Lee E. Farr Lecture given by Dr. Jeffrey Flier on May 8, 2012, at the culmination of the annual Student Research Day at the Yale School of Medicine. In this presentation, Dr. Flier discusses his and his wife's research on insulin, leptin, and FGF21 in the context of his reflections upon his life's work and his advice for young investigators.

Topics: Adipose Tissue; Animals; Body Weight; Diabetes Mellitus; Diet, Ketogenic; Fatty Liver; Fibroblast Growth Factors; Humans; Insulin; Insulin Resistance; Leptin; Mice; Mice, Knockout; Obesity

Leptin is produced by mature adipocytes. Its amount correlates positively with the mass of the adipose tissue. Leptin plays a crucial role in maintaining body weight and glucose homeostasis. It is transported through the blood-brain barrier to the central nervous system, where it activates the autonomic nervous system, causing the feeling of satiety and inhibiting appetite. It also acts through central and peripheral pathways, including the regulation of insulin secretion by pancreatic β cells. Leptin may also directly affect the metabolism and function of peripheral tissues. It has been found to play a role in peripheral insulin resistance by attenuating insulin action, and perhaps also insulin signaling, in various insulin-responsive cell types. Recent data provide convincing evidence that leptin has a beneficial influence on glucose homeostasis. Studies suggest that leptin could be used as an adjunct of insulin therapy in insulin-deficient diabetes, thereby providing an insight into the therapeutic implications of leptin as an anti-diabetic agent. Extensive research will be needed to determine long-term safety and efficacy of such a therapy.

Topics: Adipocytes; Carbohydrate Metabolism; Diabetes Mellitus; Ghrelin; Homeostasis; Humans; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Leptin; Receptors, Leptin; Satiety Response; Signal Transduction

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

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

Leptin is an important adipose tissue-derived hormone that has been shown to be involved in pathophysiological mechanisms related to cardiovascular disease and diabetes. However, few studies have examined the association between plasma leptin and diabetes mellitus in humans. Also, it is not clear if this association is present among women as well as in men. Therefore, we examined the association between plasma leptin levels and diabetes mellitus in a representative multiethnic sample of U.S. adults.. We examined the 1988-1994 third National Health and Nutrition Examination Survey (NHANES III) participants >20 years of age (n = 5,599, 54.7% women). Plasma leptin levels were categorized into quartiles (women, <7.68 fg/L, 7.68-13.18 fg/L, 13.19-21.70 fg/L, >21.70 fg/L; men, <2.64 fg/L, 2.64-4.36 fg/L, 4.37-7.12 fg/L, >7.12 fg/L). Diabetes mellitus was defined as fasting glucose ≥126 mg/dL, non-fasting glucose ≥200 mg/dL or use of oral hypoglycemic medication or insulin (n = 395).. Higher plasma leptin levels were initially found to be associated with diabetes mellitus after adjusting for age, sex, race/ethnicity, education, smoking, alcohol intake, hypertension, serum cholesterol and C-reactive protein [odds ratio (OR), 3.79; confidence interval (CI), 2.05-7.00; P trend <0.0001). However, when we additionally adjusted for body mass index (BMI), the association between plasma leptin levels and diabetes mellitus disappeared in both men (OR, 1.07; CI, 0.59-1.94; P trend = 0.5004) and women (OR, 0.86; CI, 0.49-1.51; P trend = 0.2819).. Higher plasma leptin levels are not independently associated with diabetes mellitus after adjustment for BMI. The null association was evident both in women as well as in men.

Topics: Adult; Aged; Body Mass Index; Case-Control Studies; Cohort Studies; Diabetes Mellitus; Female; Humans; Leptin; Male; Middle Aged; Overweight; United States; Young Adult

Blood pressure in female SDT-fa/fa rats was periodically investigated at ages 8, 16, and 24 weeks. Furthermore, an insulin therapy was performed for 5 weeks in the female rats at age 11 weeks, and the change of blood pressure was examined. In addition to obesity, hyperglycemia, hyperinsulinemia, and hyperlipidemia, hyperleptinemia and increased urinary angiotensinogen level were observed during the experimental period. Blood pressure was elevated at ages 8 and 16 weeks, but that at 24 weeks was comparable to that in Sprague-Dawley (SD) rats. Heart rate was decreased from age 8 to 24 weeks. Insulin therapy induced good glycemic control and improvement of hyperlipidemia, but the blood pressure was not reduced. Blood pressure in female SDT-fa/fa rats was elevated temporarily. The blood pressure was not decreased by insulin treatment. SDT-fa/fa rat is a useful model to investigate the relation between diabetes mellitus and hypertension.

Topics: Animals; Blood Glucose; Blood Pressure; Body Weight; Cholesterol; Diabetes Mellitus; Female; Insulin; Leptin; Rats; Rats, Sprague-Dawley; Triglycerides

Mutations in LMNA, encoding A-type lamins, lead to multiple laminopathies, including lipodystrophies, progeroid syndromes, and cardiomyopathies. Alterations in the prelamin-A posttranslational maturation, resulting in accumulation of farnesylated isoforms, cause human progeroid syndromes. Accumulation of mutant nonfarnesylated prelamin-A leads to cardiomyopathy or progeria in mice, but no data have been provided in humans. OBJECTIVE, DESIGN, SETTING, AND PATIENTS: We searched for LMNA mutations in seven women originating from Reunion Island who were referred for a severe lipodystrophic syndrome. Clinical, molecular, genealogical, and cellular studies were performed in probands and relatives.. The seven probands showed a severe partial lipodystrophic syndrome with diabetes and/or acanthosis nigricans, liver steatosis, hypertriglyceridemia, and low serum leptin and adiponectin levels. Three probands also had severe cardiac rhythm and conduction disturbances. We identified in all probands a homozygous LMNA p.T655fsX49 mutation leading to expression of a mutated prelamin-A with 48 aberrant C-terminal amino acids, preventing its physiological posttranslational farnesylation and maturation. Genealogical and haplotype analyses were consistent with a founder mutation transmitted from a common ancestor in the 17th century. In probands' cultured fibroblasts, mutated prelamin-A was associated with typical laminopathic nuclear dysmorphies, increased oxidative stress, and premature senescence. Heterozygous relatives were asymptomatic or partially affected, in favor of a codominant transmission of the disease with incomplete penetrance in heterozygotes.. We reveal that a homozygous mutation of prelamin-A preventing its farnesylation leads to a severe lipodystrophic laminopathy in humans, which can be associated with cardiac conduction disturbances, stressing the pathogenicity of nonfarnesylated prelamin-A in human laminopathies.

Topics: Acanthosis Nigricans; Adiponectin; Adult; Arrhythmias, Cardiac; Cellular Senescence; Diabetes Mellitus; Fatty Liver; Female; Fibroblasts; Founder Effect; Humans; Hypertriglyceridemia; Lamin Type A; Leptin; Lipodystrophy; Middle Aged; Mutation; Nuclear Proteins; Oxidative Stress; Phenotype; Prenylation; Protein Precursors; Young Adult

To report the genetic and metabolic profile of patients with Berardinelli-Seip syndrome (BSCL) followed at Instituto da Criança, HC-FMUSP.. Patients with clinical features of BSCL (n = 5), all female, were evaluated through serum levels of glucose, insulin, lipids, leptin, and liver enzymes. Abdominal sonography and DNA analysis were also performed.. Leptin deficiency and hypertriglyceridemia were found in all the patients. Three progressed to diabetes mellitus. Four patients have mutations in AGPAT2 gene and one have a mutation in CAV1 gene.. The earliest metabolic abnormalities were hypertriglyceridemia and insulin resistance, culminating in the onset of diabetes at the time of puberty. Mutations in the AGPAT2 gene were the most frequent in our patients.

Topics: 1-Acylglycerol-3-Phosphate O-Acyltransferase; Adolescent; Caveolin 1; Child; Diabetes Mellitus; Female; Humans; Hypertriglyceridemia; Leptin; Lipodystrophy, Congenital Generalized; Mutation; Puberty; Young Adult

Extreme replacement of skeletal muscles by adipose tissue was found in an 86-year old Japanese male cadaver during dissection practice for medical students at Oita University School of Medicine. Especially, the bilateral sartorius muscles looked overall like adipose tissue. The man had suffered from diabetes mellitus, renal failure, hypertension and hypothyroidism before his death. He was also an alcohol drinker. He had been bedridden late in life. The cause of death was renal failure. In microscopy, the adipose tissue-like sartorius muscle was shown to consist of leptin-positive adipocytes with a small number of degenerated muscle fibers. Fatty replacement, or fatty degeneration, appears to result from endocrine and metabolic disorders, and being bedridden leads to muscle atrophy and damage, although the origin of the adipocytes which emerged in the degenerated muscles is unknown.

Topics: Adipocytes, White; Adipose Tissue, White; Aged, 80 and over; Body Fat Distribution; Cadaver; Comorbidity; Diabetes Mellitus; Humans; Hypertension; Hypothyroidism; Leptin; Male; Muscle, Skeletal; Renal Insufficiency

Patients with diabetes mellitus (DM) suffer from an increased risk of cardiovascular events caused by thrombotic conditions. Adipose tissue might play a crucial role in this pathogenesis by synthesis of procoagulant mediators. This study was performed to elucidate the role of the adipocytokines leptin and resistin in the development of hypercoagulability and hypofibrinolysis under diabetic conditions.. Sixty two patients with or without DM were included in our study to measure leptin, resistin and tissue factor (TF) plasma concentrations. Moreover, flow chamber experiments were performed to assess factor Xa and plasmin activity on the surface of HUVECs. Western blot and real-time PCR were performed to determine mRNA and protein expression of main factors of the coagulation and fibrinolytic system.. Patients with diabetes showed increased levels of leptin and resistin (leptin: 25.69±13.9 vs. 15.98±17.5 ng/mL, p<0.05; resistin: 2.61±0.6 vs. 1.19±0.7 ng/mL, p<0.05), which were positively correlated with TF. In vitro, leptin and resistin induced increased factor Xa activity (leptin: 4.29±0.57-fold, p<0.05; resistin 4.19±0.7-fold, p<0.05 vs. control) on HUVECs as also reflected by elevated TF mRNA and protein expression. Moreover, stimulatory (plasminogen activator inhibitor 1) and inhibitory (tissue plasminogen activator) mediators of the fibrinolytic cascade were induced by leptin and resistin, leading to a balanced plasmin activity regulation.. Leptin and resistin lead to a procoagulant state in HUVECs by inducing TF expression. This mechanism might be one explanation for the prothrombotic state observed under diabetic conditions.

Topics: Blood Coagulation; Blotting, Western; Cells, Cultured; Diabetes Mellitus; Humans; Leptin; Real-Time Polymerase Chain Reaction; Resistin

Recent studies have demonstrated that circadian clocks are impaired in liver and adipose tissue of both leptin-deficient ob/ob and leptin-resistant KK-A(y) mice. Because impairment of peripheral clocks precedes metabolic abnormalities in ob/ob mice, leptin signaling might be important for modulating peripheral clocks. To assess this hypothesis, the authors determined daily mRNA expression profiles of clock genes Clock, Arntl, Per1, Per2, Cry1, Dbp, and Nr1d1 in several tissues of leptin-receptor-deficient Zucker diabetic fatty (ZDF) rats. Transcript levels of some of these genes around the respective peak times decreased significantly in the liver, but not in the suprachiasmatic nucleus, mesenteric adipose tissue, and heart, compared to those in control rats. In contrast, mRNA levels of Per1 and Dbp around the peak time increased in the aorta of ZDF rats. However, expression rhythms of these clock genes in serum-stimulated cultured cells isolated from the aorta of ZDF rats were quite similar to those in serum-stimulated aortic cells of control rats. These results show that systemic leptin signaling defect influences peripheral clocks in a tissue-dependent manner, suggesting the possibility that leptin indirectly modulates the clocks in at least a subset of peripheral tissues.

Topics: Animals; Circadian Rhythm; CLOCK Proteins; Diabetes Mellitus; Gene Expression Regulation; Hyphae; Leptin; Male; Mice; Muscle, Smooth, Vascular; Obesity; Rats; Rats, Zucker

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

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

Obesity is considered to be associated with high levels of oxidative stress and inflammation. Anticipated weight loss secondary to bariatric surgery may offer an opportunity to evaluate this association. We studied a few markers of oxidative stress and inflammation in 20 obese patients submitted to Roux-en-Y gastric bypass (RYGBP).. Variations in plasma levels of indicators of oxidative stress (malondialdehyde (MDA), superoxide dismutase (SOD), catalase, glutathione (GSH), glutathione disulfide (GSSG), and total radical antioxidant parameter (TRAP)) and inflammation (alpha1-acid glycoprotein (AGP) and C-reactive protein (CRP)), as well as variations in plasma levels of leptin, glucose, glycated hemoglobin (HbA1c), and insulin were investigated in the preoperative period and 12 months postsurgery in 20 class III obese individuals submitted to bariatric surgery (obese group) and 20 non-obese individuals (control group).. Twelve months postsurgery, there was a significant reduction (p < 0.01) in median values of BMI (46.75/30.17 kg/m(2)) and in plasma levels of MDA (16.70/9.11 nmol/g prot), SOD (10.70/9.24 U/mgHb), GSSG (210.80/148.20 mM/g of Hb), AGP (125.70/75.80 mg/dL), CRP (1.31/0.38 mg/dL), and leptin (15.04/3.58 ng/mL). A significant drop (p < 0.05) in plasma levels of HbA1c (5.81/4.98%) was also observed. On the other hand, a significant increase in plasma levels of GSH (2.002/2.823 mM/g of Hb) and TRAP (585.40/815.48 microM Trolox), p < 0.01, and in catalase plasma levels (12.06/13.22 Deltat/mgHb/min), p < 0.05, was seen. No statistically significant variations in glucose (96.3/84.8 mg/dL) or insulin plasma levels (9.91/7.88 U/mL) occurred. Calculated homeostasis model assessment index did not statistically change 12 months postsurgery (2.36/1.66).. In the preoperative period, the obese group individuals showed higher oxidation and inflammation levels and lower indices of antioxidant defense than those of the control group. One year after RYGBP, an improvement in antioxidant protection, associated with a reduction in inflammatory and oxidative markers, was observed, indicating that these individuals presented a lower degree of oxidative stress.

Topics: Adult; Antioxidants; Blood Glucose; C-Reactive Protein; Catalase; Diabetes Mellitus; Female; Gastric Bypass; Glutathione; Glutathione Disulfide; Glycated Hemoglobin; Humans; Insulin; Leptin; Male; Malondialdehyde; Middle Aged; Obesity, Morbid; Orosomucoid; Oxidative Stress; Superoxide Dismutase

The plasma leptin concentration was evaluated in dogs with diabetes mellitus. Twenty normal and sixteen diabetic dogs were divided into nonobese and obese groups based on body condition score, respectively. The obese normal dogs had significantly higher plasma leptin concentrations than the nonobese normal dogs, whereas there was no significant difference between the nonobese and obese diabetic dogs. In addition, the plasma leptin concentration in the obese diabetic dogs was significantly lower than that in the obese normal dogs. In conclusion, the plasma leptin concentrations in the diabetic dogs were affected by factors other than adiposity.

Topics: Animals; Blood Glucose; Cholesterol; Diabetes Mellitus; Dog Diseases; Dogs; Female; Insulin; Leptin; Male; Obesity; Reference Values; Triglycerides

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

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

Panax notoginseng (Burk) F.H. Chen (Araliaceae) is a well-known and commonly used traditional Chinese herb for treatment of various diseases, such as hemostasis, edema and odynolysis.. Our aim was to investigate the mechanisms of anti-hyperglycemic and anti-obese effects of Panax notoginseng saponins (PNS) in KK-Ay mice, and explore the components in PNS for such effects.. KK-Ay mice received daily intraperitoneal injections of PNS 200mg/kg or vehicle for 30 days while ginsenoside Re 14 mg/kg, Rd 15 mg/kg, Rg1 40 mg/kg, Rb1 60 mg/kg and notoginsenoside R1 6 mg/kg for 12 days. Fasting blood glucose levels (FBGL), glucose tolerance (GT), serum insulin, leptin levels, body weight changes, food intake, adipose tissues and blood fat levels were measured at different time points.. The PNS group had significantly lower FBGL, improved GT and smaller body weight incremental percentage after the 30-day treatment. Additionally, Rb1 exhibited significant reduction of FBGL on day 12, and Re also exhibited a decreasing trend after the 12-day treatment.. PNS possess anti-hyperglycemic and anti-obese activities by improving insulin- and leptin sensitivity, and Rb1 is responsible for the anti-hyperglycemic effect among the five saponins in KK-Ay mice.

Topics: Adiposity; Animals; Anti-Obesity Agents; Biomarkers; Blood Glucose; Body Weight; Diabetes Mellitus; Disease Models, Animal; Eating; Glucose Tolerance Test; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Lipids; Male; Mice; Mice, Inbred C57BL; Panax notoginseng; Plant Roots; Saponins; Time Factors

The adipocyte hormone, leptin has been demonstrated to have profibrogenic actions in vitro and in animal models. However, no correlation was found between plasma leptin levels and fibrosis stage in humans. Thus, our aim was to study whether soluble leptin receptor (SLR) or free leptin index (FLI; calculated as the ratio of leptin to SLR), may correlate better with the features of metabolic syndrome and with the histological grade and stage of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). We studied a population (n = 104) of morbidly obese patients undergoing bariatric surgery. Data including BMI, type 2 diabetes mellitus, hypertension, and hyperlipidemia were obtained. Plasma fasting leptin and SLR, fasting glucose and insulin were measured, and homeostasis model of assessment insulin resistance (HOMA(IR)) index and FLI were calculated. All patients had intraoperative liver biopsies. Leptin levels correlated with the BMI. The multiple regression analysis indicated that increasing HOMA and decreasing FLI were predictors of steatosis in the liver (P < 0.0003). SLR levels were positively correlated with the presence of diabetes mellitus and the stage of fibrosis. In conclusion, increased SLR levels in morbidly obese patients with diabetes are correlated with the stage of liver fibrosis, and may reflect progressive liver disease.

Topics: Adult; Bariatric Surgery; Body Mass Index; Diabetes Mellitus; Disease Progression; Fatty Liver; Female; Humans; Insulin Resistance; Leptin; Liver; Male; Middle Aged; Obesity, Morbid; Receptors, Leptin; Regression Analysis

Fetuin-A, also known as alpha2-Heremans Schmid glycoprotein, is an abundant plasma protein synthesized predominantly in the liver. Fetuin-A inhibits insulin receptor autophosphorylation, which is mediated by its intrinsic tyrosine kinase activity. In this study, we examined the association between the serum fetuin-A level and insulin resistance in Japanese men.. We recruited 300 unrelated Japanese men without known chronic diseases, such as diabetes mellitus, or a history of regular drug use, and who underwent health examinations. From a 75-g oral glucose tolerance test, the study population included 194 individuals with normal glucose tolerance, 91 with impaired glucose tolerance and/or impaired fasting glucose, and 15 with diabetes mellitus. Serum fetuin-A concentrations were measured using an ELISA kit.. Serum fetuin-A concentrations were positively correlated with fasting insulin levels (r = 0.269, p<0.001), HOMA-IR (r = 0.274, p<0.001) and LDL-cholesterol (r = 0.172, p<0.01), and negatively correlated with HDL-cholesterol concentrations (r = -0.191, p<0.001). Fetuin-A concentrations were also positively correlated with serum leptin (r = 0.150, p<0.01) and negatively with adiponectin concentrations (r = -0.208, p<0.001). Stepwise regression analyses confirmed that the fetuin-A concentration was independently associated with the fasting insulin level and HOMA-IR, as were body mass index, triglyceride, LDL-cholesterol, leptin and adiponectin concentrations.. Our data suggest that increased serum fetuin-A levels constitute an independent marker of insulin resistance and an atherogenic lipid profile in Japanese men.

Topics: Adiponectin; Adiposity; Adult; Aged; alpha-2-HS-Glycoprotein; Asian People; Atherosclerosis; Biomarkers; Blood Proteins; C-Reactive Protein; Diabetes Mellitus; Glucose Tolerance Test; Humans; Insulin Resistance; Japan; Leptin; Lipids; Male; Middle Aged

Leptin is an adipose tissue-derived hormone shown to be related to metabolic, inflammatory, and hemostatic factors involved in hypertension development. Animal studies suggest that higher leptin levels may activate the sympathetic nervous system and cause elevations in blood pressure (BP). However, few studies have examined the association between leptin and hypertension in humans. Also it is not clear whether this association is present among women as well as men. Therefore, we examined the association between plasma leptin levels and hypertension in a representative sample of US adults. We examined the third National Health and Nutrition Examination Survey participants >20 years of age (n=5599; 54.7% women). Plasma leptin levels were categorized into quartiles (women: <7.68, 7.68 to 13.18, 13.19 to 21.70, >21.70 fg/L; men: <2.64, 2.64 to 4.36, 4.37 to 7.12, >7.12 fg/L). Hypertension was defined as BP-reducing medication use or having systolic BP ≥140 mm Hg and/or diastolic BP ≥90 mm Hg. We found that higher plasma leptin levels were positively associated with hypertension after adjusting for age, sex, race/ethnicity, education, smoking, alcohol intake, body mass index, diabetes mellitus, serum cholesterol, and C-reactive protein. Compared with quartile 1 of leptin (referent), the odds ratio (95% CI) of hypertension associated with quartile 4 was 1.89 (1.24 to 2.09; P for trend=0.0036). Subgroup analyses examining the relation between leptin and hypertension by sex and body mass index categories also showed a consistent positive association. In conclusion, higher plasma leptin levels are associated with hypertension both among women as well as men in a representative sample of US adults.

Topics: Adult; Black or African American; Blood Pressure; Body Mass Index; C-Reactive Protein; Cholesterol; Diabetes Mellitus; Educational Status; Fasting; Female; Humans; Hypertension; Leptin; Logistic Models; Male; Mexican Americans; Middle Aged; Multivariate Analysis; Nutrition Surveys; Odds Ratio; Sex Factors; United States; White People

Topics: Animals; Bone and Bones; Bone Remodeling; Diabetes Mellitus; Energy Metabolism; Female; Glucose; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Leptin; Mice; Obesity; Osteocalcin; Osteoporosis; Receptor, Insulin

Multiple lines of evidence suggest innate immune response pathways to be involved in the development of obesity-associated diabetes although the molecular mechanism underling the disease is unknown. Recent observations suggest that saturated fatty acids can act as a ligand for toll-like receptor (TLR) 4, which is thought to mediate obesity-associated insulin resistance. Myeloid differentiation factor 88 (MyD88) is an adapter protein for TLR/IL-1 receptor signaling, which is involved in the activation of inflammatory pathways. To evaluate molecular mechanisms linking obesity-associated diabetes down-stream of TLR4, we investigated physiological role of MyD88 in high-fat diet (HFD)-induced obesity.. In the present study, we found MyD88-deficient mice fed a HFD had increased circulating levels of insulin, leptin and cholesterol, as well as liver dysfunction (increased induction of ALT levels, increased activation of JNK and cleavage of PARP), which were linked to the onset of severe diabetes. On the other hand, TNF-alpha would not be involved in HFD-induced diabetes in MyD88-deficient mice, because TNF-alpha level was attenuated in MyD88-deficient mice fed with HFD.. The present finding of an unexpected role for MyD88 in preventing diabetes may provide a potential novel target/strategy for treating metabolic syndrome.

Topics: Animals; Diabetes Mellitus; Disease Models, Animal; Humans; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid Differentiation Factor 88; Obesity; Risk Factors; Tumor Necrosis Factor-alpha

The adipocyte-derived cytokine leptin was implicated to link inflammation and metabolic alterations. We investigated the potential role of leptin components in critically ill patients, because systemic inflammation, insulin resistance, and hyperglycemia are common features of critical illness. Upon admission to Medical Intensive Care Unit (ICU), free leptin and soluble leptin-receptor serum concentrations were determined in 137 critically ill patients (95 with sepsis, 42 without sepsis) and 26 healthy controls. Serum leptin or leptin-receptor did not differ between patients or controls and were independent of sepsis. However, serum leptin was closely associated with obesity and diabetes and clearly correlated with markers of metabolism and liver function. Leptin-receptor was an unfavourable prognostic indicator, associated with mortality during three years follow-up. Our study indicates a functional role of leptin in the pathogenesis of severe illness and emphasizes the impact of complex metabolic alterations on the clinical outcome of critically ill patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Critical Illness; Diabetes Mellitus; Diagnosis, Differential; Female; Glucose; Humans; Inflammation; Intensive Care Units; Kaplan-Meier Estimate; Leptin; Lipid Metabolism; Male; Middle Aged; Obesity; Prognosis; Receptors, Leptin; Sepsis; Young Adult

Topics: Adipose Tissue; Animals; Blood Glucose; Diabetes Mellitus; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Leptin; Liver; Muscle, Skeletal

Topics: Animals; Biochemistry; Diabetes Mellitus; History, 20th Century; Humans; Insulin; Leptin; Mice; Pancreatic Extracts; United States

Glycosylated haemoglobin (HbA1c), leptin, leptin soluble receptors (sOB-R) and free leptin index (FLI) may all be influenced by diabetes, but their associations remain unclear. Therefore, we put forward a hypothesis that serum leptin, sOBR and FLI might be parallel to Hb1c, as they all reflect the metabolic status.. We measured leptin and sOB-R concentrations in 97 obese non-diabetic (47 women and 50 men), and 65 obese diabetic (32 women and 33 men) humans, and examined whether they were related to HbA1c. Under the condition, the presence of diabetes was the only differentiating factor between two groups of frankly obese humans.. Non-diabetic vs. diabetic, median and interquartile range, respectively: Leptin (ng/ml), 30.83, 37.27 vs. 28.24, 23.34; p>0.05; sOB-R (ng/ml), 17.62, 17.05 vs. 21.81, 16.61, p<0.05; FLI, 231.23, 310.00 vs. 131.76, 157.68, p<0.05. To investigate the influence of HbA1c on leptin and sOB-R, both groups were divided into tertiles based on HbA1c. In diabetics, leptin did not differ between the high, intermediate, and low HbA1c levels subgroups, p>0.05, and leptin was not influenced by HbA1c levels: r=0.086; p>0.05. For sOB-R, respectively: p>0.05; r=0.080; p>0.05. In non-diabetics, respectively: p<0.05; r=0.2923; p<0.05 for leptin; and p<0.0001, r=0.5103; p<0.0001, for s-OB-R.. Not leptin alone but serum sOB-R and FLI are the markers of leptin action impairment in type 2 diabetes. Further, HbA1c is not associated with metabolic status of leptin in obese diabetic patients, whereas this association is found in obese non-diabetic humans.

Topics: Adult; Biomarkers; Blood Glucose; Body Mass Index; Case-Control Studies; Comorbidity; Diabetes Mellitus; Diabetes Mellitus, Type 2; Enzyme-Linked Immunosorbent Assay; Female; Glycated Hemoglobin; Humans; Insulin; Leptin; Male; Middle Aged; Obesity; Poland; Predictive Value of Tests; Receptors, Leptin

Influences of genetic and nutritional factors on body weight, fat mass, and leptin production and effects of leptin were assessed in normal [Wistar-Kyoto (WKY)] and diabetic [Goto-Kakizaki (GK)] rats by mechanism-based modeling. The study included 60 WKY and 60 GK rats; half received high-fat diet (HF), and the others received normal rat chow (N). Body weights and food consumption were measured twice weekly. Six rats per group were sacrificed at 4, 8, 12, 16, and 20 weeks. Abdominal fat was weighed, and plasma leptin was measured by enzyme-linked immunosorbent assay. All data were comodeled using NONMEM version VI level 1.1 (first-order conditional estimation with interaction) (Beal SL, Boeckmann AJ, Sheiner LB, and NONMEM Project Group, NONMEM Users Guides, University of California, San Francisco, CA, 2007). Weight gain was modeled as differences between energy intake and metabolic rate based on allometrically scaled lean body mass (LBM). The GK had higher metabolic rates (1.15 kcal/day/g LBM(0.75)) than WKY-N (0.92) and WKY-HF (1.02) rats and higher efficiency in transforming energy into body weight. Leptin effect was modeled as inhibition of food consumption. Total body fat was estimated from abdominal fat. Leptin production from fat was 4.7-fold higher for GK (3.03 ng/ml/day/g) than WKY (0.66 ng/ml/day/g). Leptin production rate from LBM was 0.53 ng/ml/day/g for all groups. The IC(50) for inhibition of food intake by leptin was approximately 3-fold higher in GK versus WKY, indicating leptin resistance for the effect on food consumption in GK. The GK had similar intake of kilocalories but lower body weights and fat mass than WKY, possibly because of higher metabolic rates. Our mechanism-based model explains intrinsic reasons for differences in growth, food intake, and leptin concentrations among these two strains of rats.

Topics: Animals; Biological Phenomena; Body Weight; Diabetes Mellitus; Disease Models, Animal; Eating; Growth; Leptin; Male; Obesity; Rats; Rats, Inbred WKY

To clarify the association of circulating levels of leptin with risk for cardiovascular disease (CVD) events and new-onset diabetes in men and women.. We related baseline leptin levels to CVD events (n = 864) and incident diabetes (n = 289) in an elderly population (n = 5,672) over 3.2 years of follow-up.. In treatment-, age-, and country-adjusted models, leptin was not associated with risk of CVD in men (hazard ratio 1.02 [95% CI 0.90-1.16] per unit log-leptin increase) or women (1.05 [0.91-1.20]) but was associated with risk of diabetes in men (2.75 [2.14-3.52]) and women (1.54 [1.22-1.94]). After adjusting for classic risk factors and BMI, C-reactive protein, and glucose, the diabetes association retained significance in men (1.85 [1.30-2.63]) but not in women (0.89 [0.64-1.26]).. Leptin, similar to other markers of adiposity in general, is more strongly related to risk of diabetes than CVD in the elderly.

Topics: Aged; Aged, 80 and over; Biomarkers; Cardiovascular Diseases; Diabetes Mellitus; Female; Humans; Ireland; Leptin; Male; Myocardial Infarction; Netherlands; Proportional Hazards Models; Prospective Studies; Risk Assessment; Risk Factors; Scotland; Stroke

Genetic factors underlying the association of NAFLD with diabetes and atherosclerosis are unknown. Recent human studies suggest transcription factor 7-like 2 (TCF7L2) polymorphism predisposes to diabetes through modulation of beta-cell function and modulates lipid levels in familial dyslipidemia. Emerging experimental evidence connects TCF7L2 to adipocyte metabolism and lipid homeostasis, as well. We tested if TCF7L2 polymorphism is a risk factor for nonalcoholic fatty liver disease (NAFLD) and if it modulates liver injury, glucose homeostasis, lipoprotein, and adipokine profiles in NASH. TCF7L2 genotype and dietary habits of 78 nondiabetic normolipidemic NAFLD subjects and 156 age-, body mass index-, sex-matched healthy controls were assessed. In 39 biopsy-proven nonalcoholic steatohepatitis (NASH) and matched controls TCF7L2 polymorphism was correlated to liver histology and oral glucose tolerance test-derived parameters of glucose homeostasis. Patients with NASH and controls consumed a high-fat meal and TCF7L2 genotype was correlated to postprandial circulating lipoproteins, adipokines, and cytokeratin-18 fragments. The TCF7L2 CT/TT genotype was more frequent in NAFLD and predicted the presence and severity of liver disease, of beta-cell dysfunction, of reduced incretin effect and hepatic insulin resistance in NASH; it also modulated postprandial hepatocyte apoptosis, lipoproteins, and adipokine profiles in both groups.. TCF7L2 polymorphism predisposes to NAFLD and significantly impacts liver injury, glucose homeostasis, and postprandial lipoprotein and adipokine responses to fat ingestion. This polymorphism also modulates a fat-induced increase in circulating markers of hepatocyte apoptosis in NASH. Targeting postprandial lipemia, at least in at-risk TCF7L2 genotypes, may improve liver disease and glucose dysmetabolism in these patients.

Topics: Adipokines; Adiponectin; Adipose Tissue; Apoptosis; Diabetes Mellitus; Fatty Liver; Female; Glucose; Hepatocytes; Humans; Leptin; Male; Patient Selection; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Resistin; TCF Transcription Factors; Transcription Factor 7-Like 2 Protein; Tumor Necrosis Factor-alpha

A growing percentage of the population is resistant to two key hormones - insulin and leptin - as a result of increased obesity, often leading to significant health consequences such as type 2 diabetes. Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of signalling by both of these hormones, so that inhibitors of this enzyme may provide promise for correcting endocrine abnormalities in both diabetes and obesity. As with other tyrosine phosphatases, identification of viable drug candidates targeting PTP1B has been elusive because of the nature of its active site. Beginning with novel phosphotyrosine mimetics, we have designed some of the most potent PTP1B inhibitors. However, their highly acidic structures limit intrinsic permeability and pharmacokinetics. Ester prodrugs of these inhibitors improve their drug-like properties with the goal of delivering these nanomolar inhibitors to the cytoplasm of cells within target tissues. In addition to identifying prodrugs that is able to deliver active drugs into cells to inhibit PTP1B and increase insulin signalling, these compounds were further modified to gain a variety of cleavage properties for targeting activity in vivo. One such prodrug candidate improved insulin sensitivity in ob/ob mice, with lowered fasting blood glucose levels seen in the context of lowered fasting insulin levels following 4 days of intraperitoneal dosing. The results presented in this study highlight the potential for design of orally active drug candidates targeting PTP1B, while also delineating the considerable challenges remaining.

Topics: Administration, Oral; Animals; Biomimetics; Blood Glucose; Diabetes Mellitus; Disease Models, Animal; Drug Design; Fasting; Insulin; Leptin; Male; Mice; Obesity; Prodrugs; Protein Kinase Inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Rats; Rats, Zucker; Signal Transduction

For the early identification of patients at risk of developing diabetes mellitus, and to prevent the onset of diabetes by performing dietary counseling and exercise guidance, we have developed an ultra-sensitive immune complex transfer enzyme immunoassay (ICT-EIA) to measure soluble human insulin receptor ectodomain (sIRalpha) in urine which is collected non-invasively.. We developed ICT-EIA for sIRalpha and measured urinary sIRalpha from 106 healthy volunteers, 35 obese volunteers and 42 patients with diabetes.. The detection limit of ICT-EIA (0.04 pg/mL), using a urine sample of as little as 100 microL, was a few hundred-fold higher than that of conventional ELISA. Using ICT-EIA, the urinary sIRalpha level in patients with diabetes (9.7+/-20.1 pg/mg creatinine) was significantly higher than those in healthy volunteers (1.4+/-0.9; P<0.001).. ICT-EIA for sIRalpha may be useful as a good marker for evaluating diabetes risk.

Topics: Adolescent; Adult; Antigens, CD; Binding Sites; Blood Glucose; Calibration; Circadian Rhythm; Diabetes Mellitus; Female; Glucose Tolerance Test; Humans; Immunoenzyme Techniques; Insulin; Leptin; Male; Middle Aged; Obesity; Receptor, Insulin; Reproducibility of Results; Resistin; Sensitivity and Specificity; Young Adult

Biotransformation of blueberry juice by the Serratia vaccinii bacterium gave rise to adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and glucose uptake in muscle cells and adipocytes, but inhibited adipogenesis. This study investigated the antiobesity and antidiabetic potential of biotransformed blueberry juice (BJ) in KKA(y) mice, rodent model of leptin resistance.. BJ was incorporated in drinking water of KKA(y) mice. Parameters of body weight, food intake, plasma glucose, insulin, leptin, and adiponectin were measured. Before and after therapy, animals were subjected to an oral glucose tolerance test. At the end of treatment, liver, muscle, kidney, epididymal fat pad, abdominal fat pad, and dorsal fat pad were collected and weighed.. Incorporating BJ in drinking water protected young KKA(y) mice from hyperphagia and significantly reduced their weight gain. Moreover, BJ protected young KKA(y) mice against the development of glucose intolerance and diabetes mellitus. Chronic BJ administration in obese and diabetic KKA(y) mice reduced food intake and body weight. This effect could not fully explain the associated antidiabetic effect because BJ-treated mice still showed lower blood glucose level when compared with pair-fed controls. The adipokines pathway also seems to be involved because BJ significantly increased adiponectin levels in obese mice.. This study shows that BJ decreases hyperglycemia in diabetic mice, at least in part by reversing adiponectin levels. BJ also protects young pre-diabetic mice from developing obesity and diabetes. Thus, BJ may represent a novel complementary therapy and a source of novel therapeutic agents against diabetes mellitus.

Topics: Adiponectin; Animals; Beverages; Blueberry Plants; Body Weight; Diabetes Mellitus; Hyperglycemia; Hyperphagia; Hypoglycemic Agents; Leptin; Male; Mice; Obesity

Calorie restriction improves life span whereas nutrient excess leads to obesity and unfavorable metabolic consequences, supporting the role for a cellular "nutrient sensor" in aging. Hexosamine biosynthetic pathway (HBP) is a candidate nutrient-sensing pathway. We hypothesized that altered nutrient sensing (by HBP) with age may provide a link among aging, nutrient flux, and insulin resistance. Using a hyperinsulinemic clamp in young rats, we show that experimental activation of HBP, through the systemic infusion of glucosamine, induced severe insulin resistance (36% decline in peripheral insulin action; P<0.05), increased adipose tissue gene expression of fat-derived peptides (PAI-1 by 4-fold, angiotensinogen 3-fold, leptin 2-fold, resistin 4-fold, and adiponectin 4-fold; P<0.01 compared with young saline-infused), and enhanced glycosylation of transcription factors, thus mimicking a physiological and biological phenotype of aging. We further demonstrate a greater activation of nutrient-sensing HBP with age in both old ad libitum-fed and calorie-restricted rats. Interestingly, old calorie-restricted animals rapidly develop insulin resistance when exposed to glucosamine, despite their "young" phenotype. These results suggest that altered nutrient sensing by HBP with age may be the link among nutrients, insulin resistance, and age-related diabetes.

Topics: Adiponectin; Adipose Tissue; Age Factors; Aging; Angiotensinogen; Animals; Diabetes Mellitus; Gene Expression; Glucosamine; Glycosylation; Hexosamines; Insulin; Insulin Resistance; Leptin; Plasminogen Activator Inhibitor 1; Rats; Rats, Inbred Strains; Resistin; Sp1 Transcription Factor

Atherosclerotic vascular diseases such as cerebrovascular and cardiovascular diseases are major causes for fatality of hemodialysis (HD) patients. Since adipocytokines are key players for arteriosclerosis in the concept of metabolic syndrome (MetS), we aimed to determine whether circulating levels of major three adipocytokines, adiponectin, TNF-alpha, and leptin, could be associated with various parameters and clinical events in HD patients who are diagnosed as MetS using a new criteria designed for the Japanese population.. We enrolled 53 very stable patients under maintenance HD at Minami-Senju Hospital. Basically, clinical and laboratory data were taken just before HD therapy. HD sessions were performed regularly and all the participants took oral administration and injection as usual. A cross-sectional study was performed to evaluate clinical and laboratory data related to three major adipocytokines, adiponectin, TNF-alpha and leptin.. We observed no significant differences of three adipocytokines when the participants were divided in accordance with existence of MetS or past cerebrocascular/cardiovascular diseases. Only the serum adiponectin levels were significantly different in two groups categorized by existence of diabetes mellitus. Serum triglycerides (TG) were significantly correlated with two circulating adipocytokines, adiponectin (r=-0.328, p<0.016) and leptin (r=0.397, p<0.003), when we analyzed all 53 patients together.. Plasma adiponectin and leptin are expected as contributors related to dyslipidemia, suggesting these may be targets of prevention of vascular diseases in maintenance HD patients.

Topics: Adipokines; Adiponectin; Aged; Biomarkers; Cardiovascular Diseases; Cross-Sectional Studies; Diabetes Mellitus; Female; Humans; Kidney Failure, Chronic; Leptin; Male; Metabolic Syndrome; Middle Aged; Renal Dialysis; Treatment Outcome; Triglycerides; Tumor Necrosis Factor-alpha

Recent epidemiological and clinical studies indicate that the control of sleep-wake states may be an important factor in the regulation of energy metabolism. Leptin is a peripherally synthesized hormone that has critical signaling properties in the brain for the control of long-term energy homeostasis. In this study, we examined the hypothesis that leptin signaling exerts a role in sleep-wake regulation and that leptin may represent an important mechanistic link in the coordination of sleep-wake states and metabolism. Sleep-wake patterns were recorded in a genetic mouse model of obesity and diabetes, the db/db mouse, which harbors a mutation in a particular isoform of the leptin receptor (long form, LRb). We found that db/db mice exhibit a variety of alterations in sleep regulation, including an increase in overall sleep time, a dramatic increase in sleep fragmentation, attenuated diurnal rhythmicity in rapid eye movement sleep and non-rapid eye movement EEG delta power (a measure of sleep homeostatic drive), and a decrease in the compensatory response to acute (i.e., 6 h) sleep deprivation. The db/db mice also generated low amounts of locomotor activity and a reduction in the diurnal rhythm of activity. These results indicate that impaired leptin signaling has deleterious effects on the regulation of sleep amount, sleep architecture, and temporal consolidation of these arousal states. In summary, leptin may represent an important molecular component in the integration of sleep, circadian rhythms, and energy metabolism.

Topics: Animals; Behavior, Animal; Circadian Rhythm; Diabetes Mellitus; Disease Models, Animal; Electroencephalography; Electromyography; Energy Metabolism; Leptin; Male; Mice; Mice, Obese; Motor Activity; Mutation; Obesity; Phenotype; Receptors, Leptin; Recovery of Function; Signal Transduction; Sleep; Sleep Deprivation; Wakefulness

To investigate how serotonin and leptin interact in the regulation of energy balance and glucose homeostasis, we generated a genetic mouse model, the OB2C mouse, which lacks functional serotonin 2C receptors and the adipocyte hormone leptin. The OB2C mice exhibited a dramatic diabetes phenotype, evidenced by a synergistic increase in serum glucose levels and water intake. The severity of the animals' diabetes phenotype would not have been predicted from the phenotypic characterization of mice bearing mutations of either the leptin (OB mutant mice) or the serotonin 2C receptor gene (2C mutant mice). The synergistic impairment in glucose homeostasis developed at an age when OB2C mice did not differ in body weight from OB mice, suggesting that this impairment was not an indirect consequence of increased adiposity. We also demonstrated that the improvement in glucose tolerance in wild-type mice treated with the serotonin releaser and reuptake inhibitor fenfluramine was blunted in 2C mutant mice. These pharmacological and genetic findings provide evidence that the serotonin 2C receptor has direct effects on glucose homeostasis.

Topics: Animals; Diabetes Mellitus; Disease Models, Animal; Drinking; Eating; Female; Fenfluramine; Glucose; Homeostasis; Islets of Langerhans; Leptin; Male; Mice; Mice, Obese; Obesity; Receptor, Serotonin, 5-HT2C; Serotonin; Serotonin Agents

Protein-tyrosine phosphatase 1B (PTP1B) is a major negative regulator of insulin and leptin sensitivity. PTP1B overexpression in adipose tissue and skeletal muscle of humans and rodents may contribute to insulin resistance and obesity. The mechanisms mediating PTP1B overexpression in obese and diabetic states have been unclear. We find that adipose tissue inflammation and the pro-inflammatory cytokine tumor necrosis factor alpha (TNFalpha) regulate PTP1B expression in vivo. High fat feeding of mice increased PTP1B expression 1.5- to 7-fold in adipose tissue, liver, skeletal muscle, and arcuate nucleus of hypothalamus. PTP1B overexpression in high fat-fed mice coincided with increased adipose tissue expression of the macrophage marker CD68 and TNFalpha, which is implicated in causing obesity-induced insulin resistance. TNFalpha increased PTP1B mRNA and protein levels by 2- to 5-fold in a dose- and time-dependent manner in adipocyte and hepatocyte cell lines. TNFalpha administration in mice increased PTP1B mRNA 1.4- to 4-fold in adipose tissue, liver, skeletal muscle, and hypothalamic arcuate nucleus and PTP1B protein 2-fold in liver. Actinomycin D treatment blocked, and high dose salicylate treatment inhibited by 80%, TNFalpha-induced PTP1B expression in adipocyte cell lines, suggesting TNFalpha may induce PTP1B transcription via nuclear factor kappaB (NFkappaB) activation. Chromatin immunoprecipitation from adipocyte cell lines and liver of mice demonstrated TNFalpha-induced recruitment of NFkappaB subunit p65 to the PTP1B promoter in vitro and in vivo. In mice with diet-induced obesity, TNFalpha deficiency also partly blocked PTP1B overexpression in adipose tissue. Our data suggest that PTP1B overexpression in multiple tissues in obesity is regulated by inflammation and that PTP1B may be a target of anti-inflammatory therapies.

Topics: Animal Feed; Animals; Base Sequence; Cells, Cultured; Diabetes Mellitus; Gene Expression Regulation, Enzymologic; Inflammation; Insulin; Insulin Resistance; Leptin; Mice; Molecular Sequence Data; Obesity; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Rats; Transcription, Genetic; Tumor Necrosis Factor-alpha

1. Inhibitors of intestinal glucosidases have been shown to improve glycaemic control in diabetic and obese humans and animals. In the present study, we have investigated the effect of 3 months treatment with acarbose on adiposity, food intake and the modulation of hypothalamic neuropeptide Y (NPY) in obese diabetic Wistar (WDF) rats and the possible correlation between changes in overall insulin sensitivity and the level of circulating adipokines, leptin and adiponectin. In addition, we investigated the effect of acarbose on adipocyte insulin signalling. 2. Mature male WDF rats were randomly distributed to one of three treatment groups (no acarbose or 20 or 40 mg of acarbose/100 g diet). After 3 months, blood glucose, cholesterol, triglyceride, insulin, leptin and adiponectin were analysed. Insulin signalling was determined in isolated adipocytes as the stimulation of mitogen-activated protein kinase (MAPK) and Akt phosphorylation; the level of hypothalamic NPY was assessed by immunohistochemistry. 3. Acarbose-treated rats had lower levels of blood glucose, cholesterol, triglyceride, insulin and leptin and an increase in adiponectin compared with untreated animals. There were no changes in bodyweight and adiposity. Stimulation of adipocyte MAPK activity by insulin was higher in rats treated with both doses of acarbose, whereas higher stimulation of Akt phosphorylation was observed with the highest dose of acarbose. Although food intake was not significantly reduced in rats treated with acarbose, the acarbose-treated rats had lower NPY expression in the arcuate nucleus. 4. We conclude that the improvement in overall insulin sensitivity in WDF rats after prolonged acarbose treatment is paralleled by increases in circulating adiponectin and adipocyte insulin responsiveness. Acarbose neither decreases food intake nor reverts obesity, but decreases leptin levels and the expression of the orexigenic NPY in the hypothalamus.

Topics: Acarbose; Adipocytes; Adiponectin; Animals; Diabetes Mellitus; Dose-Response Relationship, Drug; Drug Administration Schedule; Gene Expression Regulation; Hypoglycemic Agents; Hypothalamus; Insulin; Leptin; Male; Neuropeptide Y; Obesity; Rats; Rats, Wistar

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

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

Microalbuminuria increases cardiovascular risk and is considered a metabolic disorder. Low glomerular filtration rate is also associated with increased cardiovascular risk, but the relation of low glomerular filtration rate to metabolic disorders is not well understood.. Designed as a cross-sectional, epidemiologic study, the Insulin Resistance Atherosclerosis Study was conducted in four centers: San Antonio (Texas), San Luis Valley (Colorado), and Oakland and Los Angeles (California). The Modification of Diet in Renal Disease equation was used to classify individuals without diabetes and with normoalbuminuria (n = 856; age 40 to 69 yr) by the presence or absence of low glomerular filtration rate (<60 ml/min per 1.73 m(2)). A direct marker of insulin resistance, the insulin sensitivity index, was measured by the frequently sampled intravenous glucose tolerance test.. Low glomerular filtration rate was related to hypertension and the metabolic syndrome. Low glomerular filtration rate was associated with fasting insulin concentration and insulin sensitivity index. Low glomerular filtration rate was also associated with insulin concentration after adjustment for potential determinants of glomerular filtration rate but was not associated with insulin sensitivity index.. Low glomerular filtration rate is associated with increased insulin concentration in individuals without diabetes and with normoalbuminuria. Longitudinal analyses are needed to determine whether insulin concentration (insulin resistance) precedes the deterioration of renal function.

Topics: Adult; Aged; Albuminuria; C-Reactive Protein; Cross-Sectional Studies; Diabetes Mellitus; Fasting; Glomerular Filtration Rate; Humans; Hypertension; Insulin; Insulin Resistance; Leptin; Metabolic Syndrome; Middle Aged; Southwestern United States

Obesity and diabetes, termed "diabesity," are serious health problems that are increasing in frequency. However, the molecular mechanisms and neuronal regulation of these metabolic disorders are not fully understood. We show here that Shp2, a widely expressed Src homology 2-containing Tyr phosphatase, plays a critical role in the adult brain to control food intake, energy balance, and metabolism. Mice with a neuron-specific, conditional Shp2 deletion were generated by crossing a pan-neuronal Cre-line (CRE3) with Shp2(flox/flox) mice. These congenic mice, CRE3/Shp2-KO, developed obesity and diabetes and the associated pathophysiological complications that resemble those encountered in humans, including hyperglycemia, hyperinsulinemia, hyperleptinemia, insulin and leptin resistance, vasculitis, diabetic nephropathy, urinary bladder infections, prostatitis, gastric paresis, and impaired spermatogenesis. This mouse model may help to elucidate the molecular mechanisms that lead to the development of diabesity in humans and provide a tool to study the in vivo complications of uncontrolled diabetes.

Topics: Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Crosses, Genetic; Diabetes Complications; Diabetes Mellitus; Eating; Female; Hyperglycemia; Hyperinsulinism; Insulin Resistance; Leptin; Male; Mice; Mice, Mutant Strains; Mice, Transgenic; Neurons; Obesity; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Signal Transduction

It has been suggested that hyperleptinemia could be caused by hyperinsulinemia in infants of diabetic mothers (IDMs).. To compare leptin, insulin, and glucose levels in large-for-gestational-age (LGA) and appropriate-for-gestational-age (AGA) infants.. A cross-sectional study was conducted in IDMs, infants of non-diabetic mothers (INDM) and AGA infants.. Seventy-seven newborns were studied (11 IDM, 16 INDM, and 50 AGA infants). Leptin levels were significantly higher in LGA infants than in the AGA group and a trend for higher levels in IDM than NIDM was observed. Insulin levels and insulin resistance were significantly higher in IDMs. Glucose levels were lower in both groups of LGA infants.. We found insulin resistance, hyperinsulinism and hyperleptinemia in IDMs, and the trend of higher leptin levels in IDMs than INDMs shows that leptin could be related to insulin resistance in these infants.

Topics: Birth Weight; Blood Glucose; Cross-Sectional Studies; Diabetes Mellitus; Female; Fetal Macrosomia; Gestational Age; Humans; Hyperinsulinism; Infant, Newborn; Infant, Newborn, Diseases; Insulin; Insulin Resistance; Leptin; Male; Obesity; Pregnancy; Pregnancy in Diabetics

Diabetic Akita male mice are more hyperphagic because of downregulation of proopiomelanocortin (POMC) caused by hypoleptinemia. We investigated the role of estrogen receptor alpha (ERalpha) in the regulation of the hypothalamic POMC in females. ERaKOAkt mice consumed 30% greater food (g/3 weeks) than the Akita diabetic controls. Ovariectomized diabetic (AFO) and nondiabetic (B6FO) mice had significantly lower food intake and elevated serum leptin levels. ERaKOAkt and ERaKO mice also increased serum leptin concentrations, while hypoinsulinemia was observed in ERaKOAkt and hyperinsulinemia in ERaKO mice. RT-PCR showed a significant attenuation of POMC expression in both ERaKOAkt and ERaKO mice, irrespective of the elevated leptin serum levels or hyperinsulinemia, while elevated serum leptin levels in AFO and B6FO mice upregulated POMC gene expression. These results indicate that ERalpha plays an essential role in leptin- and insulin-stimulated upregulation of the POMC gene. This action of ERalpha is likely mediated in a ligand-independent manner.

Topics: Animals; Diabetes Mellitus; Disease Models, Animal; Estrogen Receptor alpha; Gene Expression; Gene Expression Regulation; Hyperphagia; Hypothalamus; Insulin; Leptin; Mice; Mice, Knockout; Pro-Opiomelanocortin; Up-Regulation

Topics: Adipocytes; Adiponectin; Animals; Diabetes Mellitus; Humans; Leptin

Type 2 diabetes results from impaired insulin action and beta-cell dysfunction. There are at least two components to beta-cell dysfunction: impaired insulin secretion and decreased beta-cell mass. To analyze how these two variables contribute to the progressive deterioration of metabolic control seen in diabetes, we asked whether mice with impaired beta-cell growth due to Irs2 ablation would be able to mount a compensatory response in the background of insulin resistance caused by Insr haploinsufficiency. As previously reported, approximately 70% of mice with combined Insr and Irs2 mutations developed diabetes as a consequence of markedly decreased beta-cell mass. In the initial phases of the disease, we observed a robust increase in circulating insulin levels, even as beta-cell mass gradually declined, indicating that replication-defective beta-cells compensate for insulin resistance by increasing insulin secretion. These data provide further evidence for a heterogeneous beta-cell response to insulin resistance, in which compensation can be temporarily achieved by increasing function when mass is limited. The eventual failure of compensatory insulin secretion suggests that a comprehensive treatment of beta-cell dysfunction in type 2 diabetes should positively affect both aspects of beta-cell physiology.

Topics: Adaptation, Physiological; Adiponectin; Adipose Tissue; Animals; Animals, Newborn; Diabetes Mellitus; Glucose Tolerance Test; Growth Disorders; Hyperinsulinism; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Insulin-Secreting Cells; Intracellular Signaling Peptides and Proteins; Leptin; Liver; Mice; Mice, Inbred Strains; Mice, Knockout; Muscle, Skeletal; Mutation; Organ Size; Osmolar Concentration; Phosphatidylinositol 3-Kinases; Phosphoproteins; Proto-Oncogene Proteins c-akt; Receptor, Insulin

The aim of the present study was to evaluate the serum levels of leptin in the first year post-renal transplantation. Thirty-two patients and 19 healthy individuals were included. Serum leptin and biochemical markers were evaluated prospectively starting at transplant time (t(0)), and then every 3 months up to 1 year posttransplantation. The mean serum levels of leptin were higher in the pretransplant (t(0)) evaluation as compared with a control group of healthy volunteers (11.9 [9.2-25.2] and 7.7 [5.2-9.9] ng/mL, respectively; P < .0001). Leptinemia decreased significantly in the first 3 months after the renal transplantation (t(3)) (11.9 [9.2-25.2] to 7.1 [4.14-12.5] ng/mL; P < .0001) increased at t(6) to 10.6 (5.6-14.6) ng/mL and remained stable at t(9) (9.0 [5.2-18.3] ng/mL) and t(12) (9.3 [4.9-16.4] ng/mL). No correlation was found between leptin and renal function at any time during the study. In conclusion, during the first posttransplant year the serum leptin levels decreased significantly in relation to pretransplant period.

Topics: Adult; Diabetes Mellitus; Female; Humans; Kidney Transplantation; Leptin; Male; Middle Aged; Patient Selection; Prospective Studies; Radioimmunoassay; Reference Values; Reoperation

The diagnostic criteria and the clinical usefulness of the metabolic syndrome (MetSy) are currently questioned. The objective was to describe the structure of MetSy and to evaluate its components for prediction of diabetes type 2 (T2DM).. This was a case-referent study nested within a population-based health survey. Among 33,336 participants, we identified 177 initially non-diabetic individuals who developed T2DM after 0.1 to 10.5 years (mean, 5.4 years), and, for each diabetes case, two referents matched for sex, age, and year of health survey. Baseline variables included oral glucose tolerance test, BMI, blood pressure, blood lipids, adipokines, inflammatory markers, insulin resistance, and beta-cell function. Exploratory and confirmative factor analyses were applied to hypothesize the structure of the MetSy. The prediction of T2DM by the different factors was evaluated by multivariate logistic regression analysis.. A hypothetical five-factor model of intercorrelated composite factors was generated. The inflammation, dyslipidemia, and blood pressure factors were predicitive only in univariate analysis. In multivariable analyses, two factors independently and significantly predicted T2DM: an obesity/insulin resistance factor and a glycemia factor. The composite factors did not improve the prediction of T2DM compared with single variables. Among the original variables, fasting glucose, proinsulin, BMI, and blood pressure values were predictive of T2DM.. Our data support the concept of a MetSy, and we propose five separate clusters of components. The inflammation and dyslipidemia factors were not independently associated with diabetes risk. In contrast, obesity and accompanying insulin resistance and beta-cell decompensation seem to be two core perturbations promoting and predicting progression to T2DM.

Topics: Adult; Analysis of Variance; Biomarkers; Blood Glucose; Blood Pressure; Body Mass Index; Diabetes Mellitus; Dyslipidemias; Female; Health Surveys; Humans; Inflammation; Leptin; Male; Metabolic Syndrome; Middle Aged; Predictive Value of Tests; Proinsulin; Risk Factors; Sweden

Obesity is characterized by hyperinsulinemia, hyperleptinemia, and an increase in islet volume. While the mechanisms that hasten the onset of diabetes in obese individuals are not known, it is possible that the adipose-derived hormone leptin plays a role. In addition to its central actions, leptin exerts biological effects by acting in peripheral tissues including the endocrine pancreas. To explore the impact of disrupting leptin signaling in the pancreas on beta cell growth and/or function, we created pancreas-specific leptin receptor (ObR) KOs using mice expressing Cre recombinase under the control of the pancreatic and duodenal homeobox 1 (Pdx1) promoter. The KOs exhibited improved glucose tolerance due to enhanced early-phase insulin secretion, and a greater beta cell mass secondary to increased beta cell size and enhanced expression and phosphorylation of p70S6K. Similar effects on p70S6K were observed in MIN6 beta cells with knockdown of the ObR gene, suggesting crosstalk between leptin and insulin signaling pathways. Surprisingly, challenging the KOs with a high-fat diet led to attenuated acute insulin secretory response to glucose, poor compensatory islet growth, and glucose intolerance. Together, these data provide direct genetic evidence, from a unique mouse model lacking ObRs only in the pancreas, for a critical role for leptin signaling in islet biology and suggest that altered leptin action in islets is one factor that contributes to obesity-associated diabetes.

Topics: Animals; Body Weight; Cell Size; Diabetes Mellitus; Female; Glucose; Glucose Tolerance Test; Hyperplasia; Insulin; Insulin Secretion; Insulin-Secreting Cells; Leptin; Male; Mice; Mice, Knockout; Obesity; Pancreas; Phosphorylation; Receptors, Leptin; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction

Recent studies suggest that adipocyte-secreted factors called adipokines are involved in obesity-associated complications including hyperlipidemia, diabetes mellitus, arterial hypertension, atherosclerosis, and heart failure. Among those, adiponectin is an antidiabetic and antiatherogenic protein, concentrations of which are decreased in obesity-associated metabolic and vascular disorders. In contrast, leptin, tumor necrosis factor a, interleukin-6, monocyte chemoattractant protein-1, and plasminogen activator inhibitor-1 are upregulated in obesity and contribute to the development of diabetes and vascular disease. In this review, the relevance of adipokines in obesity, insulin resistance, diabetes mellitus, atherosclerosis, and cardiovascular diseases is discussed.

Topics: Adipokines; Adiponectin; Adipose Tissue; Animals; Atherosclerosis; Cardiovascular Diseases; Chemokine CCL2; Diabetes Mellitus; Humans; Inflammation; Interleukin-6; Leptin; Metabolic Syndrome; Mice; Obesity; Plasminogen Activator Inhibitor 1; Species Specificity; Tumor Necrosis Factor-alpha

The link between obesity and diabetes is not fully understood but there is evidence to suggest that hypothalamic signalling pathways may be involved. The hypothalamic neuropeptides, pro-opiomelanocortin (POMC), neuropeptide Y (NPY) and agouti-related protein (AGRP) are central to the regulation of food intake and have been implicated in glucose homeostasis. Therefore, the expression of these genes was quantified in hypothalami from diabetic Zucker fatty (ZDF) rats and nondiabetic Zucker fatty (ZF) rats at 6, 8, 10 and 14 weeks of age. Although both strains are obese, only ZDF rats develop pancreatic degeneration and diabetes over this time period. In both ZF and ZDF rats, POMC gene expression was decreased in obese versus lean rats at all ages. By contrast, although there was the expected increase in both NPY and AGRP expression in obese 14-week-old ZF rats, the expression of NPY and AGRP was decreased in 6-week-old obese ZDF rats with hyperinsulinaemia and in 14-week-old rats with the additional hyperglycaemia. Therefore, candidate genes involved in glucose, and insulin signalling pathways were examined in obese ZDF rats over this age range. We found that expression of the ATP-sensitive potassium (K(ATP)) channel component, Kir6.2, was decreased in obese ZDF rats and was lower compared to ZF rats in each age group tested. Furthermore, immunofluorescence analysis showed that Kir6.2 protein expression was reduced in the dorsomedial and ventromedial hypothalamic nuclei of 6-week-old prediabetic ZDF rats compared to ZF rats. The Kir6.2 immunofluorescence colocalised with NPY throughout the hypothalamus. The differences in Kir6.2 expression in ZF and ZDF rats mimic those of NPY and AGRP, which could infer that the changes occur in the same neurones. Overall, these data suggest that chronic changes in hypothalamic Kir6.2 expression may be associated with the development of hyperinsulinaemia and hyperglycaemia in ZDF rats.

Topics: Agouti-Related Protein; Animals; Diabetes Mellitus; Gene Expression; Glucose; Hyperglycemia; Hyperinsulinism; Hypothalamus; Immunohistochemistry; Inflammation; Insulin; Leptin; Male; Neuropeptide Y; Obesity; Pancreas; Potassium Channels, Inwardly Rectifying; Pro-Opiomelanocortin; Rats; Rats, Wistar; Rats, Zucker; Signal Transduction

No data have been so far reported on the relationship between polymorphisms of LEP gene and cardiovascular disease.. We genotyped a tetranucleotide repeat mapped in the 3'UTR of the LEP gene (LEP-tet) in 109 subjects with cardiovascular events and in 109 control subjects.. Univariate analysis and multivariate logistic regression analysis adjusted for age, gender, smoking status, history of hyperlipidemia, hypertension or diabetes showed not significant association between the genotype of the LEP-tet and cardiovascular diseases. Moreover, no differences were observed in the plasma leptin concentrations between cases and control subjects (22 +/- 19 vs 22 +/- 14 ng/ml, P = 0.52) and in relation to the LEP-tet classes or carriage of specific alleles (P = 0.76 for the association between LEP-tet classes and leptin levels in overall analysis).. In conclusion, our data do not support an association between the LEP-tet microsatellite polymorphism of the human LEP gene and cardiovascular diseases.

Topics: 3' Untranslated Regions; Age Factors; Aged; Cardiovascular Diseases; Case-Control Studies; Diabetes Mellitus; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Hypertension; Leptin; Logistic Models; Male; Microsatellite Repeats; Middle Aged; Polymorphism, Genetic; Sex Factors; Smoking

Intake of whole grains is inversely associated with risk of diabetes and ischemic heart disease in observational studies. The lower risk associated with high whole-grain intakes may be mediated through improvements in glycemic control, lipid profiles, or reduced inflammation.. The aim was to examine whether the intake of whole grains, bran, and germ is related to homocysteine, plasma markers of glycemic control (fasting insulin, hemoglobin A1c, C-peptide, and leptin), lipids (total cholesterol, triacylglycerol, HDL cholesterol, and LDL cholesterol), and inflammation (C-reactive protein, fibrinogen, and interleukin 6).. This was a cross-sectional study of the relations of whole grains, bran, and germ intakes with homocysteine and markers of glycemic control, lipids, and inflammation in 938 healthy men and women.. Whole-grain intake was inversely associated with homocysteine and markers of glycemic control. Compared with participants in the bottom quintile of whole-grain intake, participants in the highest quintile had 17%, 14%, 14%, and 11% lower concentrations of homocysteine (P < 0.01), insulin (P = 0.12), C-peptide (P = 0.03), and leptin (P = 0.03), respectively. Inverse associations were also observed with total cholesterol (P = 0.02), HDL cholesterol (P = 0.05), and LDL cholesterol (P = 0.10). Whole-grain intake was not associated with the markers of inflammation. Whole-grain intake was most strongly inversely associated with markers of glycemic control in this population.. The results suggest a lower risk of diabetes and heart disease in persons who consume diets high in whole grains.

Topics: Adult; Aged; Biomarkers; Blood Glucose; C-Reactive Protein; Cohort Studies; Cross-Sectional Studies; Diabetes Mellitus; Edible Grain; Female; Fibrinogen; Health Surveys; Heart Diseases; Homocysteine; Humans; Inflammation; Insulin; Interleukin-6; Leptin; Lipid Metabolism; Male; Middle Aged; Risk Factors

By locally infecting epididymal adipocytes of obese diabetic mice with the uncoupling protein-1 transgene, Yamada et al. (2006[this issue of Cell Metabolism]) unexpectedly induce leptin sensitivity with hypophagia and improvement in abnormal glucose and lipid abnormalities.

Topics: Adipocytes; Animals; Carrier Proteins; Diabetes Mellitus; Glucose; Homeostasis; Ion Channels; Leptin; Membrane Proteins; Mice; Mitochondrial Proteins; Obesity; Uncoupling Protein 1

Topics: Administration, Intranasal; Animals; Biological Transport; Blood-Brain Barrier; Brain; Central Nervous System; Diabetes Mellitus; Drug Industry; Female; Humans; Hypothalamus; Leptin; Male; Obesity; Peptides

We have tested the hypothesis that sustained leptin action in the hypothalamus alone can engender and maintain euglycemia in wild type mice and in two monogenic diabetic models, the insulin-deficient nonobese Akita mice and the hyperinsulinemic leptin-deficient obese, ob/ob mice. A single intracerebroventricular injection of recombinant adeno-associated virus vector encoding leptin (rAAV-lep) enhanced leptin transgene expression in the hypothalamus without any evidence of leptin leakage to the peripheral circulation, and promptly reinstated euglycemia that persisted along with severe insulinopenia in all three genotypes through the 7-week period of observation. A comparative evaluation of known etiologic factors of hyperglycemia showed that this long-term benefit on glucose homeostasis was not due to diminished energy consumption, weight and adiposity, but was conferred by at least two mechanisms operating simultaneously, enhanced glucose metabolism to meet the demand for the rAAV-lep induced increased non-shivering thermogenesis mediated by brown adipose tissue and insulin hypersensitivity. These findings endorse the hypothesis that increased leptin action locally in the hypothalamus can impose euglycemia independent of pancreatic insulin, and central leptin reinforcement may serve as a newer adjunct therapy to treat type 1 and type 2 diabetes.

Topics: Adenoviridae; Animals; Blood Glucose; Body Weight; Diabetes Mellitus; Eating; Genetic Vectors; Glucose Clamp Technique; Glucose Tolerance Test; Hypothalamus; Insulin; Ion Channels; Leptin; Male; Mice; Mice, Obese; Mice, Transgenic; Mitochondrial Proteins; Time Factors; Transgenes; Uncoupling Protein 1

Male mice that are pttg-null develop sexually dimorphic diabetes with hypoinsulinemia secondary to reduced postnatal-cell proliferation and an inability to expand islet cell mass with aging. We therefore examined the effects of sex-steroid manipulation on diabetes development in pttg-/- male mice. Surgical gonadectomy was followed by implantation of 90-day slow-release pellets releasing 17beta-estradiol (0.36 mg/pellet), placebo or dihydrotestosterone (DHT; 12.5 mg/pellet). Mean fasting blood sugars at the end of the study were 414 +/- 54 mg/dl for pttg-/- controls and 371 +/- 14 mg/dl for pttg-/- mice gonadectomized and treated with DHT compared with 124 +/- 40 and 85 +/- 12 mg/dl in gonadectomized pttg-/- males treated with placebo or estradiol, respectively (P < 0.01 compared with control pttg-/-). Gonadectomy with and without estradiol treatment did not increase the very low circulating insulin levels in pttg-null males (fasting insulin 0.44 +/- 0.04 ng/ml in pttg-/- controls, 0.47 +/- 0.07 and 0.4 ng/ml in pttg-/- gonadectomized males treated with placebo or estradiol, respectively). Gonadectomy increased serum adiponectin levels (4.9 +/- 008 microg/ml in pttg-/- controls versus 13 +/- 0.08 and 7.5 +/- 0.6 microg/ml in pttg-/- gonadectomized males treated with placebo or estradiol, respectively; P < 0.001 and P < 0.05), accompanied by increased insulin sensitivity. The results show that gonadectomy delayed, and gonadectomy with additional estradiol treatment prevented, diabetes development in pttg-/- males, possibly through increased insulin sensitivity mediated by elevated serum adiponectin levels. Male-selective effects of disrupted beta-cell proliferation in the absence of pttg are restored by sex-steroid effects on peripheral insulin sensitivity.

Topics: Adiponectin; Androgens; Animals; Blood Glucose; C-Peptide; Carrier Proteins; Cell Proliferation; Diabetes Mellitus; Dihydrotestosterone; Estradiol; Gonadal Steroid Hormones; Insulin; Insulin-Secreting Cells; Leptin; Male; Mice; Mice, Knockout; Neoplasm Proteins; Orchiectomy; Securin; Sex Characteristics

Fatty acid elongases and desaturases play an important role in hepatic and whole body lipid composition. We examined the role that key transcription factors played in the control of hepatic elongase and desaturase expression. Studies with peroxisome proliferator-activated receptor alpha (PPARalpha)-deficient mice establish that PPARalpha was required for WY14643-mediated induction of fatty acid elongase-5 (Elovl-5), Elovl-6, and all three desaturases [Delta(5) desaturase (Delta(5)D), Delta(6)D, and Delta(9)D]. Increased nuclear sterol-regulatory element binding protein-1 (SREBP-1) correlated with enhanced expression of Elovl-6, Delta(5)D, Delta(6)D, and Delta(9)D. Only Delta(9)D was also regulated independently by liver X receptor (LXR) agonist. Glucose induction of l-type pyruvate kinase, Delta(9)D, and Elovl-6 expression required the carbohydrate-regulatory element binding protein/MAX-like factor X (ChREBP/MLX) heterodimer. Suppression of Elovl-6 and Delta(9)D expression in livers of streptozotocin-induced diabetic rats and high fat-fed glucose-intolerant mice correlated with low levels of nuclear SREBP-1. In leptin-deficient obese mice (Lep(ob/ob)), increased SREBP-1 and MLX nuclear content correlated with the induction of Elovl-5, Elovl-6, and Delta(9)D expression and the massive accumulation of monounsaturated fatty acids (18:1,n-7 and 18:1,n-9) in neutral lipids. Diabetes- and obesity-induced changes in hepatic lipid composition correlated with changes in elongase and desaturase expression. In conclusion, these studies establish a role for PPARalpha, LXR, SREBP-1, ChREBP, and MLX in the control of hepatic fatty acid elongase and desaturase expression and lipid composition.

Topics: Acetyltransferases; Adult; Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Diabetes Mellitus; Fatty Acid Desaturases; Fatty Acid Elongases; Female; Glucose; Humans; Hydrocarbons, Fluorinated; Insulin; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Middle Aged; Obesity; PPAR alpha; Pyrimidines; Rats; Rats, Sprague-Dawley; Sterol Regulatory Element Binding Protein 1; Sulfonamides

Histamine H3 receptors (H3Rs) are located on the presynaptic membranes and cell soma of histamine neurons, where they negatively regulate the synthesis and release of histamine. In addition, H3Rs are also located on nonhistaminergic neurons, acting as heteroreceptors to regulate the releases of other amines such as dopamine, serotonin, and norepinephrine. The present study investigated the effects of H3R ligands on appetite and body-weight regulation by using WT and H3R-deficient mice (H3RKO), because brain histamine plays a pivotal role in energy homeostasis. The results showed that thioperamide, an H3R inverse agonist, increases, whereas imetit, an H3R agonist, decreases appetite and body weight in diet-induced obese (DiO) WT mice. Moreover, in DiO WT mice, but not in DiO H3RKO mice, imetit reduced fat mass, plasma concentrations of leptin and insulin, and hepatic triglyceride content. The anorexigenic effects of imetit were associated with a reduction in histamine release, but a comparable reduction in histamine release with alpha-fluoromethylhistidine, an inhibitor of histamine synthesis, increased appetite. Moreover, the anorexigenic effects of imetit were independent of the melanocortin system, because imetit comparably reduced appetite in melanocortin 3 and 4 receptor-deficient mice. The results provide roles of H3Rs in energy homeostasis and suggest a therapeutic potential for H3R agonists in the treatment of obesity and diabetes mellitus.

Topics: Animals; Appetite; Body Weight; Diabetes Mellitus; Histamine Agonists; Imidazoles; Insulin; Leptin; Mice; Mice, Knockout; Obesity; Piperidines; Receptors, Histamine H3; Thiourea

The present study aimed to examine whether hyperphagia, which is frequently observed in type 1 diabetic patients and model animals, also occurs in type 2 diabetic Goto-Kakizaki (GK) rats and, if so, to explore underlying abnormalities in the hypothalamus. GK rats at postnatal weeks 6-12, compared to control Wistar rats, exhibited hyperphagia, hyperglycaemia, hyperleptinemia and increased visceral fat accumulation, whereas body weight was unaltered. The ability of leptin to suppress feeding was reduced in GK rats compared to Wistar rats of these ages. In GK rats, leptin-induced phosphorylation of signal transducer and activator of transcription 3 was significantly reduced in the cells of the hypothalamic arcuate nucleus (ARC), but not of the ventromedial hypothalamus, whereas the mRNA level of functional leptin receptor was unaltered. By real-time polymerase chain reaction and in situ hybridisation, mRNA levels of neuropeptide Y, but not pro-opiomelanocortin and galanin-like peptide, were significantly increased in the ARC of GK rats at 11 weeks, but not 26 weeks. Following i.c.v. injection of a NPY Y1 antagonist, 1229U91, the amount of food intake in GK rats was indistinguishable from that in Wistar rats, thus eliminating the hyperphagia of GK rats. These results demonstrate that young adult GK rats display hyperphagia in association with leptin resistance and increased NPY mRNA level in the ARC.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Blood Glucose; Diabetes Mellitus; Eating; Hyperphagia; Hypothalamus; Immunohistochemistry; In Situ Hybridization; Injections, Intraventricular; Leptin; Neuropeptide Y; Peptides, Cyclic; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; STAT3 Transcription Factor

Recent deorphanization efforts have paired the G-protein-coupled receptors GPR40, GPR41 and GPR43 with fatty acids as endogenous ligands. While carboxylic acids have been historically known to serve as fuel sources and biomarkers of disease, these studies demonstrate that fatty acids can act as signalling molecules at the cell-surface level. This receptor subfamily shares approx. 30% identity among members, with some limited cross-over between ligand activities. Generalized expression patterns within the pancreatic beta-cell, adipose depots and the gastrointestinal tract infer involvement in energy source recognition, absorption, storage and/or metabolism. GPR40, activated by medium and long-chain fatty acids, has been shown to potentiate insulin secretion at the beta-cell, and has been hypothesized to participate in the detrimental effects of chronic fatty acid exposure on beta-cell function. GPR41 and GPR43 have been reported to stimulate leptin release and adipogenesis respectively via activation by short-chain fatty acids. These common themes implicate GPR40, GPR41 and GPR43 in playing significant roles in metabolic diseases, such as diabetes, obesity and the metabolic syndrome.

Topics: Animals; Diabetes Mellitus; Humans; Leptin; Metabolic Syndrome; Obesity; Receptors, Cell Surface; Receptors, G-Protein-Coupled

This study aimed to investigate the regulation of adiponectin receptors 1 (AdipoR1) and 2 (AdipoR2) gene expression in primary skeletal muscle myotubes, derived from human donors, after exposure to globular adiponectin (gAd) and leptin.. Four distinct primary cell culture groups were established [Lean, Obese, Diabetic, Weight Loss (Wt Loss); n = 7 in each] from rectus abdominus muscle biopsies obtained from surgical patients. Differentiated myotube cultures were exposed to gAd (0.1 microg/mL) or leptin (2.5 microg/mL) for 6 hours. AdipoR1 and AdipoR2 gene expression was measured by real-time polymerase chain reaction analysis.. AdipoR1 mRNA expression in skeletal muscle myotubes derived from Lean subjects (p < 0.05) was stimulated 1.8-fold and 2.5-fold with gAd and leptin, respectively. No increase in AdipoR1 gene expression was measured in myotubes derived from Obese, Diabetic, or Wt Loss subjects. AdipoR2 mRNA expression was unaltered after gAd and leptin exposure in all myotube groups.. Adiponectin and leptin are rapid and potent stimulators of AdipoR1 in myotubes derived from lean healthy individuals. This effect was abolished in myotubes derived from obese, obese diabetic subjects, and obese-prone individuals who had lost significant weight after bariatric surgery. The incapacity of skeletal muscle of obese and diabetic individuals to respond to exogenous adiponectin and leptin may be further suppressed as a result of impaired regulation of the AdipoR1 gene.

Topics: Adiponectin; Adult; Cells, Cultured; Diabetes Mellitus; Female; Gene Expression Regulation; Humans; Leptin; Male; Middle Aged; Muscle Fibers, Skeletal; Muscle, Skeletal; Obesity; Receptors, Adiponectin; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger; Weight Loss

Topics: Adiponectin; Animals; Asian People; C-Reactive Protein; Diabetes Mellitus; Female; Genetic Predisposition to Disease; Humans; India; Leptin; Male; Mice; Obesity; Phenotype; Prevalence; Resistin; Tumor Necrosis Factor-alpha

Asian Indians have a unique phenotype characterized by increased abdominal obesity and visceral fat despite low body mass index [BMI]. Though studies have indicated some adipocytokines to be associated with diabetes and obesity in Indians, there are virtually no studies relating adipocytokines and proinsulin with diabetes and obesity in Asian Indians. In this study we looked at adipocytokines--leptin, adiponectin and tumour necrosis factor-a [TNF-alpha] and insulin and proinsulin in subjects with diabetes and obesity. Thirty five diabetic subjects and 50 healthy controls were recruited for the study. Leptin [p=0.002J and adiponectin levels [p=0.011] were lower and proinsulin values higher [p<0.001] in diabetic subjects compared to non-diabetic subjects. In addition, leptin [p<0.001] and proinsulin [p<0.001] were higher and adiponectin [p<0.001] lower, in obese subjects compared to non-obese subjects. TNF-alpha failed to show any significant difference between the study groups. Leptin and proinsulin showed a significant and positive correlation with BMI [p<0.001] and waist circumference [p<0.001]. Adiponectin showed an inverse correlation with BMI [p=0.050] and waist circumference [p=0.002]. Proinsulin showed a significant negative association with adiponectin [p=0.002]. Logistic regression analysis revealed leptin to be negatively associated [Odds ratio [OR]: 0.864, 95% confidence interval [95% CI]: 0.775 -0.963, p=0.008] and proinsulin [OR: 1.567, 95% CI: 1.246-1.971, p<0.001] to be positively associated with diabetes even after adjusting for age, gender and BMI. Leptin [OR: 1.365, 95% CI: 1.170-1.592, p<0.001] and proinsulin [OR: 1.617, 95% CI: 1.218 -2.147, p=0.001] showed a significant positive association with obesity, while adiponectin [OR: 0.927, 95% CI: 0.865 - 0.995, p=0.035] had a significant inverse association. Linear regression analysis revealed that adiponectin is inversely associated with proinsulin even after the addition of age, gender and diabetes status [beta= -0.61, p=0.033] into the model. In conclusion, in urban Asian Indians in western India, proinsulin levels showed a positive association, while leptin and adiponectin showed a negative association with diabetes. With regard to obesity, leptin and proinsulin had a positive association, while adiponectin had a negative association. Proinsulin levels showed an inverse association with adiponectin indicating a possible link between insulin secretion and insulin resistance.

Topics: Adiponectin; Asian People; Biomarkers; Diabetes Mellitus; Female; Humans; India; Insulin; Insulin Resistance; Leptin; Male; Obesity; Proinsulin; Regression Analysis; Tumor Necrosis Factor-alpha; Urban Population

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

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

We examined the relationships among IGF binding protein (IGFBP)-1, insulin sensitivity, and leptin in different ethnic groups (Asian Indians, Chinese, and Caucasians) using the euglycemic hyperinsulinemic clamp. Ten healthy, young and nondiabetic subjects of each ethnic group, matched for body mass index, age, and physical activity were studied. A euglycemic clamp was performed on all subjects. IGFBP-1, insulin, and leptin were measured after fasting and during the clamp. Fasting IGFBP-1 concentration was highest in Chinese (P = 0.027). Asian Indians had the lowest insulin sensitivity index (P = 0.006). The ratio of insulin to IGFBP-1 at fasting and throughout the euglycemic clamp was higher in Asian Indians. Fasting IGFBP-1 had a strong negative correlation with fasting leptin levels (r = -0.715, P = 0.001). Multiple linear regression demonstrated that fasting insulin, leptin, ethnicity, and insulin sensitivity were significant predictors for fasting IGFBP-1. IGFBP-1 is independently determined by ethnicity, insulin sensitivity, and leptin in glucose-tolerant men. The presence of relative insulin resistance and low fasting IGFBP-1 levels in Asian Indians may contribute to their higher risk of developing diabetes and cardiovascular disease.

Topics: Adult; Asian People; Cardiovascular Diseases; Diabetes Mellitus; Fasting; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Insulin Resistance; Insulin-Like Growth Factor Binding Protein 1; Leptin; Male; Risk Factors; White People

Leptin is a hormone that regulates body weight homeostasis mainly via the hypothalamic functional leptin receptor Ob-Rb. Recently, we proposed that the taste organ is a new peripheral target for leptin. Leptin selectively inhibits mouse taste cell responses to sweet substances and thereby may act as a sweet taste modulator. The present study further investigated leptin action on the taste system by examining expression of Ob-Rb in taste cells and behavioral responses to sweet substances in leptin-deficient ob/ob, and Ob-Rb-deficient db/db mice and their normal litter mates. RT-PCR analysis showed that Ob-Rb was expressed in taste cells in all strains tested. The db/db mice, however, had a RT-PCR product containing an abnormal db insertion that leads to an impaired shorter intracellular domain. In situ hybridization analysis showed that the hybridization signals for normal Ob-Rb mRNA were detected in taste cells in lean and ob/ob mice but not in db/db mice. Two different behavioral tests, one using sweet-bitter mixtures as taste stimuli and the other a conditioned taste aversion paradigm, demonstrated that responses to sucrose and saccharin were significantly decreased after ip injection of leptin in ob/ob and normal littermates, but not in db/db mice. These results suggest that leptin suppresses behavioral responses to sweet substances through its action on Ob-Rb in taste cells. Such taste modulation by leptin may be involved in regulation for food intake.

Topics: Animals; Behavior, Animal; Diabetes Mellitus; Female; Gene Expression; In Situ Hybridization; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Saccharin; Sucrose; Taste; Taste Buds

We have generated mice that are homozygous for a leptin receptor transgene that is expressed exclusively in neurons (NSE-LEPR-B). We had previously shown that this transgene in the hemizygous state is effective in ameliorating almost all aspects of leptin receptor deficiency. Now, we show that the transgene, in the homozygous state, almost fully corrects the excess adiposity of LEPR-deficient (db/db) mice. Body composition analyses indicate that the transgene is able to restrain the massive increase in adiposity observed in LEPR-deficient mice. Examination of hypothalamic agouti gene-related peptide and proopiomelanocortin mRNA shows normalization of these leptin-regulated transcripts. Interestingly, despite normalization of circulating leptin concentrations by the transgene in the fed state, transgenic db3J/db mice did not show fasting-induced reductions of circulating leptin. Increased adiposity of the transgenic db/db mice at 4 wk of age, immediately postweaning, suggests that the transgene is less effective in correcting the preferential fat deposition caused by LEPR deficiency. We noted that the morphology of brown adipose tissue is nearly normal, concordant with the cold tolerance conferred by the transgene. Aspects of the diabetes phenotype are also corrected: glucose and insulin concentrations are nearly normal, and islet hyperplasia is greatly diminished. The transgene also corrects the infertility of db/db females and confers the ability to lactate sufficiently to nurse normal-sized litters. Finally, the slightly increased adiposity and mild insulin resistance of transgenic db/db dams were not a contributory factor to the increased fat content of transgenic db/db male progeny.

Topics: Adaptation, Physiological; Adipose Tissue; Animals; Body Composition; Body Weight; Diabetes Mellitus; Female; Fertility; Gene Dosage; Gene Expression Regulation; Lactation; Leptin; Male; Mice; Mice, Knockout; Mice, Transgenic; Obesity; Receptors, Cell Surface; Receptors, Leptin; Transgenes

High-fat and high-fructose diets are usually used to induce animal model diabetes mellitus. The purposes of this research were to compare the abnormalities of glucose metabolism caused by high-fructose diet and a high-fat diet and the effects of the high-fructose diet and high-fat diet on plasma leptin.. In this research, 24 Sprague-Dawley rats were used as the experimental animals, which were divided into three groups: chow diet (control group), high-fructose diet (60% fructose w/w) and high-fat diet (20% lard w/w). They were fed for a period of 8 weeks, during which an oral glucose tolerance test was conducted in the seventh week, and after completion of the eighth week, the abdominal adipose tissue and liver of the rats were excised and weighed, and the plasma cholesterol, triglyceride, insulin and leptin concentrations were assayed.. The high-fat diet group presented a fasting blood glucose concentration that was higher than that of the control group. Furthermore, after 2 h of glucose challenge, the rats in the high-fat and high-fructose diet groups all presented higher plasma glucose concentrations than did the control group. The high-fat diet group showed higher body weight, higher relative liver weight, a higher plasma cholesterol concentration and higher amylase activity than did the other groups, whereas the high-fructose diet group showed higher fasting insulin and triglyceride concentrations. As for adipose tissue, the high-fat diet group presented an amount that was higher than that of the high-fructose and control groups, but the plasma leptin concentration of the high-fructose group was higher than that of the control group.. It can be concluded from the above-mentioned experimental results that a high-fructose diet can cause hyperinsulinaemia, while a high-fat diet can result in impaired pancreatic function of insulin secretion and glucose intolerance, indicating that high-fructose diet and a high-fat diet may exert divergent effects on glucose metabolism in rats.

Topics: 3-Hydroxybutyric Acid; Amylases; Animals; Blood Glucose; Diabetes Mellitus; Dietary Fats; Dietary Sucrose; Fructose; Glucose Tolerance Test; Insulin; Leptin; Lipids; Male; Models, Animal; Rats; Rats, Sprague-Dawley

Resistin is an adipose-derived hormone that has been proposed as a link among obesity, insulin resistance, and diabetes. In agreement with a role of resistin in insulin resistance, the administration of recombinant resistin led to glucose intolerance in mice and impaired insulin action in rat liver. However, the regulation of resistin expression by physiological conditions, hormones, or agents known to modulate insulin sensitivity does not always support the association between resistin and obesity-induced insulin resistance. In the present study we investigated the effects of leptin administration on adipose resistin expression in insulin-resistant and obese ob/ob mice. We show that the expression of resistin mRNA and protein in adipose tissue is lower in ob/ob than in wild-type control mice, in agreement with the reduced adipocyte resistin mRNA level reported in several models of obesity. Leptin administration in ob/ob mice resulted in improvement of insulin sensitivity concomitant with a decrease in resistin gene expression. The lack of effect of leptin on resistin in db/db mice indicated that the leptin inhibitory action on resistin expression requires the long leptin receptor isoform. In addition, we demonstrated that the effect of leptin on resistin expression was centrally mediated. High-fat feeding in C57BL/6J wild-type mice, which is known to induce the development of obesity and insulin resistance, produced an increase in resistin expression. Interestingly, in both ob/ob and high fat-fed mice we obtained a striking positive correlation between glycemia and resistin gene expression. In conclusion, our results demonstrate that leptin decreases resistin expression and suggest that resistin may influence glucose homeostasis.

Topics: 11-beta-Hydroxysteroid Dehydrogenases; Adipose Tissue; Animals; Blood Glucose; Carrier Proteins; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dietary Fats; Disease Models, Animal; Fatty Acid-Binding Protein 7; Fatty Acid-Binding Proteins; Gene Expression; Homeostasis; Hormones, Ectopic; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Nerve Tissue Proteins; Obesity; Resistin; RNA, Messenger

Hormonal control of metabolic rate can be important in regulating the imbalance between energy intake and expenditure that underlies the development of obesity. In mice fed a high-fat diet, human fibroblast growth factor 19 (FGF19) increased metabolic rate [1.53 +/- 0.06 liters O(2)/h.kg(0.75) (vehicle) vs. 1.93 +/- 0.05 liters O(2)/h.kg(0.75) (FGF19); P < 0.001] and decreased respiratory quotient [0.82 +/- 0.01 (vehicle) vs. 0.80 +/- 0.01 (FGF19); P < 0.05]. In contrast to the vehicle-treated mice that gained weight (0.14 +/- 0.05 g/mouse.d), FGF19-treated mice lost weight (-0.13 +/- 0.03 g/mouse.d; P < 0.001) without a significant change in food intake. Furthermore, in addition to a reduction in weight gain, treatment with FGF19 prevented or reversed the diabetes that develops in mice made obese by genetic ablation of brown adipose tissue or genetic absence of leptin. To explore the mechanisms underlying the FGF19-mediated increase in metabolic rate, we profiled the FGF19-induced gene expression changes in the liver and brown fat. In brown adipose tissue, chronic exposure to FGF19 led to a gene expression profile that is consistent with activation of this tissue. We also found that FGF19 acutely increased liver expression of the leptin receptor (1.8-fold; P < 0.05) and decreased the expression of acetyl coenzyme A carboxylase 2 (0.6-fold; P < 0.05). The gene expression changes were consistent with the experimentally determined increase in fat oxidation and decrease in liver triglycerides. Thus, FGF19 is able to increase metabolic rate concurrently with an increase in fatty acid oxidation.

Topics: Acetyl-CoA Carboxylase; Adipose Tissue, Brown; Animals; Body Weight; Diabetes Mellitus; Diet; Fibroblast Growth Factors; Gene Expression; Humans; Leptin; Liver; Metabolism; Mice; Mice, Transgenic; Obesity; Receptors, Cell Surface; Receptors, Leptin; Recombinant Proteins

Signal transducer and activator of transcription (STAT)3 is widely expressed in the CNS during development and adulthood. STAT3 has been implicated in the control of neuron/glial differentiation and leptin-mediated energy homeostasis, but the physiological role and degree of involvement of STAT3 in these processes is not defined and controversial because of the lack of a direct genetic model. To address this, we created mice with a neural-specific disruption of STAT3 (STAT3(N-/-)). Surprisingly, homozygous mutants were born at the expected Mendelian ratio without apparent developmental abnormalities but susceptible to neonatal lethality. Mutants that survived the neonatal period were hyperphagic, obese, diabetic, and infertile. Administering a melanocortin-3/4 receptor agonist abrogated the hyperphagia and hypothalamic immunohistochemistry showed a marked reduction in proopiomelanocortin with an increase in neuropeptide Y and agouti-related protein. Mutants had reduced energy expenditure and became hypothermic after fasting or cold stress. STAT3(N-/-) mice are hyperleptinemic, suggesting a leptin-resistant condition. Concomitant with neuroendocrine defects such as decreased linear growth and infertility with accompanying increased corticosterone levels, this CNS knockout recapitulates the unique phenotype of db/db and ob/ob obese models and distinguishes them from other genetic models of obesity. Thus, STAT3 in the CNS plays essential roles in the regulation of energy homeostasis and reproduction.

Topics: Acute-Phase Proteins; Adipose Tissue, Brown; Animals; Body Temperature Regulation; Corticosterone; Diabetes Mellitus; DNA-Binding Proteins; Female; Infertility, Female; Infertility, Male; Intermediate Filament Proteins; Kinetics; Leptin; Male; Mice; Mice, Knockout; Mice, Transgenic; Nerve Tissue Proteins; Nestin; Obesity; Rats; STAT3 Transcription Factor; Time Factors; Trans-Activators

Topics: Adiponectin; Adult; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Hormones, Ectopic; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Male; Middle Aged; Obesity; Proteins; Resistin

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

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

New Zealand Obese (NZO) male mice develop a polygenic juvenile-onset obesity and maturity-onset hyperinsulinemia and hyperglycemia (diabesity). Here we report on metabolic and molecular changes associated with the antidiabesity action of CL316,243 (CL), a beta(3)-adrenergic receptor agonist. Dietary CL treatment initiated at weaning reduced the peripubertal rise in body weight and adiposity while promoting growth without suppressing hyperphagia. The changes in adiposity, in turn, suppressed development of hyperinsulinemia, hyperleptinemia, hyperlipidemia, and hyperglycemia. These CL-induced alterations were reflected by decreased adipose tissue mass, increased expression of transcripts for uncoupling protein-1 (UCP-1), peroxisome proliferator-activated receptor alpha (PPARalpha), peroxisome proliferater-activated receptor coactivator-1 (PGC-1), and robust development of brown adipocyte function in white fat. Increased drug-mediated energy dissipation elicited a 1.5 degrees C increase in whole body temperature under conditions of increased food intake but with no change in physical activity. Indirect calorimetry of mice treated with CL showed both increased energy expenditure and a restoration of a prominent diurnal pattern in the respiratory exchange ratio suggesting improved nutrient sensing. Our data suggest that CL promotes increased energy dissipation in white and brown fat depots by augmenting thermogenesis and by metabolic re-partitioning of energy in a diabesity-protective fashion. This is the first report demonstrating the effects of dietary beta(3)-agonist in preventing the onset of diabesity in a polygenic rodent model of type 2 diabetes.

Topics: Adipose Tissue; Adrenergic beta-Agonists; Animals; Blood Glucose; Body Weight; Carrier Proteins; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dioxoles; Eating; Energy Metabolism; Insulin; Ion Channels; Islets of Langerhans; Leptin; Liver; Male; Membrane Proteins; Mice; Mice, Inbred Strains; Mitochondrial Proteins; Muscle, Skeletal; Obesity; Receptors, Cytoplasmic and Nuclear; Thermogenesis; Transcription Factors; Uncoupling Protein 1

Resistin was originally reported as an adipose tissue-specific hormone that provided a link between obesity and diabetes. Resistin protein level was elevated in obese mice and decreased by insulin-sensitizing thiazolidinediones. Immunoneutralization of resistin improved insulin sensitivity in diet-induced obese mice, while the administration of exogenous resistin induced insulin resistance. More recently, we have shown that ablation of the resistin gene in mice decreased fasting glucose through impairment of gluconeogenesis, while resistin treatment in these knockout mice increased hepatic glucose production. However, the link between resistin and glucose homeostasis has been questioned by studies demonstrating reduced, rather than increased, resistin mRNA expression in obese and diabetic mice. To better understand the regulation of resistin, we developed a sensitive and specific RIA resistin that could accurately measure serum resistin levels in several mouse models. We show that while resistin mRNA is indeed suppressed in obese mice, the circulating resistin level is significantly elevated and positively correlated with insulin, glucose, and lipids. Both resistin mRNA expression and protein levels in Lep(ob/ob) mice are suppressed by leptin treatment in parallel with reductions in glucose and insulin. In wild-type mice, serum resistin increases after nocturnal feeding, concordant with rising levels of insulin. Resistin mRNA and protein levels decline in parallel with glucose and insulin during fasting and are restored after refeeding. We performed clamp studies to determine whether resistin is causally related to insulin and glucose. Adipose resistin expression and serum resistin increased in response to hyperinsulinemia and further in response to hyperglycemia. Taken together, these findings suggest that the nutritional regulation of resistin and changes in resistin gene expression and circulating levels in obesity are mediated, at least in part, through insulin and glucose.

Topics: Adipose Tissue; Animals; Blood Glucose; Diabetes Mellitus; Diet; Fasting; Female; Hormones, Ectopic; Hyperglycemia; Hyperinsulinism; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Radioimmunoassay; Resistin; RNA, Messenger

To test whether leptin and adiponectin are risk markers for a first-ever stroke. RESEARCH DESIGN, METHODS AND SUBJECTS: A nested case-referent study identified 276 cases with first-ever stroke (234 cases with ischaemic and 42 with haemorrhagic stroke). Prior to the stroke, they had participated in population-based health surveys in northern Sweden (median time between survey and stroke was 4.9 years). Referents were matched for sex, age, date and type of health survey, and geographical region. Putative risk markers for first-ever stroke, including blood pressure (BP), diabetes, smoking, body mass index (BMI), cholesterol, leptin, and adiponectin, were analysed by conditional logistic regression analysis.. Increased BMI, high cholesterol and fasting glucose levels, diabetes mellitus and hypertension were found in future stroke patients. Whereas leptin levels were higher in male subjects (P = 0.004), adiponectin did not differ between groups. A high leptin level independently predicted stroke in men (OR = 2.46; 95% CI 1.08-5.62) but not in women. Adiponectin levels did not predict stroke. Males with high leptin levels developed stroke faster than males with low leptin levels (P = 0.0009), independently of traditional risk factors.. Leptin may be an important link to the development of cerebrovascular disease in men, whereas adiponectin does not associate with future stroke.

Topics: Adiponectin; Adult; Aged; Biomarkers; Blood Glucose; Body Mass Index; Cholesterol; Diabetes Complications; Diabetes Mellitus; Epidemiologic Methods; Female; Gender Identity; Health Surveys; Humans; Hypertension; Intercellular Signaling Peptides and Proteins; Leptin; Male; Middle Aged; Myocardial Infarction; Proteins; Stroke

Obesity is associated with diabetes and gallstone formation. Obese leptin-deficient (Lepob) and leptin-resistant (Lepdb) mice are hyperglycemic and have enlarged gallbladders with diminished response in vitro to cholecystokinin (CCK) and acetylcholine (ACh). Whether this phenomenon is secondary to hyperosmolar myocytes and/or decreased neuromuscular transmission remains unclear. We hypothesize that myocytes from Lepob and Lepdb obese mice would not respond normally to neurotransmitters.. Cholecystectomy was performed on 39 lean, 19 Lepob, and 20 Lepdb 12-week-old female mice. The gallbladder was divided and enzymatically digested. Half of each gallbladder's myocytes had contraction induced by CCK (10(-8) mol/L, n = 38) or ACh (10(-5) mol/L, n = 40).. Body weights, gallbladder volumes, and serum glucoses were greater for Lep(ob) and Lepdb mice compared to controls (P < .001). Resting myocyte lengths from Lepob and Lepdb mice were 93% and 91% of the length of controls (P < .001). In response to CCK, lean myocytes shortened 6% (P < .01), while myocytes from obese mice demonstrated no shortening. None of the myocytes demonstrated significant shortening with ACh.. These data suggest that gallbladder myocytes from obese mice are (1) foreshortened and (2) have a diminished response to cholecystokinin. We conclude that altered leptin and/or increased glucose may foreshorten myocytes and decrease response to cholecystokinin.

Topics: Acetylcholine; Animals; Blood Glucose; Body Weight; Cholecystokinin; Diabetes Mellitus; Female; Gallbladder; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Muscle Contraction; Myocytes, Smooth Muscle; Obesity

The effects of recombinant human erythropoietin (rHuEPO) in diabetes-related healing defects were investigated by using an incisional skin-wound model produced on the back of female diabetic C57BL/KsJ-m(+/+)Lept(db) mice (db(+)/db(+)) and their normoglycemic littermates (db(+/+)m). Animals were treated with rHuEPO (400 units/kg in 100 microl s.c.) or its vehicle alone (100 microl). Mice were killed on different days (3, 6, and 12 days after skin injury) for measurement of vascular endothelial growth factor (VEGF) mRNA expression and protein synthesis, for monitoring angiogenesis by CD31 expression, and for evaluating histological changes. Furthermore, we evaluated wound-breaking strength at day 12. At day 6, rHuEPO injection in diabetic mice resulted in an increase in VEGF mRNA expression (vehicle = 0.33 +/- 0.1 relative amount of mRNA; rHuEPO = 0.9 +/- 0.09 relative amount of mRNA; P < 0.05) and protein wound content (vehicle = 23 +/- 5 pg/wound; rHuEPO = 92 +/- 12 pg/wound; P < 0.05) and caused a marked increase in CD31 gene expression (vehicle = 0.18 +/- 0.05 relative amount of mRNA; rHuEPO = 0.98 +/- 0.21 relative amount of mRNA; P < 0.05) and protein synthesis. Furthermore, rHuEPO injection improved the impaired wound healing and, at day 12, increased the wound-breaking strength in diabetic mice (vehicle = 12 +/- 2 g/mm; rHuEPO 21 +/- 5 g/mm; P < 0.05). Erythropoietin may have a potential application in diabetes-related wound disorders.

Topics: Animals; Blood Glucose; Diabetes Complications; Diabetes Mellitus; Erythrocyte Count; Erythropoietin; Female; Glycated Hemoglobin; Hemoglobins; Humans; Leptin; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Neovascularization, Physiologic; Platelet Endothelial Cell Adhesion Molecule-1; Recombinant Proteins; RNA, Messenger; Skin; Vascular Endothelial Growth Factor A; Wound Healing; Wounds and Injuries

Adiponectin is an anti-diabetic and anti-atherogenic hormone that is exclusively secreted from fat cells. Serum adiponectin levels are reduced in obese patients and obese model mice, despite increased adipose tissue mass. Elucidation of the mechanism(s) by which plasma adiponectin levels are decreased in obese and diabetic patients would provide insight into the cause of obesity-induced diabetes and the development of therapeutic advances. In the present study, the regulation of adiponectin secretion was investigated using 3T3-L1 adipocytes and a diabetic-/obese-mouse model. A novel insulin sensitizer, IkappaB kinase beta (IKKbeta) inhibitor, ameliorated insulin resistance and up-regulated plasma levels of adiponectin without producing a significant change in body weight in KKAy mice that were fed a high-fat diet. The IKKbeta inhibitor cancelled the TNFalpha-mediated down-regulation of adiponectin secretion and simultaneously up-regulated the phosphorylation of Akt in 3T3-L1 adipocytes. Using dominant-negative mutants of Akt or PKClambda (downstream effectors of phosphoinositide 3-kinase), insulin-stimulated Akt activity was found to be important in the regulation of adiponectin secretion by insulin in 3T3-L1 adipocytes. These observations suggest that "insulin-stimulated Akt activity in adipocytes" may play an important role in the regulation of adiponectin secretion.

Topics: 3T3-L1 Cells; Adipocytes; Adiponectin; Animals; Benzamides; Blood Glucose; Body Weight; Chromones; Diabetes Mellitus; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Enzyme Inhibitors; Gene Expression Regulation; Genes, Dominant; Glucose; I-kappa B Kinase; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Mice; Mice, Obese; Models, Biological; Morpholines; Obesity; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Time Factors; Up-Regulation

The anorexigenic and orexigenic hormones leptin and ghrelin act in opposition to one another. When leptin signaling is reduced, as in the Zucker fatty rat, or when circulating ghrelin is increased during fasting, the effect of ghrelin becomes more dominant, indicating an influence of both hormones on ghrelin action. This effect could be mediated via the level of expression of ghrelin receptor (growth hormone secretagogue receptor [GHS-R]). For testing this, GHS-R expression was measured using in situ hybridization in Zucker fatty versus lean rats; in fed versus fasted (48 h) rats, treated with either ghrelin or leptin; and in GH-deficient, dwarf versus control rats. In the arcuate nuclei of the Zucker fatty rat and in fasted rats, GHS-R expression is significantly increased. A single leptin intracerebroventricular injection attenuated the fasting-induced increase in GHS-R but had no effect in fed rats 2 h after injection, whereas leptin infusion for 24 h or longer significantly decreased GHS-R expression in fed rats. Ghrelin significantly increased GHS-R expression but not in dwarf rats. These results show that the level of GHS-R expression in the ARC is reduced by leptin and increased by ghrelin and that the effect of ghrelin may be GH dependent.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Diabetes Mellitus; Gene Expression Regulation; Ghrelin; Injections, Intraventricular; Leptin; Obesity; Peptide Hormones; Rats; Rats, Zucker; Receptors, G-Protein-Coupled; Receptors, Ghrelin; RNA, Messenger; Ventromedial Hypothalamic Nucleus

It has been proposed that the hexosamine pathway acts as a nutrient-sensing pathway, protecting the cell against abundant fuel supply, and that accumulation of hexosamines represents a biochemical mechanism by which hyperglycemia and hyperlipidemia induce insulin resistance. We hypothesized that if an increased flux through the hexosamine pathway caused insulin resistance in humans, the hexosamine levels should be increased in adipose and/or muscle tissue in insulin-resistant subjects, such as patients with type 2 diabetes and obese individuals. In addition, we reasoned that if the hexosamine pathway were a nutrient-sensing pathway, hexosamine levels in adipose and skeletal muscle tissue should be correlated with levels of circulating nutrients, such as glucose and free fatty acids (FFAs) and leptin concentrations. In a human cross-sectional study of 55 patients [20 with type 2 diabetes mellitus (DM) and 21 normal-lean (NL) and 14 normal-obese (NO) subjects] who underwent hip replacement surgery, adipose and muscle tissue biopsies were obtained and analyzed for levels of hexosamines [UDP-N-acetylglucosamine (UDP-GlcNAc) and UDP-N-acetylgalactosamine] and hexoses (UDP-glucose and UDP-galactose). Fasting plasma glucose, glycosylated hemoglobin, serum insulin and homeostasis model assessment calculations, serum lipids, and leptin were measured on the same day. Hexosamines were not elevated in adipose and muscle tissue of patients with type 2 DM compared with NL and NO subjects (UDP-GlcNac DM vs. NL vs. NO, 3.3 +/- 2.3 vs. 2.2 +/- 2.1 vs. 3.0 +/- 2.0 nmol/g tissue in adipose tissue and 8.1 +/- 2.9 vs. 7.8 +/- 2.8 vs. 7.6 +/- 2.8 nmol/g tissue in muscle tissue, respectively). Hexosamines in adipose tissue were positively correlated with circulating levels of FFA (UDP-GlcNAc, r = 0.33, P < 0.05; UDP-N-acetylgalactosamine, r = 0.41, P < 0.01). Adipose tissue UDP-GlcNAc was correlated with leptin levels (r = 0.33; P < 0.05). No such relationship was identified in muscle tissue. In conclusion, these findings argue against a pathophysiological role of the hexosamine pathway in insulin resistance in humans but support the hypothesis that the hexosamine pathway in adipose tissue, not in muscle, is a FFA-sensing pathway and could be involved in the regulation of leptin expression.

Topics: Adipose Tissue; Aged; Blood Glucose; Diabetes Mellitus; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Hexosamines; Hexuronic Acids; Humans; Hyperglycemia; Insulin Resistance; Leptin; Male; Middle Aged; Muscle, Skeletal; Uridine Diphosphate Sugars

Thiazolidinediones (TZDs) increase peripheral tissue insulin sensitivity in patients with type 2 diabetes mellitus by activating the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma). In bone marrow stromal cell cultures and in vivo, activation of PPARgamma by high doses (20 mg/kg/day) of TZDs has been reported to alter stem cell differentiation by promoting commitment of progenitor cells to the adipocytic lineage while inhibiting osteoblastogenesis. Here, we have examined the in vivo effects of low-dose rosiglitazone (3 mg/kg/day) on bone, administered to mice by gavage for 90 days. Rosiglitazone-treated mice had increased weight when compared with controls, with no significant alterations in serum levels of glucose, calcium or parathyroid hormone (PTH). Bone mineral density (BMD) at the lumbar vertebrae (L1-L4), ilium/sacrum, and total body was diminished by rosiglitazone treatment. Histologically, bone was characterized by decreased trabecular bone volume and increased marrow space with no significant change in bone marrow adipocity. Decreased osteoblast number and activity due to increased apoptotic death of osteoblasts and osteocytes was apparent while osteoclast parameters and serum levels of osteocalcin, alkaline phosphatase activity, and leptin were unaltered by rosiglitazone treatment. Therefore, the imbalance in bone remodeling that follows rosiglitazone administration arises from increased apoptotic death of osteogenic cells and diminished bone formation leading to the observed decrease in trabecular bone volume and BMD. These novel in vivo effects of TZDs on bone are of clinical relevance as patients with type 2 diabetes mellitus and other insulin resistant states treated with these agents may potentially be at increased risk of osteoporosis.

Topics: Animals; Apoptosis; Biomarkers; Blood Glucose; Bone and Bones; Bone Density; Calcium; Cells, Cultured; Diabetes Mellitus; Histocytochemistry; Hypoglycemic Agents; Image Processing, Computer-Assisted; Leptin; Male; Mice; Mice, Inbred C57BL; Osteoblasts; Osteocalcin; Osteocytes; Parathyroid Hormone; Rosiglitazone; Thiazolidinediones

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

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

Chronic inflammation is prevalent in dialysis patients. We investigated the relationship between inflammation and newly identified adipokines: leptin and adiponectin in this population. A total of 129 chronic hemodialysis patients were collected. Serum high sensitivity C-reactive protein (CRP), interleukin-6 (IL-6), leptin and adiponectin levels were determined as well as other metabolic variables. Correlation studies and multiple regression analysis were performed among variables. Our results showed that hemodialysis patients had elevated levels of inflammatory markers, leptin and adiponectin. Diabetic subjects had higher serum CRP and lower albumin levels than non-diabetics. Serum CRP levels were positively correlated with IL-6 levels and negatively correlated with albumin levels. Serum leptin levels were directly related to CRP levels while adiponectin levels were inversely related to CRP levels. A significant negative correlation was observed between serum leptin and adiponectin levels. Serum IL-6 levels were the single independent factor affecting CRP levels. Body mass index can predict both serum leptin and adiponectin levels. We conclude that hemodialysis patients are at an increased risk of chronic inflammation and diabetes patients are even more susceptible to this status. Both serum leptin and adiponectin levels are associated with inflammatory markers. As adipose tissue is the major secreting site of these adipokines, our results suggest that adipose tissue plays an important role in the pathogenesis of chronic inflammation in dialysis patients.

Topics: Adiponectin; Age Factors; Biomarkers; Body Mass Index; C-Reactive Protein; Cross-Sectional Studies; Diabetes Mellitus; Female; Humans; Inflammation; Intercellular Signaling Peptides and Proteins; Interleukin-6; Leptin; Male; Middle Aged; Regression Analysis; Renal Dialysis; Renal Insufficiency; Serum Albumin; Sex Factors

Leptin has been shown to activate AMP-activated protein kinase (AMPK), an enzyme that regulates the activities of key enzymes of lipid synthesis and metabolism. We assess here (i) whether AMPK activity is diminished in rodents deficient in leptin or the leptin receptor, and (ii) the effects of treating the diabetes-prone, leptin-receptor-deficient Zucker Diabetic Fatty (ZDF) rat with an AMPK activator.. AMPK activity and related parameters were measured in muscle and or liver of fa/fa and ZDF rats and ob/ob mice. We also explored the effect of treatment with the AMPK activator 5-aminoimidazole 4-carboxamide 1-beta-D ribofuranoside (AICAR) (7.4 mmol/l, on Monday, Wednesday and Friday for 15 weeks, beginning at 7 weeks of age) on the phenotype of the ZDF rat.. AMPK activity was diminished in muscle and/or liver of fa/fa (leptin-receptor-deficient, non-diabetic) and ZDF (leptin-receptor-deficient, diabetes-prone) rats and ob/ob mice (leptin-deficient). ZDF rats that had free access to food became hyperglycaemic (22.2 mmol/l) and hyperphagic after 2 to 5 weeks and remained so during the remainder of the study. Treatment of ZDF rats with AICAR prevented the development of diabetes, as well as increases of triglyceride content in liver, muscle and the pancreatic islets. It also attenuated the morphological abnormalities observed in the islets of untreated rats. Rats diet-matched with the AICAR-treated animals developed diabetes of intermediate severity and showed decreases in triglyceride content in the islets, but not in liver or muscle.. The results indicate that a deficiency of leptin or the leptin receptor is associated with a decrease in AMPK activity in muscle and/or liver. They also suggest that treatment with an AMPK activator prevents the development of diabetes and ectopic lipid accumulation in the ZDF rat.

Topics: Adenylate Kinase; Aminoimidazole Carboxamide; Animals; Diabetes Mellitus; Diglycerides; Enzyme Activation; Homozygote; Leptin; Lipid Metabolism; Male; Malonyl Coenzyme A; Mice; Mice, Obese; Prediabetic State; Rats; Rats, Mutant Strains; Rats, Zucker; Ribonucleotides

Dietary supplementation of conjugated linoleic acids (CLA) is known to have some beneficial effects such as anti-carcinogenic and anti-obesity effects in several animal species, while it also induces insulin resistance and fatty liver, especially in mice. To explore the possible factors responsible for the CLA-induced insulin resistance, we examined the plasma and mRNA expression levels of several adipocytokines, which are likely involved in the regulation of insulin sensitivity, in normal C5 7BL, mildly obese/diabetic KK and morbidly obese/diabetic KKAy mice. Feeding a diet supplemented with 0.5%, CLA oil consisting of 30.5/% c9, t11-CLA and 28.9% t10, c12-CLA for 4 wk resulted in a decrease in white adipose tissue (WAT), an increase in liver weight with excess accumulation of triglyceride, and insulin resistance associated with hyperglycemia and hyperinsulinemia. The plasma and WAT mRNA levels of leptin were higher in KK and KKAy mice than C57BI. mice, whereas those of adiponectin were higher in C5 7BL mice. CLA-feeding decreased the levels of leptin, adiponectin and resistin, especially in KK and KKAy mice. In contrast, tumor necrosis factor-alpha (TNFalpha) mRNA levels were higher in KK and KKAy mice than C57BL mice, and were increased by CLA feeding. The present results thus indicate that CLA feeding promotes insulin resistance in obese/diabetic mice by at least inverse regulation of leptin and adiponectin, and TNFalpha, adipocytokines known to either ameliorate or deteriorate insulin sensitivity, respectively.

Topics: Adiponectin; Adipose Tissue; Animals; Diabetes Mellitus; Dietary Fats, Unsaturated; Female; Hormones, Ectopic; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Linoleic Acids, Conjugated; Mice; Mice, Inbred C57BL; Obesity; Resistin; RNA, Messenger; Tumor Necrosis Factor-alpha

Leptin, an important hormone for body weight regulation, may be involved in the pathogenesis of cardiovascular manifestations of obesity. We tested whether leptin may be an independent risk marker for stroke in a case-referent study.. Definitive acute stroke events, defined by MONICA criteria, were identified from October 1, 1995 to April 30, 1999. Referents without known cardiovascular disease were randomly selected from a population census. Patient characteristics were taken from hospital files and leptin was analyzed in stored samples. Logistic regression analysis was used to determine possible differences in leptin levels between groups.. One hundred and thirty-seven cases with ischemic stroke and 69 cases with hemorrhagic stroke were identified. In comparison with referents, male patients with stroke had significantly higher leptin levels. Both male and female stroke patients had increased blood pressure compared with the referents. In multivariate analyses, high leptin levels were associated with both ischemic (OR = 4.89; 95% CI: 1.89-12.62) and hemorrhagic (OR = 3.86; 95% CI: 1.13-13.16) stroke in men, and with ischemic stroke in women (OR = 4.10; 95% CI: 1.45-11.62). The combination of high leptin levels and increased blood pressure (systolic or diastolic) was associated with a strong positive interaction in males with hemorrhagic stroke.. Leptin may be an important link for the development of cerebrovascular disease in the insulin resistance syndrome in men.

Topics: Aged; Aged, 80 and over; Biomarkers; Blood Pressure; Brain Ischemia; Case-Control Studies; Cerebral Hemorrhage; Diabetes Mellitus; Diastole; Female; Humans; Hypertension; Length of Stay; Leptin; Male; Middle Aged; Multivariate Analysis; Obesity; Risk Factors; Statistics as Topic; Stroke; Sweden; Systole

Secretion of leptin from adipocytes communicates body energy status to the brain by activating the leptin receptor long form (LRb). LRb regulates energy homeostasis and neuroendocrine function; the absence of LRb in db/db mice results in obesity, impaired growth, infertility and diabetes. Tyr 1138 of LRb mediates activation of the transcription factor STAT3 during leptin action. To investigate the contribution of STAT3 signalling to leptin action in vivo, we replaced the gene encoding the leptin receptor (lepr) in mice with an allele coding for a replacement of Tyr 1138 in LRb with a serine residue (lepr(S1138)) that specifically disrupts the LRb-STAT3 signal. Here we show that, like db/db mice, lepr(S1138) homozygotes (s/s) are hyperphagic and obese. However, whereas db/db mice are infertile, short and diabetic, s/s mice are fertile, long and less hyperglycaemic. Furthermore, hypothalamic expression of neuropeptide Y (NPY) is elevated in db/db mice but not s/s mice, whereas the hypothalamic melanocortin system is suppressed in both db/db and s/s mice. LRb-STAT3 signalling thus mediates the effects of leptin on melanocortin production and body energy homeostasis, whereas distinct LRb signals regulate NPY and the control of fertility, growth and glucose homeostasis.

Topics: Alleles; alpha-MSH; Animals; Blood Glucose; Body Weight; Cell Line; Diabetes Mellitus; DNA-Binding Proteins; Energy Metabolism; Estrous Cycle; Female; Homeostasis; Humans; Infertility; Leptin; Male; Mice; Neuropeptide Y; Obesity; Phenotype; Receptors, Cell Surface; Receptors, Leptin; Reproduction; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Trans-Activators

Obesity in rodents and humans is mostly associated with elevated plasma leptin concentrations, suggesting a new pathological concept of 'leptin resistance'. We have demonstrated that brain-derived neurotrophic factor (BDNF) can improve obesity and diabetes of C57BL/KsJ db/db (db/db) mice. In this study, we investigated whether or not BDNF is effective in two different models of leptin resistance, an acquired model and a genetic model.. C57BL/6J mice rendered obese by consumption of a high-fat diet (diet-induced obesity (DIO) mice) were used as an acquired model and lethal yellow agouti mice (KKA(y) mice) as a genetic model of leptin resistance. Food intake and glucose metabolism were studied after acute or repetitive administration of BDNF.. Intraperitoneal administration of BDNF (10 mg/kg, twice/day) significantly reduced cumulative food intake of DIO and KKA(y) mice, whereas they were unresponsive to leptin administration. Repetitive subcutaneous administration of BDNF (10 mg/kg daily for 6 days) reduced food intake and improved impaired glucose tolerance in DIO mice. Pair feeding of vehicle-treated DIO mice with the same amount of chow consumed by the BDNF-treated group did not improve the impaired glucose homeostasis, indicating that the antidiabetic effect is not due to decreased food intake. We also observed that BDNF is effective in improving obesity and diabetes of KKA(y) mice.. This study demonstrated antiobesity and antidiabetic effects of BDNF in two different models of leptin resistance, thereby suggesting the therapeutic potential of BDNF in the treatment of leptin-resistant obesity and diabetes.

Topics: Animals; Blood Glucose; Brain-Derived Neurotrophic Factor; Diabetes Mellitus; Drug Evaluation, Preclinical; Drug Resistance; Eating; Glucose Tolerance Test; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity

Advanced glycation end products (AGEs) and other carbonyl and oxidative stress compounds are supposed to play a critical role in the pathogenesis of several diseases and their complications, i.e., diabetes mellitus, diabetic retinopathy, atherosclerosis, and chronic renal failure. In the present investigation, we were interested in the relationship of AGEs in plasma to other prominent factors in the patients on chronic hemodialysis treatment-27 patients with diabetes mellitus, 35 patients without diabetes mellitus. AGE-group reactivity was estimated using a spectrofluorometric method (excitation 350 nm, emission 430 nm) and is expressed in arbitrary units (AU). We found significantly higher AGEs levels in diabetics than in non-diabetics on regular hemodialysis treatment both before (2.7 +/- 0.7 x 10(4) AU vs. 2.2 +/- 0.6 x 10(4) AU, p < 0.001) and after the dialysis session (2.3 +/- 0.5 x 10(4) AU vs. 1.8 +/- 0.7 x 10(4) AU, p < 0.005). AGEs were significantly reduced during hemodialysis in both groups of patients--by 15.4% in the diabetic go (p < 0.001) and by 17.3% in non-diabetics (p < 0.005). In the patients with diabetes mellitus, AGEs did not correlate with parameters of the glucose metabolism correction (blood glucose, HbA1c). We observed a significant correlation between AGEs and leptin (r = 0.48, p < 0.05) as well as the leptin/body fat ratio (r = 0.56, p < 0.05) only in hemodialyzed patients with diabetes mellitus. These findings suggest more detailed studies to identify the molecular links between carbonyl stress, i.e., advanced glycation end products, and leptin metabolism, sign of microinflammation and hypertension.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Blood Glucose; Body Composition; Cross-Sectional Studies; Diabetes Complications; Diabetes Mellitus; Female; Glycated Hemoglobin; Glycation End Products, Advanced; Humans; Kidney Failure, Chronic; Leptin; Male; Middle Aged; Renal Dialysis; Skinfold Thickness; Time Factors

Mice double heterozygous (DH) for deletion of insulin receptor and insulin receptor substrate-1 are lean, insulin resistant, and have a phenotype that strongly depends on the genetic background of the mouse. On the C57BL/6 (B6) background, DH mice develop marked hyperinsulinemia and diabetes, whereas on the 129S6 background, DH mice exhibit only mild elevations of insulin and remain free of diabetes. F2 male mice created by an intercross between these two strains exhibit a 60% incidence of diabetes and a bell-shaped distribution of insulin levels as related to glucose, reminiscent of that in humans with type 2 diabetes. These mice also exhibit a wide range of leptin levels as related to body weight. A genome-wide scan of F2 mice reveals a quantitative trait locus (QTL) related to hyperinsulinemia on chromosome 14 (D14Mit55) with a peak logarithm of odds (LOD) score of 5.6, accounting for up to 69% of this trait. A QTL with a LOD score of 3.7 related to hyperleptinemia is present on chromosome 7 at D12Mit38 (a marker previously assigned to chromosome 12) in the area of the uncoupling protein 2/3 gene cluster. This locus also interacts synergistically with D14Mit55 in development of hyperinsulinemia and with a QTL on chromosome 12 (D12Mit231) related to hyperglycemia. These data demonstrate how multiple genetic modifiers can interact and influence the development of diabetes and the phenotype of animals with genetically programmed insulin resistance and provide evidence as to the location and nature of these genes.

Topics: Animals; Blood Glucose; Crosses, Genetic; Diabetes Mellitus; Female; Gene Deletion; Heterozygote; Hyperinsulinism; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphoproteins; Receptor, Insulin; Receptors, Leptin; Species Specificity

The purpose of this study was to determine the relationships between plasma adiponectin and leptin levels, total and central obesity, and glucose utilization across the adult age span.. We studied 148 women aged 18-81 years with a BMI range of 17.2-44.3 kg/m(2). Total percent body fat was determined by dual-energy X-ray absorptiometry and abdominal fat by computed tomography. Glucose tolerance in non-type 2 diabetic volunteers was determined with an oral glucose tolerance test. Glucose utilization (M) was measured during the last 60 min of hyperinsulinemic-euglycemic clamps (240 pmol x m(-2) x min(-1)). Plasma adiponectin levels were measured by radioimmunoassay. The women were separated into three age-groups: young, middle, and old (<40, 40-59, and >or=60 years, respectively), as well as by glucose tolerance status.. Adiponectin concentrations did not differ by age-groups. There were significant age effects for BMI, percent body fat, visceral fat, subcutaneous abdominal fat, VO(2max), and M. Adiponectin levels were lower in the prediabetic women (n = 18) than in the normal glucose-tolerant women (n = 108) and the women with type 2 diabetes (n = 22) (both P < 0.05). Univariate correlations revealed significant negative relationships between plasma adiponectin levels and BMI, percent body fat, visceral fat, subcutaneous abdominal fat, fasting leptin, and fasting insulin and positive relationship with M (all P < 0.05). In a multiple stepwise regression model to predict adiponectin, only M remained in the model at P < 0.001. Multivariate analyses revealed a significant relation for M as a function of adiponectin, insulin, and VO(2max).. The data suggest that plasma adiponectin does not change with age but levels are negatively associated with percent body fat, visceral fat, subcutaneous abdominal fat, insulin, and leptin levels in women. Adiponectin is positively associated with M across the age span in women.

Topics: Adiponectin; Adipose Tissue; Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Blood Glucose; Body Composition; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Middle Aged; Obesity; Proteins; Regression Analysis

Zucker (fa/fa) rats with defective leptin receptors are obese, hyperphagic, and hyperinsulinemic. For testing whether chronic activation of the central melanocortin pathway can bypass the defective leptin signaling and normalize altered energy homeostasis in these rats, recombinant adeno-associated virus encoding pro-opiomelanocortin (rAAV-POMC) or control vector was delivered bilaterally into the basal hypothalamus with coordinates targeting the arcuate nucleus. Thirty-eight days after POMC gene delivery, hypothalamic POMC expression increased fourfold and melanocortin signaling (indicated by phosphorylation of CREB) increased by 62% with respect to controls. There was a sustained reduction in food intake, a moderate but significant attenuation of weight gain, and a 24% decrease in visceral adiposity in rAAV-POMC rats. POMC gene delivery enhanced uncoupling protein 1 in brown adipose tissue (BAT) by more than fourfold. Fasting serum leptin, insulin, and cholesterol levels were also significantly reduced by rAAV-POMC treatment. This study demonstrates that targeted POMC gene delivery in the hypothalamus suppresses food intake and weight gain and reduces visceral adiposity and hyperinsulinemia in leptin-resistant obese Zucker rats. The mechanisms may involve the sustained hypophagia and the augmentation of thermogenesis in BAT.

Topics: Adipose Tissue, Brown; Agouti-Related Protein; Animals; Blood Glucose; Carrier Proteins; Cell Line; Cholesterol; Cyclic AMP Response Element-Binding Protein; Diabetes Mellitus; Eating; Fasting; Fatty Acids, Nonesterified; Feeding Behavior; Genetic Therapy; Humans; Hypothalamus; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Ion Channels; Kidney; Leptin; Membrane Proteins; Mitochondrial Proteins; Obesity; Phosphorylation; Pro-Opiomelanocortin; Proteins; Rats; Rats, Zucker; Receptors, Cell Surface; Receptors, Leptin; Signal Transduction; Uncoupling Protein 1; Viscera

Topics: Communicable Diseases; Diabetes Mellitus; Disease Susceptibility; Humans; Leptin

Topics: Adaptation, Physiological; Animals; Cardiovascular Diseases; Causality; Comorbidity; Diabetes Mellitus; Energy Intake; Humans; Hypertrophy, Left Ventricular; Leptin; Mice; Obesity; Risk

To investigate whether normal glucose-tolerant and type II diabetic overweight adults differ in response to weight regain with regard to substrate oxidation and metabolic parameters.. A total of 15 overweight-obese subjects: seven normal glucose tolerant (NGT) and eight with type II diabetes (DM) were restudied 5 y after significant weight loss. Prediet, after 28 days calorie restriction and at 5 y, subjects were characterised for weight, height, waist-to-hip ratio (WHR) and body composition by dual-energy X-ray absorptiometry. Fasting glucose, insulin, leptin and lipid levels were measured and subjects underwent euglycaemic-hyperinsulinaemic clamp (insulin 0.25 U/kg/h for 150 min). Indirect calorimetry was performed resting and in the final 30 min of the clamp. Dietary assessment was by 4-day diet-diary.. Both NGT and DM groups regained weight at 5 y and were not different to prediet. Total body fat (%) and WHR were higher at 5 y compared to prediet in both groups. Fasting glucose was increased in NGT subjects at 5 y, and fasting insulin was higher in both groups at 5 y compared to prediet. Insulin sensitivity (GIR) was similar at 5 y compared to prediet, but at 5 y DM subjects were more insulin resistant than NGT subjects. At 5 y, both DM and NGT groups had significantly reduced basal fat oxidation and no significant suppression of fat oxidation with insulin. Clamp respiratory quotient levels at 5 y were significantly higher in NGT compared to DM subjects.. Reduced basal fat oxidation, and reduced variation in substrate oxidation in response to insulin develop with fat regain and fasting hyperinsulinaemia in both NGT and DM obese adults.

Topics: Adipose Tissue; Blood Glucose; Body Composition; Body Constitution; Carbohydrate Metabolism; Diabetes Mellitus; Diabetes Mellitus, Type 2; Fasting; Fatty Acids, Nonesterified; Female; Humans; Insulin; Leptin; Lipids; Male; Middle Aged; Obesity; Oxidation-Reduction; Time Factors; Weight Gain; Weight Loss

In this study, we investigated the role of leptin for the inflammatory response in diabetes-impaired skin repair. We demonstrated, that systemic treatment of diabetic ob/ob mice with leptin blunted polymorphonuclear neutrophil (PMN), but not macrophage influx into the wound site. Closed wounds of leptin-administered mice were characterized by tremendous numbers of macrophage within the granulation tissue. In line, leptin supplementation potently attenuated epithelium-derived CXC- but not CC-chemokine expression. PMNs were preferentially located in the scab, but macrophages predominantly resided within the wound stroma of the animals. The scabs of nonhealing wounds were most likely to serve as sinks for bioactive inflammatory mediators, which were still capable to drive gene expression in keratinocytes in vitro. Differential effects of leptin on PMN and macrophage axes of inflammation must be indirect, as topical administration of leptin onto wounds of ob/ob mice did not reduce PMN influx into the wounded areas. Moreover, caloric-restricted, pair-fed ob/ob mice were characterized by impaired healing conditions that were associated with persisting PMNs. Interestingly, we documented the absence of leptin receptor expression in human diabetic foot ulcers. Thus, we show that leptin might function as a regulatory link between the endocrine and the immune system in the context of skin repair.

Topics: Administration, Topical; Animals; Blood Glucose; Chemokines; Diabetes Mellitus; Diabetes Mellitus, Type 2; Disease Models, Animal; Female; Gene Expression Regulation; Inflammation; Leptin; Macrophages; Mice; Mice, Inbred C57BL; Mice, Obese; Neutrophils; Obesity; Recombinant Proteins; RNA, Messenger; Transcription, Genetic; Wound Healing

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

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

Within the past years, an important role for nitric oxide (NO) in skin repair has been well defined. As NO is synthesized from L-arginine by NO synthases (NOS), the availability of L-arginine might be one rate-limiting factor of NO production at the wound site. Upon injury, arginase-1 and -2 mRNA, protein, and activity were strongly induced reaching a maximum between day 3 and day 7 postwounding. Immunohistochemistry colocalized both arginases and the inducible NOS (iNOS) at epithelial sites at the margins of the wound. Notably, diabetes-impaired skin repair in leptin-deficient mice (diabetes/diabetes, db/db; and obese/obese, ob/ob) was characterized by an abnormally elevated arginase activity in wound tissue in the absence of an expression of iNOS. Expression analyses demonstrated that arginase-1 contributed to increased arginase activities in impaired repair. Interestingly, an improved healing of chronic wound situations in leptin-supplemented ob/ob mice was strongly associated with an adjustment of the dysregulated expression of L-arginine-converting enzymes: an attenuated iNOS expression was upregulated early in repair and an augmented arginase-1 expression and activity was downregulated in the presence of markedly elevated numbers of macrophages during late repair. These data suggest a coordinated consumption of L-arginine by the NOS and arginase enzymatic pathways at the wound site as a prerequisite for a balanced NO (via iNOS) and polyamine (via arginases) synthesis that drives a normal skin repair.

Topics: Animals; Arginase; Arginine; Chronic Disease; Diabetes Complications; Diabetes Mellitus; Female; Gene Expression Regulation, Enzymologic; Isoenzymes; Leptin; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Mutant Strains; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Skin; Wound Healing

It has been reported that neuropeptides may play a role in the control of appetite and in the mechanism of hormone release. Neuropeptides such as beta-endorphin, neuropeptide Y (NPY), galanin and leptin may affect hormones release, on the other hand the hormonal status may modulate neuropeptide activity.. The material consisted of 90 obese women, 30 women with Anorexia Nervosa, and 30 healthy, lean women of control group. Plasma beta-endorphin, NPY, leptin, somatostatin and serum pituitary and gonadal hormones concentrations were measured with RIA methods.. We observed the highest plasma NPY levels in obese hypertensive and diabetic patients. After carbohydrate administration (OGTT) a marked increase of insulin, beta-endorphin and NPY was found. The blunted response of GH to GH-RH may be connected with increased somatostatin activity and hyperinsulinemia. The abnormal response of LH to opioid blockade may be a result of disturbed opioid and NPY activities in obese patients. However in patients with anorexia nervosa, plasma leptin and NPY concentrations were low. The disturbances in beta-endorphin release are also observed.. The neuroendocrine disturbances in obesity and in anorexia nervosa are opposite. The feedback mechanism between leptin and NPY is disturbed in both in obesity and in anorexia nervosa. An abnormal activity of neuropeptides may lead to disturbed control of appetite and hormonal dysregulation in eating disorders.

Topics: Adult; Anorexia Nervosa; Appetite; beta-Endorphin; Diabetes Mellitus; Feedback, Physiological; Female; Glucose Tolerance Test; Human Growth Hormone; Humans; Hypertension; Leptin; Luteinizing Hormone; Neuropeptide Y; Neuropeptides; Obesity; Somatostatin

Leptin increases the proliferation of various cell types in vitro, and we reported that background strain influences the metabolic responses to leptin in db/db mice, which express short-form, but not long-form, leptin receptors. Here, we examined the effects of leptin on growth of young C57BL/Ks, C57BL/6J, and C57BL/3J db/db mice. Intraperitoneal infusions of 20 micro g leptin/d for 26 d increased the food intake of C57BL/6J mice by 15% (P < 0.01), but had no effect in C57BL/Ks db/db mice. Leptin-infused C57BL/6J db/db mice gained more weight ( approximately 20%; P < 0.04) than PBS-infused controls. The increased weight was sustained after leptin infusion ended. Leptin had no effect on weight gain or food intake of C57BL/3J db/db mice, which only express the soluble leptin receptor. A single leptin injection increased MAPK phosphorylation in liver by 40% (P < 0.001) and that in muscle tissues by 20% (P < 0.001) in C57BL/6J mice, but did not change phosphorylation in C57BL/3J db/db mice. These results suggest that leptin increases the weight gain of C57BL/6J db/db mice by activating the MAPK pathway through a mechanism that is dependent on short-form leptin receptors. This response may be masked by activation of the long-form receptor in wild-type animals that lose body fat during leptin treatment.

Topics: Animals; Animals, Newborn; Diabetes Mellitus; Dose-Response Relationship, Drug; Infusions, Parenteral; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mitogen-Activated Protein Kinases; Obesity; Species Specificity

The subject was a 26-year-old Japanese woman of 148 cm height, 96.2 kg of body weight (BW) (body mass index (BMI) of 43.8 kg/m(2)). She was referred to our hospital on May 1, 2000 for the evaluation of marked hyperglycemia with clinical symptom of general malaise, polydipsia, and ketonuria (3+). She did not smoke, or drink alcohol. But, she tended to eat lots of sweet food every day before the onset of this symptom. Her father was diagnosed type 2 diabetes mellitus. Her fasting plasma glucose and HbA(1c), and serum C-peptide were 398 mg/dl, 7.8% and less than 0.05 ng/ml [normal range: 0.94-2.8], respectively. She tested negative for anti-glutamic acid decarboxylase (GAD) antibodies and islet-cell antibodies. C-peptide level in her urine was as low as 3.4 microg/day. We immediately started insulin treatment under the diagnosis of abrupt onset of diabetes mellitus with diabetic ketoacidosis on the day of her admission, and the insulin treatment was continued after her being discharged. She showed continuous BW reduction until her BW reached approximately 60 kg, followed by her BW being plateau. During the period, intra-abdominal visceral fat (VF) and subcutaneous fat (SF) volume assessed by helical computerized tomography (CT) showed a substantial reduction [3.9-0.5 l for VF, 19-3.2 l for SF volume]. Pre-heparin plasma lipoprotein lipase (LPL) mass showed a considerably lower value when she had continuous BW reduction than did it when her BW reduction discontinued. These findings suggest that in this subject, continuous BW reduction after the abrupt onset of diabetes is closely associated with intra-abdominal fat mass reduction, which may be related to decreased production of LPL.

Topics: Adipose Tissue; Adult; Body Mass Index; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Female; Glycated Hemoglobin; Humans; Insulin; Japan; Leptin; Lipids; Obesity; Regression Analysis; Tomography, X-Ray Computed

Elevated serum leptin (S-leptin) levels have been reported in patients with end-stage renal disease (ESRD). Apart from the decreased glomerular filtration rate (GFR), body composition and inflammation may affect leptin levels in ESRD. Leptin circulates both free of and bound to soluble leptin receptors (sOB-R), which are the main determinants of leptin activity and have not been described in ESRD until now.. To analyze the association between S-leptin, sOB-R, and inflammation and body composition, we studied 149 (62% males) normal weight (BMI 24.7 +/- 0.4 kg m(-2)) ESRD patients (51 +/- 1 years old) shortly before the start of dialysis (GFR 7.0 +/- 0.2 mL min(-1)). sOB-R and plasma interleukin-6 (IL-6; n= 113) levels were evaluated using ELISA, S-leptin using RIA, and body composition was assessed by X-ray absorptiometry (n = 139). Forty-one healthy subjects age (51 +/- 1 years), BMI (23.6 +/- 0.5 kg m(-2)) and gender-matched (59% males) were used as controls.. Median S-leptin was higher in the ESRD patients (10.0 ng mL(-1)) compared with the controls (3.9 ng mL(-1)) (P < 0.001). The median sOB-R did not differ significantly between the ESRD patients (44 U mL-1) and the controls (37 U mL-1). Thus, the sOB-R/S-leptin ratio was lower in the ESRD patients (9.5 +/- 1.2 vs. 12.3 +/- 1.8; P < 0.01) than the controls. A negative correlation was observed between S-leptin and sOB-R (Rho = -0.42; P < 0.0001) in the ESRD patients, a positive correlation was observed between lean body mass and the sOB-R/S-leptin ratio (Rho = 0.33, P = 0.0001) whereas fat mass was negatively correlated to both sOB-R (Rho = -0.26, P = 0.002), and the sOB-R/S-leptin ratio (Rho = -0.62, P < 0.0001). Positive correlations were observed between IL-6 and S-leptin (Rho = 0.19; P < 0.05) and weak but significant body fat mass (Rho = 0.20; P < 0.05), respectively.. This study demonstrates that despite markedly elevated S-leptin levels in the ESRD patients, sOB-R did not differ from the controls. In view of the anorexigenic and pro-atherogenic effects of leptin, further elucidation of the consequences of free bioactive leptin in the development of complications such as malnutrition and cardiovascular disease in ESRD patients is required.

Topics: Body Composition; Case-Control Studies; Diabetes Mellitus; Female; Humans; Interleukin-6; Kidney Failure, Chronic; Leptin; Male; Middle Aged; Prospective Studies; Receptors, Cell Surface; Receptors, Leptin; Statistics, Nonparametric

Leptin is involved in the regulation of body weight and metabolism. Previous data have suggested that leptin levels are related to insulin resistance and in a few reports with impaired insulin secretion. Some even revealed the existence of adipoinsular axis. However, little is known of these relations in Chinese population. With the availability of measurements of true insulin (TI), proinsulin (PI) and leptin, we examined the possible correlation of leptin with TI, PI and with insulin resistance (the HOMA model) in non-diabetic subjects of north China. We also evaluated whether leptin levels were associated with impaired insulin secretion, as evaluated by the fasting PI/TI ratio.. 902 non-diabetic subjects (670 with normal and 232 impaired glucose tolerance, aged 30 - 80 y) from a population of Beijing residents who underwent a diabetes survey in 2000 were studied. Fasting serum leptin, PI and TI levels were detected by sensitive and specific enzyme-linked immunosorbent assays (ELISA) which were all developed in our laboratory.. Serum leptin values were higher in women. Correlation analysis showed that leptin levels were significantly correlated with fasting TI, PI and insulin resistance (HOMA-IR) (in men, n = 794, r = 0.345, 0.236 and 0.364 respectively; in women, n = 110, r = 0.574, 0.375 and 0.576 respectively, P < 0.001), but not with PI/TI ratio (r = -0.09, P < 0.01) in both sex. After adjustment for age, body mass index (BMI) and waist-to-hip ratio (WHR), leptin levels remained significantly correlated with TI, PI and HOMA-IR, although the magnitude of the association was considerably attenuated.. TI and PI levels were positively related to leptin levels independent of obesity and body fat distribution. Thus, subjects with increased insulin levels and/or insulin resistance may be relatively resistant to the effects of leptin, suggesting a dysfunction of leptin-insulin axis. However, leptin levels are not significantly associated with the fasting PI/TI ratio suggesting that leptin levels are not associated with an impairment in insulin secretion. The role of association between hyperinsulinemia/insulin resistance and hyperleptinemia/leptin resistance in the pathogenesis of insulin resistance-related diseases needs further study.

Topics: Adult; Aged; Aged, 80 and over; Diabetes Mellitus; Female; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Proinsulin

The relationship among body fat distribution, blood pressure, serum leptin levels, and insulin resistance was investigated in hypertensive obese women with central distribution of fat.. We studied 74 hypertensive women (age, 49.8 +/- 7.5 years; body mass index, 39.1 +/- 5.5 kg/m(2); waist-to-hip ratio, 0.96 +/- 0.08). All patients were submitted to 24-hour blood pressure ambulatory monitoring (24h-ABPM). Abdominal ultrasonography was used to estimate the amount of visceral fat (VF). Fasting blood samples were obtained for serum leptin and insulin determinations. Insulin resistance was estimated by homeostasis model assessment insulin resistance index (HOMA-r index).. Sixty-four percent of the women were postmenopausal, and all patients showed central distribution of fat (waist-to-hip ratio > 0.85). The VF correlated with systolic 24h-ABPM values (r = 0.28, p = 0.01) and with HOMA-r index (r = 0.27; p = 0.01). VF measurement (7.5 +/- 2.3 vs. 5.9 +/- 2.2 cm, p < 0.001) and the systolic 24h-ABPM (133 +/- 14.5 vs. 126 +/- 9.8 mm Hg, p = 0.04), but not HOMA-r index, were significantly higher in the postmenopausal group (n = 48) than in the premenopausal group (n = 26). No correlations were observed between blood pressure levels and HOMA-r index, leptin, or insulin levels. In the multiple regression analysis, visceral fat, but not age, body fat mass, or HOMA-r index, correlated with the 24h-ABPM (p = 0.003).. In centrally obese hypertensive women, the accumulation of VF, more often after menopause, is associated with higher levels of blood pressure and insulin resistance. The mechanism through which VF contributes to higher blood pressure levels seems to be independent of leptin or insulin levels.

Topics: Adipose Tissue; Adult; Blood Pressure; Body Composition; Body Constitution; Body Mass Index; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus; Fasting; Female; Glucose Tolerance Test; Homeostasis; Humans; Hypertension; Hypertriglyceridemia; Insulin; Insulin Resistance; Leptin; Middle Aged; Obesity; Postmenopause; Regression Analysis; Viscera

Obesity-driven type 2 diabetes (diabesity) involves complex genetic and environmental interactions to trigger disease. Here, we combine variable numbers of known quantitative trait loci (QTL) for obesity and diabetes contributed by New Zealand Obese (NZO/HlLt) and Nonobese Nondiabetic (NON/Lt) strains in the form of 10 interval-directed recombinant congenic strains (RCS), with NON/Lt as the background strain, to dissect the genetic interactions involved. All 10 RCS gain significantly more weight than the NON parental strain, but none are as obese as the parental, diabetes-prone NZO. Diabetes development in these RCS at F12 ranges between 0 and 100%, depending on genetic constitution. RCS-2, -1, and -10 represent a step-wise increase in numbers of specific diabetogenic QTL, resulting in a step-wise increase in diabetes incidence. RCS-10 recreates the 100% incidence seen in (NZOxNON)F1 males, but with less weight gain. Similarly, RCS-6, -7, -8, and -9 represent diabetes-prone strains with different combinations of diabetogenic QTL. RCS-3, -4, and -5 represent obese strains that do not transit to diabetes. Because these obesity and diabetes syndromes reflect different collections of QTL, rather than null mutations in the leptin or leptin receptor genes, they are extremely relevant as models for the polygenic obesity/diabesity syndromes in humans.

Topics: Animals; Carrier Proteins; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Genetic Predisposition to Disease; Humans; Islets of Langerhans; Leptin; Liver; Male; Mice; Mice, Obese; Mutation; Obesity; Phenotype; Quantitative Trait, Heritable; Receptors, Cell Surface; Receptors, Leptin; Weight Gain

C57BL/6J mice were fed a high-fat, carbohydrate-free diet (HFD) for 9 mo. Approximately 50% of the mice became obese and diabetic (ObD), approximately 10% lean and diabetic (LD), approximately 10% lean and nondiabetic (LnD), and approximately 30% displayed intermediate phenotype. All of the HFD mice were insulin resistant. In the fasted state, whole body glucose clearance was reduced in ObD mice, unchanged in the LD mice, and increased in the LnD mice compared with the normal-chow mice. Because fasted ObD mice were hyperinsulinemic and the lean mice slightly insulinopenic, there was no correlation between insulin levels and increased glucose utilization. In vivo, tissue glucose uptake assessed by 2-[(14)C]deoxyglucose accumulation was reduced in most muscles in the ObD mice but increased in the LnD mice compared with the values of the control mice. In the LD mice, the glucose uptake rates were reduced in extensor digitorum longus (EDL) and total hindlimb but increased in soleus, diaphragm, and heart. When assessed in vitro, glucose utilization rates in the absence and presence of insulin were similar in diaphragm, soleus, and EDL muscles isolated from all groups of mice. Thus, in genetically homogenous mice, HFD feeding lead to different metabolic adaptations. Whereas all of the mice became insulin resistant, this was associated, in obese mice, with decreased glucose clearance and hyperinsulinemia and, in lean mice, with increased glucose clearance in the presence of mild insulinopenia. Therefore, increased glucose clearance in lean mice could not be explained by increased insulin level, indicating that other in vivo mechanisms are triggered to control muscle glucose utilization. These adaptive mechanisms could participate in the protection against development of obesity.

Topics: Adaptation, Physiological; Adipose Tissue, Brown; Animals; Blood Glucose; Diabetes Mellitus; Dietary Fats; Fatty Acids, Nonesterified; Glucagon; Glucose; Glucose Tolerance Test; Glucose Transporter Type 4; Insulin; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Monosaccharide Transport Proteins; Muscle Proteins; Muscle, Skeletal; Myocardium; Obesity; RNA, Messenger; Weight Gain

Otsuka Long Evans Tokushima Fatty (OLETF) rats were developed as a model of non-insulin-dependent diabetes mellitus (NIDDM) with mild obesity. We reported that the daily profiles of energy expenditure associated with two peaks (one between 05:00 and 08:00 and the other between 20:00 and 22:00) were observed at 8 weeks of age (without NIDDM), while these two peaks disappeared at 24 weeks of age with NIDDM. As a new anti-diabetic drug, a peroxisome proliferator-activated receptor y agonist pioglitazone hydrochloride has been developed, we examined whether pioglitazone normalized daily profiles of energy expenditure at 24 weeks of age. A control diet and pioglitazone (0.1%)-containing diet were fed from 6 weeks of age. The two peaks of daily profiles of energy expenditure, which disappeared in OLETF rats with the control diet at 24 weeks of age, were reproduced by administration of pioglitazone. The respiratory quotient was lower and fat derived energy used for combustion was increased by pioglitazone at both ages. The body weight, daily food intake, plasma levels of fat, insulin, leptin and the wet weight of visceral fat were not influenced, but the levels of blood hemoglobin Alc and plasma tumor necrosis factor a were decreased by pioglitazone. Administration of pioglitazone improved daily profiles of energy expenditure via affecting glucose and fat metabolisms.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus; Diet; Energy Metabolism; Hypoglycemic Agents; Leptin; Lipids; Obesity; Organ Size; Pancreas; Pioglitazone; Rats; Rats, Inbred OLETF; Receptors, Cytoplasmic and Nuclear; Thiazoles; Thiazolidinediones; Transcription Factors; Tumor Necrosis Factor-alpha

Negative energy balance inhibits reproduction by restraining GnRH secretion. Leptin is a permissive metabolic signal for reproduction, but GnRH neurons do not appear to express leptin receptors, suggesting that interneurons transmit leptin signals to these cells. Serotonin (5HT) has satiety effects similar to those of leptin and alters LH release, and serotonergic neurons, which have been shown to express leptin receptors, terminate on GnRH neurons. We hypothesized that serotonergic neurons convey leptin signals to the reproductive neuroendocrine axis. To test this, mice were fasted for 48 h beginning on Diestrous Day 1. While fasting, mice received saline or leptin every 12 h or the 5HT-selective reuptake-inhibitor fluoxetine once at the start of the fast. Estrous cycles of fasted mice were longer (mean +/- SEM, 10.2 +/- 0.5 days; P < 0.0001) than those of fed mice (4.5 +/- 0.2 days). As previously reported, leptin prevented fasting-induced cycle lengthening (4.6 +/- 0.7 days). Fluoxetine also rescued estrous cycles in fasted mice (4.7 +/- 0.6 days), suggesting that 5HT and leptin have similar positive effects on reproduction. Coadministration of the 5HT 1/2/7 receptor-antagonist metergoline blocked rescue of cycle length by fluoxetine and by leptin. Treating leptin-deficient ob/ob and leptin receptor-deficient db/db mice with fluoxetine did not normalize body weight or rescue fertility, perhaps due to altered serotonergic tone in these animals. Together, these data demonstrate a permissive role for serotonergic systems in the metabolic control of reproduction and are consistent with the hypothesis that serotonergic neurons convey leptin signals to GnRH neurons.

Topics: Animals; Body Weight; Diabetes Mellitus; Eating; Estrous Cycle; Fasting; Female; Fertility; Fluoxetine; Gonadotropin-Releasing Hormone; Leptin; Metergoline; Mice; Mice, Inbred C57BL; Mice, Obese; Neurons; Obesity; Reproduction; Selective Serotonin Reuptake Inhibitors; Serotonin; Serotonin Antagonists; Signal Transduction; Time Factors

Tumor necrosis factor (TNFalpha) has been invoked as an adipostat. Accordingly, the adipose tissue expression of TNFalpha has been shown to be proportional to the degree of adiposity. The regulatory role of TNFalpha in obesity may be controlled by several mechanisms. These include the inhibitory effect on LPL activity, the mediation on glucose homeostasis or the effect on leptin. To assess the role of TNFalpha in obesity we measured adipocyte TNFalpha expression in 96 females with a wide range of adiposity and with or without type 2 diabetes. We analysed the relationship between TNFalpha expression, adipocyte LPL activity, insulin resistance and leptin in this population.. The TNFalpha and leptin expression of the adipose tissue in obese and morbid obese patients were significantly higher than in controls. Obese and morbid obese patients had slightly higher levels of LPL activity, but these differences were not significant. We observed a significant relationship between adipose TNFalpha expression and body mass index (r=0.35, P<0.001). TNFalpha expression was negatively related to LPL activity (r=-0.28, P<0.05) and positively related to leptin expression (r=0.35, P<0.001).. Our results indicate that obese women, even those with morbid obesity, over-express TNFalpha in subcutaneous adipose tissue in proportion to the magnitude of the fat depot and independently of the presence of type 2 diabetes. The TNFalpha system may be a homeostatic mechanism that prevents further fat deposition by regulating LPL activity and leptin production.

Topics: Adipocytes; Adipose Tissue; Adolescent; Adult; Aged; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cholesterol, VLDL; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Gene Expression; Humans; Insulin; Insulin Resistance; Leptin; Lipoprotein Lipase; Middle Aged; Obesity; Obesity, Morbid; RNA, Messenger; Triglycerides; Tumor Necrosis Factor-alpha

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

The mechanism by which the specific beta3-adrenoceptor agonist AJ-9677 relieves insulin resistance in vivo was investigated by studying its effects in the white and brown adipose tissues of the KK-Ay/Ta diabetic obese mouse model. AJ-9677 reduced the total weight of white adipose tissues by reducing the size of the adipocytes, an effect associated with the normalization of tumor necrosis factor-alpha (TNF-alpha) and leptin expression levels. The levels of uncoupling protein (UCP)-1 mRNA in brown adipose tissue were increased threefold. AJ-9677 caused a marked increase (20- to 80-fold) in the expression of UCP-1 in white adipose tissues. The levels of UCP-2 mRNA were increased in both the white and brown adipose tissues of diabetic obese mice, and AJ-9677 further upregulated UCP-2 mRNA levels in brown adipose tissue, but reduced its levels in white adipose tissue. UCP-3 mRNA levels were not essentially changed by AJ-9677. However, AJ-9677 significantly (two- to four-fold) upregulated the GLUT4 mRNA and protein levels in white and brown adipose tissues and the gastrocnemius. The generation of small adipocytes, presumably mediated by increased expression of UCP-1 in addition to increased lipolysis in response to AJ-9677, was associated with decreased TNF-alpha and free fatty acid production and may be the mechanism of amelioration of insulin resistance in KK-Ay/Ta diabetic obese mice.

Topics: Acetates; Adipose Tissue; Adrenergic beta-Agonists; Animals; Blood Glucose; Carrier Proteins; Diabetes Mellitus; Fatty Acids, Nonesterified; Glucose Transporter Type 4; Indoles; Insulin; Insulin Resistance; Ion Channels; Leptin; Membrane Proteins; Membrane Transport Proteins; Mice; Mitochondrial Proteins; Monosaccharide Transport Proteins; Muscle Proteins; Obesity; Proteins; RNA, Messenger; Triglycerides; Tumor Necrosis Factor-alpha; Uncoupling Protein 1; Uncoupling Protein 2; Uncoupling Protein 3

The Pro(12)Ala (P12A) variant of exon B of the peroxisome proliferator-activated receptor gamma(2) (PPAR gamma) been variably associated with obesity, insulin sensitivity, diabetes, and dyslipidemia, but its role in insulin resistance-associated traits remains uncertain. We tested the hypothesis that this variant is associated with the insulin resistance syndrome by genotyping 619 members of 52 familial type 2 diabetes kindreds. A subset of 124 family members underwent iv glucose tolerance tests and minimal model determination of insulin sensitivity. We estimated the frequency of the A12 allele as 0.12, within the range observed in random Caucasian samples. We were unable to demonstrate any effect on direct measures of insulin sensitivity, and no trait was linked to markers near PPAR gamma on chromosome 3q. However, body mass index, serum total cholesterol levels, triglyceride levels, systolic and diastolic blood pressures, and glucose concentration showed at least a trend to association (P < 0.1) when tested separately for a family-based association. When these 6 traits were included in a multivariate analysis, body mass index, systolic and diastolic blood pressures, triglyceride levels, and glucose concentration remained significantly associated with the P12A variant (P < 0.05), whereas the effect of P12A on liability for diabetes was not significant. The predicted means for each trait and each genotype suggested that the P12A variant acted most like a recessive mutation, with the major effect among homozygous individuals who comprise only 1--2% of the population. We confirm an association of the P12A variant in traits commonly ascribed to the insulin resistance syndrome, but not with direct measures of insulin sensitivity. The tendency for this variant to act in a recessive manner with effects on multiple traits may explain the inconsistent associations noted in previous studies.

Topics: Alanine; Amino Acid Substitution; Blood Glucose; Blood Pressure; Body Mass Index; Chromosomes, Human, Pair 3; Diabetes Mellitus; Diabetes Mellitus, Type 2; Family; Gene Frequency; Genetic Variation; Glucose Tolerance Test; Humans; Leptin; Microbodies; Middle Aged; Nuclear Family; Obesity; Proline; Receptors, Cytoplasmic and Nuclear; Transcription Factors; White People

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

Topics: Adipocytes; Animals; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hormones, Ectopic; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Obesity; Receptors, Cytoplasmic and Nuclear; Resistin; Transcription Factors; Tumor Necrosis Factor-alpha

Serum leptin levels correlate with fat cell mass and are elevated in patients with massive obesity and type 2 diabetes mellitus, which are strong risk factors for the development of glomerulosclerosis. We have previously shown in cultured glomerular endothelial cells that leptin stimulates cellular proliferation and expression of the prosclerotic cytokine transforming growth factor-beta1 (TGF-beta1). Although the effect of leptin on the hypothalamus to regulate energy homeostasis is well known, the effect of leptin on the kidney, and specifically on the glomerular mesangial cell, is unclear.. The obese, diabetic db/db mouse, which lacks the functional full-length Ob-Rb leptin receptor, is a suitable model to assess the effects of hyperleptinemia on peripheral tissues that express other receptor isoforms. The effects of leptin on glucose uptake, the TGF-beta system, and type I collagen production were evaluated in db/db mouse mesangial cells in culture. A phosphatidylinositol-3 kinase (PI-3K) inhibitor was used to assess the role of PI-3K in mediating the effects of leptin.. A short form of the leptin receptor (Ob-Ra), but not Ob-Rb, was present by reverse transcription-polymerase chain reaction in the kidney and mesangial cells of both nondiabetic db/m and diabetic db/db mice. In db/db mesangial cells, leptin increased 2-deoxy-D-glucose (2DOG) uptake dose dependently and stimulated gene expression of TGF-beta type II receptor (TbetaRII) and alpha1(I) collagen, but not TGF-beta1. Protein production of type I collagen (enzyme-linked immunosorbent assay) was also increased by leptin. Both leptin-stimulated 2DOG uptake and type I collagen production were suppressed by a PI-3K inhibitor, LY294002. Mesangial cells pretreated with leptin exhibited increased responsiveness to exogenous TGF-beta1, as evidenced by a greater production of type I collagen protein in leptin-pretreated cells exposed to low-dose TGF-beta1 (0.5 ng/mL). The addition of both TGF-beta1 (2 ng/mL) and leptin (100 ng/mL) increased type I collagen production more than addition of either TGF-beta1 or leptin alone.. Leptin increases glucose uptake and type I collagen in db/db mesangial cells through a PI-3K-dependent pathway. We postulate that increased leptin levels may transmit a signal through the short-form leptin receptor to up-regulate TbetaRII and activate the intraglomerular TGF-beta system, which may contribute to the glomerulosclerosis of obesity or type 2 diabetes.

Topics: Animals; Cells, Cultured; Collagen; Diabetes Mellitus; Glomerular Mesangium; Glucose; Leptin; Mice; Protein Isoforms; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type II; Receptors, Leptin; Receptors, Transforming Growth Factor beta; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta1

Insulin resistance and hyperinsulinemia are strong correlates of obesity and type 2 diabetes, but little is known about their genetic determinants. Using data on nondiabetics from Mexican American families and a multipoint linkage approach, we scanned the genome and identified a major locus near marker D6S403 for fasting "true" insulin levels (LOD score 4.1, empirical P<.0001), which do not crossreact with insulin precursors. Insulin resistance, as assessed by the homeostasis model using fasting glucose and specific insulin (FSI) values, was also strongly linked (LOD score 3.5, empirical P<.0001) with this region. Two other regions across the genome were found to be suggestively linked to FSI: a location on chromosome 2q, near marker D2S141, and another location on chromosome 6q, near marker D6S264. Since several insulin-resistance syndrome (IRS)-related phenotypes were mapped independently to the regions on chromosome 6q, we conducted bivariate multipoint linkage analyses to map the correlated IRS phenotypes. These analyses implicated the same chromosomal region near marker D6S403 (6q22-q23) as harboring a major gene with strong pleiotropic effects on obesity and on lipid measures, including leptin concentrations (e.g., LOD(eq) for traits-specific insulin and leptin was 4.7). A positional candidate gene for insulin resistance in this chromosomal region is the plasma cell-membrane glycoprotein PC-1 (6q22-q23). The genetic location on chromosome 6q, near marker D6S264 (6q25.2-q26), was also identified by the bivariate analysis as exerting significant pleiotropic influences on IRS-related phenotypes (e.g., LOD(eq) for traits-specific insulin and leptin was 4.1). This chromosomal region harbors positional candidate genes, such as the insulin-like growth factor 2 receptor (IGF2R, 6q26) and acetyl-CoA acetyltransferase 2 (ACAT2, 6q25.3-q26). In sum, we found substantial evidence for susceptibility loci on chromosome 6q that influence insulin concentrations and other IRS-related phenotypes in Mexican Americans.

Topics: Adult; Blood Glucose; Body Mass Index; Chromosome Mapping; Chromosomes, Human, Pair 6; Diabetes Mellitus; Fasting; Female; Genetic Markers; Genetic Predisposition to Disease; Hispanic or Latino; Humans; Insulin; Insulin Resistance; Leptin; Lod Score; Male; Mexico; Obesity; Phenotype; Skinfold Thickness; Texas; Triglycerides

Adiponectin is an adipose-specific plasma protein whose plasma concentrations are decreased in obese subjects and type 2 diabetic patients. This protein possesses putative antiatherogenic and anti-inflammatory properties. In the current study, we have analyzed the relationship between adiponectin and insulin resistance in rhesus monkeys (Macaca mulatta), which spontaneously develop obesity and which subsequently frequently progress to overt type 2 diabetes. The plasma levels of adiponectin were decreased in obese and diabetic monkeys as in humans. Prospective longitudinal studies revealed that the plasma levels of adiponectin declined at an early phase of obesity and remained decreased after the development of type 2 diabetes. Hyperinsulinemic-euglycemic clamp studies revealed that the obese monkeys with lower plasma adiponectin showed significantly lower insulin-stimulated peripheral glucose uptake (M rate). The plasma levels of adiponectin were significantly correlated to M rate (r = 0.66, P < 0.001). Longitudinally, the plasma adiponectin decreased in parallel to the progression of insulin resistance. No clear association was found between the plasma levels of adiponectin and its mRNA levels in adipose tissue. These results suggest that reduction in circulating adiponectin may be related to the development of insulin resistance.

Topics: Adiponectin; Adipose Tissue; Amino Acid Sequence; Animals; Blood Glucose; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Type 2; Disease Progression; Glucose Clamp Technique; Humans; Hyperinsulinism; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Macaca mulatta; Male; Molecular Sequence Data; Obesity; Organ Size; Primate Diseases; Proteins; Sequence Alignment; Sequence Homology, Amino Acid

Topics: Animals; CCAAT-Enhancer-Binding Proteins; Chromans; Diabetes Mellitus; DNA-Binding Proteins; Fatty Liver; Hepatitis; Hypoglycemic Agents; Islets of Langerhans; Leptin; Liver; Obesity; Rats; Rats, Sprague-Dawley; Rats, Zucker; RNA, Messenger; Sterol Regulatory Element Binding Protein 1; Thiazoles; Thiazolidinediones; Transcription Factors; Troglitazone

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 diabetic patients impaired wound healing conditions are a therapeutic problem of clinical importance. Recently, we showed that supplemented leptin induced an acceleration of impaired wound closure in diabetic ob/ob mice by reversion of the delayed re-epithelialization process. Additionally, angiogenesis is central to a normal repair. As leptin has been reported to represent an angiogenic factor, we hypothesized that leptin-mediated angiogenic processes at the wound site might participate in leptin-mediated improvement of disturbed repair in ob/ob mice.. Using a model of excisional wounding, C57BL/6J-ob/ob mice were treated systemically and topically with recombinant murine leptin during the phase of repair. Changes in blood glucose concentrations and body weight were monitored. We measured expression of the vascular endothelial growth factor (VEGF) and the endothelial cell marker protein CD31 as a read-out for angiogenic processes at the wound site.. Expression of VEGF protein upon injury was reduced (30 to 40%) in ob/ob mice compared with wild-type C57BL/6 animals. Systemic and topical administration of leptin reconstituted normal wound VEGF expressions but failed to reverse the strongly reduced angiogenic response in ob/ob mice. Immunohistochemistry confirmed that the epithelium and blood vessels located in the granulation tissue expressed the functional leptin receptor obRb isoform during skin repair.. These data suggest that leptin reconstituted epithelial expression of VEGF during skin repair in ob/ob mice but failed to improve wound angiogenesis in the granulation tissue. Thus, the accelerated wound closure observed in leptin-supplemented ob/ob mice is not coupled to an improved wound angiogenesis.

Topics: Administration, Topical; Animals; Blood Glucose; Body Weight; Diabetes Complications; Diabetes Mellitus; Endothelial Growth Factors; Endothelium, Vascular; Female; Gene Expression; Keratinocytes; Leptin; Lymphokines; Mice; Mice, Inbred C57BL; Mice, Obese; Neovascularization, Physiologic; Obesity; Recombinant Proteins; RNA, Messenger; Skin; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Wound Healing

Obese, diabetic C57BL/Ks db/db mice that lack the long-form leptin receptor exhibit no decrease in body weight or food intake when treated with leptin. Here we compared responses to leptin in two strains of db/db mice: C57BL/6J mice that are hyperglycemic and hyperinsulinemic and C57BL/Ks that are hyperglycemic and normo- or hypoinsulinemic. Chronic intraperitoneal infusion of 10 microgram leptin/day partially reversed hyperglycemia in C57BL/6J male mice but exaggerated the diabetic state of female mice. Bolus intraperitoneal injections of 40 microgram leptin/day did not effect glucose in either strain of male db/db mice, whereas chronic intraperitoneal infusion of 20 microgram leptin/day significantly reduced fasting blood glucose in male mice from both strains, especially C57BL/6J mice. Food intake, body weight, rectal temperature, and body fat did not change. Chronic intraperitoneal infusion of 10 microgram leptin/day significantly reduced body fat in lean db/+ C57BL/6J but not in C57BL/Ks mice. Thus peripherally administered leptin is active in mice that have only short-form leptin receptors, and the response is dependent on the method of leptin administration and the background strain.

Topics: Adipose Tissue; Animals; Blood Glucose; Body Composition; Carrier Proteins; Diabetes Mellitus; Fasting; Glucose Tolerance Test; Heterozygote; Homozygote; Hyperglycemia; Hyperinsulinism; Infusions, Parenteral; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Receptors, Cell Surface; Receptors, Leptin; Species Specificity

A deficiency of leptin synthesis in mice results in a complex phenotype characterized by morbid obesity, diabetes, sterility, and defective thermogenesis. To determine whether the genetic background could alter the pleiotropic effects of leptin deficiency, we backcrossed the ob mutation for 10 generations from the C57BL/6J to the BALB/cJ genetic background. Compared with C57BL/6J ob/ob mice, BALB/cJ ob/ob mice showed at 27 wk of age a 35-40% reduction in body weight attributed to a 60% decrease in white adipose tissue mass. Food intake was not significantly different between the two obese strains, suggesting distinct utilization of energy intake. In the fed state, BALB/cJ ob/ob mice had elevated insulin and triglycerides levels, demonstrating a worsening effect on diabetes. At the reproductive level and in contrast to sterile C57BL/6J ob/ob mice, male and female BALB/cJ ob/ob mice were capable of reproducing after a mating period of 16 and 32 wk, respectively. At thermoneutrality, the body temperature of BALB/cJ ob/ob mice was 2.9 C higher than that of C57BL/6J ob/ob mice, whereas exposure of both groups to 4 C demonstrated a prolonged cold tolerance of BALB/cJ ob/ob mice. These studies show that the abnormalities caused by leptin deficiency can be genetically dissected and separated from each other, suggesting discrete pathways controlled by leptin modifier genes.

Topics: Adipose Tissue; Animals; Blood; Body Temperature; Body Temperature Regulation; Body Weight; Diabetes Mellitus; Eating; Fertility; Hybridization, Genetic; Leptin; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Mutant Strains; Obesity; Reference Values

Obesity and its related disorders are the most prevalent health problems in the Western world. Using the paradigm of fetal programming we developed a rodent model which displays the phenotype of obesity and metabolic disorders commonly observed in human populations. We apply maternal undernutrition throughout gestation, generating a nutrient-deprived intrauterine environment to induce fetal programming. Maternal undernutrition results in fetal growth retardation and in significantly decreased body weight at birth. Programmed offspring develop hyperphagia, obesity, hypertension, hyperleptinemia and hyperinsulinism during adult life and postnatal hypercaloric nutrition amplifies the metabolic abnormalities induced by fetal programming. The adipoinsular axis has been proposed as a primary candidate for linking the status of body fat mass to the function of the pancreatic beta-cells. We therefore investigated the relationship between circulating plasma concentrations of leptin and insulin and immunoreactivity in the endocrine pancreas for leptin and leptin receptor (OB-R) in genetically normal rats that were programmed to become obese during adult life. Virgin Wistar rats were time mated and randomly assigned to receive food either available ad libitum (AD group) or at 30% of the ad libitum available intake (UN group). Offspring from UN mothers were significantly smaller at birth than AD offspring (AD 6.13+/-0.04 g, UN 4.02+/-0.03 g, P<0.001). At weaning, offspring were assigned to one of two diets (a standard control diet or a hypercaloric diet consisting of 30% fat) for the remainder of the study. At the time of death (125 days of age), UN offspring had elevated (P<0.005) fasting plasma insulin (AD control 1.417+/-0.15 ng/ml, UN control 2.493+/-0.33 ng/ml, AD hypercaloric 1.70+/-0.17 ng/ml, UN hypercaloric 2.608+/-0.41 ng/ml) and leptin (AD control 8.8+/-1.6 ng/ml, UN control 14.32+/-1.9 ng/ml, AD hypercaloric 15.11+/-1.8 ng/ml, UN hypercaloric 30.18+/-5.3 ng/ml) concentrations, which were further increased (P<0.05) by postnatal hypercaloric nutrition. The elevated plasma insulin and leptin concentrations were paralleled by increased immunolabeling for leptin in the peripheral cells of the pancreatic islets. Dual immunofluorescence histochemistry for somatostatin and leptin revealed that leptin was co-localized in the pancreatic delta-cells. OB-R immunoreactivity was evenly distributed throughout the pancreatic islets and was not changed by programming nor

Topics: Adipose Tissue; Animals; Blood Glucose; Carrier Proteins; Diabetes Mellitus; Female; Immunohistochemistry; Insulin; Islets of Langerhans; Leptin; Models, Animal; Nutrition Disorders; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Radioimmunoassay; Random Allocation; Rats; Rats, Wistar; Receptors, Cell Surface; Receptors, Leptin; Somatostatin; Somatostatin-Secreting Cells

South Asians who immigrate to the United States have a propensity toward insulin resistance, central obesity, and elevated total cholesterol:high-density lipoprotein (HDL) ratio. To evaluate whether these alterations are apparent at a younger age, we studied 32 offspring of South Asian immigrants and compared them with 29 of European descent between 18 to 30 years of age. American-born South Asian males had significantly higher total cholesterol, low-density lipoprotein (TC:LDL) ratios, triglycerides, and fasting insulin levels (13.9 +/- 7.1 and 10.0 +/- 5.5 microU/mL, P <.01) than their European counterparts. The South Asian females only had increased plasma insulin levels (15.3 +/- 8.8 and 10.0 +/- 5.1 microU/mL, P =.05). The entire South Asian group had higher truncal skinfold thickness (40.1 +/- 18.1 and 30.3 +/- 12.6 mm, P = <.05) and lower insulin-like growth factor binding protein (IGFBP)-1 levels (46.8 +/- 33.4 and 56.0 +/- 33.4 microg/L, P =.05). Plasma leptin levels were also significantly higher in both males (4.3 +/- 2.5 v 2.8 +/- 1.3 ng/mL, P =.0001) and females (20.5 +/- 10.3 v 10.3 +/- 6.3 ng/mL, P =.002) South Asian subjects. A significant correlation between plasma leptin and insulin, triglycerides, TC, and body mass index (BMI) was seen in the South Asian males. South Asians born in the United States show evidence for an altered metabolic profile in young adulthood. The relative contributions of inheritance and nutritional practices early in life to this alteration remain unclear.

Topics: Adolescent; Adult; Analysis of Variance; Anthropometry; Asia; Body Mass Index; Child; Densitometry; Diabetes Mellitus; Female; Humans; Insulin; Leptin; Lipids; Male; Sex Factors; Skinfold Thickness; United States

The aim of this study was to investigate the effects of combined hypocaloric diet and metformin on circulating testosterone and leptin levels in obese men with or without type 2 diabetes.. Twenty obese men with type 2 diabetes (mean body mass index [BMI]: 35.5 +/- 1.1 kg/m(2)) and 20 nondiabetic obese men were enrolled in the study. We measured serum follicle-stimulating hormone, luteinizing hormone (LH), total testosterone (TT), free testosterone (FT), sex-hormone-binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEAS), and plasma leptin levels before and 3 months after metformin treatment. Both groups were placed on a hypocaloric diet and 850 mg of metformin taken orally twice daily for 3 months.. Metformin and hypocaloric diets led to decreases in BMI and waist and hip circumferences in both groups. A significant decrease in TT levels in the diabetic group and FT levels in the control group was found, whereas follicle-stimulating hormone, LH, and DHEAS levels were not changed significantly. A significant increase in SHBG levels was observed in the control group but not in the patient group. Leptin levels also decreased after treatment in both groups. Decreased testosterone levels were not correlated to changes in waist and hip circumference, waist-to-hip ratio, BMI, and levels of fasting blood glucose, leptin, SHBG, or DHEAS in the diabetic group. However, a decrease in FT was correlated to changes in the levels of SHBG (r = -0.71, p = 0.001) and LH (r = 0.80, p = 0.001) but not to other parameters.. We conclude that metformin treatment combined with a hypocaloric diet leads to reduced FT levels in obese nondiabetic men and to reduced TT levels in obese men with type 2 diabetes. Increased SHBG levels may account for the decrease in FT levels in the former group.

Topics: Adult; Body Constitution; Body Mass Index; Dehydroepiandrosterone Sulfate; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diet, Reducing; Energy Intake; Female; Follicle Stimulating Hormone; Humans; Hypoglycemic Agents; Leptin; Luteinizing Hormone; Male; Metformin; Middle Aged; Obesity; Sex Hormone-Binding Globulin; Testosterone

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

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

To evaluate the changes of serum leptin levels after weight reduction in diabetic subjects with and without microalbuminuria, we studied 10 obese healthy subjects, 12 obese diabetics with persistent microalbuminuria and 10 obese diabetic subjects without microalbuminuria. Obese diabetic patients with microalbuminuria showed serum leptin levels significantly higher than normoalbuminuric diabetics, while no difference was found between obese diabetics without microalbuminuria and healthy controls. All obese subjects followed a 12-month intensive weight reduction program during which the mean change in body mass index was similar between obese diabetic and obese healthy subjects (obese diabetics without microalbuminuria: 35.2+/-4.3 vs 29.9+/-4.1, p<0.05; obese diabetics with microalbuminuria: 35.7+/-3.9 vs 30.3+/-4.0, p<0.05; obese healthy subjects: 35.5+/-4.0 vs 30.1+/-3.9, p<0.05). The mean changes in serum leptin levels tended to be similar in two groups of subjects studied (obese diabetics without microalbuminuria: 37.6+/-4.1 vs 19.7+/-4.9, p<0.001; obese healthy subjects: 37.1+/-4.3 vs 20.1+/-5.1, p<0.001); obese microalbuminuric subjects showed higher leptin levels (42.4+/-4.0 vs 30.3+/-4.2, p<0.001) than normoalbuminuric diabetic and obese healthy subjects. In conclusion, during weight loss, independently from the quality of metabolic control, serum leptin concentrations declined in both groups of obese diabetics. The changes of leptin in diabetics seem to be similar to those observed in healthy obese subjects.

Topics: Adolescent; Albuminuria; Body Mass Index; Body Weight; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Follow-Up Studies; Humans; Leptin; Obesity; Weight Loss

Five allelic mutants of the diabetes (db) gene have been previously described in mice and rats causing obesity, infertility, and varying degrees of diabetes. We have identified a new, spontaneous mutation resulting in obesity and diabetes in a colony of CD-1 outbred mice, Mus musculus domesticus. Genetic complementation studies indicated that the new mutation was an allele of the diabetes locus. Sequence analysis of cDNA fragments showed a deletion of one G residue located in exon 12 of the leptin receptor gene. The mutation, Lepr(db-NCSU), results in a frameshift and reduces Lepr transcript levels 10-fold. Mutant mice drank up to four times more water and were up to two times heavier than wild-type mice. Blood glucose and plasma insulin and leptin concentrations were sexually dimorphic among affected mice, suggesting an effect of sex steroids. Mortality of affected males was 100% by 5 mo, whereas affected females survived up to 10 mo of age.

Topics: Alleles; Animals; Base Sequence; Carrier Proteins; Diabetes Mellitus; Drinking; Eating; Gases; Gene Expression; Insulin; Leptin; Mice; Molecular Sequence Data; Mutation; Obesity; Receptors, Cell Surface; Receptors, Leptin

Leptin, the product of the ob gene, is an adipocyte-derived hormone that positively correlates with body fat percantage and body mass index (BMI). There are many data which demonstrate a significant relationship between leptin and insulin, but the mechanism underlying the changes of leptin induced by insulin and vice versa remains to be studied in more detail. In this review, we analysed the data on the behaviour of serum leptin levels in non-obese and obese children with type 1 diabetes mellitus. It has been shown that the diminished serum leptin concentrations in patients with newly discovered insulin-dependent diabetes mellitus (IDDM) could be caused by insulin deficiency and/or increased lipolysis. Moreover, while in some studies in diabetic children with good metabolic control the serum leptin levels are similar to those of healthy children, in other studies children with IDDM have leptin levels higher than non diabetic children; it is possible that in some diabetic children intensified insulin therapy could cause chronic hyperinsulinemia with high leptin levels. The mean serum leptin concentrations in the obese diabetic subjects were significantly higher when compared with non-obese diabetics. Obese diabetic patients showed no significant differences in leptin concentrations in comparison to the non diabetic obese group matched by age, sex and BMI. In obese diabetics, during weight loss, independent of the quality of metabolic control, serum leptin concentration declines. The changes of leptin in diabetes seem to be similar to those observed in healthy obese subjects.

Topics: Adult; Age Factors; Child; Child, Preschool; Diabetes Mellitus; Diabetes Mellitus, Type 1; Female; Humans; Insulin; Leptin; Male; Obesity; Sex Factors; Weight Gain; Weight Loss

Orexins (hypocretins) are lateral hypothalamic neuropeptides implicated in regulating feeding and the sleep-wake cycle. To study their possible relevance to obesity and diabetes, we measured hypothalamic prepro-orexin mRNA levels in obese, normoglycemic Zucker fatty (fa/fa) and in hyperglycemic, non-obese Zucker diabetic fatty (ZDF) rats. Hypothalamic prepro-orexin mRNA concentrations in Zucker fatty rats were 31% lower than those in lean controls (0. 69+/-0.06 vs. 1.00+/-0.10 arbitrary units, P<0.05), but did not differ between ZDF diabetic rats and non-diabetic controls. Treatment of ZDF diabetic rats with rosiglitazone (1 or 3 mg/kg body weight daily for 13 weeks) normalized plasma glucose and significantly reduced plasma insulin, while leptin levels were 67% higher than in untreated ZDF rats (20.2+/-0.5 vs. 12.1+/-2.5, P<0. 001). Rosiglitazone treatment markedly enhanced weight gain compared with untreated ZDF rats (final weight 732+/-13 g vs. 409+/-13 g, P<0. 001) even though they were restricted to the same food intake. Rosiglitazone-treated ZDF rats had significantly lower hypothalamic prepro-orexin mRNA levels (0.68+/-0.07 arbitrary units) than both non-diabetic lean controls (1.00+/-0.10, P=0.02) and untreated diabetics (1.03+/-0.14, P=0.03). Our data suggest that prepro-orexin gene expression may be suppressed by substantial weight gain. Obesity-related signals that might mediate this effect have not been identified, but plasma leptin, insulin and glucose are not obviously involved.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Diabetes Mellitus, Type 2; Gene Expression Regulation; Hyperglycemia; Hypoglycemic Agents; Hypothalamus; Insulin; Intracellular Signaling Peptides and Proteins; Leptin; Neuropeptides; Obesity; Orexins; Protein Precursors; Rats; Rats, Zucker; RNA, Messenger; Rosiglitazone; Thiazoles; Thiazolidinediones; Thinness; Transcription, Genetic

To identify chromosomal regions linked to plasma leptin concentrations.. Autosomal genome-wide scan, including 516 microsatellite markers. Sib-pair (Haseman-Elston) and variance components methods were used to assess genetic linkage.. 770 Pima Indians comprising 239 nuclear families (for a total of 1199 sibling-pairs).. Plasma leptin concentrations and body mass index (BMI), adjusted for age and sex.. The strongest evidence for linkage with plasma leptin concentration was on chromosome 6p logarithm of odds (LOD) = 2.1 by variance components analysis). There was no evidence for linkage to BMI in this region. Additional regions with marginal evidence for linkage to plasma leptin concentration (LOD > or =1.0) were detected on chromosomes 3, 11, 13, 15 and 16.. The results suggest that a locus on chromosome 6p influences plasma leptin concentrations. Replication studies are needed to exclude the possibility that linkage has been falsely detected.

Topics: Adolescent; Adult; Aged; Body Mass Index; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Genetic Linkage; Genotype; Humans; Indians, North American; Leptin; Lod Score; Male; Microsatellite Repeats; Middle Aged; Obesity

Peripheral blood DNA from 12 subjects affected by familial obesity and from 35 subjects affected by type 2 diabetes were analysed for mutations in the coding sequence of the OB gene. Mutational analysis, conducted using the single strand conformation polymorphism (SSCP) technique, followed by direct sequencing did not reveal the presence of nucleotide variants in the coding region of the OB gene. The lack of mutations in the coding sequence is consistent with previous data suggesting that mutations in the coding sequence of the OB gene are not common in human familial obesity. In 2 samples displaying a non-informative pattern of SSCP and in 8 additional samples the nucleotide sequence of portion of the intron 2 bordering the coding sequence of exon 2 identified a G in the positions +14IVS and +18IVS, according to a sequence reported previously, but in contrast with some others. All samples were homozygous for these intron variants.

Topics: Adult; Aged; Diabetes Mellitus; Diabetes Mellitus, Type 2; DNA Mutational Analysis; Female; Humans; Introns; Leptin; Male; Middle Aged; Molecular Sequence Data; Obesity; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational

Topics: Animals; Diabetes Mellitus; Diabetes Mellitus, Experimental; Humans; Leptin; Obesity

Obesity is an important factor predisposing to type 2 diabetes mellitus, especially for postmenopausal women. Experimental studies provided evidences that leptin, cholecystokinin (CCK), galanin (GAL), neuropeptide Y (NPY) and insulin are involved in feeding behaviour. The aim of the study was to evaluate their possible relationships in obese and diabetic women. Three groups of postmenopausal women (FSH > 30 mIU/ml) were evaluated: 8 diabetic (mean age 56.6 +/- 6.9 y, BMI 29.8 +/- 5.3 kg/m2), 10 obese non-diabetic (mean age 49.6 +/- 5.4 y, BMI 36.0 +/- 3.7 kg/m2) and 12 non-diabetic controls (mean age 52.7 +/- 3.5 y, BMI 27.3 1.9 kg/m2). For each patient BMI and WHR were measured and calculated. Blood samples were collected at 8:00 a.m. after an overnight fast. Plasma concentrations of FSH, leptin, CCK, GAL, NPY and insulin were determined using commercial RIA kits. Mean plasma NPY concentration was significantly higher in diabetic women than in controls (190.1 pg/ml +/- 85.4 vs 120.4 +/- 36.6). Compared to controls, mean plasma leptin level was significantly higher in obese non-diabetic women (32.9ng/ml +/- 9.2 vs 18.9 +/- 9.1). No significant differences were found between obese non-diabetic and diabetic women. In diabetic subjects positive correlations were found between: CCK and leptin (r= 0.8295; P= 0.011), CCK and insulin (r=0.7832; P=0.022), leptin and insulin (r=0.9302; P=0.001). In obese subjects a positive correlation between WHR and GAL (r= 0.6624; P= 0.037) and a negative between GAL and insulin (r= -0.6795; P= 0.031) were found. In controls positive correlations were found between WHR and CCK (r=0.6412; P=0.025), GAL and insulin (r=0.630; P=0.028) and negative between CCK and NPY (r = -0.6505; P= 0.022). Our results, ie higher mean plasma NPY levels in postmenopausal diabetic women and positive correlation of CCK with leptin and insulin, may suggest the role of these neuropeptides in metabolic disorders leading to type 2 diabetes mellitus.

Topics: Body Constitution; Body Mass Index; Cholecystokinin; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Galanin; Humans; Insulin; Leptin; Middle Aged; Neuropeptide Y; Neuropeptides; Obesity

We previously demonstrated that the expression and function of the adipocyte-specific beta3-adrenergic receptor (beta3AR) are significantly depressed in single gene and diet-induced rodent models of obesity. Furthermore, these models are relatively unresponsive to the anti-obesity effects of beta3AR agonists. Because all of these models are hyperinsulinemic, we hypothesized that hyperinsulinemia could be responsible for this abnormality in beta3AR function. The goal of this study was to determine whether lowering insulin with the K-ATP channel agonist, diazoxide (Dz) would reverse the depressed expression and function of the beta3AR found in a model of diet-induced diabetes and obesity in C57BL/6J (B6) mice. B6 male mice were placed on either high fat (HF) or low fat experimental diets. After 4 weeks, HF-fed mice were assigned to a group: HF or HF containing disodium (R,R)-5- [2-( [2-(3-chlorophenyl)-2-hydroxyethyl]-amino]propyl-1,3-benzodioxole-2,2-di carboxylate (CL; 0.001%, wt/wt), Dz (0.32%, wt/wt), or their combination (CLDz). Dz animals exhibited significantly reduced plasma insulin levels as well as increased 3pAR expression and agonist-stimulated adenylyl cyclase activity in adipocytes. CLDz was more effective in reducing percent body fat, lowering nonesterified fatty acids, improving glucose tolerance, and reducing feed efficiency than either treatment alone.

Topics: Adipocytes; Adipose Tissue; Animals; Blood Glucose; Body Weight; Diabetes Mellitus; Diazoxide; Diet; Energy Intake; Glucose; Insulin; Leptin; Lipids; Male; Mice; Mice, Inbred Strains; Muscle, Skeletal; Obesity; Organ Size; Receptors, Adrenergic, beta; Syndrome

Dominant mutations at the mouse Agouti locus lead to ectopic expression of the Agouti gene and exhibit diabetes, obesity, and yellow coat color. Obese yellow mice are hyperinsulinemic and hyperleptinemic, and we hypothesized that Agouti directly induces leptin secretion. Accordingly, we used transgenic mice expressing agouti in adipocytes (under the control of aP2 promoter, aP212) to examine changes in leptin levels. Agouti expression in adipose tissue did not significantly alter food intake, weight gain, fat pad weight, or insulinemia; however, the transgenic mice were hyperglycemic. We demonstrated that plasma leptin levels are approximately twofold higher in aP212 transgenic mice compared with their respective controls, whereas ubiquitous expression of agouti (under the control of beta-actin promoter, BAP20) led to a sixfold increase in leptin. Insulin treatment of aP212 mice increased adipocyte leptin content without affecting plasma leptin levels. These findings were further confirmed in vitro in 3T3-L1 adipocytes treated with recombinant Agouti protein and/or insulin. Agouti but not insulin significantly increased leptin secretion, indicating that insulin enhances leptin synthesis but not secretion while Agouti increases both leptin synthesis and secretion. This increased leptin synthesis and secretion was due to increased leptin mRNA levels by Agouti. Interestingly, agouti regulation of leptin was not mediated by melanocortin receptor 4, previously implicated in agouti regulation of food intake. These results suggest that increased leptin secretion by agouti may serve to limit agouti-induced obesity, independent of melanocortin receptor antagonism, and indicate that interaction between obesity genes may play a key role in obesity.

Topics: Adipocytes; Adipose Tissue; Agouti Signaling Protein; Animals; Carrier Proteins; Cells, Cultured; Diabetes Mellitus; DNA-Binding Proteins; Drug Administration Schedule; Fatty Acid-Binding Protein 7; Fatty Acid-Binding Proteins; Homozygote; Injections, Subcutaneous; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Male; Melanocyte-Stimulating Hormones; Mice; Mice, Transgenic; Neoplasm Proteins; Nerve Tissue Proteins; Obesity; Promoter Regions, Genetic; Proteins; Receptor, Melanocortin, Type 4; Receptors, Corticotropin; Receptors, Leptin; Receptors, Melanocortin; Receptors, Peptide; RNA, Messenger

To assess differences in circulating leptin and glucagon-like peptide (GLP)-1 concentrations before and after an oral glucose load, in euglycaemic and isoinsulinaemic conditions, between obese patients with and without Type 2 diabetes mellitus.. Ten male obese (body mass index (BMI) > 30 kg/m2) patients with Type 2 diabetes and 20 matched non-diabetic subjects were studied. Leptin, GLP-1(7-36)amide and GLP-1(7-37) concentrations were measured 0, 30, 60, and 90 min after a 50-g oral glucose load administered 90 min after the beginning of a euglycaemic hyperinsulinaemic clamp.. GLP-1(7-36)amide concentrations before the glucose load were significantly lower in diabetic patients than in controls (median (quartiles): 50.5 (44.7-53.2) vs. 128.7(100-172.5) pg/ml; P < 0.01), while no difference was observed in baseline GLP-1(7-37). In non-diabetic subjects, GLP-1(7-36)amide and GLP-1(7-37) concentrations increased significantly after the oral glucose load, while no glucose-induced increase in GLP-1 concentration was observed in diabetic patients. GLP-1(7-36)amide at 30, 60, and 90 min, and GLP-1(7-37) at 30 min, of the glucose challenge, were significantly lower in diabetic patients. Leptin concentrations were not significantly different in diabetic patients when compared to non-diabetic subjects, and they did not change after the oral glucose load.. Leptin concentrations are not significantly modified in obese Type 2 diabetic patients. GLP-1(7-36)amide baseline concentrations are reduced in Type 2 diabetes; moreover, diabetic subjects show an impaired response of GLP-1 to oral glucose in euglycaemic, isoinsulinaemic conditions. This impairment, which is not the result of differences in glycaemia or insulinaemia during assessment, could contribute to the pathogenesis of hyperglycaemia in Type 2 diabetes mellitus.

Topics: Blood Glucose; Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Glucose Clamp Technique; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hyperinsulinism; Insulin; Leptin; Male; Middle Aged; Obesity; Peptide Fragments; Protein Precursors

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

There is a high prevalence of type 2 diabetes mellitus and coronary artery disease among urban and migrant Asian Indians despite the absence of traditional risk factors. Evidence exists that Asian Indians are more hyperinsulinemic than Caucasians and that hyperinsulinemia may be important in the development of these diseases. To test whether insulin action was related to total or regional adiposity and to explore the potential role of plasma leptin and lipids, we measured insulin-mediated glucose disposal by the euglycemic insulin clamp, adipose distribution and muscle volume using computed axial tomography, and fasting serum leptin and lipid levels in 20 healthy Asian Indian male volunteers (age, 36 +/- 10 yr). A mean body mass index of 24.5 +/- 2.5 kg/m2 was associated with an unusually high percentage of body fat (33 +/- 7%). The majority of the fat was sc, and 16% was visceral (intraabdominal) adipose tissue. The majority (66%) of these nonobese men were insulin resistant. The mean fasting serum leptin level was 7.6 +/- 3.3 ng/mL. Insulin action was inversely correlated with visceral adipose tissue, not total or abdominal sc adipose tissue. In contrast, leptin levels correlated with sc and total (not visceral) adipose tissue. Serum triglyceride and high density lipoprotein cholesterol levels were inversely correlated with each other and were directly related to insulin resistance and visceral (not subcutaneous) fat. Increased visceral fat in Asian Indians is associated with increased generalized obesity, which is not apparent from their nonobese body mass index. Increased visceral fat is related to dyslipidemia and increased frequency of insulin resistance and may account for the increased prevalence of diabetes mellitus and cardiovascular disease in Asian Indians.

Topics: Adipose Tissue; Adult; Body Composition; Diabetes Mellitus; Humans; India; Insulin Resistance; Leptin; Lipids; Male; Middle Aged; Proteins; Viscera; White People

Previously we demonstrated the expression of the long form of the leptin receptor in rodent pancreatic beta-cells and an inhibition of insulin secretion by leptin via activation of ATP-sensitive potassium channels. Here we examine pancreatic islets isolated from pancreata of human donors for their responses to leptin. The presence of leptin receptors on islet beta-cells was demonstrated by double fluorescence confocal microscopy after binding of a fluorescent derivative of human leptin (Cy3-leptin). Leptin (6.25 nM) suppressed insulin secretion of normal islets by 20% at 5.6 mM glucose. Intracellular calcium responses to 16.7 mM glucose were rapidly reduced by leptin. Proinsulin messenger ribonucleic acid expression in islets was inhibited by leptin at 11.1 mM, but not at 5.6 mM glucose. Leptin also reduced proinsulin messenger ribonucleic acid levels that were increased in islets by treatment with 10 nM glucagon-like peptide-1 in the presence of either 5.6 or 11.1 mM glucose. These findings demonstrate direct suppressive effects of leptin on insulin-producing beta-cells in human islets at the levels of both stimulus-secretion coupling and gene expression. The findings also further indicate the existence of an adipoinsular axis in humans in which insulin stimulates leptin production in adipocytes and leptin inhibits the production of insulin in beta-cells. We suggest that dysregulation of the adipoinsular axis in obese individuals due to defective leptin reception by beta-cells may result in chronic hyperinsulinemia and may contribute to the pathogenesis of adipogenic diabetes.

Topics: Calcium; Carrier Proteins; Cells, Cultured; Diabetes Mellitus; Gene Expression; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Leptin; Obesity; Peptide Fragments; Potassium Channels; Proinsulin; Protein Precursors; Proteins; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger

It is proposed that an important function of leptin is to confine the storage of triglycerides (TG) to the adipocytes, while limiting TG storage in nonadipocytes, thus protecting them from lipotoxicity. The fact that TG content in nonadipocytes normally remains within a narrow range, while that of adipocytes varies enormously with food intake, is consistent with a system of TG homeostasis in normal nonadipocytes. The facts that when leptin receptors are dysfunctional, TG content in nonadipocytes such as islets can increase 100-fold, and that constitutively expressed ectopic hyperleptinemia depletes TG, suggest that leptin controls the homeostatic system for intracellular TG. The fact that the function and viability of nonadipocytes is compromised when their TG content rises above or falls below the normal range suggests that normal homeostasis of their intracellular TG is critical for optimal function and to prevent lipoapoptosis. Thus far, lipotoxic diabetes of fa/fa Zucker diabetic fatty rats is the only proven lipodegenerative disease, but the possibility of lipotoxic disease of skeletal and/or cardiac muscle may require investigation, as does the possible influence of the intracellular TG content on autoimmune and neoplastic processes.

Topics: Adipocytes; Aged; Animals; Cell Transformation, Neoplastic; Colorectal Neoplasms; Diabetes Mellitus; Diabetes Mellitus, Type 1; Energy Intake; Fatty Acids; Fatty Acids, Nonesterified; Homeostasis; Humans; Islets of Langerhans; Leptin; Liver Diseases; Models, Biological; Obesity; Proteins; Rats; Rats, Zucker; Risk Factors; Triglycerides

Conventional treatment of obesity reduces fat in mature adipocytes but leaves them with lipogenic enzymes capable of rapid resynthesis of fat, a likely factor in treatment failure. Adenovirus-induced hyperleptinemia in normal rats results in rapid nonketotic fat loss that persists after hyperleptinemia disappears, whereas pair-fed controls regain their weight in 2 weeks. We report here that the hyperleptinemia depletes adipocyte fat while profoundly down-regulating lipogenic enzymes and their transcription factor, peroxisome proliferator-activated receptor (PPAR)gamma in epididymal fat; enzymes of fatty acid oxidation and their transcription factor, PPARalpha, normally low in adipocytes, are up-regulated, as are uncoupling proteins 1 and 2. This transformation of adipocytes from cells that store triglycerides to fatty acid-oxidizing cells is accompanied by loss of the adipocyte markers, adipocyte fatty acid-binding protein 2, tumor necrosis factor alpha, and leptin, and by the appearance of the preadipocyte marker Pref-1. These findings suggest a strategy for the treatment of obesity by alteration of the adipocyte phenotype.

Topics: Adenoviridae; Adipocytes; Adipose Tissue; Animals; Body Temperature Regulation; Cell Differentiation; Cytomegalovirus; Diabetes Mellitus; Epididymis; Gene Expression Regulation; Genetic Therapy; Genetic Vectors; Leptin; Lipids; Male; Obesity; Protein Biosynthesis; Proteins; Rats; Rats, Zucker; Receptors, Cytoplasmic and Nuclear; Recombinant Proteins; Transcription Factors; Triglycerides

To investigate the effects of leptin administration to Psammomys obesus, a polygenic animal model of obesity and type 2 diabetes mellitus.. Longitudinal intervention study utilising three separate leptin treatment protocols lasting 7-14 d.. Body weight and food intake were measured daily, body fat and muscle content were estimated by carcass analysis on completion of the study. Blood glucose, plasma insulin, leptin, triglycerides and cholesterol were measured at baseline and twice each week during the study.. Relatively high doses of leptin were required to significantly reduce food intake and body fat content in lean Psammomys obesus, but had no discernible effect on their obese littermates.. As a species, Psammomys obesus appear to be relatively insensitive to the effects of leptin administration, compared with other rodents. Obese Psammomys obesus are leptin resistant relative to their lean littermates.

Topics: Animals; Blood Glucose; Body Weight; Cholesterol; Diabetes Mellitus; Diabetes Mellitus, Type 2; Disease Models, Animal; Eating; Energy Intake; Gerbillinae; Insulin; Leptin; Obesity; Proteins; Triglycerides

Topics: Association; Diabetes Mellitus; Exercise; Humans; Insulin Resistance; Leptin; Obesity; Proteins; United States; Weight Loss

To examine in a population sample of cord blood the time structure (chronome) of leptin, an adipocyte-derived hormone, and to assess any effect of a familial history of noninsulin-dependent diabetes mellitus and obesity, separately, on both the maternal and the paternal side.. Leptin concentration was determined in cord blood from 93 infants. Effects of gender, gestational age, birth weight, maternal weight, familial antecedents of obesity and noninsulin-dependent diabetes mellitus, and circadian and about-yearly stage were assessed by linear regression and ANOVA.. Cord blood leptin concentration is elevated in the presence of a family history of obesity on the paternal side, but not on the maternal side. Leptin concentrations are higher in spring and summer than in fall and are higher in infants born before noon. In keeping with earlier work, leptin concentration in cord blood correlates positively with birth weight and height and is higher in infants who are appropriate for or large for gestational age than in infants who are small for gestational age or born prematurely.. Changes along the scales of the day and the seasons point to synchronizing environmental as well as genetic influence. An association of cord blood leptin concentration with obesity on the paternal side may help clarify the role of leptin in parental contributions to human obesity and may prompt focus on cholesterol metabolism.

Topics: Circadian Rhythm; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Fetal Blood; Humans; Infant, Newborn; Infant, Small for Gestational Age; Leptin; Male; Obesity; Proteins; Random Allocation; Seasons; Sex Factors; Time Factors

Plasma leptin levels correlate strongly with increased total adipose tissue, a known risk factor for type 2 diabetes, yet the role of leptin in the etiology of diabetes remains unclear. We sought to determine whether leptin is a risk factor for development of diabetes in Japanese Americans.. We compared baseline leptin levels in 370 nondiabetic Japanese Americans who remained nondiabetic for 5-6 years of follow-up with those of 40 nondiabetic Japanese Americans who developed diabetes during follow-up. All participants had computed tomography measurements of baseline subcutaneous chest, abdomen, thigh, and intra-abdominal fat, with total fat defined as the sum of all these measurements.. The mean age was 51.7 +/- 11.7 years for men and 51.9 +/- 12.0 years for women. The 23 men who developed diabetes had significantly higher leptin levels than the 212 men who remained nondiabetic (P < 0.01). Among men, baseline leptin levels predicted diabetes risk independent of baseline total fat, insulin, insulin resistance, glucose, or age in separate multiple logistic regression models (relative risk adjusted for baseline total fat = 1.80 per SD increase [2.7 ng/ml], 95% CI 1.02-3.17). This association was particularly strong among men in the top decile for intra-abdominal fat. In contrast, the 17 women who developed diabetes had leptin levels similar to those of the 158 women who remained nondiabetic (P = 0.31).. Among Japanese Americans, increased baseline leptin levels are associated with increased risk of developing diabetes in men but not in women.

Topics: Adipose Tissue; Blood Glucose; Body Mass Index; Diabetes Mellitus; Female; Humans; Insulin; Insulin Resistance; Japan; Leptin; Male; Middle Aged; Obesity; Predictive Value of Tests; Proteins; Risk Factors; Washington

Topics: Adult; Coronary Disease; Cytokines; Diabetes Mellitus; Female; Humans; India; Interleukin-6; Leptin; Male; Proteins; Risk Factors; Rural Population; Social Class; Tumor Necrosis Factor-alpha; Urban Population

The effects of n-3 polyunsaturated fatty acids (n-3PUFA) on obesity and diabetes were examined using KK-Ay mice fed with perilla oil (P), soybean oil (S), or lard (L), and those containing 30% fish oil (PF, SF, or LF), containing eicosapentaenoic acid (EPA = 9.9%) and docosahexaenoic acid (DHA = 18.0%). Perilla oil contained the largest proportion of linolenic acid (LNA = 61.9%). Computerized tomography (CT) scans showed narrower areas of visceral fat in the abdominal cross sections of groups given fish oil (PF, SF, and LF) and lower leptin levels (p < 0.05-p < 0.001) compared with controls (P, S, and L), without significant changes in energy intake and body weight. The highest plasma n-3PUFA content (21.31 +/- 0.35%) was attained with PF. This group contained 2.6-fold more plasma DHA (p < 0.001), and expressed 2.7-fold more UCP2 mRNA in white adipose tissue (p < 0.01) than in the P group. The epididymal fat pad (p < 0.05) weighed less, and levels of blood glucose (p < 0.05) and total cholesterol (p < 0.01) were reduced in PF compared with P.

Topics: Adipose Tissue; alpha-Linolenic Acid; Animals; Blood Glucose; Body Weight; Cholesterol; Diabetes Mellitus; Diet; Docosahexaenoic Acids; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Ion Channels; Leptin; Male; Membrane Transport Proteins; Mice; Mice, Inbred Strains; Mitochondrial Proteins; Obesity; Organ Size; Proteins; RNA, Messenger; Tomography, X-Ray Computed; Uncoupling Protein 2

The adipocyte hormone leptin reduces food intake in normal animals. During uncontrolled type 1 diabetes, plasma leptin levels fall, whereas food intake increases. To test the hypothesis that low leptin levels contribute to diabetic hyperphagia, we investigated the effect on food intake of replacement of leptin at basal plasma concentrations for 7 days in Long-Evans rats with uncontrolled diabetes induced by streptozotocin (STZ). One group of STZ diabetic rats received saline (STZ + Sal) (n = 11), while the other group (STZ + Lep) (n = 15) received a subcutaneous infusion of recombinant rat leptin (100 microg x kg(-1) x day(-1)) via osmotic minipumps. A nondiabetic control group (Con) (n = 11) received saline only. In the STZ + Sal group, plasma leptin levels decreased by 75% (P < 0.05) from 2.4+/-0.5 on the day before STZ/citrate buffer vehicle (Veh) injection (day 0) to 0.6+/-0.2 ng/ml on day 7. In contrast, plasma leptin levels on days 3-7 were comparable to pretreatment values in both the STZ + Lep group (day 0: 2.6+/-0.4 vs. day 7: 2.5+/-0.3 ng/ml, NS) and the Con group (day 0: 3.8+/-0.4 vs. day 7: 2.9+/-1.0 ng/ml, NS). In the STZ + Sal group, daily food intake increased gradually to values 43% above basal by day 7 (day 0: 24+/-2 to day 7: 33+/-3 g, P < 0.05), whereas food intake did not increase in either the STZ + Lep group (day 0: 24+/-1 vs. day 7: 21+/-2 g, NS), or the Con group (day 0: 23+/-1 vs. day 7: 23+/-2 g). Plasma glucose levels exceeded nondiabetic control values (7.7+/-0.2 mmol/l) in both diabetic groups, but were lower in the STZ + Lep group (17.2+/-1.8 mmol/l) than in the STZ + Sal group (24.3+/-1.1 mmol/l, P < 0.05). To determine if sensitivity to leptin-induced anorexia was affected by STZ treatment, a second experiment was performed in which the effect of intracerebroventricular leptin injection (at doses of 0.35, 1.0, or 3.5 microg) on food intake was measured 10 days after STZ or Veh treatment. Leptin suppressed both 4- and 24-h food intake in the two groups to an equal extent at every dose (by 15, 22, and 35%, respectively). These findings support the hypothesis that the effect of uncontrolled diabetes to lower leptin levels contributes to diabetic hyperphagia and that this effect is not due to altered leptin sensitivity.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Diabetes Mellitus, Experimental; Hyperphagia; Insulin; Leptin; Male; Obesity; Proteins; Rats; Rats, Long-Evans

Leptin acts as an adipocyte-derived blood-borne satiety factor that can increase glucose metabolism. To elucidate the therapeutic implications of leptin for obesity-associated diabetes, we crossed transgenic skinny mice overexpressing leptin (Tg/+), which we have developed recently, and lethal yellow KKAy mice (Ay/+), a genetic model for obesity-diabetes syndrome, and examined the metabolic phenotypes of F1 animals. At 6 weeks of age, plasma leptin concentrations in Tg/+ mice with the Ay allele (Tg/+:Ay/+) were significantly higher than those in Ay/+ mice. Although no significant differences in body weight were noted among Tg/+:Ay/+ mice, Ay/+ mice, and their wild-type lean littermates (+/+), glucose and insulin tolerance tests revealed increased glucose tolerance and insulin sensitivity in Tg/+:Ay/+ compared with Ay/+ mice. However, at 12 weeks of age, when plasma leptin concentrations in Ay/+ mice were comparable to those in Tg/+:Ay/+ mice, Tg/+:Ay/+ mice developed obesity-diabetes syndrome similar to that of Ay/+ mice. Body weights of 12-week-old Tg/+:Ay/+ and Ay/+ mice were reduced to those of +/+ mice by a 3-week food restriction; when plasma leptin concentrations remained high in Tg/+:Ay/+ mice but were markedly reduced in Ay/+ and +/+ mice, glucose tolerance and insulin sensitivity in Tg/+:Ay/+ mice were markedly improved as compared with Ay/+ and +/+ mice. The present study demonstrates that hyperleptinemia can delay the onset of impaired glucose metabolism and accelerate the recovery from diabetes during caloric restriction in Tg/+:Ay/+ mice, thereby suggesting the potential usefulness of leptin in combination with a long-term caloric restriction for the treatment of obesity-associated diabetes.

Topics: Aging; Animals; Body Weight; Diabetes Mellitus; Eating; Female; Food Deprivation; Glucose; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Transgenic; Mutation; Obesity; Proteins

Exogenous leptin enhances energy utilization in ob/ob mice by binding its hypothalamic receptor and selectively increasing peripheral fat oxidation. Leptin also increases uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT), but the neurotransmitter that mediates this effect has not been established. The present experiments sought to determine whether leptin regulates UCP1 expression in BAT and its own expression in white adipose tissue (WAT) through the long or short forms of leptin receptor and modulation of norepinephrine release. Mice lacking dopamine beta-hydroxylase (Dbh-/-), the enzyme responsible for synthesizing norepinephrine and epinephrine from dopamine, were treated with leptin (20 microg/g body weight/day) for 3 days before they were euthanized. UCP1 messenger RNA (mRNA) and protein expression were 5-fold higher in BAT from control (Dbh+/-) compared with Dbh-/- mice. Leptin produced a 4-fold increase in UCP1 mRNA levels in Dbh+/- mice but had no effect on UCP1 expression in Dbh-/-. The beta3-adrenergic agonist, CL-316,243 increased UCP1 expression and established that BAT from both groups of mice was capable of responding to beta-adrenergic stimulation. Similarly, exogenous leptin reduced leptin mRNA in WAT from Dbh+/- but not Dbh-/- mice. In separate experiments, leptin produced comparable reductions in food intake in both Dbh+/- and Dbh-/- mice, illustrating that norepinephrine is not required for leptin's effect on food intake. Lastly, db/db mice lacking the long form of the leptin receptor failed to increase UCP1 mRNA in response to exogenous leptin but increased UCP1 mRNA in response to CL-316,243. These studies establish that norepinephrine is required for leptin to regulate its own expression in WAT and UCP1 expression in BAT and indicate that these effects are likely mediated through the centrally expressed long form of the leptin receptor.

Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Body Weight; Carrier Proteins; Diabetes Mellitus; Dopamine beta-Hydroxylase; Eating; Gene Expression; Ion Channels; Leptin; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondrial Proteins; Norepinephrine; Proteins; RNA, Messenger; Uncoupling Protein 1

TNF-alpha, IGF-I and leptin are agents which influence insulin resistance, they play probably a part in the pathogenesis of diabetic nephropathy and influence mutually their production. The objective of the submitted investigation was to assess whether there exist relations between their concentrations in the plasma of diabetic patients.. The authors examined 37 patients aged 18-67 years from a diabetic clinic, 10 with normal albuminuria and normal renal function, 12 with microalbuminuria and 15 with macroalbuminuria and/or reduced renal function. TNF alpha, IGF-I and leptin were assessed in plasma, using commercial kits, by the ELISA method. IgF-I in plasma correlated inversely with glycated haemoglobin (r = -0.20, p < 0.05). In women a correlation was found between IGF-I and TNF-alpha concentrations (r = 0.65, p < 0.01). No other mutual correlations were found between concentrations of the investigated substances and between cytokine concentrations and serum creatinine, glycated haemoglobin, the blood glucose level and body mass index.. IGF-I plasma levels correlate inversely with glycated haemoglobin and in women with the TNF-alpha level. No other correlations were found between IGF-I. TNF-alpha and leptin plasma levels. The levels do not correlate with age, renal function and compensation of diabetes.

Topics: Adipose Tissue; Adult; Diabetes Mellitus; Female; Humans; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Male; Middle Aged; Tumor Necrosis Factor-alpha

To determine whether leptin secretion is impaired in diabetes, we compared basal and stimulated plasma leptin levels in diabetic subjects and healthy controls.. Blood samples for assay of leptin and other hormones were obtained at baseline in 54 diabetic patients and 65 controls, and 8 hours, 16 hours, and 40 hours following ingestion of dexamethasone (4 mg) in 6 healthy and 12 controls. C-peptide status was defined as "negative" if < or =0.1 ng/mL or "positive" if > or =0.3 ng/mL, in fasting plasma.. Basal plasma leptin levels were 19.7+/-2.2 ng/mL in nondiabetic subjects, 13.4+/-1.5 ng/ml in C-peptide negative (n = 28) and 26.1+/-3.7 ng/mL in C-peptide positive (n = 26, p = 0.001) diabetic patients. Dexamethasone increased leptin levels of controls (n = 6) to 145+/-17% of baseline values at 8 hours (p = 0.03), 224+/-18% at 16 hours (p = 0.01), and 134+/-18% at 40 hours (p=0.05). The corresponding changes were 108+/-13%, 126+/-23%, and 98+/-16% in C-peptide negative (n=6), and 121+/-10%, 144+/-16% (p=0.03), and 147+/-23% (p=0.11) in C-peptide positive (n = 6) diabetic patients, respectively. The peak stimulated leptin levels were lower in the diabetic patients, compared with controls. Plasma insulin increased (p = 0.02) in controls, but not in the diabetic patients, following dexamethasone.. Although diabetic patients have normal plasma leptin levels under basal conditions, their leptin responses to glucocorticoid are impaired, probably because of the concomitant insulin secretory defect. A subnormal leptin secretory response could worsen obesity and insulin resistance in diabetes.

Topics: Adult; Blood Glucose; Body Mass Index; C-Peptide; Dexamethasone; Diabetes Mellitus; Female; Glucocorticoids; Humans; Insulin; Leptin; Male; Middle Aged; Reference Values

Children with diabetes mellitus are prone to develop obesity and to experience a delay in onset of the pubertal process. In order to understand the role of leptin in these abnormalities, serum leptin levels were analysed in children with type 1 diabetes mellitus.. Twenty diabetic girls, 23 diabetic boys and 66 healthy children (selected from a reference population of 706 normal children), age-, sex- and BMI-matched with diabetic patients, were studied.. Standing height, weight and BMI were determined in each child. Serum testosterone, oestradiol and leptin were measured by specific radioimmunoassays, and HBA1c by high performance liquid chromatography.. Both diabetic girls and boys showed higher leptin levels than the normative healthy population and a group of age-, sex- and BMI-matched normal children. In an age-related analysis, leptin levels in diabetic girls rose from 7.4 +/- 1.2 and 8.1 +/- 2.1 microg/l for the 5-7.99 and 8-10.99 year groups, to 12.6 +/- 2.4 microg/l for the 11-13.99 year group, and to 15.6 +/- 4.0 microg/l in the 14-15.99 year group in parallel with body weight. Leptin concentrations were parallel but higher (P < 0.05) than those of healthy girls. Diabetic boys had lower leptin levels than girls and, in contrast with normal boys, did not show a drop after the 10-year period. Leptin levels were 4.9 +/- 2.2, 3.9 +/- 0.2, 5.5 +/- 0.6 and 5.1 +/- 0.9 microg/l for the 5-7.99, 8-10. 99, 11-13.99 and 14-15.99 year groups, respectively. When divided by pubertal stage, leptin levels in the prepuberty stage of diabetic girls (8.6 +/- 1.0 microg/l) were higher (P < 0.05) than those in the controls (4.1 +/- 0.4 microg/l). In overt puberty girls, leptin was higher (P < 0.05) for diabetic (15.9 +/- 2.9 microg/l) than for healthy girls (9.2 +/- 1.1 microg/l). In prepubertal boys, differences were observed in leptin levels (4.9 +/- 0.5 microg/l for diabetic boys and 3.4 +/- 0.6 microg/l for healthy boys). In the overt puberty stage, diabetic boys showed higher (P < 0.05) levels of leptin (5.2 +/- 0.7 microg/l) than the healthy matched controls (2.1 +/- 0.2 microg/l). A multiple step regression analysis in the diabetic children revealed no associations between leptin and other relevant variables such as glycosylated haemoglobin, daily insulin dose, or years of suffering from the disease.. Serum leptin levels were higher in diabetic than in healthy children. These differences were not attributable to age, adiposity or stage of pubertal development, and were probably conditioned by the metabolic perturbation intrinsic to the diabetic state, or the chronic hyperinsulinemia.

Topics: Adolescent; Age Factors; Body Mass Index; Case-Control Studies; Child; Child, Preschool; Cross-Sectional Studies; Diabetes Mellitus; Diabetes Mellitus, Type 1; Estradiol; Female; Humans; Leptin; Male; Obesity; Puberty; Regression Analysis; Sex Factors; Testosterone

Lipoatropic diabetes (LD) designates a group of syndromes characterized by diabetes mellitus with marked insulin resistance and either a localized or generalized absence of adipose tissue. In this study, we evaluated plasma leptin levels in subjects with congenital generalized lipoatropic diabetes (CGLD, n = 11) or acquired generalized lipoatropic diabetes (AGLD, n = 11), and assessed correlations between leptin levels and estimations of insulin secretion and insulin sensitivity using homeostasis model assessment (HOMA). Leptin levels were 0.86 +/- 0.32, 1.76 +/- 0.78, and 6.9 +/- 4.4 ng/mL in subjects with CGLD, AGLD, and controls (n = 19), respectively (ANOVA P < 0.0001). Specific insulin levels were 154 +/- 172, 177 +/- 137 and 43 +/- 22 pmol/L, respectively (P < 0.0001). Insulin sensitivity was significantly decreased in both groups with LD (P < 0.0001), whereas HOMA beta-cell function was not significantly different when compared with controls. Leptin levels were significantly correlated with body mass index, insulin levels, and HOMA beta-cell function, and inversely correlated with insulin sensitivity in control subjects but not in subjects with generalized LD. In conclusion, decreased leptin levels were observed in subjects with generalized LD, with a trend towards lower levels in the acquired than in the congenital form (P = 0.06). The temporal relationship between the decrease in leptin levels and the development of lipoatrophy should be investigated in at-risk young relatives of subjects with the acquired forms to assess the usefulness of leptin levels as a marker of lipoatrophy.

Topics: Adipose Tissue; Adolescent; Adult; Atrophy; Body Mass Index; Child; Diabetes Mellitus; Female; Homeostasis; Humans; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Leptin; Male; Middle Aged; Proteins

This investigation was designed to determine the relationship of leptin concentration to gender, sex hormones, menopause, age, diabetes, and fat mass in African Americans. Participants included 101 African Americans, 38 men (mean age, 34.2 +/- 7.4 years), 29 age-matched premenopausal women (mean age, 32.6 +/- 3.7 years), and 36 postmenopausal women (mean age, 57.8 +/- 5.9 years). The women were not taking exogenous sex hormones, and 12 subjects were diabetic. Percent body fat was calculated with the Siri formula, fat mass (FM) was calculated as weight x percent body fat, and Fat-free mass (FFM) was calculated as weight minus FM. Fasting plasma was assayed for leptin, estradiol, free testosterone, glucose, and insulin concentrations. The nondiabetics had an oral glucose tolerance test (OGTT). The diabetics compared with the non-diabetics had a higher central fat index (p=0.04) but otherwise were similar to nondiabetics in all parameters measured. Body mass index, percent body fat, and FM were greater in women than men (p<0.001). Leptin concentrations in men, premenopausal, and postmenopausal women were: 7.51 +/- 8.5, 33.9 +/- 17.3, 31.4 +/- 22.3 ng/mL. Leptin/FM x 100 in the three groups were: 28.9 +/- 16.1, 98.65 +/- 44.9, 77.1 +/- 44.5 ng/mL/kg. The gender difference in leptin concentration and leptin/FM was significant (p<0.001), but the difference between premenopausal and postmenopausal women was not. In each group, weight, percent body fat, and FM were highly correlated with leptin concentration. Multiple regression analyses with leptin concentration as the dependent variable and age, diabetic status, percent body fat, weight, FM, FFM, estradiol, and free testosterone concentrations as independent variables demonstrated that the determinants of leptin concentration in men was weight only (R=0.83, p<0.001), in premenopausal women it was FM only (R=0.57, p<0.001), and in postmenopausal women it was weight only (R=0.67, p<0.001). With diabetics excluded, the multiple regression analysis was repeated with fasting insulin concentration and the area under the insulin curve during the OGTT included as independent variables. The results for this multiple regression analyses were the same as the first. Therefore, leptin concentration in African Americans is determined by gender and fat mass. Menopause, age, and diabetes do not affect leptin concentration.

Topics: Adult; Aged; Aging; Black People; Body Composition; Diabetes Mellitus; Estradiol; Female; Glucose Tolerance Test; Humans; Leptin; Male; Middle Aged; Postmenopause; Premenopause; Proteins; Regression Analysis; Sex Characteristics; Testosterone; United States

Topics: Animals; Apolipoproteins B; Bile Acids and Salts; CCAAT-Enhancer-Binding Proteins; Diabetes Mellitus; DNA-Binding Proteins; Humans; Hydroxymethylglutaryl CoA Reductases; Leptin; Lipid Metabolism; Lipoproteins; Methyltransferases; Molecular Biology; Mutation; Niemann-Pick Diseases; Nuclear Proteins; Phosphatidylcholines; Phosphatidylethanolamine N-Methyltransferase; Protein Prenylation; Proteins; Receptors, LDL; Saccharomyces cerevisiae; Sterol O-Acyltransferase; Sterol Regulatory Element Binding Protein 1; Transcription Factors

Adipose tissue leptin mRNA levels are decreased by food deprivation or induction of insulin-deficient diabetes. To determine whether plasma leptin concentrations are similarly affected, whether treatment of diabetes with insulin restores plasma leptin, and whether this requires restoration of body weight (lost as a result of diabetes) and/or normalization of glycemia, we measured plasma leptin concentrations in control, untreated streptozotocin (STZ)-diabetic, and insulin-treated STZ-diabetic rats. Plasma leptin was markedly reduced in untreated STZ-diabetic rats. Insulin treatment for 4 to 17 days increased plasma leptin approximately twofold above control levels. However, despite the hyperleptinemia, insulin-treated diabetic rats gained weight at a rate equal to that of sham-treated controls. Epididymal adipose tissue leptin mRNA levels in 17-day insulin-treated diabetic rats were equal to but did not exceed sham-control levels, unlike plasma leptin. Plasma glucose concentrations in insulin-treated STZ-diabetic rats were lower than in sham controls. Therefore, to determine whether hypoglycemia may be important in increasing plasma leptin, we measured plasma leptin levels in diabetic rats infused with insulin for 3 hours along with a variable-rate glucose infusion targeting glycemia to 200 or 40 mg/100 mL. Plasma leptin rapidly increased in these rats irrespective of target glycemia. Plasma leptin also increased rapidly in normal rats infused with insulin and glucose (target glycemia, 200 mg/100 mL). We conclude that plasma leptin concentrations are markedly reduced under conditions of insulin deficiency and rapidly increased by insulin treatment. The increase in plasma leptin does not require restoration of body weight and, under glucose clamp conditions, does not depend on target glycemia. Hyperleptinemia in insulin-treated diabetic rats is not explained on the basis of steady-state leptin mRNA levels, at least as reflected in epididymal fat.

Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Experimental; Epididymis; Glucose; Hypoglycemic Agents; Insulin; Leptin; Male; Obesity; Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger; Streptozocin

The ob protein, termed leptin, is produced by adipocytes and is thought to act as an afferent satiety signal regulating weight through suppressing appetite and stimulating energy expenditure in humans and/or rodents. Insulin has been found to be a potent stimulator of leptin expression in rodents. It is unclear at present whether this insulin action is a direct or an indirect effect. To investigate whether leptin concentrations in children and adolescents with type 1 diabetes (IDDM) were related to metabolic status, body weight, body mass index and insulin treatment, we have measured leptin concentrations in serum from 13 newly diagnosed IDDM patients before the beginning of insulin treatment (8 girls, 5 boys, aged 4.7-17.5 years) and in 134 patients with IDDM during treatment (64 girls, 70 boys, aged 2.6-20.1 years) using a specific radioimmunoassay. The data from patients with diabetes were compared with normative data that were derived from a large cohort of healthy children and adolescents. Serum from children with newly diagnosed diabetes had significantly lower levels of leptin (mean 1.28+/-1.60 ng/ml, range 0.14-6.13 ng/ml) compared with healthy children (n=710) (mean 2.2 ng/ml, range 0.26-14.4ng/ml) and compared with insulin-treated children and adolescents (mean 5.18+/-5.48 ng/ml, range 0.26-29.77 ng/ml) (P<0.0001) even after adjustment for gender and body mass index (BMI). Serum leptin levels in patients with IDDM were significantly correlated with BMI (r=0.42, P<0.0001). Multiple regression analysis showed that age and BMI were significantly correlated with leptin levels, while duration of diabetes, mean HbA1c levels, insulin dose and plasma glucose, triglyceride and cholesterol levels were not. Females had higher serum leptin concentrations than males even when adjusted for BMI (P<0.0001). Surprisingly and most importantly, leptin levels in insulin-treated young adult (Tanner stage 5) patients were significantly higher than values found in the healthy nondiabetic reference population when adjusted for sex, Tanner stage and BMI. These findings suggest that leptin levels in IDDM patients show a similar dependency on adipose tissue and age as in healthy, normal children. The data provide evidence that insulin may be of importance as a regulator of serum leptin levels in vivo not only in rodents but also in humans. It is hypothesized that the elevated BMI-adjusted leptin levels in adolescents with IDDM could indicate either that these patients may

Topics: Adolescent; Body Mass Index; Child; Child, Preschool; Diabetes Mellitus; Diabetes Mellitus, Type 1; Female; Humans; Leptin; Male; Obesity; Proteins; Reference Values; Regression Analysis

In an earlier study, we observed only a weak association between plasma insulin (non-specific assay) and leptin in South Asian Indians. This was in contrast to the observations in many other ethnic groups. With the availability of measurements of specific insulin (SI) and proinsulin (PI) in the same study group, we have reanalysed the data to look for possible correlation of leptin with proinsulin and with insulin resistance calculated from the fasting values of specific insulin and glucose using the HOMA model. Subjects with normoglycaemia (n = 117) and impaired glucose tolerance (n = 27, WHO criteria) were included in the analysis. Leptin values were higher in women. Multiple linear regression analysis showed that the variations in leptin concentrations in men were associated with BMI, WHR, and 2 h SI values (R2 = 56.2%) while fasting SI and proinsulin concentrations had no significant association. In women BMI and age showed a significant association with serum leptin values (R2 = 40.1%). Univariate and multivariate analyses using insulin resistance as the dependent variable showed that it had no association with leptin in both genders. Leptin had no correlation with proinsulin also. This study confirmed that in Asian Indians the association between plasma leptin and insulin concentrations is weak and that leptin has no influence on insulin resistance. Proinsulin and leptin are also not correlated in this population. Insulin resistance shows correlation with the beta-cell function both in men and women.

Topics: Adult; Analysis of Variance; Diabetes Mellitus; Female; Humans; India; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Proinsulin; Proteins; Reference Values

To evaluate serum leptin levels in children and young adults with type 1 (insulin-dependent) diabetes mellitus and to investigate whether they are different in prepuberty, puberty and young adulthood.. Three groups of diabetics (prepubertal, pubertal and young adults) subdivided into obese and non-obese were studied. Three groups of healthy subjects matched for sex, age and body mass index served as controls.. Diabetic patients had serum leptin concentrations similar to those of controls in all three groups. A small non-significant increase in leptin from the prepubertal to the young adult age group for both diabetics and controls was found. A significant association of serum leptin level with body mass index (P < 0.001), female sex (P < 0.001) and age (P < 0.01) in both the diabetic and control group was present. Insulin-dependent diabetes was not associated with higher leptin concentration.. Serum leptin concentrations are similar in diabetic patients and healthy controls. The association between obesity and leptin concentration was similar in the diabetic and non-diabetic subjects. Type 1 diabetes mellitus does not modify serum leptin concentration.

Topics: Adolescent; Adult; Aging; Body Mass Index; Child; Diabetes Mellitus; Diabetes Mellitus, Type 1; Female; Humans; Leptin; Male; Obesity; Proteins; Regression Analysis; Sex Characteristics

Topics: Adipose Tissue; Diabetes Complications; Diabetes Mellitus; Humans; Insulin; Leptin; Obesity; Proteins; Recombinant Proteins; Weight Loss

Topics: Adipose Tissue; Animals; Carrier Proteins; Diabetes Mellitus; Diabetes Mellitus, Type 2; Humans; Insulin; Insulin Resistance; Leptin; Mice; Mice, Obese; Neuropeptide Y; Obesity; Proteins; Receptor, Insulin; Receptors, Cell Surface; Receptors, Leptin

Leptin, the product of the ob gene, has been reported to regulate feeding behavior and energy metabolism. Plasma leptin concentration was strongly correlated with body fat content in humans. It is well known that increased body fat content is accompanied by insulin insensitivity. In order to study the relationship between serum leptin level and metabolic variables, we performed caloric restriction on Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats, a model of noninsulin dependent diabetes mellitus. The male OLETF rats were allocated at random to three groups: 100% group, and 85% and 70% groups (which consumed 85% and 70% of the amount of food consumed by the 100% group, respectively). A significant correlation between serum leptin level and the body fat content, body weight, triglyceride, and fasting plasma glucose was observed. Using a partial correlation analysis to control for body fat content, however, the correlation between serum leptin and these variables disappeared. No significant changes in serum leptin levels were observed before and after a 1 h hyperinsulinemic euglycemic clamp test. In conclusion, serum leptin was significantly correlated with body fat content rather than fasting plasma glucose, serum insulin and insulin sensitivity. This suggests that circulating leptin per se may not result in hyperinsulinemia and insulin insensitivity in the OLETF rat.

Topics: Animals; Body Constitution; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Type 2; Disease Models, Animal; Energy Intake; Fats; Food; Hyperglycemia; Hyperinsulinism; Insulin Resistance; Leptin; Male; Obesity; Proteins; Radioimmunoassay; Rats; Rats, Inbred Strains

Overaccumulation of fat in pancreatic islets of obese ZDF fa/fa rats is believed to cause beta-cell failure and diabetes. Previously, we demonstrated that ZDF islets have an increased capacity to esterify fatty acids imported via the circulation. Here we examine the capacity of ZDF islets to synthesize fatty acids de novo. Compared with age-matched wild-type (+/+) control islets, acetyl CoA carboxylase (ACC) mRNA was fivefold and sixfold higher and fatty acid synthetase (FAS) was fourfold and sevenfold higher in prediabetic and diabetic ZDF islets, respectively. Incorporation of label from [14C]glucose into lipids was 84% higher in ZDF islets and was not suppressed normally by fatty acids. Chronic hyperleptinemia, induced by adenoviral transfer of leptin cDNA, reduced ACC and FAS mRNA in +/+ islets by 93 and 80%, respectively, but did not decrease the high ACC and FAS expression in islets of fa/fa rats. Recombinant leptin cultured with islets isolated from +/+ rats lowered ACC and FAS expression by 66 and 47%, respectively, but had no effect in fa/fa islets. We conclude that de novo lipogenesis in islets is controlled by leptin and remains low in leptin-responsive islets. It is increased in leptin-insensitive fa/fa islets, contributing to the fat overload that leads to beta-cell dysfunction and diabetes.

Topics: Acetyl-CoA Carboxylase; Animals; Diabetes Mellitus; Fatty Acid Synthases; Fatty Acids, Nonesterified; Female; Gene Expression; Gene Expression Regulation, Enzymologic; Glucose; Islets of Langerhans; Leptin; Lipids; Male; Obesity; Prediabetic State; Proteins; Rats; Rats, Zucker; Recombinant Fusion Proteins; RNA, Messenger

Topics: Aging; Cognition; Diabetes Mellitus; Dietary Carbohydrates; Energy Intake; Energy Metabolism; Insulin Resistance; Leptin; Nutritional Physiological Phenomena; Obesity

We measured plasma leptin and insulin concentrations across a spectrum of obesity in 829 white Caucasian, 154 Afro-Caribbean, and 204 Asian type 2 diabetic subjects. Although the leptin concentrations covered a large range, there were no subgroups of diabetic subjects with very high or low leptin levels that would suggest mutations in the leptin gene or leptin receptor gene comparable to the obese diabetic ob/ob and db/db mice models respectively. In all three ethnic groups, leptin concentrations correlated with body mass index (BMI) in a similar manner to nondiabetic patients and were higher in females than males after adjustment for BMI, with no difference between ethnic groups. In a multivariate regression analysis, plasma leptin was associated with gender and BMI, (both P < 1 x 10(-17)) and with fasting plasma insulin concentrations (P = 5 x 10(-9)). Subjects treated with insulin had both raised insulin and leptin concentrations. When matched for different therapies, gender, and BMI, diabetic subjects with high leptin levels also had high insulin levels (P < 0.0009). High leptin concentrations may in part be influenced by hyperinsulinemia or impaired insulin sensitivity.

Topics: Aged; Black People; Body Mass Index; Diabetes Mellitus; Diabetes Mellitus, Type 2; Fasting; Female; Humans; Insulin; Leptin; Male; Middle Aged; Obesity; Osmolar Concentration; Proteins; Sex Characteristics; White People

The response of serum leptin to short (4 days) and prolonged (28 days) energy restriction (50% reduction in energy intake) was determined in 18 (9 male, 9 female) moderately obese humans (body mass index 32.0 +/- 0.6 kg/m2 mean +/- SEM), 9 of whom had mild non-insulin-dependent diabetes mellitus (NIDDM). Body composition was assessed before and at the end of the energy restriction using DEXA. The subjects lost a measured 2.6 +/- 0.4 kg of body fat after 28 days and an estimated 0.3 kg at 4 days. Serum leptin fell to 64 +/- 3% of baseline levels at day 4 and further to 46 +/- 4% at day 28. In a multiple correlation analysis, the change in leptin concentration at day 4 was significantly related to the change in dietary carbohydrate intake (partial r = 0.68, p < 0.005) but not to changes in fat (r = 0.12) or protein (r = 0.02) intakes. There was a 1:1 relationship between the changes in leptin and dietary carbohydrate (regression slope = 1.0 +/- 0.3). Gender, or the presence of NIDDM had no effects on these responses. This pronounced fall in serum leptin in association with reduced carbohydrate intake before substantial loss of body fat suggests a role for leptin in defending the body's carbohydrate stores and implicates leptin in the satiating effects of carbohydrate. Dietary or other interventions which maintain leptin levels during weight reduction may lead to improvements in weight loss.

Topics: Analysis of Variance; Body Composition; Body Mass Index; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diet, Diabetic; Diet, Reducing; Dietary Carbohydrates; Dietary Fats; Dietary Proteins; Energy Intake; Female; Homeostasis; Humans; Leptin; Male; Obesity; Proteins; Regression Analysis

Topics: Animals; Carrier Proteins; Diabetes Mellitus; Diabetes Mellitus, Type 2; Energy Metabolism; Humans; Leptin; Mice; Mice, Obese; Obesity; Parabiosis; Proteins; Rats; Receptors, Adrenergic, beta; Receptors, Adrenergic, beta-3; Receptors, Cell Surface; Receptors, Leptin; Satiation

Obesity is associated with both insulin resistance and hyperinsulinemia. Initially hyperinsulinemia compensates for the insulin resistance and thereby maintains normal glucose homeostasis. Obesity is also associated with increased tissue triglyceride (TG) content. To determine whether both insulin resistance and hyperinsulinemia might be secondary to increased tissue TG, we studied correlations between TG content of skeletal muscle, liver, and pancreas and plasma insulin, plasma [insulin] x [glucose], and beta-cell function in four rat models with widely varying fat content: obese Zucker diabetic fatty rats, free-feeding lean Wistar rats, hyperleptinemic Wistar rats with profound tissue lipopenia, and rats pair fed to hyperleptinemics. Correlation coefficients >0.9 (P < 0.05) were obtained among TG of skeletal muscle, liver, and pancreas and among plasma insulin, [insulin] x [glucose] product, and beta-cell function as gauged by basal, glucose-stimulated, and arginine-stimulated insulin secretion by the isolated perfused pancreas. Although these correlations cannot prove cause and effect, they are consistent with the hypothesis that the TG content of tissues sets the level of both insulin resistance and insulin production.

Topics: Animals; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hyperinsulinism; Insulin; Insulin Resistance; Islets of Langerhans; Leptin; Liver; Male; Muscle, Skeletal; Obesity; Pancreas; Protein Biosynthesis; Proteins; Rats; Rats, Wistar; Rats, Zucker; Regression Analysis; Transcription, Genetic; Triglycerides

The recently discovered ob gene and its circulating product, leptin, may be critical factors in the control of energy balance. Recent studies in ob/ob mice, which lack circulating leptin, have shown dramatic reductions in food intake and bodyweight after leptin treatment. In addition, studies in both humans with obesity and animal models of obesity have demonstrated hyperleptinemia. Here, we report a longitudinal study examining changes in circulating leptin during the development of obesity and diabetes in Psammomys obesus. Over the 8 weeks of the study, lean animals increased their bodyweight by 154% and leptin levels remained essentially unchanged. In contrast, animals that developed obesity (223% increase in bodyweight), hyperglycemia, and hyperinsulinemia also developed hyperleptinemia between 4 weeks and 8 weeks of age. These results demonstrate that the development of hyperleptinemia is associated with the development of obesity and subsequent metabolic abnormalities.

Topics: Adipose Tissue; Aging; Animals; Blood Glucose; Body Composition; Body Weight; Diabetes Mellitus; Disease Models, Animal; Drug Resistance; Eating; Gerbillinae; Insulin; Leptin; Obesity; Proteins; Weight Gain

Leptin is the protein product of the ob gene, an adipocyte-specific gene, recently discovered in mice. Plasma leptin levels were determined in six normals, twenty-one subjects with impaired glucose tolerance, and forty-nine untreated NIDDM subjects. They increased with the augmentation of obesity (body mass index, BMI kg/m2) and were higher in females than in males: in BMI less than 25 kg/m2 the values of plasma leptin were 2.24 +/- 0.25 ng/ml (n=29) in males and 3.01 +/- 0.39 ng/ml (n=13) in females (P<0.054), respectively, in BMI between 25 kg/m2 and 30 kg/m2 they were 3.14 +/- 0.31 ng/ml (n=10) in males and 10.66 +/- 2.86 ng/ml (n=7) in females (P<0.0018) and in BMI higher than 30 kg/m2 their levels were 8.98 +/- 1.5 ng/ml (n=11) and 11.74 +/- 2.2 ng/ml (n=6) (P<0.23), respectively. The severity of diabetes mellitus judged from the fasting plasma glucose level had no influence on the plasma leptin levels during OGTT, but the leptin levels decreased significantly during a tolerance test (P<0.001), and similar results were also seen during a breakfast test. The fasting plasma leptin in the male with FBS less than 140 mg/dl had a significant correlation with the fasting plasma IRI level, but this correlation disappeared after taking obesity into consideration. Thus the plasma leptin was chiefly dependent on the body weight and gender and had no special relation to diabetic severity.

Topics: Adult; Blood Glucose; Body Mass Index; Cohort Studies; Diabetes Mellitus; Diabetes Mellitus, Type 2; Fasting; Female; Glucose Tolerance Test; Humans; Insulin; Leptin; Male; Middle Aged; Obesity; Proteins; Sex Factors

High leptin levels in Prader-Willi (P-W) syndrome may occur as a result of the existence of leptin resistance, because a hypothalamic disturbance may underlay this disorder. In order to study whether there is a defective action of leptin on the hypothalamus in P-W syndrome, we have measured leptin and insulin twice during the daily profile of blood glucose, comparing the results with the recent reports. The patient was a 22-year-old female, who showed the typical feature of P-W syndrome complicated overt diabetes. This case of P-W syndrome was only made to maintain a diet of 1840 kcal/day of examination under hospitalization and was not made to maintain a calorie diet on any other day of examination in clinic. There was no reduction of leptin observed during the day, especially around noon and mid-afternoon, both under hospitalization and in clinic. Our experience suggests that an absence of the normal fall in leptin during the day was not related to eating pattern in this case, but to the defective action of leptin on the hypothalamus as well as excessive production by adipose tissue.

Topics: Adult; Blood Glucose; Circadian Rhythm; Diabetes Complications; Diabetes Mellitus; Female; Humans; Insulin; Leptin; Prader-Willi Syndrome; Proteins

Obesity is a disease with distinct genetic determination and its phenotype is defined by the still unknown number of genes whose expression can be influenced by environmental factors. Several years ago, "obesity gene" was isolated in animals. This gene, coding protein which consists of 165 amino acids, is called leptin. Leptin is supposed to be a key substance controlling homeostasis of body weight and energy balance; it is produced by adipocytes and its value correlates highly significantly with anthropometric parameters that characterize physical constitution and amount of subcutaneous fatty tissue. The obese individuals often display hyperleptinemia which is frequently caused by a postreceptor disorder; sporadically, a different leptin structure or hypoleptinemia (caused by genetic anomaly) are reported. It is supposed that either absolute or relative leptin deficiency in obese persons are associated with causal obesity (e.g. appetite stimulation). Leptinemia values correlate with percentage of subcutaneous fatty tissue, insulinemia and sometimes with glycemia. In our study we examined 200 probands, patients of the Metabolic and Diabetologic Out-Patient Department, Hospital in Sternberk. A very close correlation between the amount of subcutaneous fatty tissue (measured by a caliper in 10 skinfolds) and the leptine serum concentration was found. The values of leptinemia in men of normal constitution ranged within 1-11 ng/ml, non-obese women had 3-4 times higher values. Leptinemia in some obese individuals reached up to 70 ng/ml. However, the currently calculated and reported parameters of physical constitution (BMI, WHR, Grant index) did not correlate significantly with leptinemia. Similarly, biochemical parameters considered as general markers of insulin resistance (often associated with obesity) did not correlate significantly with leptinemia. This finding indicates that some calculated parameters, quantifying and gualifying physical constitution, may be ambiguous and leptinemia was found to give more detailed information about the amount of subcutaneous fatty tissue than WHR or BMI. An accidental finding was an important positive correlation between myoglobin concentration and creatinemia. At monitoring the effect of hypolipidemic agents we use the myoglobin examination and therefore we consider this correlation to be very important and every physician performing this analysis should be informed about it. The present study thus confirmed that a more

Topics: Adipose Tissue; Adult; Aged; Aged, 80 and over; Diabetes Mellitus; Female; Humans; Leptin; Male; Middle Aged; Obesity; Proteins

Topics: Animals; Carrier Proteins; Chromosome Mapping; Cloning, Molecular; Diabetes Mellitus; Humans; Leptin; Mice; Mutation; Obesity; Proteins; Rats; Receptors, Cell Surface; Receptors, Cytokine; Receptors, Leptin; RNA, Messenger

Mice harboring mutations in the obese (ob) and diabetes (db) genes display similar phenotypes, and it has been proposed that these genes encode the ligand and receptor, respectively, for a physiologic pathway that regulates body weight. The cloning of ob, and the demonstration that it encodes a secreted protein (leptin) that binds specifically to a receptor (OB-R) in the brain, have validated critical aspects of this hypothesis. Here it is shown by genetic mapping and genomic analysis that mouse db, rat fatty (a homolog of db), and the gene encoding the OB-R are the same gene.

Topics: Animals; Base Sequence; Blotting, Southern; Carrier Proteins; Chromosome Mapping; Cloning, Molecular; Diabetes Mellitus; DNA Mutational Analysis; Genetic Markers; Leptin; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Molecular Sequence Data; Obesity; Phenotype; Polymerase Chain Reaction; Proteins; Rats; Rats, Inbred Strains; Receptors, Cell Surface; Receptors, Cytokine; Receptors, Leptin

The mouse obese (ob) gene has recently been isolated through the positional cloning technique and has been proved to result in the obese and NIDDM phenotype in mice when mutated (Nature 372:425-432, 1994). More recently, it has been demonstrated, by experiments with recombinant ob protein, that ob gene product can cause mice, including ob/ob mice, diet-induced obesity mice, and normal mice, to lower their food intake and body weight (Science 269:540-549, 1995). To investigate the genetic and/or environmental influences underlying the development of NIDDM associated with obesity, we isolated and partially sequenced the human obese (OB) gene. The human OB gene isolated in this study encoded 167 amino acids and its open reading frame was revealed to be divided into two parts with an intermediate intron of approximately 2.4 kb. Using the single-strand conformation polymorphism (SSCP) technique, we screened Japanese and Asian Indian subjects for mutations in the protein coding regions of the OB gene. A total of 75 NIDDM patients with obesity (54 Japanese and 21 Asian Indians), 40 NIDDM patients without obesity (34 Japanese and 6 Asian Indians), and 34 Japanese patients with simple obesity showed no abnormal SSCP patterns in either component of the coding sequences. These results suggested that mutations in the coding regions of the OB gene are not likely to be commonly identifiable and that there would likely be a kind of obesity-associated NIDDM not caused by mutations of the OB gene.

Topics: Adult; Age of Onset; Animals; Base Sequence; Cloning, Molecular; Diabetes Mellitus; Diabetes Mellitus, Type 2; DNA Primers; DNA, Complementary; Female; Humans; India; Japan; Leptin; Male; Mice; Mice, Obese; Middle Aged; Molecular Sequence Data; Obesity; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Proteins; Restriction Mapping

The product of the obese (ob) gene, leptin, is a secreted protein that is important in the regulation of body weight. Mice with mutations in the ob gene are obese and diabetic and manifest reduced physical as well as metabolic activity. In this study, we tested the possibility that mutations in the OB gene may contribute to human obesity. We report the isolation and partial sequence of the human OB gene and the screening of 105 obese patients for mutations in the protein coding sequence using the technique of single-strand conformational polymorphism. No coding sequence polymorphism was found, suggesting that mutations in the coding sequence of the OB gene do not constitute a common cause of increased body weight in humans. We also identified a highly polymorphic simple dinucleotide repeat DNA polymorphism in this gene that will be useful for genetic studies.

Topics: Amino Acid Sequence; Animals; Base Sequence; Diabetes Mellitus; Genomic Library; Humans; Leptin; Male; Mice; Molecular Sequence Data; Mutation; Obesity; Oligodeoxyribonucleotides; Polymorphism, Genetic; Proteins; Repetitive Sequences, Nucleic Acid

Obese (ob) is a recently identified gene involved in the regulation of energy balance in the mouse. We report here that AD-5075, a potent thiazolidinedione which lowered plasma glucose and triglyceride in Zucker diabetic fatty (ZDF) rats and db/db mice, decreased the expression of the ob gene in these animal models of obesity and non-insulin-dependent diabetes mellitus. The level of adipose ob mRNA in ZDF rats was 3-fold greater than that detected in the Zucker lean littermates. Chronic treatment with AD-5075 elicited a 67 and 70% reduction of ob mRNA in ZDF and control lean rats, respectively. Furthermore, the amount of adipose ob mRNA in db/db mice was 7 times higher than that detected in lean littermates. Treatment of db/db mice with AD-5075 resulted in a 78% reduction of the level of ob mRNA with parallel changes in circulating level of the ob gene product, leptin. The reduction of the ob mRNA in the Zucker lean rats was accompanied by significantly greater food intake and weight gain. However, in ZDF rats and db/db mice, there was profound increase in body weight without hyperphagia. The results demonstrate that the expression of the ob gene is up-regulated in these two rodent models of diabetes compared to their lean counterparts and that such overexpression is attenuated by treatment with an agent that improves insulin sensitivity and glucose homeostasis in vivo.

Topics: Adipose Tissue; Amino Acid Sequence; Animals; Base Sequence; Blood Glucose; Diabetes Mellitus; Diabetes Mellitus, Type 2; DNA Primers; DNA Probes; DNA, Complementary; Gene Expression Regulation; Glucose; Homeostasis; Hypoglycemic Agents; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Molecular Sequence Data; Obesity; Polymerase Chain Reaction; Protein Biosynthesis; Proteins; Rats; Rats, Zucker; Reference Values; RNA, Messenger; Thiazoles; Thiazolidinediones; Triglycerides

Leptin (OB protein) fused to the FLAG epitope and a kinase recognition site was expressed in bacteria, immunopurified, and phosphorylated using [gamma-(33)P] ATP. The resulting probe was used to characterize the distribution of leptin binding sites within brain sections of normal, ob/ob, and db/db C57BL/6J male mice. Leptin binding sites were found in leptomeninges and choroid plexus. Leptin binding within the choroid plexus is slightly elevated in ob/ob mice when compared to normal males (p<0.05). Binding of leptin by the choroid plexus of db/db male mice is lower than in normal males (p<0.05), but normally distributed. Based on the association and dissociation rates of leptin binding on tissue sections, we estimate the K(D) of the choroid plexus site at 0.25X10(-9) M. From our results, we hypothesize that the binding of leptin to its site may cause the release or transport of uncharacterized factor(s) into the cerebral spinal fluid (CSF) to affect neuronal populations controlling feeding and metabolism.

Topics: Animals; Autoradiography; Binding Sites; Central Nervous System; Diabetes Mellitus; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Proteins; Reference Values; Tissue Distribution

Studies in mice have identified the ob gene product, leptin, as a signaling factor regulating body weight homeostasis and energy balance. Defective production of the encoded protein may be one of the causes for the development of obesity. Using a high affinity antibody, that in immunohistochemical studies specifically stained human adipocytes, a radioimmunoassay was established and leptin immunoreactivity was quantified in plasma of lean and obese human subjects. Chromatographic analysis suggested that the immunoreactive material in plasma is identical to that found in extracts from human fat and represent a protein with a molecular size of approximately 16 kD. Fasting levels were measured in plasma of 75 lean and obese human subjects (body mass index (BMI) 17.7 - 87.3). The mean concentration of leptin in plasma of lean subjects (BMI < or = 28) was 69.3 +/- 36.9 fmol/ml plasma (mean +/- SD, n=27). The highest concentration measured in obese was 533.3 fmol/ml plasma. The levels showed a strong positive correlation with BMI (r=0.77, p<0.001). A subgroup of diabetic patients did not significantly differ in their leptin plasma levels from non-diabetic subjects with similar BMI.

Topics: Adult; Aged; Aged, 80 and over; Amino Acid Sequence; Body Mass Index; Diabetes Mellitus; Female; Humans; Immunohistochemistry; Leptin; Male; Middle Aged; Molecular Sequence Data; Obesity; Proteins; Radioimmunoassay

The obese gene product, leptin, is synthesized in adipose tissue and is a circulating factor regulating body weight. To identify the location of leptin receptors in the brain we have performed an autoradiographic study of the binding of [(125)I]leptin to frozen sections of mouse brain. Dense specific binding of [(125)I]leptin was found only in the choroid plexus which is located in the dorsal part of the third ventricle and lateral ventricles. Specific binding of [(125)I]leptin was found the ob/ob and db/db mice. These findings further our understanding of the sites and mechanism of action of leptin on brain centers regulating body weight.

Topics: Animals; Autoradiography; Binding Sites; Binding, Competitive; Brain; Carrier Proteins; Diabetes Mellitus; Female; Iodine Radioisotopes; Kinetics; Leptin; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mice, Obese; Obesity; Proteins; Receptors, Cell Surface; Receptors, Cytokine; Receptors, Leptin; Species Specificity

Leptin (Ob protein) is a recently isolated hormone produced by adipocytes and is a powerful regulator of satiety centers in the brain. A defect in either leptin production or transmission of the leptin signal in animal models, i.e. ob/ob and db/db mice, respectively, results in a syndrome of obesity and diabetes which closely resembles that which occurs in humans. Leptin release is regulated in part by nutritional status and its expression in adipose tissue is up-regulated by insulin. Since hyperinsulinemia is a primary defect in ob/ob and db/db mice which manifests early in the disease, we postulated that leptin may also regulate insulin release as part of a "adipoinsular' feedback loop. We demonstrate the expression of leptin receptor mRNA in primary rat pancreatic islets and in the insulinoma cell line beta TC-3. Furthermore, we find binding of 125I-leptin to beta TC-3 cells which is significantly displaced by leptin. These findings suggest the possibility that the binding of leptin to its receptor in beta-cells may modulate insulin expression in a negative feedback loop, and thereby may have an anti-obesity effect.

Topics: Animals; Base Sequence; Blotting, Northern; Brain; Carrier Proteins; Cells, Cultured; Diabetes Mellitus; Diabetes Mellitus, Type 2; DNA Primers; Islets of Langerhans; Kinetics; Leptin; Lung; Male; Mice; Mice, Inbred Strains; Models, Biological; Molecular Sequence Data; Obesity; Polymerase Chain Reaction; Proteins; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger

The homologues of single genes that cause obesity in rodents are suggested as candidate genes for modulation of body composition in humans. Among these genes are the four mouse mutations-diabetes (db), obesity (ob), tubby (tub), and yellow agouti (Ay). Variation in the human counterparts to these genes (OB, DB, TUB, and ASP, respectively) may contribute to human obesity, which is thought to have a substantial genetic component. To initially assess the potential contribution of these genes to human obesity, we examined polymorphic DNA markers that, by virtue of syntenic relationships to appropriate regions of the mouse genome, should be closely linked to the human counterparts of these genes. Using combined data from 716 Pima Indians comprising 217 nuclear families, we have tested a number of polymorphic microsatellite markers (three at DB, two at OB, five at TUB, and three at ASP) for sib-pair linkage to BMI, percentage body fat, resting metabolic rate, 24-h energy expenditure, and 24-h respiratory quotient. No significant linkages were found in an analysis of all sibships or in an analysis restricted to discordant sib pairs.

Topics: Adipose Tissue; Animals; Arizona; Diabetes Mellitus; DNA, Satellite; Energy Metabolism; Ethnicity; Female; Gene Frequency; Genetic Linkage; Genetic Markers; Genetic Variation; Humans; Indians, North American; Leptin; Male; Mice; Nuclear Family; Obesity; Phenotype; Polymorphism, Genetic; Prospective Studies; Proteins; Sex Characteristics; Species Specificity

We have cloned the rhesus monkey obese cDNA and have analyzed its expression in monkeys with a wide range of body weights (lean to very obese) and with or without non-insulin-dependent diabetes mellitus to examine the relationship of ob gene expression to obesity and non-insulin-dependent diabetes mellitus. The sequence of monkey ob protein, excluding the signal peptide, showed 91% identity with the human protein. We observed a significant correlation between the level of ob mRNA and body weight. We also found a significant relationship between ob mRNA and fasting plasma insulin concentration; however, insulin stimulation during a 100-140-min euglycemic/hyperinsulinemic clamp did not result in any changes in ob mRNA levels. Circulating levels of the ob gene product leptin were also significantly correlated with body weight. These results show that ob gene expression is related to body weight and is not acutely regulated by insulin.

Topics: Amino Acid Sequence; Animals; Base Sequence; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Type 2; DNA, Complementary; Gene Expression Regulation; Humans; Hyperinsulinism; Leptin; Macaca mulatta; Mice; Molecular Sequence Data; Obesity; Organ Specificity; Primate Diseases; Protein Biosynthesis; Protein Sorting Signals; Proteins; Rats; Regression Analysis; RNA, Messenger; Sequence Homology, Amino Acid; Transcription, Genetic

Many hormones circulate bound to serum proteins that modulate ligand bioactivity and bioavailability. To understand the biology of leptin action, we investigated the presence of leptin binding proteins in serum. 125I-labeled leptin binds competitively to at least three serum macromolecules with molecular masses of approximately 85, approximately 176, and approximately 240 kDa in rodents and approximately 176 and approximately 240 kDa in humans. The ability to bind appears to involve sulfhydryl/disulfide interactions because it is inhibited under reducing conditions. When serum is added to recombinant 125I-leptin, there is a shift in sedimentation of 125I-leptin as analyzed by sucrose gradient centrifugation from approximately S1.9 to approximately S4.3. This shift is markedly attenuated in serum from obese mice (ob/ob, db/db, brown-fat ablated, gold-thioglucose treated, high-fat fed) compared with that from nonobese controls. The size distribution of endogenous serum leptin as determined by radioimmunoassay (RIA) after sucrose gradient centrifugation is also consistent with saturation of binding in hyperleptinemic obesity. In humans, free leptin increases with BMI. Thus, in lean rodents and humans a large proportion of leptin circulates bound to several serum proteins. Free leptin is increased in serum of obese subjects, which may alter leptin bioactivity, transport, and/or clearance.

Topics: Adult; Aged; Animals; Aurothioglucose; Blood Proteins; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dietary Fats; Female; Humans; Leptin; Male; Mice; Mice, Obese; Middle Aged; Obesity; Obesity, Morbid; Protein Binding; Proteins; Radioimmunoassay; Reference Values; White People

Topics: Adipocytes; Animals; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Glycation End Products, Advanced; Glycosylation; Humans; Hypoglycemic Agents; Kidney Failure, Chronic; Leptin; Metformin; Mice; Mice, Mutant Strains; Mice, Obese; Obesity; Protein Biosynthesis; Proteins

To measure serum leptin concentrations in the Polynesian population of Western Samoa and to examine epidemiological associations of leptin with anthropometric, demographic, behavioural, and metabolic factors in this population with a high prevalence of obesity and non-insulin dependent diabetes mellitus.. Cross sectional study, leptin concentration being measured in a subgroup of a population based sample.. 240 Polynesian men and women aged 28-74 years were selected to cover the full range of age, body mass index, and glucose tolerance.. Serum leptin, insulin, and glucose concentrations; anthropometric measures; physical activity; and area of residence.. Leptin concentrations were correlated with body mass index (r = 0.80 in men, 0.79 in women) and waist circumference (r = 0.82 in men, 0.78 in women) but less so with waist to hip ratio. At any body mass index, leptin concentration was higher in women than men (geometric mean adjusted for body mass index 15.3 v 3.6 pg/l, P < 0.001). Leptin concentration also correlated with fasting insulin concentration (r = 0.63 in men, 0.64 in women) and insulin concentration 2 hours after a glucose load (r = 0.58 in men, 0.52 in women). These associations remained significant after controlling for body mass index; effects of physical activity and of rural or urban living on leptin concentration were eliminated after adjusting for obesity, except values remained high in urban men. 78% of variance in leptin was explained by a model including fasting insulin concentration, sex, body mass index, and a body mass index by sex interaction term. Similar results were obtained if waist circumference replaced body mass index.. The strong relation of leptin with obesity is consistent with leptin production being proportional of mass to adipose tissue. The relation with insulin independent of body mass index suggests a possible role for leptin in insulin resistance or hyperinsulinaemia.

Topics: Adult; Age Factors; Aged; Blood Glucose; Body Mass Index; Cross-Sectional Studies; Diabetes Complications; Diabetes Mellitus; Female; Humans; Independent State of Samoa; Insulin; Leptin; Male; Middle Aged; Obesity; Proteins; Rural Health; Sex Factors; Urban Health

The obesity syndrome of ob/ob mice results from lack of leptin, a hormone released by fat cells that acts in the brain to suppress feeding and stimulate metabolism. Neuropeptide Y (NPY) is a neuromodulator implicated in the control of energy balance and is overproduced in the hypothalamus of ob/ob mice. To determine the role of NPY in the response to leptin deficiency, ob/ob mice deficient for NPY were generated. In the absence of NPY, ob/ob mice are less obese because of reduced food intake and increased energy expenditure, and are less severely affected by diabetes, sterility, and somatotropic defects. These results suggest that NPY is a central effector of leptin deficiency.

Topics: Adipose Tissue; Animals; Blood Glucose; Body Composition; Body Height; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Type 2; Eating; Energy Metabolism; Female; Fertility; Insulin-Like Growth Factor I; Leptin; Male; Mice; Mice, Mutant Strains; Mice, Obese; Neuropeptide Y; Obesity; Oxygen Consumption; Proteins; RNA, Messenger

Topics: Adipocytes; Animals; Carrier Proteins; Diabetes Mellitus; Diabetes Mellitus, Type 2; Gene Expression Regulation, Enzymologic; Humans; Insulin; Insulin Antagonists; Insulin Receptor Substrate Proteins; Insulin Resistance; Leptin; Liver; Mice; Mice, Obese; Obesity; Phosphoenolpyruvate Carboxykinase (GTP); Phosphoproteins; Phosphorylation; Proteins; Receptor, Insulin; Receptors, Cell Surface; Receptors, Leptin; Signal Transduction

We addressed the relationship between plasma leptin and body mass index in 48 able-bodied male controls and 34 male subjects with spinal cord injury, as well as the association between plasma leptin with body fat by dual energy x-ray absorptiometry in those with spinal cord injury. In subjects with spinal cord injury, the effect of an oral glucose tolerance test and the relationship of the serum lipid profile with plasma leptin levels were determined. Body mass index was not significantly different between the spinal cord injury and control groups. Plasma leptin was significantly higher in the group with spinal cord injury than in the control group (12.7 +/- 1.7 vs. 7.6 +/- 0.9 ng/ml, p < 0.005). A linear relationship was found between plasma leptin and body mass index in both groups separately (spinal cord injury: r = 0.59, p < 0.0002; control: r = 0.67, p < 0.0001). In those with SCI, a polynomial relationship was evident between plasma leptin and percent fat (r = 0.82, p < 0.0001). After an oral glucose load, plasma insulin levels and serum glucose concentrations were not related to plasma leptin levels. Serum triglycerides were found to be weakly correlated with plasma leptin levels (r = 0.35, p < 0.05). The higher plasma leptin levels in the group with spinal cord injury compared with the control group was probably due to a relatively increased percentage of adiposity in those with spinal cord injury.

Topics: Absorptiometry, Photon; Adipose Tissue; Body Composition; Body Mass Index; Diabetes Mellitus; Glucose Tolerance Test; Humans; Insulin; Leptin; Lipids; Male; Proteins; Spinal Cord Injuries; Triglycerides

Topics: Adipocytes; Adipose Tissue, Brown; Animals; Antibodies, Monoclonal; Cell Nucleus; Cytoplasm; Dexamethasone; Diabetes Mellitus; Glucocorticoids; Humans; Immunohistochemistry; Leptin; Male; Proteins; Rats

The recent positional cloning of the mouse ob gene and its human homology has provided the basis to investigate the potential role of the ob gene product in body weight regulation. A biologically active form of recombinant mouse OB protein was overexpressed and purified to near homogeneity from a bacterial expression system. Peripheral and central administration of microgram doses of OB protein reduced food intake and body weight of ob/ob and diet-induced obese mice but not in db/db obese mice. The behavioral effects after brain administration suggest that OB protein can act directly on neuronal networks that control feeding and energy balance.

Topics: Animals; Brain; Diabetes Mellitus; Diet; Dose-Response Relationship, Drug; Eating; Female; Injections, Intraperitoneal; Injections, Intravenous; Injections, Intraventricular; Leptin; Male; Mice; Mice, Inbred AKR; Mice, Inbred C57BL; Mice, Obese; Nerve Net; Obesity; Proteins; Recombinant Proteins; Weight Loss

The gene product of the ob locus is important in the regulation of body weight. The ob product was shown to be present as a 16-kilodalton protein in mouse and human plasma but was undetectable in plasma from C57BL/6J ob/ob mice. Plasma levels of this protein were increased in diabetic (db) mice, a mutant thought to be resistant to the effects of ob. Daily intraperitoneal injections of either mouse or human recombinant OB protein reduced the body weight of ob/ob mice by 30 percent after 2 weeks of treatment with no apparent toxicity but had no effect on db/db mice. The protein reduced food intake and increased energy expenditure in ob/ob mice. Injections of wild-type mice twice daily with the mouse protein resulted in a sustained 12 percent weight loss, decreased food intake, and a reduction of body fat from 12.2 to 0.7 percent. These data suggest that the OB protein serves an endocrine function to regulate body fat stores.

Topics: Adipose Tissue; Animals; Blood Glucose; Body Composition; Diabetes Mellitus; Eating; Energy Metabolism; Female; Humans; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Proteins; Recombinant Proteins; Weight Loss