leptin and Insulin-Resistance

Abdominal obesity has been associated with an increased risk of insulin resistance, metabolic syndrome, and diabetes. Central fat removal procedures such as liposuction, lipectomy, and abdominoplasty are among the most common surgical procedures. The impact of the latter on the former is controversial and understudied. The authors aimed to explore the effect of subcutaneous fat elimination procedures on insulin resistance measures and adipokine levels.. Relevant studies regarding the effects of surgical subcutaneous fat removal on glucose, insulin, adipokines, and lipid metabolism, as well as blood pressure, were identified by searching PubMed and Ovid-Cochrane without limits in date, type of publication, or language. After the selection process, 24 studies were obtained. The results of the articles were summarized using descriptive statistics. For the final analysis, a randomized effects model was used to evaluate heterogeneity; averages and meta-analytic differences were expressed with a confidence interval of 95%.. All studies reported a reduction in weight (-2.64 kg; 95% CI, -4.32 to -0.96; P = 0.002; I 2 = 36%; P of I 2 < 0.001) and body mass index after liposuction. A significant improvement in triglycerides (-10.06 mg/dL; 95% CI, -14.03 to -6.09; P < 0.001; I 2 = 48%; P of I 2 = 0.05), serum glucose concentration (-4.25 mg/dL; 95% CI, -5.93 to -2.56; P < 0.001; I 2 = 68%; P of I 2 < 0.001), serum insulin concentration (-2.86 μIU/mL; 95% CI, -3.75 to -1.97; P < 0.001; I 2 = 59%; P of I 2 = 0.003), and serum leptin concentration (-7.70 ng/mL; 95% CI, -11.49 to -3.92; P = 0.0001; I 2 = 96%; P of I 2 < 0.001) was consistently observed.. In addition to weight loss, there is a significant decrease in leptin, triglyceride, glucose, and insulin serum concentrations after liposuction, a fact that should be considered in future discussions.

Topics: Blood Glucose; Body Mass Index; Body Weight; Glucose; Humans; Insulin; Insulin Resistance; Leptin; Lipectomy; Lipids; Obesity

Obesity-related asthma is associated with a high disease burden and a poor response to existent asthma therapies, suggesting that it is a distinct asthma phenotype. The proposed mechanisms that contribute to obesity-related asthma include the effects of the mechanical load of obesity, adipokine perturbations, and immune dysregulation. Each of these influences airway smooth muscle function. Mechanical fat load alters airway smooth muscle stretch affecting airway wall geometry, airway smooth muscle contractility, and agonist delivery; weight loss strategies, including medically induced weight loss, counter these effects. Among the metabolic disturbances, insulin resistance and free fatty acid receptor activation influence distinct signaling pathways in the airway smooth muscle downstream of both the M2 muscarinic receptor and the β

Topics: Asthma; Humans; Insulin Resistance; Leptin; Pediatric Obesity; Weight Loss

Microbiota dysbiosis and metabolic syndrome, consequences of a non-adequate diet, generate a feedback pathogenic state implicated in Alzheimer's disease development. The lower production of short chain fatty acids (SCFAs) under dysbiosis status leads to lipid homeostasis deregulation and decreases Angptl4 release and AMPK activation in the adipose tissue, promoting higher lipid storage (adipocyte hypertrophy) and cholesterol levels. Also, low SCFA generation reduces GPR41 and GPR43 receptor activation at the adipose tissue (increasing leptin release and leptin receptor resistance) and intestinal levels, reducing the release of GLP-1 and YPP. Therefore, lower satiety sensation and energy expenditure occur, promoting a weight gaining environment mediated by higher food intake and lipid storage, developing dyslipemia. In this context, higher glucose levels, together with higher free fatty acids in the bloodstream, promote glycolipotoxicity, provoking a reduction in insulin released, insulin receptor resistance, advanced glycation products (AGEs) and type 2 diabetes. Intestinal dysbiosis and low SCFAs reduce bacterial biodiversity, increasing lipopolysaccharide (LPS)-producing bacteria and intestinal barrier permeability. Higher amounts of LPS pass to the bloodstream (endotoxemia), causing a low-grade chronic inflammatory state characterized by higher levels of leptin, IL-1β, IL-6 and TNF-α, together with a reduced release of adiponectin and IL-10. At the brain and neuronal levels, the generated insulin resistance, low-grade chronic inflammation, leptin resistance, AGE production and LPS increase directly impact the secretase enzymes and tau hyperphosphorylation, creating an enabling environment for β-amyloid senile plaque and tau tangled formations and, as a consequence, Alzheimer's initiation, development and maintenance.

Topics: Alzheimer Disease; Diabetes Mellitus, Type 2; Dietetics; Dysbiosis; Humans; Insulin Resistance; Leptin; Lipopolysaccharides; Metabolic Syndrome; Microbiota

Bariatric procedures are considered to be the most effective treatment options for obesity. One of them is laparoscopic sleeve gastrectomy (LSG), which is nowadays very popular and widely used. LSG leads to weight loss and metabolic improvement and also changes adipokine levels, although it is just a restrictive operation. We describe changes in pro-inflammatory (leptin, resistin, visfatin and chemerin) and anti-inflammatory adipokines (adiponectin, omentin), with adiponectin and leptin being most studied. Their levels are markedly changed after LSG and this may partially explain the weight loss seen after LSG. Adipokines are closely connected to insulin resistance and chronic inflammation both being positively influenced after LSG. Leptin regulates amount of body fat, appetite, thermogenesis and metabolic rate and its levels are positively correlated with both weight and BMI changes after operation. Resistin influences insulin sensitivity, modulates body cholesterol trafficking and its changes after operation correlate with BMI, waist circumference, fat mass, LDL cholesterol and C-reactive protein. Chemerin, an important component of immune system, decreases after bariatric surgery and its levels correlate with BMI, triglyceride levels, and blood glucose. On the other hand, pro-inflammatory adipokine adiponectin, which influences fatty acid oxidation, browning of fat tissue and energy metabolism, is declining after LSG. This decline explains improvement of glucose status after bariatric surgery in patients with diabetes and is correlated with BMI loss, waist circumference and LDL cholesterol level. Effect of LSG goes beyond calory restriction and the changes of adipokines have a great impact on health status of the bariatric patients.

Topics: Adipokines; Adiponectin; Cholesterol, LDL; Gastrectomy; Humans; Insulin Resistance; Laparoscopy; Leptin; Obesity, Morbid; Resistin; Weight Loss

Cardiovascular and metabolic complications associated with excess adiposity are linked to chronic activation of the sympathetic nervous system, resulting in a high risk of mortality among obese individuals. Obesity-related positive energy balance underlies the progression of hypertension, end-organ damage, and insulin resistance, driven by increased sympathetic tone throughout the body. It is, therefore, important to understand the central network that drives and maintains sustained activation of the sympathetic nervous system in the obese state. Experimental and clinical studies have identified structural changes and altered dynamics in both grey and white matter regions in obesity. Aberrant activation in certain brain regions has been associated with altered reward circuitry and metabolic pathways including leptin and insulin signaling along with adiposity-driven systemic and central inflammation. The impact of these pathways on the brain via overactivity of the sympathetic nervous system has gained interest in the past decade. Primarily, the brainstem, hypothalamus, amygdala, hippocampus, and cortical structures including the insular, orbitofrontal, temporal, cingulate, and prefrontal cortices have been identified in this context. Although the central network involving these structures is much more intricate, this review highlights recent evidence identifying these regions in sympathetic overactivity in obesity.

Topics: Brain; Humans; Hypertension; Insulin Resistance; Leptin; Obesity; Sympathetic Nervous System

Insulin and leptin are classically regarded as peptide hormones that play key roles in metabolism. In actuality, they serve several functions in both the periphery and central nervous system (CNS). Likewise, insulin and leptin resistance can occur both peripherally and centrally. Metabolic disorders such as diabetes and obesity share several key features including insulin and leptin resistance. While the peripheral effects of these disorders are well-known (i.e. cardiovascular disease, hypertension, stroke, dyslipidemia, etc.), the CNS complications of leptin and insulin resistance have come into sharper focus. Both preclinical and clinical findings have indicated that insulin and leptin resistance are associated with cognitive deficits and neuropsychiatric diseases such as depression. Importantly, these studies also suggest that these deficits in neuroplasticity can be reversed by restoration of insulin and leptin sensitivity. In view of these observations, this review will describe, in detail, the peripheral and central functions of insulin and leptin and explain the role of insulin and leptin resistance in various metabolic disorders, cognition, and neuropsychiatric diseases.

Topics: Animals; Cognitive Dysfunction; Humans; Insulin; Insulin Resistance; Leptin; Mental Disorders; Metabolic Diseases

Lipodystrophy includes a heterogeneous group of rare diseases characterized by different amounts of adipose tissue loss and several metabolic complications, including hypertriglyceridemia, steatohepatitis and particularly insulin resistance, that may lead to severe morbidity and, sometimes, mortality. Therefore, therapy for lipodystrophy primarily consists of a conventional approach that involves standard treatments of metabolic abnormalities. Given the evidence of leptin deficiency in lipodystrophy syndromes, leptin replacement therapy has been considered as a treatment option. Long-term studies on the use of therapy with a methionylated analog of human leptin, metreleptin, first on animals and subsequently on human patients, demonstrated enormous improvements of patients' clinical features and metabolic conditions. Recently, metreleptin was approved by Food and Drug Administration (FDA) for the treatment of generalized lipodystrophy and by European Medicines Agency (EMA) for the treatment of both generalized and partial lipodystrophy. However, further research is being conducted for new and different therapeutic agents, especially helpful for the treatment of patients with partial lipodystrophy, as some of them do not have access to metreleptin therapy or show poor response.

Topics: Animals; Humans; Insulin Resistance; Leptin; Lipodystrophy; Lipodystrophy, Congenital Generalized; United States

Integration of genomic and other data has begun to stratify type 2 diabetes in prognostically meaningful ways, but this has yet to impact on mainstream diabetes practice. The subgroup of diabetes caused by single gene defects thus provides the best example to date of the vision of 'precision diabetes'. Monogenic diabetes may be divided into primary pancreatic beta cell failure, and primary insulin resistance. In both groups, clear examples of genotype-selective responses to therapy have been advanced. The benign trajectory of diabetes due to pathogenic GCK mutations, and the sulfonylurea-hyperresponsiveness conferred by activating KCNJ11 or ABCC8 mutations, or loss-of-function HNF1A or HNF4A mutations, often decisively guide clinical management. In monogenic insulin-resistant diabetes, subcutaneous leptin therapy is beneficial in some severe lipodystrophy. Increasing evidence also supports use of 'obesity therapies' in lipodystrophic people even without obesity. In beta cell diabetes the main challenge is now implementation of the precision diabetes vision at scale. In monogenic insulin-resistant diabetes genotype-specific benefits are proven in far fewer patients to date, although further genotype-targeted therapies are being evaluated. The conceptual paradigm established by the insulin-resistant subgroup with 'adipose failure' may have a wider influence on precision therapy for common type 2 diabetes, however. For all forms of monogenic diabetes, population-wide genome sequencing is currently forcing reappraisal of the importance assigned to pathogenic mutations when gene sequencing is uncoupled from prior suspicion of monogenic diabetes.

Topics: Diabetes Mellitus, Type 2; Humans; Insulin; Insulin Resistance; Leptin; Mutation; Obesity

Consumption of a high calorie diet with irregular eating and sedentary behavior habits is typical of the current suboptimal lifestyle, contributing to the development of metabolic diseases such as obesity and type 2 diabetes mellitus. Most notably, the disorder of adipokine secretion in visceral adiposity is a major contributor to metabolic diseases with advancing age. In this regard, spexin and leptin are established as anorexigenic adipokines that can modulate adipogenesis and glucose metabolism by suppressing food intake or increasing energy expenditure, respectively. Emerging evidence points out that spexin levels are lower in the serum and adipose tissue of patients with obesity and/or insulin resistance, whereas circulating levels of leptin are higher in obesity and comorbidities. In turn, spexin and leptin pharmacologically induce beneficial effects on the brain's modulation of food intake and energy expenditure. On the other hand, endocrine crosstalk via spexin and leptin has also been reported in patients suffering from obesity and diabetes. Spexin plays a crucial role in the regulation of leptin secretion and leptin resistance. It should therefore be taken into account that studying the role of spexin in leptin regulation will help us combat the pathologies of obesity caused by leptin resistance.

Topics: Diabetes Mellitus, Type 2; Energy Metabolism; Feeding Behavior; Humans; Insulin Resistance; Leptin; Metabolic Diseases; Obesity

The World Health Organization (WHO) refers to obesity as abnormal or excessive fat accumulation that presents a health risk. Obesity was first designated as a disease in 2012 and since then the cost and the burden of the disease have witnessed a worrisome increase. Obesity and hypertension are closely interrelated as abdominal obesity interferes with the endocrine and immune systems and carries a greater risk for insulin resistance, diabetes, hypertension, and cardiovascular disease. Many factors are at the interplay between obesity and hypertension. They include hemodynamic alterations, oxidative stress, renal injury, hyperinsulinemia, and insulin resistance, sleep apnea syndrome and the leptin-melanocortin pathway. Genetics, epigenetics, and mitochondrial factors also play a major role. The measurement of blood pressure in obese patients requires an adapted cuff and the search for other secondary causes is necessary at higher thresholds than the general population. Lifestyle modifications such as diet and exercise are often not enough to control obesity, and so far, bariatric surgery constitutes the most reliable method to achieve weight loss. Nonetheless, the emergence of new agents such as Semaglutide and Tirzepatide offers promising alternatives. Finally, several molecular pathways are actively being explored, and they should significantly extend the treatment options available.

Topics: Humans; Hypertension; Insulin Resistance; Leptin; Melanocortins; Obesity

Lipodystrophies are a heterogeneous group of rare conditions characterised by the loss of adipose tissue. The most common forms are the familial partial lipodystrophy (FPLD) syndromes, which include a set of disorders, usually autosomal dominant, due to different pathogenetic mechanisms leading to improper fat distribution (loss of fat in the limbs and gluteal region and variable regional fat accumulation). Affected patients are prone to suffering serious morbidity via the development of metabolic complications associated to insulin resistance and an inability to properly store lipids. Although no well-defined diagnostic criteria have been established for lipodystrophy, there are certain clues related to medical history, physical examination and body composition evaluation that may suggest FPLD prior to confirmatory genetic analysis. Its treatment must be fundamentally oriented towards the control of the metabolic abnormalities. In this sense, metreleptin therapy, the newer classes of hypoglycaemic agents and other investigational drugs are showing promising results. This review aims to summarise the current knowledge of FPLD syndromes and to describe their clinical and molecular picture, diagnostic approaches and recent treatment modalities.

Topics: Body Composition; Exercise Therapy; Humans; Hypoglycemic Agents; Insulin Resistance; Leptin; Lipid Metabolism; Lipodystrophy, Familial Partial; Medical History Taking; Metabolic Diseases; Phenotype; Physical Examination; Syndrome

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

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

Lipodystrophy syndromes are rare diseases originating from a generalized or partial loss of adipose tissue. Adipose tissue dysfunction results from heterogeneous genetic or acquired causes, but leads to similar metabolic complications with insulin resistance, diabetes, hypertriglyceridemia, nonalcoholic fatty liver disease, dysfunctions of the gonadotropic axis and endocrine defects of adipose tissue with leptin and adiponectin deficiency. Diagnosis, based on clinical and metabolic investigations, and on genetic analyses, is of major importance to adapt medical care and genetic counseling. Molecular and cellular bases of these syndromes involve, among others, altered adipocyte differentiation, structure and/or regulation of the adipocyte lipid droplet, and/or premature cellular senescence. Lipodystrophy syndromes frequently present as systemic diseases with multi-tissue involvement. After an update on the main molecular bases and clinical forms of lipodystrophy, we will focus on topics that have recently emerged in the field. We will discuss the links between lipodystrophy and premature ageing and/or immuno-inflammatory aggressions of adipose tissue, as well as the relationships between lipomatosis and lipodystrophy. Finally, the indications of substitutive therapy with metreleptin, an analog of leptin, which is approved in Europe and USA, will be discussed.

Topics: Adipocytes; Adipose Tissue; Aging, Premature; Humans; Inflammation; Insulin Resistance; Leptin; Lipodystrophy; Lipomatosis; Syndrome

Obesity is rapidly dispersing all around the world and is closely associated with a high risk of metabolic diseases such as insulin resistance, dyslipidemia, and nonalcoholic fatty liver disease (NAFLD), leading to carcinogenesis, especially hepatocellular carcinoma (HCC). It results from an imbalance between food intake and energy expenditure, leading to an excessive accumulation of adipose tissue (AT). Adipocytes play a substantial role in the tumor microenvironment through the secretion of several adipokines, affecting cancer progression, metastasis, and chemoresistance via diverse signaling pathways. AT is considered an endocrine organ owing to its ability to secrete adipokines, such as leptin, adiponectin, resistin, and a plethora of inflammatory cytokines, which modulate insulin sensitivity and trigger chronic low-grade inflammation in different organs. Even though the precise mechanisms are still unfolding, it is now established that the dysregulated secretion of adipokines by AT contributes to the development of obesity-related metabolic disorders. This review focuses on several obesity-associated adipokines and their impact on obesity-related metabolic diseases, subsequent metabolic complications, and progression to HCC, as well as their role as potential therapeutic targets. The field is rapidly developing, and further research is still required to fully understand the underlying mechanisms for the metabolic actions of adipokines and their role in obesity-associated HCC.

Topics: Adipokines; Adiponectin; Adipose Tissue; Amino Acids, Branched-Chain; Animals; Carcinoma, Hepatocellular; Hepatocytes; Humans; Insulin Resistance; Leptin; Lipid Metabolism; Liver; Liver Neoplasms; Obesity

The role of the autonomic nervous system in obesity and insulin-resistant conditions has been largely explored. However, the exact mechanisms involved in this relation have not been completely elucidated yet, since most of these mechanisms display a bi-directional effect. Insulin-resistance, for instance, can be caused by sympathetic activation, but, in turn, the associated hyperinsulinemia can activate the sympathetic branch of the autonomic nervous system. The picture is made even more complex by the implicated neural, hormonal and nutritional mechanisms. Among them, leptin plays a pivotal role, being involved not only in appetite regulation and glucose homeostasis but also in energy expenditure. The purpose of this review is to offer a comprehensive view of the complex interplay between leptin and the central nervous system, providing further insights on the impact of autonomic nervous system balance on adipose tissue and insulin-resistance. Furthermore, the link between the circadian clock and leptin and its effect on metabolism and energy balance will be evaluated.

Topics: Animals; Autonomic Nervous System; Central Nervous System; Humans; Insulin Resistance; Leptin; Obesity

Obesity is a global health issue for which no major effective treatments have been well established. High-fat diet consumption is closely related to the development of obesity because it negatively modulates the hypothalamic control of food intake due to metaflammation and lipotoxicity. The use of animal models, such as rodents, in conjunction with in vitro models of hypothalamic cells, can enhance the understanding of hypothalamic functions related to the control of energy balance, thereby providing knowledge about the impact of diet on the hypothalamus, in addition to targets for the development of new drugs that can be used in humans to decrease body weight. Recently, sphingolipids were described as having a lipotoxic effect in peripheral tissues and the central nervous system. Specifically, lipid overload, mainly from long-chain saturated fatty acids, such as palmitate, leads to excessive ceramide levels that can be sensed by the hypothalamus, triggering the dysregulation of energy balance control. However, no systematic review has been undertaken regarding studies of sphingolipids, particularly ceramide and sphingosine-1-phosphate (S1P), the hypothalamus, and obesity. This review confirms that ceramides are associated with hypothalamic dysfunction in response to metaflammation, endoplasmic reticulum (ER) stress, and lipotoxicity, leading to insulin/leptin resistance. However, in contrast to ceramide, S1P appears to be a central satiety factor in the hypothalamus. Thus, our work describes current evidence related to sphingolipids and their role in hypothalamic energy balance control. Hypothetically, the manipulation of sphingolipid levels could be useful in enabling clinicians to treat obesity, particularly by decreasing ceramide levels and the inflammation/endoplasmic reticulum stress induced in response to overfeeding with saturated fatty acids.

Topics: Animals; Ceramides; Diet, High-Fat; Endoplasmic Reticulum Stress; Energy Metabolism; Fatty Acids; Humans; Hypothalamus; Insulin Resistance; Leptin; Lysophospholipids; Obesity; Signal Transduction; Sphingolipids; Sphingosine

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

Adiponectin is an adipokine associated with the healthy obese phenotype. Adiponectin increases insulin sensitivity and has cardio and vascular protection actions. Studies related to adiponectin, a modulator of the innate and acquired immunity response, have suggested a role of this molecule in asthma. Studies based on various asthma animal models and on the key cells involved in the allergic response have provided important insights about this relation. Some of them indicated protection and others reversed the balance towards negative effects. Many of them described the cellular pathways activated by adiponectin, which are potentially beneficial for asthma prevention or for reduction in the risk of exacerbations. However, conclusive proofs about their efficiency still need to be provided. In this article, we will, briefly, present the general actions of adiponectin and the epidemiological studies supporting the relation with asthma. The main focus of the current review is on the mechanisms of adiponectin and the impact on the pathobiology of asthma. From this perspective, we will provide arguments for and against the positive influence of this molecule in asthma, also indicating the controversies and sketching out the potential directions of research to complete the picture.

Topics: Adipokines; Adiponectin; Asthma; Humans; Insulin Resistance; Leptin; Obesity

Diet-induced hypothalamic inflammation, which leads to hypothalamic dysfunction and a loss of regulation of energy balance, is emerging as a potential driver of obesity. Excessive intake of long-chain saturated fatty acids is held to be the causative dietary component in hypothalamic inflammation. This review summarizes current evidence on the role of long-chain saturated fatty acids in promoting hypothalamic inflammation and the related induction of central insulin and leptin insensitivity. Particularly, the present review focuses on the molecular mechanisms linking long-chain saturated fatty acids and hypothalamic inflammation, emphasizing the metabolic fate of fatty acids and the resulting lipotoxicity, which is a key driver of hypothalamic dysfunction. In conclusion, long-chain saturated fatty acids are key nutrients that promote hypothalamic inflammation and dysfunction by fostering the build-up of lipotoxic lipid species, such as ceramide. Furthermore, when long-chain saturated fatty acids are consumed in combination with high levels of refined carbohydrates, the proinflammatory effects are exacerbated via a mechanism that relies on the formation of advanced glycation end products.

Topics: Animals; Diet, High-Fat; Dietary Fats; Energy Metabolism; Fatty Acids; Humans; Hypothalamus; Insulin; Insulin Resistance; Leptin; Obesity

Maternal pregestational obesity is a well-known risk factor for offspring obesity, metabolic syndrome, cardiovascular disease and type 2 diabetes. The mechanisms by which maternal obesity can induce alterations in fetal and later neonatal metabolism are not fully elucidated due to its complexity and multifactorial causes. Two adipokines, leptin and adiponectin, are involved in fetal and postnatal growth trajectories, and both are altered in women with pregestational obesity. The placenta synthesizes leptin, which goes mainly to the maternal circulation and in lesser amount to the developing fetus. Maternal pregestational obesity and hyperleptinemia are associated with placental dysfunction and changes in nutrient transporters which directly affect fetal growth and development. By the other side, the embryo can produce its own leptin from early in development, which is associated to fetal weight and adiposity. Adiponectin, an insulin-sensitizing adipokine, is downregulated in maternal obesity. High molecular weight (HMW) adiponectin is the most abundant form and with most biological actions. In maternal obesity lower total and HMW adiponectin levels have been described in the mother, paralleled with high levels in the umbilical cord. Several studies have found that cord blood adiponectin levels are related with postnatal growth trajectories, and it has been suggested that low adiponectin levels in women with pregestational obesity enhance placental insulin sensitivity and activation of placental amino acid transport systems, supporting fetal overgrowth. The possible mechanisms by which maternal pregestational obesity, focusing in the actions of leptin and adiponectin, affects the fetal development and postnatal growth trajectories in their offspring are discussed.

Topics: Adipokines; Adiponectin; Diabetes, Gestational; Female; Fetal Development; Humans; Insulin Resistance; Leptin; Molecular Weight; Obesity, Maternal; Placenta; Pregnancy; Pregnancy Complications; Receptors, Adiponectin; Receptors, Leptin

Obstructive sleep apnea (OSA), obesity, and disturbed glucose homeostasis are usually considered distinct clinical condition, although they are tightly related to each other. The aim of our manuscript is to provide an overview of the current evidence on OSA, obesity, and disturbed glucose homeostasis providing epidemiologic evidence, biological insights, and therapeutic strategies.. The mechanisms hypothesized to be involved in this complex interplay are the following: (1) "direct weight-dependent" mechanisms, according to which fat excess compromises respiratory mechanics, and (2) "indirect weight-dependent" mechanisms such as hyperglycemia, insulin resistance and secondary hyperinsulinemia, leptin resistance and other hormonal dysregulations frequently found in subjects with obesity, type 2 diabetes, and/or sleep disorders. Moreover, the treatment of each of these clinical conditions, through weight loss induced by diet or bariatric surgery, the use of anti-obesity or antidiabetic drugs, and continuous positive airway pressure (CPAP), seems to positively influence the others. These recent data suggest not only that there are multiple connections among these diseases but also that treating one of them may result in an improvement of the others.

Topics: Bariatric Surgery; Body Weight; Continuous Positive Airway Pressure; Diabetes Mellitus, Type 2; Diet; Glucose; Homeostasis; Humans; Hyperinsulinism; Insulin Resistance; Leptin; Obesity; Risk Factors; Sleep Apnea, Obstructive; Weight Loss

Hyperinsulinemia and insulin resistance were proposed more than 30 years ago to be important contributors to elevated blood pressure (BP) associated with obesity and the metabolic syndrome, also called syndrome X. Support for this concept initially came from clinical and population studies showing correlations among hyperinsulinemia, insulin resistance, and elevated BP in individuals with metabolic syndrome. Short-term studies in experimental animals and in humans provided additional evidence that hyperinsulinemia may evoke increases in sympathetic nervous system (SNS) activity and renal sodium retention that, if sustained, could increase BP. Although insulin infusions may increase SNS activity and modestly raise BP in rodents, chronic insulin administration does not significantly increase BP in lean or obese insulin-resistant rabbits, dogs, horses, or humans. Multiple studies in humans and experimental animals have also shown that severe insulin resistance and hyperinsulinemia may occur in the absence of elevated BP. These observations question whether insulin resistance and hyperinsulinemia are major factors linking obesity/metabolic syndrome with hypertension. Other mechanisms, such as physical compression of the kidneys, activation of the renin-angiotensin-aldosterone system, hyperleptinemia, stimulation of the brain melanocortin system, and SNS activation, appear to play a more critical role in initiating hypertension in obese subjects with metabolic syndrome. However, the metabolic effects of insulin resistance, including hyperglycemia and dyslipidemia, appear to interact synergistically with increased BP to cause vascular and kidney injury that can exacerbate the hypertension and associated injury to the kidneys and cardiovascular system.

Topics: Animals; Humans; Hyperinsulinism; Hypertension; Insulin Resistance; Kidney; Leptin; Metabolic Syndrome; Obesity; Renin-Angiotensin System; Sodium; Sympathetic Nervous System

Leptin and adiponectin are two adipokines. Their circulating concentrations, high for leptin and low for adiponectin, are predictive of insulin resistance and of an unfavorable cardiometabolic evolution in patients with obesity, metabolic syndrome or type 2 diabetes. In addition, recently, the adiponectin/leptin ratio has been proposed as an index of adipose tissue dysfunction together with threshold values for cardiometabolic risk for this index. The relevance and potential applications of the adiponectin/leptin and leptin/adiponectin ratios are discussed in the light of recent literature in this brief update.

Topics: Adiponectin; Biomarkers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diagnostic Techniques, Endocrine; Humans; Insulin Resistance; Leptin; Metabolic Syndrome; Obesity; Prognosis; Risk Factors

Leptin and adiponectin are two adipokines currently used as biomarkers for diagnostic orientation and phenotyping in syndromes of lipodystrophy and severe insulin resistance. The level of these biomarkers also has an impact on the therapeutic management of the patients. These aspects, as well as our experience as a reference center, are described in this brief overview.

Topics: Adiponectin; Biomarkers; Humans; Insulin Resistance; Leptin; Lipodystrophy; Metabolic Syndrome; Phenotype; Severity of Illness Index

Studies on the effect of Ramadan diurnal intermittent fasting (RDIF) on glucometabolic markers have yielded conflicting results. We conducted ameta-analysis to estimate the effect size for changes in glucometabolic markers in healthy, non-athletic Muslims during Ramadan, and to assess the effect of variable covariates using meta-regression.. CINAHL, Cochrane, EBSCOhost, EMBASE, Google Scholar, ProQuest Medical, PubMed/MEDLINE, ScienceDirect, Scopus, and Web of Science databases were searched from date of inceptionto January 2020. The glucometabolic markers analyzed were: fasting glucose (FG), insulin, insulin resistance (HOMA-IR), leptin, and adiponectin.. We identified seventy-two studies (3134 participants in total) that were conducted in 22 countries between 1982 and 2020. RDIF-induced effect sizes for the glucometabolic markers were: FG (no. of studies K = 61, number of subjects N = 2743, Hedges'g = -0.102, 95% CI: -0.194, -0.01); serum insulin (K = 16, N = 648, Hedges'g = 0.030 95% CI: -0.165, 0.226); HOMA-IR (K = 10, N = 349, Hedges'g = -0.012, 95% CI: -0.274, 0.250); leptin (K = 13, N = 442, Hedges'g = -0.010, 95% CI: -0.243, 0.223); and adiponectin (K = 11, N = 511, Hedges'g = 0.034, 95% CI: -0.227, 0.296).. RDIF imposes no adverse metabolic impacts, and might help in improving some glucometabolic markers in healthy subjects.

Topics: Adiponectin; Adolescent; Adult; Biomarkers; Blood Glucose; Circadian Rhythm; Fasting; Female; Healthy Volunteers; Holidays; Humans; Insulin; Insulin Resistance; Islam; Leptin; Male; Middle Aged; Young Adult

We aimed to perform a systematic review and meta-analysis of studies assessing the homeostasis model assessment for insulin resistance (HOMA-IR) values, serum adiponectin, leptin and resistin levels in patients with systemic lupus erythematosus (SLE).. Online databases were searched on 31 March 2019 in order to identify studies comparing HOMA-IR, serum adiponectin, leptin and resistin levels between patients with SLE and controls. A random-effects model was adopted.. Fifty-six studies involving a total of 4460 patients with SLE were included. Patients with SLE had significantly higher HOMA-IR values (standardized mean difference (SMD)=0.425; 95% confidence interval (CI) 0.156-0.693;. Patients with SLE have higher HOMA-IR values and serum levels of adiponectin, leptin and resistin than individuals without SLE. The serum level of resistin correlates with SLE disease activity.

Topics: Adiponectin; Disease Progression; Humans; Insulin Resistance; Leptin; Lupus Erythematosus, Systemic; Resistin; Severity of Illness Index

Polycystic ovary syndrome (PCOS) is the most common cause of female endocrine infertility. Insulin resistanсе is supposed to be one of the essential factors of this disease pathways. At the same time, the mechanisms of PCOS development in insulin-resistant patients have not been completely established. Leptin and Peroxisome Proliferator-Activated Receptor γ(PPARγ) are involved in carbohydrate metabolism and reproduction function regulation. It indicates that leptin and PPARγ possibly play a role in the pathways of PCOS. This article is a review of publications on this issue. The purpose of this review was to systematize the available information on the molecular mechanisms that determine the role of leptin and PPARγ in the development of PCOS. The literature search was carried out from 04/05/2020 to 05/17/2020 using the scientific literature databases: NCBI PubMed (foreign sources) and Cyberleninka (domestic sources). We analyzed publications for the period 1990-2020.The review presents the current understanding of the possible role of leptin and PPARγ in the regulation of endocrine, immune systems, and reproductive function, as well as in the development of PCOS. Currently, no studies cover the mechanisms of interaction between leptin and PPARγ in the pathways of this syndrome. The available studies indicating the individual contribution and association of leptin and PPARγ with PCOS are conflicting and have many limitations. Therefore, more studies of direct and indirect interaction of leptin and PPARγ, as well as their role in PCOS pathways, are needed.

Topics: Female; Humans; Infertility, Female; Insulin Resistance; Leptin; Polycystic Ovary Syndrome; PPAR gamma

Sepsis has become a global health problem with rising incidence and high mortality, creating a substantial social and economic burden. Early diagnosis and treatment can improve outcome, but reliable sepsis biomarkers are lacking. This review summarizes current evidence of the pathophysiological mechanisms linking adipose tissue to sepsis and presents experimental and clinical data on adipokines and sepsis along with important insights into the obesity paradox in sepsis survival.. Sepsis is characterized by significant alterations in circulating cytokines and adipokines, biologically active molecules produced by the adipose tissue, being implicated in metabolic and inflammatory processes. Although data are inconclusive regarding classic adipokines such as leptin and adiponectin, recent evidence have highlighted the striking elevation of resistin and visfatin in critical illness and sepsis as well as their association with sepsis severity and outcomes. Given that inflammatory and metabolic pathways are involved in sepsis, studying adipokines presents an attractive, innovative, and promising research field that may provide more powerful diagnostic and prognostic biomarkers as well as novel therapeutic targets, empowering the therapeutic armamentarium for sepsis management in order to improve survival.

Topics: Adipokines; Adiponectin; Adipose Tissue; Animals; Biomarkers; Cytokines; Humans; Hyperglycemia; Insulin Resistance; Leptin; Nicotinamide Phosphoribosyltransferase; Obesity; Resistin; Sepsis; Severity of Illness Index

Lipodystrophy is a disease characterized by a partial or total absence of adipose tissue leading to severe metabolic derangements including marked insulin resistance, type 2 diabetes, hypertriglyceridemia, and steatohepatitis. Lipodystrophy is also a source of major cardiovascular disorders which, in addition to hepatic failure and infection, contribute to a significant reduction in life expectancy. Metreleptin, the synthetic analog of the adipocyte-derived hormone leptin and current therapy of choice for patients with lipodystrophy, successfully improves metabolic function. However, while leptin has been associated with hypertension, vascular diseases, and inflammation in the context of obesity, it remains unknown whether its daily administration could further impair cardiovascular function in patients with lipodystrophy. The goal of this short review is to describe the cardiovascular phenotype of patients with lipodystrophy, speculate on the etiology of the disorders, and discuss how the use of murine models of lipodystrophy could be beneficial to address the question of the contribution of leptin to lipodystrophy-associated cardiovascular disease.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Fatty Liver; Humans; Hypertriglyceridemia; Insulin Resistance; Leptin; Lipodystrophy; Mice

Lipodystrophy syndromes are rare heterogeneous disorders characterized by deficiency of adipose tissue, usually a decrease in leptin levels and, frequently, severe metabolic abnormalities including diabetes mellitus and dyslipidemia.. To describe the clinical presentation of known types of lipodystrophy, and suggest specific steps to recognize, diagnose and treat lipodystrophy in the clinical setting.. Based on literature and in our own experience, we propose a stepwise approach for diagnosis of the different subtypes of rare lipodystrophy syndromes, describing its more frequent co-morbidities and establishing the therapeutical approach.. Lipodystrophy is classified as genetic or acquired and by the distribution of fat loss, which can be generalized or partial. Genes associated with many congenital forms of lipodystrophy have been identified that may assist in diagnosis. Because of its rarity and heterogeneity, lipodystrophy may frequently be unrecognized or misdiagnosed, which is concerning because it is progressive and its complications are potentially life threatening. A basic diagnostic algorithm is proposed. Effective management of lipodystrophy includes lifestyle changes and aggressive, evidence-based treatment of comorbidities. Leptin replacement therapy (metreleptin) has been found to improve metabolic parameters in many patients with lipodystrophy. Metreleptin is approved in the United States as replacement therapy to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy and has been submitted for approval in Europe.. Here, we describe the clinical presentation of known types of lipodystrophy, present an algorithm for differential diagnosis of lipodystrophy, and suggest specific steps to recognize and diagnose lipodystrophy in the clinical setting.

Topics: Adipose Tissue; Diet, Healthy; Humans; Insulin Resistance; Leptin; Lipodystrophy; Treatment Outcome

Considering conflicting results on the consequences of all types of obesity surgery, we were to summarize them via a systematic review.. Electronic literature search was done via scientific search engines. After the removal of duplicates and selection of articles of interest, 771 studies were included.. Insulin resistance indicators were significantly improved after bariatric surgery. Leptin was also significantly decreased while adiponectin was significantly increased. Although the level of metabolic hormones changed after bariatric surgery, they were not statistically significant. Inflammation indicators were significantly decreased. Significant reduction was also detected in PAI-1 and sICAM-1.. Bariatric surgery is beneficial in morbidly obese patients. Although treating obesity in a surgical way may cause some complications, the weight loss is generally safe and effective.

Topics: Adiponectin; Bariatric Surgery; C-Reactive Protein; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Intercellular Adhesion Molecule-1; Interleukin-6; Leptin; Obesity, Morbid; Peptide YY; Plasminogen Activator Inhibitor 1; Tumor Necrosis Factor-alpha

Mammalian adipose tissue is traditionally categorized into white and brown relating to their function and morphology: while white serves as an energy storage, brown adipose tissue acts as the heat generator maintaining the core body temperature. The most recently identified type of fat, beige adipocyte tissue, resembles brown fat by morphology and function but is developmentally more related to white. The synthesis of beige fat, so-called browning of white fat, has developed into a topical issue in diabetes and metabolism research. This is due to its favorable effect on whole-body energy metabolism and the fact that it can be recruited during adult life. Indeed, brown and beige adipose tissues have been demonstrated to play a role in glucose homeostasis, insulin sensitivity, and lipid metabolism-all factors related to pathogenesis of type 2 diabetes. Many agents capable of initiating browning have been identified so far and tested widely in humans and animal models including in vitro and in vivo experiments. Interestingly, several agents demonstrated to have browning activity are in fact secreted as adipokines from brown and beige fat tissue, suggesting a physiological relevance both in beige adipocyte recruitment processes and in maintenance of metabolic homeostasis. The newest findings on agents driving beige fat recruitment, their mechanisms, and implications on type 2 diabetes are discussed in this review.

Topics: Adipose Tissue, Beige; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Diabetes Mellitus, Type 2; Energy Metabolism; Glucagon-Like Peptide 1; Glucose; Humans; Insulin Resistance; Leptin; Lipid Metabolism; Lipotropic Agents; Melatonin; Natriuretic Peptides; Thermogenesis; Tretinoin

Diabetes is a metabolic disorder with multiple complications, including cardiomyopathy, retinopathy, nephropathy and neuropathy. Diabetic complications are the major cause of disability and death in diabetic patients. Apelin, a recently identified adipokine peptide, has been found to play important roles in diabetic complications. Here we summarize the current knowledge on the role of apelin in the pathogenesis of different diabetic complications. We also propose that similar to insulin resistance or leptin resistance, diabetics may also show apelin resistance. Potential clinical application of apelin and its analogue peptides in treating diabetic complications is discussed.

Topics: Apelin; Diabetes Complications; Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Leptin; Molecular Structure; Protein Conformation; Structure-Activity Relationship

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

Sulfur amino acids (SAAs) play numerous critical roles in metabolism and overall health maintenance. Preclinical studies have demonstrated that SAA-restricted diets have many beneficial effects, including extending life span and preventing the development of a variety of diseases. Dietary sulfur amino acid restriction (SAAR) is characterized by chronic restrictions of methionine and cysteine but not calories and is associated with reductions in body weight, adiposity and oxidative stress, and metabolic changes in adipose tissue and liver resulting in enhanced insulin sensitivity and energy expenditure. SAAR-induced changes in blood biomarkers include reductions in insulin, insulin-like growth factor-1, glucose, and leptin and increases in adiponectin and fibroblast growth factor 21. On the basis of these preclinical data, SAAR may also have similar benefits in humans. While little is known of the translational significance of SAAR, its potential feasibility in humans is supported by findings of its effectiveness in rodents, even when initiated in adult animals. To date, there have been no controlled feeding studies of SAAR in humans; however, there have been numerous relevant epidemiologic and disease-based clinical investigations reported. Here, we summarize observations from these clinical investigations to provide insight into the potential effectiveness of SAAR for humans.

Topics: Adiponectin; Adipose Tissue; Amino Acids, Sulfur; Animals; Biomarkers; Blood Glucose; Cardiovascular Diseases; Diet; Energy Metabolism; Fibroblast Growth Factors; Humans; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Liver; Models, Animal; Neoplasms

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

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

Anthocyanins are food compounds which belong to polyphenols and can mainly be found in dark fruits (e.g., blueberries, black currants, cranberries) and vegetables (e.g., red cabbage, radish, eggplant). The results of large research have shown that these compounds play an important role in the prevention of type 2 diabetes (T2D). In rodent studies and in studies with isolated omental adipocytes, it was observed that anthocyanins regulated the carbohydrate metabolism in the body due to the upregulation of GLUT4 (insulinregulated glucose transporter) translocation, increased activation of PPARγ (peroxisome proliferator-activated receptor-γ) in adipose tissue and skeletal muscles as well as increased secretion of adiponectin and leptin. Moreover, these compounds reduced the inflammation status in the body. Studies conducted on humans and experimental animals showed that anthocyanins decrease insulin resistance. This effect may be achieved by the upregulation of GLUT4 gene expression, activation of AMP-activated protein kinase and downregulation of retinol binding protein 4 (RBP4) expression. Anthocyanins also increased the uptake and utilization of glucose by tissues in streptozotocin-induced diabetic rats and mice, and they also protected pancreatic cells against necrosis induced by streptozotocin. Another mechanism that might explain the lower glucose level in the blood after a meal with anthocyanins compared to a meal without them is the inhibition of intestinal α-glucosidase and pancreatic α-amylase by these compounds. Moreover, anthocyanins improve insulin secretion, which can have a special meaning for people with T2D. The evidence from the presented studies suggests that foods rich in anthocyanins may be one of the diet elements supporting the prevention and treatment of T2D.

Topics: Adiponectin; Animals; Anthocyanins; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Glucose Transporter Type 4; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Mice; Muscle, Skeletal; Pancreas; PPAR gamma; Rats; Retinol-Binding Proteins, Plasma

One-third of men with obesity or type 2 diabetes have subnormal free testosterone concentrations. The lower free testosterone concentrations are observed in obese men at all ages, including adolescents at completion of puberty. The gonadotropin concentrations in these males are inappropriately normal; thus, these patients have hypogonadotropic hypogonadism (HH). The causative mechanism of diabesity-induced HH is yet to be defined but is likely multifactorial. Decreased insulin and leptin signaling in the central nervous system are probably significant contributors. Contrary to popular belief, estrogen concentrations are lower in men with HH. Men with diabesity and HH have more fat mass and are more insulin resistant than eugonadal men. In addition, they have a high prevalence of anemia and higher mortality rates than eugonadal men. Testosterone replacement therapy results in a loss of fat mass, gain in lean mass, and increase in insulin sensitivity in men with diabesity and HH. This is accompanied by an increase in insulin-signaling genes in adipose tissue and a reduction in inflammatory mediators that interfere with insulin signaling. There is also an improvement in sexual symptoms, anemia, LDL cholesterol, and lipoprotein (a). However, testosterone therapy does not consistently affect HbA

Topics: Diabetes Mellitus, Type 2; Humans; Hypogonadism; Insulin; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Obesity; Prevalence; Testosterone

Gestational diabetes mellitus (GDM) is a serious pregnancy complication, in which women without previously diagnosed diabetes develop chronic hyperglycemia during gestation. In most cases, this hyperglycemia is the result of impaired glucose tolerance due to pancreatic β-cell dysfunction on a background of chronic insulin resistance. Risk factors for GDM include overweight and obesity, advanced maternal age, and a family history or any form of diabetes. Consequences of GDM include increased risk of maternal cardiovascular disease and type 2 diabetes and macrosomia and birth complications in the infant. There is also a longer-term risk of obesity, type 2 diabetes, and cardiovascular disease in the child. GDM affects approximately 16.5% of pregnancies worldwide, and this number is set to increase with the escalating obesity epidemic. While several management strategies exist-including insulin and lifestyle interventions-there is not yet a cure or an efficacious prevention strategy. One reason for this is that the molecular mechanisms underlying GDM are poorly defined. This review discusses what is known about the pathophysiology of GDM, and where there are gaps in the literature that warrant further exploration.

Topics: Adiponectin; Adipose Tissue; Animals; Diabetes, Gestational; Female; Glucose; Humans; Insulin Resistance; Insulin-Secreting Cells; Leptin; Oxidative Stress; Pregnancy; Risk Factors

Obesity is metabolic disorder that increases the risk of diabetes, heart disease, and other metabolic syndromes in human beings. One sign of diabetes is increased blood glucose levels in the body. Glucose levels increase due to problems with insulin secretion or insulin resistance. Maturity onset of diabetes of the young is more common in adults and occurs due to insulin resistance. Both diabetes and obesity are major problems that are responsible for the death of millions of individuals every year, worldwide. Leptin, a 164-KDa hormone that is secreted by white adipose tissue, is a product of the lep gene. Mutation in lep decreases leptin concentration and increases obesity and type-2 diabetes mellitus. Leptin has been shown to produce positive effects on hunger, energy expenditure, and behavior and is thus useful in the treatment of obesity and type-2 diabetes. Leptin controls appetite through its effect on the hypothalamus in the brain. Both leptin and insulin regulate appetite, body weight, and glucose levels in the body.

Topics: Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Leptin; Obesity

Several studies show that a significantly stronger association is obvious between increased body mass index (BMI) and higher breast cancer incidence. Furthermore, obese women are at higher risk of all-cause and breast cancer specific mortality when compared to non-obese women with breast cancer. In this context, increased levels of estrogens due to excessive aromatization activity of the adipose tissue, overexpression of pro-inflammatory cytokines, insulin resistance, hyperactivation of insulin-like growth factors (IGFs) pathways, adipocyte-derived adipokines, hypercholesterolemia and excessive oxidative stress contribute to the development of breast cancer in obese women. While higher breast cancer risk with hormone replacement therapy is particularly evident among lean women, in postmenopausal women who are not taking exogenous hormones, general obesity is a significant predictor for breast cancer. Moreover, increased plasma cholesterol leads to accelerated tumor formation and exacerbates their aggressiveness. In contrast to postmenopausal women, premenopausal women with high BMI are inversely associated with breast cancer risk. Nevertheless, life-style of women for breast cancer risk is regulated by avoiding the overweight and a high-fat diet. Estrogen-plus-progestin hormone therapy users for more than 5 years have elevated risks of both invasive ductal and lobular breast cancer. Additionally, these cases are more commonly node-positive and have a higher cancer-related mortality. Collectively, in this chapter, the impacts of obesity-related estrogen, cholesterol, saturated fatty acid, leptin and adiponectin concentrations, aromatase activity, leptin and insulin resistance on breast cancer patients are evaluated. Obesity-related prognostic factors of breast cancer also are discussed at molecular basis.

Topics: Breast Neoplasms; Cholesterol; Female; Humans; Insulin Resistance; Leptin; Obesity; Risk Factors

Leptin has been implicated in bone metabolism, but the association with parathyroid gland function has not been fully clarified. This review aimed to summarize evidence of the association between leptin and hyperparathyroidism, both primary and secondary, elucidating the potential pathophysiologic and therapeutic consequences between leptin and parathyroid hormone, hopefully prompting the design of new studies.. Experimental studies indicate a positive loop between leptin and parathyroid hormone in primary hyperparathyroidism. Dissimilar, parathyroid hormone seems to inhibit leptin expression in severe secondary hyperparathyroidism. Data from clinical studies indicate higher leptin levels in patients with primary hyperparathyroidism than controls, but no association between parathyroid hormone and leptin levels, as well as a minimal or neutral effect of parathyroidectomy on leptin levels in patients with primary hyperparathyroidism. Clinical data on secondary hyperparathyroidism, mainly derived from patients with chronic kidney disease, indicate a potential inverse association between leptin and parathyroid hormone in some, but not all studies. This relationship may be affected by the diversity of morbidity among these patients.. Data from experimental studies suggest a different association between leptin and parathyroid hormone in primary and secondary hyperparathyroidism. Data from clinical studies are conflicting and potentially affected by confounders. More focused, well-designed studies are warranted to elucidate a potential association between leptin and parathyroid hormone, which may have specific clinical implications, i.e., targeting obesity and hyperleptinemia in patients with hyperparathyroidism.

Topics: Adipose Tissue, White; Animals; Anti-Obesity Agents; Chief Cells, Gastric; Hormone Replacement Therapy; Humans; Hyperparathyroidism, Primary; Hyperparathyroidism, Secondary; Insulin Resistance; Leptin; Models, Biological; Obesity; Parathyroid Glands; Parathyroid Hormone; Recombinant Proteins; Reproducibility of Results; Severity of Illness Index

Obesity has been an epidemic worldwide over the past decades and significantly increases the risk of developing a variety of deadly diseases including type 2 diabetes, cardiovascular diseases and many cancers. The relationship between obesity and type 2 diabetes and cardiovascular disease has been well documented. The drastically increased frequency of a number of cancers in obesity has attracted growing interest. On one hand, how increased adiposity promotes cancer development remains poorly understood, despite the fact that considerable epidemiological evidence has suggested links between them. On the other hand, however, numerous studies have shown that tumorigenesis leads to substantial weight loss in a large portion of cancer patients. Here, we summarize the recent advances on our understanding of the link between obesity and cancer development with a focus on the molecular mechanisms accounting for the rising cancer incidence in the context of obesity. In addition, we also discuss how cancer-associated anorexia and cachexia causes weight loss. © 2017 IUBMB Life, 69(10):776-784, 2017.

Topics: Anorexia; Body Mass Index; Cachexia; Cytokines; Energy Metabolism; Gene Expression Regulation, Neoplastic; Humans; Insulin Resistance; Leptin; Neoplasms; NF-kappa B; Obesity; Receptors, Leptin; Risk Factors; Signal Transduction; STAT3 Transcription Factor

Despite the well-known global impact of overweight and obesity in the incidence of cerebrovascular disease, many aspects of this association are still inconsistently defined. In this chapter we aim to present a critical review on the links between obesity and both ischemic and hemorrhagic stroke and discuss its influence on functional outcomes, survival, and current treatments to acute and chronic stroke. The role of cerebrovascular endothelial function and respective modulation is also described as well as its laboratory and clinical assessment. In this context, the major contributing mechanisms underlying obesity-induced cerebral endothelial function (adipokine secretion, insulin resistance, inflammation, and hypertension) are discussed. A special emphasis is given to the participation of adipokines in the pathophysiology of stroke, namely adiponectin, leptin, resistin, apelin, and visfatin.

Topics: Adipokines; Adiponectin; Apelin; Brain Ischemia; Cerebrovascular Disorders; Endothelium, Vascular; Humans; Hypertension; Inflammation; Insulin Resistance; Intracranial Hemorrhages; Leptin; Nicotinamide Phosphoribosyltransferase; Obesity; Resistin; Stroke

Conflicting results regarding leptin levels in women with polycystic ovary syndrome (PCOS) have been reported. We summarize all available evidence from human participant studies to evaluate leptin levels in PCOS.. PubMed, ClinicalTrials.gov , and Web of Science databases were searched with English-language restriction for only human beings from the inception to December 31, 2015. Search terms included PCOS (polycystic ovary syndrome or PCOS) and leptin.. A total of 238 studies were reviewed, and a total of 19 studies, involving 991 women with PCOS and 898 controls, were eligible for our meta-analysis. Studies were eligible if provided leptin means and standard deviation in women with PCOS and healthy women controls.. Parameters, such as body mass index, insulin resistance (IR), and total testosterone, which may influence leptin levels were extracted. Data were collected and analyzed by RevMan 5.3 and Stata/SE14.0. The pooling analysis of all relevant studies revealed that leptin levels were significantly higher in patients with PCOS than in controls, with standardized mean difference of 1.62 (95% confidence interval: 1.01-2.23). However, the heterogeneity across studies was considerable and not eliminated in subgroup analyses. Meta-regression analysis further suggested that the heterogeneity might be relevant to variability in IR and study location.. Elevated leptin levels are detected in women with PCOS compared with non-PCOS controls. Higher leptin levels may be correlated with IR, metabolic disorder, infertility, and even cardiovascular disease risk in PCOS, which may contribute to the etiology and development of PCOS.

Topics: Body Mass Index; Female; Humans; Insulin Resistance; Leptin; Polycystic Ovary Syndrome; Risk Factors; Testosterone

Aging is associated with dysregulation of glucose and lipid metabolism. Various factors that contribute to the dysregulation include both modifiable (e.g. obesity, insulin resistance) and non-modifiable risk factors (age-associated physiologic changes). Although there is no linear relationship between aging and prevalence of non-alcoholic fatty liver disease, current data strongly suggests that advanced age leads to more severe histological changes and poorer clinical outcomes. Hepatic lipid accumulation could lead to significant hepatic and systemic consequences including steatohepatitis, cirrhosis, impairment of systemic glucose metabolism and metabolic syndrome, thereby contributing to age-related diseases. Insulin, leptin and adiponectin are key regulators of the various physiologic processes that regulate hepatic lipid metabolism. Recent advances have expanded our understanding in this field, highlighting the role of novel mediators such as FGF 21, and mitochondria derived peptides. In this review, we will summarize the mediators of hepatic lipid metabolism and how they are altered in aging.

Topics: Adiponectin; Aging; Fibroblast Growth Factors; Gene Expression Regulation, Developmental; Glucose; Humans; Insulin; Insulin Resistance; Leptin; Lipid Metabolism; Liver; Liver Cirrhosis; Metabolic Syndrome; Non-alcoholic Fatty Liver Disease; Obesity; Signal Transduction

T cells are highly influenced by nutrient uptake from their environment, and changes in overall nutritional status, such as malnutrition or obesity, can result in altered T-cell metabolism and behavior. In states of severe malnutrition or starvation, T-cell survival, proliferation, and inflammatory cytokine production are all decreased, as is T-cell glucose uptake and metabolism. The altered T-cell function and metabolism seen in malnutrition is associated with altered adipokine levels, most particularly decreased leptin. Circulating leptin levels are low in malnutrition, and leptin has been shown to be a key link between nutrition and immunity. The current view is that leptin signaling is required to upregulate activated T-cell glucose metabolism and thereby fuel T-cell activation. In the setting of obesity, T cells have been found to have a key role in promoting the recruitment of inflammatory macrophages to adipose depots along with the production of inflammatory cytokines that promote the development of insulin resistance leading to diabetes. Deletion of T cells, key T-cell transcription factors, or pro-inflammatory T-cell cytokines prevents insulin resistance in obesity and underscores the importance of T cells in obesity-associated inflammation and metabolic disease. Altogether, T cells have a critical role in nutritional immunometabolism.

Topics: Animals; Cytokines; Food; Glucose; Humans; Inflammation; Insulin Resistance; Leptin; Lymphocyte Activation; Malnutrition; Nutritional Status; Obesity; Signal Transduction; T-Lymphocytes

The central link between obesity and type 2 diabetes is the development of insulin resistance. To date, it is still not clear whether hyperinsulinemia causes insulin resistance, which underlies the pathogenesis of obesity-associated type 2 diabetes, owing to the sophisticated regulatory mechanisms that exist in the periphery and in the brain. In recent years, accumulating evidence has demonstrated the existence of insulin resistance within the hypothalamus. In this review, we have integrated the recent discoveries surrounding both central and peripheral insulin resistance to provide a comprehensive overview of insulin resistance in obesity and the regulation of systemic glucose homeostasis. In particular, this review will discuss how hyperinsulinemia and hyperleptinemia in obesity impair insulin sensitivity in tissues such as the liver, skeletal muscle, adipose tissue, and the brain. In addition, this review highlights insulin transport into the brain, signaling pathways associated with hypothalamic insulin receptor expression in the regulation of hepatic glucose production, and finally the perturbation of systemic glucose homeostasis as a consequence of central insulin resistance. We also suggest future approaches to overcome both central and peripheral insulin resistance to treat obesity and type 2 diabetes.

Topics: Animals; Diabetes Mellitus, Type 2; Glucose; Homeostasis; Humans; Hypothalamus; Insulin Resistance; Leptin; Obesity; Signal Transduction

Universal oral glucose tolerance-based screening is employed to identify pregnant women with gestational diabetes mellitus (GDM), as treatment of this condition decreases the risk of associated complications. A simple and accurate blood test which identifies women at low or high risk for GDM in the first trimester would have the potential to decrease costs and improve outcomes through prevention or treatment. This review summarizes published data on early pregnancy biomarkers which have been tested as predictors of GDM.. A large number of first-trimester biochemical predictors of GDM have been reported, mostly in small case-control studies. These include glycemic markers (fasting glucose, post-load glucose, hemoglobin A1C), inflammatory markers (C-reactive protein, tumor necrosis factor-alpha), insulin resistance markers (fasting insulin, sex hormone-binding globulin), adipocyte-derived markers (adiponectin, leptin), placenta-derived markers (follistatin-like-3, placental growth factor, placental exosomes), and others (e.g., glycosylated fibronectin, soluble (pro)renin receptor, alanine aminotransferase, ferritin). A few large studies suggest that first-trimester fasting glucose or hemoglobin A1C may be useful for identifying women who would benefit from early GDM treatment. To translate the findings from observational studies of first-trimester biomarkers for GDM to clinical practice, trials or cost-effectiveness analyses of screening and treatment strategies based on these novel biomarkers are needed.

Topics: Adiponectin; Adult; Biomarkers; Blood Glucose; Diabetes, Gestational; Female; Glycated Hemoglobin; Humans; Insulin; Insulin Resistance; Leptin; Pregnancy; Tumor Necrosis Factor-alpha

Experimental and clinical studies have clearly shown the role of the sympathetic nervous system in the pathophysiology of several cardiovascular and non-cardiovascular diseases. This short review will be aimed at focusing and discussing the new information collected on two specific clinical conditions such as obesity and metabolic syndrome. The paper will briefly describe the four main mechanisms that represent the common link between these two pathophysiological conditions and that through the sympathetic nervous system contribute to increase the cardiovascular risk.

Topics: Animals; Baroreflex; Biomarkers; Blood Pressure; Cardiovascular System; Humans; Hypertension; Insulin; Insulin Resistance; Leptin; Metabolic Syndrome; Obesity, Abdominal; Oxidative Stress; Prognosis; Renin-Angiotensin System; Risk Factors; Sympathetic Nervous System

In this review we discuss the mechanisms for the pleotropic effects of leptin replacement therapy to reverse liver and muscle insulin resistance in lipodystrophic individuals, as well as insulin-independent effects of leptin replacement therapy to suppress white adipose tissue lipolysis, hepatic gluconeogenesis and fasting hyperglycaemia in rodent models of poorly controlled diabetes. On the basis of these studies we conclude with a view of the potential therapeutic applications of leptin replacement therapy in humans. This review summarises a presentation given at the 'Is leptin coming back?' symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Thomas Meek and Gregory Morton, DOI: 10.1007/s00125-016-3898-3 , and by Christoffer Clemmensen and colleagues, DOI: 10.1007/s00125-016-3906-7 ) and an overview by the Session Chair, Ulf Smith (DOI: 10.1007/s00125-016-3894-7 ).

Topics: Animals; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Humans; Insulin Resistance; Leptin

The incidence of obesity, a leading modifiable risk factor for common solid tumors, is increasing. Effective interventions are needed to minimize the public health implications of obesity. Although the mechanisms linking increased adiposity to malignancy are incompletely understood, growing evidence points to complex interactions among multiple systemic and tissue-specific pathways including inflamed white adipose tissue. The metabolic and inflammatory consequences of white adipose tissue dysfunction collectively provide a plausible explanation for the link between overweight/obesity and carcinogenesis. Gaining a better understanding of these underlying molecular pathways and developing risk assessment tools that identify at-risk populations will be critical in implementing effective and novel cancer prevention and management strategies.

Topics: Adiponectin; Adipose Tissue, White; Androgens; Estrogens; Humans; Inflammation; Insulin Resistance; Leptin; Lipid Metabolism; Neoplasms; Obesity

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

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

Patients with type 2 diabetes have lower serum testosterone levels and a higher prevalence of hypogonadism than non-diabetic patients, independently of the metabolic control of disease. The mechanisms underlying a decrease in testosterone might be related to age, obesity and insulin resistance, often present in patients with type 2 diabetes. The increase in estrogens due to higher aromatase enzyme activity in increased adipose tissue might exert negative-feedback inhibition centrally. Insulin stimulates gonadal axis activity at all three levels and therefore insulin resistance might account for the lower testosterone production. Leptin exerts a central stimulatory effect but inhibits testicular testosterone secretion. Thus, resistance to leptin in obese subjects with type 2 diabetes determines lower central effects of leptin with lower gonadotropin-releasing hormone (GnRH) secretion and, on the other hand, hyperleptinemia secondary to leptin resistance inhibits testosterone secretion at the testicular level. However, lower testosterone levels in patients with diabetes are observed independently of age, weight and body mass index, which leads to the assumption that hyperglycemia per se might play a role in the decrease in testosterone. Several studies have shown that an overload of glucose results in decreased serum testosterone levels. The aim of this review is to assess changes in the male gonadal axis that occur in patients with type 2 diabetes.

Topics: Diabetes Mellitus, Type 2; Estrogens; Humans; Hyperglycemia; Hypogonadism; Insulin Resistance; Leptin; Male; Prevalence

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

β-cell failure coupled with insulin resistance plays a key role in the development of type 2 diabetes mellitus (T2DM). Changed adipokines in circulating level form a remarkable link between obesity and both β-cell failure and insulin resistance. Some adipokines have beneficial effects,whereas others have detrimental properties. The overall contribution of adipokines to β-cell failure mainly depends on the interactions among adipokines. This article reviews the role of individual adipokines such as leptin,adiponectin,and resistin in the function,proliferation,death,and failure of β-cells. Future studies focusing on the combined effects of adipokines on β-cells failure may provide new insights in the treatment of T2DM.

Topics: Adipokines; Adiponectin; Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Insulin-Secreting Cells; Leptin; Obesity; Resistin

G-protein coupled receptors (GPCRs) are involved in the regulation of adipose tissue function, but the total number of GPCRs expressed by human subcutaneous adipose tissue, as well as their function and interactions with drugs, is poorly understood. We have constructed an atlas of all GPCRs expressed by human subcutaneous adipose tissue: the 'adipose tissue GPCRome', to support the exploration of novel control nodes in metabolic and endocrine functions. This atlas describes how adipose tissue GPCRs regulate lipolysis, insulin resistance and adiponectin and leptin secretion. We also discuss how adipose tissue GPCRs interact with their endogenous ligands and with GPCR-targeting drugs, with a focus on how drug/receptor interactions may affect lipolysis, and present a model predicting how GPCRs with unknown effects on lipolysis might modulate cAMP-regulated lipolysis. Subcutaneous adipose tissue expresses 163 GPCRs, a majority of which have unknown effects on lipolysis, insulin resistance and adiponectin and leptin secretion. These GPCRs are activated by 180 different endogenous ligands, and are the targets of a large number of clinically used drugs. We identified 119 drugs, acting on 23 GPCRs, that are predicted to stimulate lipolysis and 173 drugs, acting on 25 GPCRs, that are predicted to inhibit lipolysis. This atlas highlights knowledge gaps in the current understanding of adipose tissue GPCR function, and identifies GPCR/ligand/drug interactions that might affect lipolysis, which is important for understanding and predicting metabolic side effects of drugs. This approach may aid in the design of new, safer therapeutic agents, with fewer undesired effects on lipid homeostasis.

Topics: Adiponectin; Animals; Humans; Insulin Resistance; Leptin; Ligands; Lipolysis; Receptors, G-Protein-Coupled; Subcutaneous Fat

With the steady rise in the incidence of obesity and its associated comorbidities, in the last decades research aimed at understanding molecular mechanisms that control body weight has gained new interest. Fat gain is frequently associated with chronic adipose tissue inflammation and with peripheral as well as central metabolic derangements, resulting in an impaired hypothalamic regulation of energy homeostasis. Recent attention has focused on the role of phosphatidylinositol 3-kinase (PI3K) in both immune and metabolic response pathways, being involved in the pathophysiology of obesity and its associated metabolic diseases. In this review, we focus on distinct PI3K isoforms, especially class I PI3Ks, mediating inflammatory cells recruitment to the enlarged fat as well as intracellular responses to key hormonal regulators of fat storage, both in adipocytes and in the central nervous system. This integrated view of PI3K functions may ultimately help to develop new therapeutic interventions for the treatment of obesity.

Topics: Adipocytes; Adipose Tissue; Animals; Class I Phosphatidylinositol 3-Kinases; Energy Metabolism; Gene Expression Regulation; Homeostasis; Humans; Hypothalamus; Immunity, Innate; Inflammation; Insulin Resistance; Leptin; Obesity; Receptor, Melanocortin, Type 4; Signal Transduction

Several articles have dealt with the importance and mechanisms of the sympathetic nervous system alterations in experimental animal models of hypertension. This review addresses the role of the sympathetic nervous system in the pathophysiology and therapy of human hypertension. We first discuss the strengths and limitations of various techniques for assessing the sympathetic nervous system in humans, with a focus on heart rate, plasma norepinephrine, microneurographic recording of sympathetic nerve traffic, and measurements of radiolabeled norepinephrine spillover. We then examine the evidence supporting the importance of neuroadrenergic factors as promoters and amplifiers of human hypertension. We expand on the role of the sympathetic nervous system in 2 increasingly common forms of secondary hypertension, namely hypertension associated with obesity and with renal disease. With this background, we examine interventions of sympathetic deactivation as a mode of antihypertensive treatment. Particular emphasis is given to the background and results of recent therapeutic approaches based on carotid baroreceptor stimulation and radiofrequency ablation of the renal nerves.

Topics: Animals; Antihypertensive Agents; Clinical Trials as Topic; Diagnostic Techniques, Cardiovascular; Forecasting; Heart Rate; Humans; Hyperinsulinism; Hypertension; Hypertension, Renal; Insulin Resistance; Kidney; Kidney Diseases; Leptin; Melanocortins; Metabolic Syndrome; Multicenter Studies as Topic; Neuroimaging; Norepinephrine; Obesity; Sympathectomy; Sympathetic Fibers, Postganglionic; Sympathetic Nervous System; Vasoconstriction

Excess weight gain, especially when associated with increased visceral adiposity, is a major cause of hypertension, accounting for 65% to 75% of the risk for human primary (essential) hypertension. Increased renal tubular sodium reabsorption impairs pressure natriuresis and plays an important role in initiating obesity hypertension. The mediators of abnormal kidney function and increased blood pressure during development of obesity hypertension include (1) physical compression of the kidneys by fat in and around the kidneys, (2) activation of the renin-angiotensin-aldosterone system, and (3) increased sympathetic nervous system activity. Activation of the renin-angiotensin-aldosterone system is likely due, in part, to renal compression, as well as sympathetic nervous system activation. However, obesity also causes mineralocorticoid receptor activation independent of aldosterone or angiotensin II. The mechanisms for sympathetic nervous system activation in obesity have not been fully elucidated but may require leptin and activation of the brain melanocortin system. With prolonged obesity and development of target organ injury, especially renal injury, obesity-associated hypertension becomes more difficult to control, often requiring multiple antihypertensive drugs and treatment of other risk factors, including dyslipidemia, insulin resistance and diabetes mellitus, and inflammation. Unless effective antiobesity drugs are developed, the effect of obesity on hypertension and related cardiovascular, renal and metabolic disorders is likely to become even more important in the future as the prevalence of obesity continues to increase.

Topics: Aldosterone; Animals; Antihypertensive Agents; Dyslipidemias; Heart Conduction System; Hemodynamics; Humans; Hypertension; Insulin Resistance; Intra-Abdominal Fat; Kidney; Leptin; Metabolic Syndrome; Models, Animal; Models, Cardiovascular; Natriuresis; Obesity; Organ Specificity; Parasympathetic Nervous System; Pressure; Prevalence; Pro-Opiomelanocortin; Receptors, Leptin; Renal Insufficiency, Chronic; Renin-Angiotensin System; Sodium; Sympathetic Nervous System

Diabetes and obesity are associated with nonalcoholic fatty liver disease (NAFLD) and an increased incidence of hepatocellular carcinoma (HCC). NAFLD is the commonest cause of chronic liver disease. HCC can develop in NAFLD patients even without cirrhosis, suggesting an association between the metabolic process and HCC and raising a concern that many cancers could be missed given high NAFLD prevalence and screening limitations. The increasing prevalence of these conditions and lack of effective treatments necessitate a better understanding of their connection. This article defines the known interrelationships and common pathways between NAFLD, diabetes, obesity and HCC and possible chemoprevention strategies.

Topics: Carcinoma, Hepatocellular; Chemoprevention; Diabetes Mellitus, Type 2; Endoplasmic Reticulum Stress; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Incidence; Inflammation; Insulin Resistance; JNK Mitogen-Activated Protein Kinases; Leptin; Liver Neoplasms; Metformin; Non-alcoholic Fatty Liver Disease; Obesity; Risk Factors; S-Adenosylmethionine; Toll-Like Receptors

Central obesity is involved in the pathogenesis and progression of Barrett's esophagus to esophageal adenocarcinoma. Involved are likely both mechanical and nonmechanical effects. Mechanical effects of increased abdominal fat cause disruption of the gastroesophageal reflux barrier leading to increased reflux events. Nonmechanical effects may be mediated by inflammation, via classically activated macrophages, pro-inflammatory cytokines, and adipokines such as Leptin, all of which likely potentiate reflux-mediated inflammation. Insulin resistance, associated with central obesity, is also associated with both Barrett's pathogenesis and progression to adenocarcinoma. Molecular pathways activated in obesity, inflammation and insulin resistance overlap with those involved in Barrett's pathogenesis and progression.

Topics: Adiponectin; Barrett Esophagus; Gastroesophageal Reflux; Hernia, Hiatal; Humans; Inflammation; Insulin; Insulin Resistance; Leptin; Obesity, Abdominal

Adiposity is associated with pancreatic cancer; however, the underlying mechanism(s) is uncertain. Leptin is an adipokine involved in metabolic regulation, and obese individuals have higher concentrations. We conducted a pooled, nested case-control study of cohort participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, and the Cancer Prevention Study II Nutrition Cohort to investigate whether prediagnostic serum leptin was associated with pancreatic cancer. A total of 731 pancreatic adenocarcinoma cases that occurred between 1986 and 2010 were included (maximum follow-up, 23 years). Incidence density-selected controls (n = 909) were matched to cases by cohort, age, sex, race, and blood draw date. Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals. Sex-specific quintiles were based on the distribution of the controls. Overall, serum leptin was not associated with pancreatic cancer (quintile 5 vs. quintile 1: odds ratio = 1.13, 95% confidence interval: 0.75, 1.71; Ptrend = 0.38). There was a significant interaction by follow-up time (P = 0.003), such that elevated risk was apparent only during follow-up of more than 10 years after blood draw (quintile 5 vs. quintile 1: odds ratio = 2.55, 95% confidence interval: 1.23, 5.27; Ptrend = 0.004). Our results support an association between increasing leptin concentration and pancreatic cancer; however, long follow-up is necessary to observe the relationship. Subclinical disease may explain the lack of association during early follow-up.

Topics: Aged; Biomarkers, Tumor; Case-Control Studies; Cohort Studies; Early Detection of Cancer; Female; Follow-Up Studies; Humans; Incidence; Insulin Resistance; Leptin; Logistic Models; Male; Middle Aged; Odds Ratio; Pancreatic Neoplasms; Risk Assessment; Risk Factors; United States

Since identification in 1994 of leptin, a hormone produced by adipocytes, adipose tissue has become the subject of intensive research. These studies contributed to the discovery that adipocytes have the ability to synthesize and secrete biologically active substances called "adipokines". Adipokines include a variety of cytokines, peptide hormones and enzymes that play a role in a wide variety of biological functions. For example, they are involved in the regulation of appetite, energy homeostasis, vascular hemostasis, blood pressure, inflammatory and immune processes and play a role in the metabolism of carbohydrates and fats. In obese patients, the secretion of adipokines is frequently abnormal. These changes may predispose to the development of insulin resistance, hypertension and inflammation. Therefore, adipokines are the subject of ongoing clinical trials. The family of adipokines is increasing by the newly discovered peptides. This paper presents the current state of knowledge about retinol binding protein 4 (RBP-4), fasting-induced adipose factor/angiopoietin-like protein 4 (FIAF/ANGPTL4), fibroblast growth factor-21 (FGF21), dipeptidyl peptidase-4 (DPP-4), irisin and their potential role in the pathogenesis of metabolic disorders associated with obesity. The knowledge of the role of newly discovered adipokines may help in the treatment of metabolic syndrome.

Topics: Adipocytes; Adipose Tissue; Humans; Insulin Resistance; Leptin; Metabolic Diseases; Obesity

Leptin is a protein hormone produced mainly by obese gene and secreted by adipose tissue and exerts the biological effects through leptin receptors. With the progress in research on the function and receptor signal transduction related leptin and leptin resistance, it has been found that leptin is associated with the development and progression of many cardiovascular diseases, such as hypertension and left ventricular hypertrophy. Some studies have reported that leptin resistance is the pathologic basis for a variety of cardiovascular diseases. This paper will briefly review the advances in the study of correlation between leptin and hypertensive-left ventricular hypertrophy (HLVH), focusing on the relationship between leptin and various factors related to HLVH, such as sympathetic nervous system, renin angiotensin aldosterone system, growth factors, inflammatory factors and insulin resistance.. 瘦素是主要由肥胖基因编码、脂肪组织分泌的一种蛋白质类激素，通过作用于瘦素受体发挥其生物学效应。随着对瘦素功能、瘦素受体信号转导及瘦素抵抗等方面研究的深入，发现瘦素与许多心血管疾病，尤其与高血压的发生、发展密切相关。左心室肥厚(left ventricular hypertrophy，LVH)是高血压最常见的并发症之一。瘦素与促进高血压LVH形成的各种因素如交感神经系统、肾素-血管紧张素-醛固酮系统、生长因子、炎症细胞因子及胰岛素抵抗有密切关系。.

Topics: Adipose Tissue; Cardiovascular Diseases; Humans; Hypertension; Hypertrophy, Left Ventricular; Insulin Resistance; Leptin; Receptors, Leptin; Renin-Angiotensin System; Sympathetic Nervous System

A case of Berardinelli-Seip syndrome, a congenital generalised lipodystrophy, is reported. Symptoms first appeared when the patient was 20 years old. She showed severe insulin resistance as well as micro- and macro-angiopathic complications, including chronic kidney disease, which required renal replacement therapy with peritoneal dialysis. The patient's clinical course was reviewed since paediatric age (when initial signs of the disease being already evident) to present time. Berardinelli-Seip syndrome is very uncommon, and the present case is particularly rare because it is the only case (at least as reported in the literature) in a patient receiving dialysis.

Topics: Acromegaly; Cardiomyopathy, Hypertrophic; Child; Delayed Diagnosis; Diabetic Nephropathies; Diagnosis, Differential; Exons; Female; Glomerulonephritis, Membranoproliferative; GTP-Binding Protein gamma Subunits; Humans; Insulin Resistance; Leptin; Lipodystrophy, Congenital Generalized; Peritoneal Dialysis, Continuous Ambulatory

The insulin signaling system of the brain has a key role in the regulation of fundamental cell processes in neurons and controls metabolic processes in the CNS and periphery. In hypothalamic neurons insulin signaling system interacts closely with the other signaling systems regulated by leptin, melanocortin peptides, dopamine, serotonin, and is the key component of the hypothalamic signaling network, which integrates and transforms the central and peripheral signals. The disturbances in the brain insulin system lead to central insulin resistance, which is one of the primary causes of type 2 diabetes mellitus (DM), metabolic syndrome and Alzheimer's disease. The early restoration of the functions of this system provides an effective approach to prevent and treat type 2 DM and neurodegenerative diseases associated to it. In this review the literature data and own results on structural functional organization of the brain insulin signaling system, causes and functional consequences of central insulin resistance, abnormalities of insulin signaling in the CNS and approaches to its restoration in type 2 DM are analyzed and discussed.

Topics: Alzheimer Disease; Diabetes Mellitus, Type 2; Dopamine; Humans; Hypoglycemic Agents; Hypothalamus; Insulin; Insulin Resistance; Leptin; Melanocortins; Metabolic Syndrome; Neurons; Serotonin; Signal Transduction

Endometrial cancer is one of the main cancers occurring in industrialized countries. According to the National Cancer Registry in Bulgaria, cancer of the uterine body occupies 8.6% from all cancers in women and ranks second in frequency. It is found that over weight and obesity are a major risk factor for the development of endometrial cancer and the mortality associated with it. Adipose tissue is seen as endocrine organ, synthesizing so called adipocytokine - leptin, adiponectin, vistafin, that play a key role in the carcinogenesis of endometrial cancer and can be used as new markers for establishing the potential risk of this disease. The link between obesity, insulin resistance and endometrial cancer that has been proven, determines it as a socially significant disease. All this makes it necessary to clarify and specify the role of obesity in endometrial carcinogenesis and the development of strategies for the prevention and early diagnosis.

Topics: Adiponectin; Adipose Tissue; Bulgaria; Carcinogenesis; Endometrial Neoplasms; Endometrium; Female; Humans; Insulin Resistance; Leptin; Obesity; Risk Factors

Since identification in 1994 of leptin, a hormone produced by adipocytes, adipose tissue has become the subject of intensive research. These studies contributed to the discovery that adipocytes have the ability to synthesize and secrete biologically active substances called "adipokines". Adipokines include a variety of cytokines, peptide hormones and enzymes that play a role in a wide variety of biological functions. For example, they are involved in the regulation of appetite, energy homeostasis, vascular hemostasis, blood pressure, inflammatory and immune processes and play a role in the metabolism of carbohydrates and fats. In obese patients, the secretion of adipokines is frequently abnormal. These changes may predispose to the development of insulin resistance, hypertension and inflammation. Therefore, adipokines are the subject of ongoing clinical trials. The family of adipokines is increasing by the newly discovered peptides. This paper presents the current state of knowledge about retinol binding protein 4 (RBP-4), fasting-induced adipose factor/angiopoietin-like protein 4 (FIAF/ANGPTL4), fibroblast growth factor-21 (FGF21), dipeptidyl peptidase-4 (DPP-4), irisin and their potential role in the pathogenesis of metabolic disorders associated with obesity. The knowledge of the role of newly discovered adipokines may help in the treatment of metabolic syndrome.

Topics: Adipocytes; Adipokines; Adipose Tissue; Humans; Insulin Resistance; Leptin; Metabolic Diseases; Metabolic Syndrome; Obesity

Although the brain has long been considered an insulin-independent organ, recent research has shown that insulin has significant effects on the brain, where it plays a role in maintaining glucose and energy homeostasis. To avoid peripheral insulin resistance, the brain may act via hypoinsulinemic responses, maintaining glucose metabolism and insulin sensitivity within its own confines; however, brain insulin resistance may develop due to environmental factors. Insulin has two important functions in the brain: controlling food intake and regulating cognitive functions, particularly memory. Notably, defects in insulin signaling in the brain may contribute to neurodegenerative disorders. Insulin resistance may damage the cognitive system and lead to dementia states. Furthermore, inflammatory processes in the hypothalamus, where insulin receptors are expressed at high density, impair local signaling systems and cause glucose and energy metabolism disorders. Excessive caloric intake and high-fat diets initiate insulin and leptin resistance by inducing mitochondrial dysfunction and endoplasmic reticulum stress in the hypothalamus. This may lead to obesity and diabetes mellitus (DM). Exercise can enhance brain and hypothalamic insulin sensitivity, but it is the option least preferred and/or continuously practiced by the general population. Pharmacological treatments that increase brain and hypothalamic insulin sensitivity may provide new insights into the prevention of dementia disorders, obesity, and type 2 DM in the future.

Topics: Animals; Brain; Cognition Disorders; Dementia; Glucose; Humans; Insulin; Insulin Resistance; Islets of Langerhans; Leptin; Liver; Receptor, Insulin; Signal Transduction

Numerous laboratory studies involving both animal and human models indicate that weight loss induces changes in leptin, ghrelin and insulin sensitivity, which work to promote weight regain. It is unclear, however, whether these biological changes serve as a biomarker for predicting weight regain in free-living humans in which biological, behavioral and environmental factors are likely at play. We identified 12 studies published between January 1995 and December 2011 that reported changes in leptin, ghrelin or insulin during intentional weight loss with a follow-up period to assess regain. Two of the nine studies examining leptin suggested that larger decreases were associated with greater regain, three studies found the opposite (smaller decreases were associated with greater regain), whereas four studies found no significant relationship; none of the studies supported the hypothesis that increases in ghrelin during weight loss were associated with regain. One study suggested that improvements in insulin resistance were associated with weight gain, but five subsequent studies reported no association. Changes in leptin, ghrelin or insulin sensitivity, taken alone, are not sufficient to predict weight regain following weight loss in free-living humans. In future studies, it is important to include a combination of physiological, behavioral and environmental variables in order to identify subgroups at greatest risk of weight regain.

Topics: Biomarkers; Body Mass Index; Body Weight; Diet, Reducing; Exercise; Female; Ghrelin; Humans; Insulin; Insulin Resistance; Leptin; Male; Obesity; Predictive Value of Tests; Weight Gain; Weight Loss

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

Being overweight and obese has become an increasingly serious clinical and socioeconomic problem worldwide. The rapidly rising prevalence of obesity has prompted studies on modifiable, causative factors and novel treatment options for this disorder. Recent evidence indicates that excessive weight gain that leads to being overweight and obese may result from alterations in gut microflora. Studies in humans and animals demonstrated that the composition of gut microbiota may differ in lean and obese subjects, suggesting that these differences result in the increased efficiency of caloric extraction from food, enhanced lipogenesis, and impaired central and peripheral regulation of energy balance. Other studies revealed an excessive increase in body weight in a significant percentage of people infected with human adenoviruses SMAM-1 and Ad-36. Dysregulation of adipocyte function by viruses appears to be the most likely cause of excessive fat accumulation in these individuals. Studies on the pathomechanisms related to the pathogenesis of obesity indicated that a high-fat diet triggers the inflammatory response in the hypothalamus, an event that promotes weight gain and further defends elevated body weight through the initiation of central leptin and insulin resistance and impairment of regenerative capacity of hypothalamic neurons. Exposure to a high-calorie diet appears to predispose individuals to obesity not only because of excessive caloric intake but also because of the induction of microbiota- and central inflammatory response-dependent changes that lead to a dysregulation of energy balance.

Topics: Animals; Bacterial Infections; Body Weight; Energy Intake; Energy Metabolism; Gastrointestinal Tract; Humans; Hypothalamus; Inflammation; Insulin Resistance; Leptin; Obesity; Virus Diseases

Gestational diabetes is characterised by glucose intolerance with onset or first recognition during pregnancy. The disease shows facets of the metabolic syndrome including obesity, insulin resistance, and dyslipidaemia. Adipokines are a group of proteins secreted from adipocytes, which are dysregulated in obesity and contribute to metabolic and vascular complications. Recent studies have assessed the role of various adipokines including leptin, adiponectin, tumour necrosis factor α (TNFα), adipocyte fatty acid-binding protein (AFABP), retinol-binding protein 4 (RBP4), resistin, NAMPT, SERPINA12, chemerin, progranulin, FGF-21, TIMP1, LCN2, AZGP1, apelin (APLN), and omentin in gestational diabetes. This Review provides an overview of these key adipokines, their regulation in, and potential contribution to gestational diabetes. Based on the evidence so far, the adipokines adiponectin, leptin, TNFα, and AFABP seem to be the most probable candidates involved in the pathophysiology of gestational diabetes.

Topics: Adipokines; Adiponectin; Blood Glucose; Diabetes, Gestational; Fatty Acid-Binding Proteins; Female; Humans; Insulin Resistance; Leptin; Pregnancy; Tumor Necrosis Factor-alpha

Both reduction in total sleep duration with slow-wave sleep (SWS) largely preserved and alterations of sleep quality (especially marked reduction of SWS) with preservation of total sleep duration are associated with insulin resistance without compensatory increase in insulin secretion, resulting in impaired glucose tolerance and increased risk of type 2 diabetes. When performed under rigorously controlled conditions of energy intake and physical activity, sleep restriction is also associated with a decrease in circulating levels of leptin (an anorexigenic hormone) and an increase in circulating levels of ghrelin (an orexigenic hormone), hunger and appetite. Furthermore, sleep restriction is also associated with a stimulation of brain regions sensitive to food stimuli, indicating that sleep loss may lead to obesity through the selection of high-calorie food. There is also evidence that sleep restriction could provide a permissive environment for the activation of genes that promote obesity. Indeed, the heritability of body mass index is increased in short sleepers. Thus, chronic sleep curtailment, which is on the rise in modern society, including in children, is likely to contribute to the current epidemics of type 2 diabetes and obesity.

Topics: Animals; Diabetes Mellitus, Type 2; Eating; Energy Metabolism; Ghrelin; Humans; Insulin; Insulin Resistance; Leptin; Obesity; Sleep

Among the most widely used animal models in obesity-induced type 2 diabetes mellitus (T2DM) research are the congenital leptin- and leptin receptor-deficient rodent models. These include the leptin-deficient ob/ob mice and the leptin receptor-deficient db/db mice, Zucker fatty rats, Zucker diabetic fatty rats, SHR/N-cp rats, and JCR:LA-cp rats. After decades of mechanistic and therapeutic research schemes with these animal models, many species differences have been uncovered, but researchers continue to overlook these differences, leading to untranslatable research. The purpose of this review is to analyze and comprehensively recapitulate the most common leptin/leptin receptor-based animal models with respect to their relevance and translatability to human T2DM. Our analysis revealed that, although these rodents develop obesity due to hyperphagia caused by abnormal leptin/leptin receptor signaling with the subsequent appearance of T2DM-like manifestations, these are in fact secondary to genetic mutations that do not reflect disease etiology in humans, for whom leptin or leptin receptor deficiency is not an important contributor to T2DM. A detailed comparison of the roles of genetic susceptibility, obesity, hyperglycemia, hyperinsulinemia, insulin resistance, and diabetic complications as well as leptin expression, signaling, and other factors that confound translation are presented here. There are substantial differences between these animal models and human T2DM that limit reliable, reproducible, and translatable insight into human T2DM. Therefore, it is imperative that researchers recognize and acknowledge the limitations of the leptin/leptin receptor- based rodent models and invest in research methods that would be directly and reliably applicable to humans in order to advance T2DM management.

Topics: Animals; Blood Glucose; Diabetes Complications; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Humans; Hyperglycemia; Hyperinsulinism; Insulin Resistance; Leptin; Mice; Mice, Inbred Strains; Mice, Obese; Obesity; Rats; Rats, Inbred Strains; Rats, Zucker; Receptors, Leptin

White adipose tissue secretes a large variety of compounds named adipokines amongst which, leptin exhibits pleiotropic metabolic actions. Leptin is an anorexigenic hormone, secreted in proportion of fat mass, with additional effects on the regulation of inflammation, cardiovascular system, immunity, hematopoiesis and bone metabolism. Chronic kidney disease (CKD) is characterized by an increase of plasma leptin concentration that may be explained by a lack of renal clearance. Hyperleptinemia plays a key role in the pathogenesis of complications associated with CKD such as cachexia, protein energy wasting, chronic inflammation, insulin resistance, cardiovascular damages and bone complications. Leptin is also involved in the progression of renal disease through its pro-fibrotic and pro-hypertensive actions. Most of the adverse effects of leptin have been documented both experimentally and clinically. Leptin may therefore be considered as an uremic toxin in CKD. The aim of this review is to summarize the pathophysiological and clinical role of leptin in in vitro studies, experimental models, as well as in patients suffering from CKD.

Topics: Adipose Tissue; Cachexia; Humans; Hypertension; Inflammation; Insulin Resistance; Leptin; Receptors, Leptin; Renal Insufficiency, Chronic; Toxins, Biological

Despite the known glucose-lowering effects of metformin, more recent clinical interest lies in its potential as a weight loss drug. Herein, we discuss the potential mechanisms by which metformin decreases appetite and opposes unfavorable fat storage in peripheral tissues.. Many individuals struggle to maintain clinically relevant weight loss from lifestyle and bariatric surgery interventions. Long-term follow-up from the Diabetes Prevention Program demonstrates that metformin produces durable weight loss, and decreased food intake by metformin is the primary weight loss mechanism. Although the effect of metformin on appetite is likely to be multifactorial, changes in hypothalamic physiology, including leptin and insulin sensitivity, have been documented. In addition, novel work in obesity highlights the gastrointestinal physiology and circadian rhythm changes by metformin as not only affecting food intake, but also the regulation of fat oxidation and storage in liver, skeletal muscle, and adipose tissue.. Metformin induces modest weight loss in overweight and obese individuals at risk for diabetes. A more detailed understanding of how metformin induces weight loss will likely lead to optimal co-prescription of lifestyle modification with pharmacology for the treatment of obesity independent of diabetes.

Topics: Appetite Depressants; Diabetes Mellitus, Type 2; Eating; Humans; Hypoglycemic Agents; Hypothalamus; Insulin Resistance; Leptin; Metformin; Obesity; Risk Reduction Behavior; Signal Transduction; Treatment Outcome; Weight Loss

Osteocalcin is a bone matrix protein that has been associated with several hormonal actions on energy and glucose metabolism. Animal and experimental models have shown that osteocalcin is released into the bloodstream and exerts biological effects on pancreatic beta cells and adipose tissue. Undercarboxylated osteocalcin is the hormonally active isoform and stimulates insulin secretion and enhances insulin sensitivity in adipose tissue and muscle. Insulin and leptin, in turn, act on bone tissue, modulating the osteocalcin secretion, in a traditional feedback mechanism that places the skeleton as a true endocrine organ. Further studies are required to elucidate the role of osteocalcin in the regulation of glucose and energy metabolism in humans and its potential therapeutic implications in diabetes, obesity and metabolic syndrome.

Topics: Adipose Tissue; Animals; Bone and Bones; Diabetes Mellitus, Type 2; Energy Metabolism; Glucose; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Leptin; Metabolic Syndrome; Muscles; Obesity; Osteocalcin

Insulin resistance (IR) is a general phenomenon of many physiological states, disease states, and diseases. IR has been described in diabetes mellitus, obesity, infection, sepsis, trauma, painful states such as postoperative pain and migraine, schizophrenia, major depression, chronic mental stress, and others. In arthritis, abnormalities of glucose homeostasis were described in 1920; and in 1950 combined glucose and insulin tests unmistakably demonstrated IR. The phenomenon is now described in rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, polymyalgia rheumatica, and others. In chronic inflammatory diseases, cytokine-neutralizing strategies normalize insulin sensitivity. This paper delineates that IR is either based on inflammatory factors (activation of the immune/ repair system) or on the brain (mental activation via stress axes). Due to the selfishness of the immune system and the selfishness of the brain, both can induce IR independent of each other. Consequently, the immune system can block the brain (for example, by sickness behavior) and the brain can block the immune system (for example, stress-induced immune system alterations). Based on considerations of evolutionary medicine, it is discussed that obesity per se is not a disease. Obesity-related IR depends on provoking factors from either the immune system or the brain. Chronic inflammation and/or stress axis activation are thus needed for obesity-related IR. Due to redundant pathways in stimulating IR, a simple one factor-neutralizing strategy might help in chronic inflammatory diseases (inflammation is the key), but not in obesity-related IR. The new considerations towards IR are interrelated to the published theories of IR (thrifty genotype, thrifty phenotype, and others).

Topics: Brain; Chronic Disease; Cytokines; Endocrinology; Energy Metabolism; Fasting; Humans; Inflammation; Insulin Resistance; Leptin; Models, Biological; Neuroimmunomodulation; Obesity; Selection, Genetic; Starvation; Stress, Psychological

One of the crucial factors leading to the development of pre-diabetes and type 2 diabetes mellitus (DM2) are the disturbances in the brain hormonal signaling systems regulated by insulin, insulin-like growth factor-1 (IGF-1) and leptin. The causes of these disturbances are the changes in the redox balance and lipid metabolism leading to lipotoxicity and endoplasmic reticulum stress in neuronal cells, as well as the dysfunctions in neurotransmitter systems of the brain that are functionally associated with insulin, IGF-1 and leptin signaling systems. The identification of molecular disturbances in insulin, IGF-1 and leptin systems of the brain in pre-diabetes and DM2 can be used for early diagnostics of these diseases, and to develop new strategies for preventive treatment of DM2 at the pre-diabetic stage. In the review, the literature data and the results of own investigations concerning the changes in the insulin, IGF-1 and leptin systems of the brain in pre-diabetes and DM2 and their role in the etiology and pathogenesis of DM2 are analyzed, and the approaches to restore the functional activity of these systems are discussed.

Topics: Animals; Asymptomatic Diseases; Blood Glucose; Brain; Diabetes Mellitus, Type 2; Disease Progression; Gene Expression Regulation; Humans; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Neurons; Oxidative Stress; Signal Transduction

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

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

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

Obesity is a global epidemic associated with aging-like cellular processes; in both aging and obesity, resistance to hormones such as insulin and leptin can be observed. Leptin is a circulating hormone/cytokine with central and peripheral effects that is released mainly by subcutaneous white adipose tissue. Centrally, leptin controls food intake, energy expenditure, and fat distribution, whereas it controls (among several others) insulin sensitivity, free fatty acids (FFAs) oxidation, and lipolysis in the periphery. Aging is associated with important changes in both the distribution and the composition of adipose tissue. Fat is redistributed from the subcutaneous to the visceral depot and increased inflammation participates in adipocyte dysfunction. This redistribution of adipose tissue in favor of visceral fat influences negatively both longevity and healthy aging as shown in numerous animal models. These modifications observed during aging are also associated with leptin resistance. This resistance blunts normal central and peripheral functions of leptin, which leads to a decrease in neuroendocrine function and insulin sensitivity, an imbalance in energy regulation, and disturbances in lipid metabolism. Here, we review how age-related leptin resistance triggers metabolic disturbances and affects the longevity of obese patients. Furthermore, we discuss the potential impacts of leptin resistance on the decline of brown adipose tissue thermogenesis observed in elderly individuals.

Topics: Adipose Tissue; Aged; Aging; Animals; Humans; Insulin Resistance; Leptin; Longevity; Obesity

The complex mechanisms linking fat excess to metabolic syndrome are not well understood, but several experimental studies have shown that altered production of adipokines plays a main role in development and progression of this disorder. In particular, reduced secretion of adiponectin has a crucial role in inducing insulin resistance but also in determining the clustering of elevated triglycerides and small, dense LDL particles. Increased leptin secretion may be responsible for sympathetic nervous system overactivity and hypertension, while reduced omentin may have an important permissive role in the development of atherogenic processes. Finally, cytokines and other adipokines (resistin, visfatin) determine and modulate the inflammatory process that is an essential component of this condition of cardiovascular risk. Because obesity is prevalent in polycystic ovary syndrome (PCOS), it is not surprising that patients with PCOS present altered adipokine levels and increased prevalence of metabolic syndrome. However, because of the presence of other CV risk factors (androgen excess), in PCOS adipokine dysfunction is particularly severe. Understanding and treating adipokine dysfunction in young women with PCOS is an essential component of any politics of prevention of CV diseases in the general population.

Topics: Abdominal Fat; Adipokines; Adiponectin; Androgens; Cardiovascular Diseases; Female; Humans; Insulin Resistance; Leptin; Metabolic Syndrome; Obesity; Polycystic Ovary Syndrome; Risk Factors

Treatment of epileptic patients with valproic acid (VPA) may be associated with substantial weight changes that may increase morbidity and impair adherence to the treatment regimen. VPA-induced weight gain seems to be associated with many metabolic disturbances; the most frequent are hyperinsulinemia and insulin resistance, hyperleptinemia and leptin resistance. Patients who gain weight during VPA therapy can develop dyslipidemia and metabolic syndrome that are associated with long-term vascular complications such as hypertension and atherosclerosis. Moreover, an elevation in the levels of uric acid and homocysteine, together with oxidative stress, may contribute to atherosclerotic risk in patients under long-term therapy with VPA. The aim of this review is to discuss the metabolic and endocrine effects of VPA chronic treatment in patients with epilepsy.

Topics: Anticonvulsants; Epilepsy; Humans; Hyperinsulinism; Insulin Resistance; Leptin; Metabolic Syndrome; Valproic Acid; Weight Gain

Adipose tissue is a major source of energy for the human body. It is also a source of major adipocytokines adiponectin and leptin. Insulin resistance is a condition in which insulin action is impaired in adipose tissue and is more strongly linked to intra-abdominal fat than to fat in other depots. The expression of adiponectin decreases with increase in the adiposity. Adiponectin mediates insulin-sensitizing effect through binding to its receptors AdipoR1 and AdipoR2, leading to activation of adenosine monophosphate dependent kinase (AMPK), PPAR-α, and presumably other yet-unknown signalling pathways. Weight loss significantly elevates plasma adiponectin levels. Reduction of adiponectin has been associated with insulin resistance, dyslipidemia, and atherosclerosis in humans. The other major adipokine is leptin. Leptin levels increase in obesity and subcutaneous fat has been a major determinant of circulating leptin levels. The leptin signal is transmitted by the Janus kinase, signal transducer and activator of transcription ((JAK-STAT) pathway. The net action of leptin is to inhibit appetite, stimulate thermogenesis, enhance fatty acid oxidation, decrease glucose, and reduce body weight and fat.

Topics: Adiponectin; Adipose Tissue; Humans; Insulin Resistance; Leptin

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

The metabolic syndrome is a cluster of common pathologies: abdominal obesity linked to an excess of visceral fat, insulin resistance, dyslipidemia and hypertension. At the molecular level, metabolic syndrome is accompanied not only by dysregulation in the expression of adipokines (cytokines and chemokines), but also by alterations in levels of leptin, a peptide hormone released by white adipose tissue. These changes modulate immune response and inflammation that lead to alterations in the hypothalamic 'bodyweight/appetite/satiety set point,' resulting in the initiation and development of metabolic syndrome. Metabolic syndrome is a risk factor for neurological disorders such as stroke, depression and Alzheimer's disease. The molecular mechanism underlying the mirror relationship between metabolic syndrome and neurological disorders is not fully understood. However, it is becoming increasingly evident that all cellular and biochemical alterations observed in metabolic syndrome like impairment of endothelial cell function, abnormality in essential fatty acid metabolism and alterations in lipid mediators along with abnormal insulin/leptin signaling may represent a pathological bridge between metabolic syndrome and neurological disorders such as stroke, Alzheimer's disease and depression. The purpose of this review is not only to describe the involvement of brain in the pathogenesis of metabolic syndrome, but also to link the pathogenesis of metabolic syndrome with neurochemical changes in stroke, Alzheimer's disease and depression to a wider audience of neuroscientists with the hope that this discussion will initiate more studies on the relationship between metabolic syndrome and neurological disorders.

Topics: Adipokines; Cannabinoid Receptor Modulators; Ceramides; Humans; Insulin; Insulin Resistance; Leptin; Lipid Metabolism; Metabolic Syndrome; Nervous System Diseases; Risk Factors

To evaluate the laboratory diagnosis aspects of obesity-related health problems with special reference to postmenopausal breast cancer.. We conducted a systemic search of the literature primarily from the PubMed to obtain the relevant data.. Obesity is associated with the dysregulations of a number of body components such as blood constituents, extracellular matrix, and hormones/growth factors axes, which could be utilized for early diagnosis.. Obesity-related disorders including breast cancer have emerged as major health problems in almost all the nations. There is a need to elucidate different biochemical markers that are being used in the clinics or have the potential for such use. A precise understanding of the complex pathologies related with obesity is useful in prevention, early diagnosis and overall clinical management.

Topics: Biomedical Research; Breast Neoplasms; Female; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Obesity; Postmenopause

The central nervous system (CNS) plays key role in the homeostatic regulation of body weight. Satiation and adiposity signals, providing acute and chronic information about available fuel, are produced in the periphery and act in the brain to influence energy intake and expenditure, resulting in the maintenance of stable adiposity. Diet-induced obesity (DIO) does not result from a failure of these central homeostatic circuits. Rather, the threshold for defended adiposity is increased in environments providing ubiquitous access to palatable, high-fat foods, making it difficult to achieve and maintain weight loss. Consequently, mechanisms by which nutritional environments interact with central homeostatic circuits to influence the threshold for defended adiposity represent critical targets for therapeutic intervention.

Topics: Adiposity; Animals; Central Nervous System; Dietary Fats; Endoplasmic Reticulum Stress; Food Supply; Homeostasis; Humans; Insulin Resistance; Leptin; Models, Biological; Obesity; Protein Kinase C

There is an intimate interplay between systemic insulin action and the actions of the adipocyte-derived proteins leptin and adiponectin. Concordant findings in humans and rodents demonstrate that leptin gates critical physiological functions to the prevailing nutritional state, however the physiological functions of adiponectin are less convincingly established. Murine evidence suggests that adiponectin can exert insulin-sensitising effects, plasma concentrations of adiponectin in humans correlate in most populations with insulin sensitivity, and increasingly strong evidence suggests an association between common genetic variation around the adiponectin gene and diabetes. However rare and severe genetic variants lowering adiponectin levels have not been convincingly associated with insulin resistance, and the discordant and sometimes extreme hyperadiponectinaemia seen in patients with severe insulin resistance due to loss of insulin receptor function poses a challenge to the widely held view that low adiponectin in humans plays a role in causing prevalent insulin resistance. The mechanism underlying this phenomenon remains to be elucidated, but the best available evidence implicates increased production of adiponectin in states of insulin receptor dysfunction, attributable at least in part to increased transcription of the ADIPOQ gene. Further investigation of the cellular basis of insulin receptoropathy-related hyperadiponectinaemia may shine further light on the human pathobiology of this most abundant and enigmatic product of adipose tissue.

Topics: Adiponectin; Animals; Humans; Insulin; Insulin Resistance; Leptin; Lipodystrophy

Recent studies have demonstrated the role of insulin resistance in renal injury related to obesity, with hyperfiltration leading to glomerulomegaly in a pattern similar to that found in diabetic nephropathy. Similarities in the histologic patterns of damage from obesity and diabetes point to overlapping mechanisms of injury. In this review, we will examine the hormonal mechanisms, signaling pathways and injury patterns in renal injury resulting from obesity and attempt to draw conclusions on the reasons for these similarities.

Topics: Adiponectin; Diabetic Nephropathies; Female; Glomerular Filtration Rate; Hemodynamics; Humans; Insulin Resistance; Insulin-Secreting Cells; Kidney; Leptin; Male; Membrane Proteins; Obesity; Podocytes; Resistin; Signal Transduction; Sleep Apnea, Obstructive

A disproportionate expansion of white adipose tissue and abnormal recruitment of adipogenic precursor cells can not only lead to obesity but also impair glucose metabolism, which are both common causes of insulin resistance and diabetes mellitus. The development of novel and effective therapeutic strategies to slow the progression of obesity, diabetes mellitus and their associated complications will require improved understanding of adipogenesis and glucose metabolism. Klotho might have a role in adipocyte maturation and systemic glucose metabolism. Klotho increases adipocyte differentiation in vitro, and mice that lack Klotho activity are lean owing to reduced white adipose tissue accumulation; moreover, mice that lack the Kl gene (which encodes Klotho) are resistant to obesity induced by a high-fat diet. Knockout of Kl in leptin-deficient Lep(ob/ob) mice reduces obesity and increases insulin sensitivity, which lowers blood glucose levels. Energy metabolism might also be influenced by Klotho. However, further studies are needed to explore the possibility that Klotho could be a novel therapeutic target to reduce obesity and related complications, and to determine whether and how Klotho might influence the regulation and function of a related protein, β-Klotho, which is also involved in energy metabolism.

Topics: Animals; Energy Metabolism; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glucuronidase; Humans; Insulin Resistance; Klotho Proteins; Leptin; Obesity

Epidemiological data have demonstrated that the prevalence of either obesity or hepatocellular carcinoma (HCC) is increasing worldwide during past decades, and obesity has been unequivocally shown to be a risk factor for HCC. It has been reported that a significant proportion of HCC in obesity develops in cryptogenic cirrhosis, which is largely associated with the progression of nonalcoholic fatty liver disease, especially nonalcoholic steatohepatitis. Since the HCC is a highly malignant tumor with a poor prognosis, a better understanding of the molecular mechanisms may help researchers to explore new approaches for preventing and treating the obesity-related HCC, and thereby facilitating a substantial reduction of morbidity and mortality. In this article, we reviewed the mechanisms underlying the relationship between obesity and HCC, with an emphasis on the roles of insulin/insulin-like growth factor axis, adipose tissue derived hormones, oxidative stress, and liver stem cells. In addition, we will discuss the impact of life-style modification on obesity-related HCC.

Topics: Adipokines; Adiponectin; Animals; Carcinoma, Hepatocellular; Growth Substances; Humans; Insulin; Insulin Resistance; Leptin; Life Style; Liver Neoplasms; Models, Biological; Obesity; Oxidative Stress; Risk Factors; Signal Transduction; Somatomedins; Stem Cells

Obesity is an important public health problem worldwide. It increases the risk of many chronic diseases such as diabetes and cardiovascular diseases. Meanwhile, obesity is a major risk factor for several types of cancer including gastric cancer. Possible mechanisms linking obesity with gastric cancer may include obesity associated gastro-oesophageal reflux, insulin resistance, altered levels of adiponectin, leptin, ghrelin, and an abnormally increased blood level of insulin-like growth factor (IGF). Helicobacter pylori (H. pylori) infection is a well-recognized risk factor for peptic ulcer and gastric cancer. Recent studies have revealed an increased prevalence of H. pylori infection in obese patients, providing another clue for the increased incidence of gastric cancer in obese population. If this connection can be confirmed in animal models and a large cohort of patients, then eradicating H. pylori together with life style modification in obese individuals may help prevent the development of gastric cancer in the increasingly obese population.

Topics: Adiponectin; Animals; Gastroenteritis; Gastroesophageal Reflux; Ghrelin; Helicobacter Infections; Helicobacter pylori; Humans; Inflammation; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Obesity; Risk Factors; Signal Transduction; Stomach Neoplasms

The spectrum of adipose tissue diseases ranges from obesity to lipodystrophy, and is accompanied by insulin resistance syndrome, which promotes the occurrence of type 2 diabetes, dyslipidemia and cardiovascular complications. Lipodystrophy refers to a group of rare diseases characterized by the generalized or partial absence of adipose tissue, and occurs with or without hypertrophy of adipose tissue in other sites. They are classified as being familial or acquired, and generalized or partial. The genetically determined partial forms usually occur as Dunnigan syndrome, which is a type of laminopathy that can also manifest as muscle, cardiac, neuropathic or progeroid involvement. Gene mutations encoding for PPAR-gamma, Akt2, CIDEC, perilipin and the ZMPSTE 24 enzyme are much more rare. The genetically determined generalized forms are also very rare and are linked to mutations of seipin AGPAT2, FBN1, which is accompanied by Marfan syndrome, or of BANF1, which is characterized by a progeroid syndrome without insulin resistance and with early bone complications. Glycosylation disorders are sometimes involved. Some genetically determined forms have recently been found to be due to autoinflammatory syndromes linked to a proteasome anomaly (PSMB8). They result in a lipodystrophy syndrome that occurs secondarily with fever, dermatosis and panniculitis. Then there are forms that are considered to be acquired. They may be iatrogenic (protease inhibitors in HIV patients, glucocorticosteroids, insulin, graft-versus-host disease, etc.), related to an immune system disease (sequelae of dermatopolymyositis, autoimmune polyendocrine syndromes, particularly associated with type 1 diabetes, Barraquer-Simons and Lawrence syndromes), which are promoted by anomalies of the complement system. Finally, lipomatosis is currently classified as a painful form (adiposis dolorosa or Dercum's disease) or benign symmetric multiple form, also known as Launois-Bensaude syndrome or Madelung's disease, which are sometimes related to mitochondrial DNA mutations, but are usually promoted by alcohol. In addition to the medical management of metabolic syndrome and the sometimes surgical treatment of lipodystrophy, recombinant leptin provides hope for genetically determined lipodystrophy syndromes, whereas modifications in antiretroviral treatment and tesamorelin, a GHRH analog, is effective in the metabolic syndrome of HIV patients. Other therapeutic options will undoubtedly be developed, depen

Topics: Adipocytes; Adipogenesis; Adipokines; Adipose Tissue; Anti-HIV Agents; Cardiomyopathies; Genes, Recessive; Humans; Insulin Resistance; Leptin; Lipodystrophy; Lipomatosis; Magnetic Resonance Imaging; Metabolic Syndrome; Mutation; Physical Examination; Skin; Syndrome

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

Obesity represents a major risk factor for the development of insulin and leptin resistance, ultimately leading to a pleiotropic spectrum of metabolic alterations. However, resistance to both hormones does not uniformly affect all target cells and intracellular signaling pathways. In contrast, numerous clinical phenotypes arise from selective hormone resistance, leading to inhibition of defined intracellular signaling pathways in some tissues, while in other cell types hormone action is maintained or even overactivated. Here, we review the molecular mechanisms and clinical outcomes resulting from selective insulin and leptin resistance, which should ultimately guide future strategies for the treatment of obesity-associated diseases.

Topics: Central Nervous System; Humans; Insulin Resistance; Leptin; Metabolic Diseases; Obesity; Signal Transduction

Obesity, defined as abnormal or excessive fat accumulation that may impair life quality, is one of the major public health problems worldwide. It results from an imbalance between food intake and energy expenditure. The control of energy balance in animals and humans is performed by the central nervous system (CNS) by means of neuroendocrine connections, in which circulating peripheral hormones, such as leptin and insulin, provide signals to specialized neurons of the hypothalamus reflecting body fat stores, and induce appropriate responses to maintain the stability of these stores. The majority of obesity cases are associated with central resistance to both leptin and insulin actions. In experimental animals, high-fat diets can induce an inflammatory process in the hypothalamus, which impairs leptin and insulin intracellular signaling pathways, and results in hyperphagia, decreased energy expenditure and, ultimately, obesity. Recent evidence obtained from neuroimaging studies and assessment of inflammatory markers in the cerebrospinal fluid of obese subjects suggests that similar alterations may be also present in humans. In this review, we briefly present the mechanisms involved with the loss of homeostatic control of energy balance in animal models of obesity, and the current evidence of hypothalamic dysfunction in obese humans.

Topics: Adipose Tissue; Animals; Eating; Energy Metabolism; Homeostasis; Humans; Hypothalamic Diseases; Hypothalamus; Insulin; Insulin Resistance; Leptin; Obesity

Topics: Adipokines; Adiponectin; Adipose Tissue; Adult; Aged; Animals; Chronic Disease; Clinical Trials as Topic; Cytokines; Diabetes Mellitus, Type 2; Exercise; Female; Humans; Inflammation; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Middle Aged; Nicotinamide Phosphoribosyltransferase; Obesity; Resistin; Serpins

During the development of type 2 diabetes mellitus, skeletal muscle is a major site of insulin resistance. The latter has been linked to mitochondrial dysfunction and impaired fatty acid oxidation. Some hormones like insulin, thyroid hormones and adipokines (e.g., leptin, adiponectin) have positive effects on muscle mitochondrial bioenergetics through their direct or indirect effects on mitochondrial biogenesis, mitochondrial protein expression, mitochondrial enzyme activities and/or AMPK pathway activation--all of which can improve fatty acid oxidation. It is therefore not surprising that treatment with these hormones has been proposed to improve muscle and whole body insulin sensitivity. However, treatment of diabetic patients with leptin and adiponectin has no effect on muscle mitochondrial bioenergetics showing resistance to these hormones during type 2 diabetes. Furthermore, treatment with most thyroid hormones has unexpectedly revealed negative effects on muscle insulin sensitivity. Future research should focus on development of agents that improve metabolic dysfunction downstream of hormone receptors.

Topics: Adiponectin; Diabetes Mellitus, Type 2; Energy Metabolism; Humans; Insulin; Insulin Resistance; Leptin; Mitochondria, Muscle; Muscle, Skeletal; Obesity

The purpose of this review was to highlight, in relation to the currently accepted pathophysiology of non-alcoholic fatty liver disease (NAFLD), the known exercise habits of patients with NAFLD and to detail the benefits of lifestyle modification with exercise (and/or physical activity) on parameters of metabolic syndrome. More rigorous, controlled studies of longer duration and defined histopathological end-points comparing exercise alone and other treatment are needed before better, evidence-based physical activity modification guidelines can be established, since several questions remain unanswered.

Topics: Diet; Exercise; Fatty Liver; Hormones; Humans; Insulin Resistance; Leptin; Life Style; Lipids; Liver; Metabolic Syndrome; Motor Activity; Non-alcoholic Fatty Liver Disease; Obesity; Practice Guidelines as Topic; Treatment Outcome

Leptin is an adipocyte-derived hormone that plays a crucial role in energy homeostasis and lipid metabolism. Most of the biological effects of leptin are exerted through activation of the Janus kinase-2/signal transducer and activator of transcription-3 pathway. Signal transducer and activator of transcription-3 activation ultimately leads to an increased transcription and expression of suppressors of cytokine signaling-3, which acts as a feedback inhibitor by attenuating leptin signaling. Apart from inhibiting leptin signaling, suppressor of cytokine signaling-3 inhibits insulin signaling. Leptin increases with increasing fatty mass as a compensatory mechanism to preserve insulin sensitivity, but persistent hyperleptinemia is implicated in liver fibrinogenesis and carcinogenesis.. Considering this dual role of leptin in the liver pathophysiology, we hypothesized that leptin resistance may vary according to the different types of liver cells and nonalcoholic fatty liver disease progression.. It is speculated that recombinant leptin, proposed to be used in common forms of obesity or nonalcoholic fatty liver disease, might have serious unfavorable therapeutical drawbacks, through promotion of insulin resistance, fibrosis, and hepatocellular carcinoma.

Topics: Animals; Carcinoma, Hepatocellular; Disease Progression; Fatty Liver; Humans; Insulin Resistance; Janus Kinase 2; Leptin; Liver Cirrhosis; Liver Neoplasms; Signal Transduction; STAT3 Transcription Factor

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

Numerous investigations have shown that mitochondrial dysfunction is a major mechanism of drug-induced liver injury, which involves the parent drug or a reactive metabolite generated through cytochromes P450. Depending of their nature and their severity, the mitochondrial alterations are able to induce mild to fulminant hepatic cytolysis and steatosis (lipid accumulation), which can have different clinical and pathological features. Microvesicular steatosis, a potentially severe liver lesion usually associated with liver failure and profound hypoglycemia, is due to a major inhibition of mitochondrial fatty acid oxidation (FAO). Macrovacuolar steatosis, a relatively benign liver lesion in the short term, can be induced not only by a moderate reduction of mitochondrial FAO but also by an increased hepatic de novo lipid synthesis and a decreased secretion of VLDL-associated triglycerides. Moreover, recent investigations suggest that some drugs could favor lipid deposition in the liver through primary alterations of white adipose tissue (WAT) homeostasis. If the treatment is not interrupted, steatosis can evolve toward steatohepatitis, which is characterized not only by lipid accumulation but also by necroinflammation and fibrosis. Although the mechanisms involved in this aggravation are not fully characterized, it appears that overproduction of reactive oxygen species by the damaged mitochondria could play a salient role. Numerous factors could favor drug-induced mitochondrial and metabolic toxicity, such as the structure of the parent molecule, genetic predispositions (in particular those involving mitochondrial enzymes), alcohol intoxication, hepatitis virus C infection, and obesity. In obese and diabetic patients, some drugs may induce acute liver injury more frequently while others may worsen the pre-existent steatosis (or steatohepatitis).

Topics: Adiponectin; Adipose Tissue; Alcoholic Intoxication; Animals; Carbohydrate Metabolism; Cell Death; Chemical and Drug Induced Liver Injury; Diabetes Mellitus, Type 2; Energy Metabolism; Fatty Acids; Fatty Liver; Genetic Predisposition to Disease; Genome, Mitochondrial; Hepatitis C; Humans; Insulin Resistance; Leptin; Lipid Metabolism; Mitochondria, Liver; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Models, Biological; Obesity; Oxidation-Reduction; Oxidative Phosphorylation; Reactive Oxygen Species

Chronic uremia is often characterized by wasting of muscle and fat mass, which has been defined as protein-energy wasting (PEW), and is responsible for substantial worsening of patient outcome in terms of morbidity and mortality, mostly from cardiovascular events. Despite major advances in patient treatment, nutritional outcome in patients with end-stage renal disease has not improved substantially in recent years. Extensive research in this field has provided plausible explanations for this limitation by indicating that the pathogenesis of PEW in kidney disease is complex and multifactorial. Complexity involves underlying metabolic alterations, including inflammation, oxidative stress, and insulin resistance. In addition, patient heterogeneity is increasing with large numbers of obese individuals as a result of the ongoing obesity epidemics. Several tissues are involved in cross-talk and contribute to metabolic derangements, including adipose tissue, the gut, and the central nervous system, with novel mediators including the gastric hormone ghrelin. Acknowledging its complex pathogenesis may favor the development of novel and more effective therapeutic tools for PEW. These should ideally be effective in treating the underlying common mechanisms of wasting, which appear to include oxidative stress, inflammation, and insulin resistance.

Topics: Animals; Ghrelin; Humans; Inflammation; Insulin Resistance; Kidney Failure, Chronic; Leptin; Obesity; Oxidative Stress; Protein-Energy Malnutrition

Elevated blood glucose, obesity, high blood pressure, elevated triglycerides and low high density lipoprotein (HDL) cholesterol are well accepted risk factors in the development of coronary artery disease. Clustering of at least three of these factors in an individual is defined as metabolic syndrome (MetS). Obesity is a central pathological mechanism in the disease and it is expected that the incidence of this condition will increase dramatically within the next years. The visceral adipose tissue is not only an energy depot but also an endocrine organ which produces a large number of bioactive molecules, the so called adipokines. In the setting of obesity, the over-production of proinflammatory and pro-thrombotic adipokines is associated with insulin resistance. This mechanism represents the pathophysiological basis for the development of MetS. Inflammation has a central role in the pathogenesis of MetS and in mediating its impact on the development of cardiovascular disease. Knowledge of these mechanisms has relevance in the context of preventive and therapeutic strategies.

Topics: Adiponectin; Adolescent; Adult; Angiotensinogen; Atherosclerosis; Biomarkers; Cardiovascular Diseases; Chemokine CCL2; Endothelium, Vascular; Humans; Inflammation; Insulin Resistance; Interleukin-6; Intra-Abdominal Fat; Leptin; Life Style; Metabolic Syndrome; Obesity; Plaque, Atherosclerotic; Plasminogen Activator Inhibitor 1; Prognosis; Resistin; Risk; Tumor Necrosis Factor-alpha

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

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

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

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

Bone remodelling, which maintains bone mass constant during adulthood, is an energy-demanding process. This, together with the observation that the adipocyte-derived hormone leptin is a major inhibitor of bone remodelling, led to the hypothesis that bone cells regulate energy metabolism through an endocrine mechanism. Studies to test this hypothesis identified osteocalcin, a hormone secreted by osteoblasts, as a positive regulator of insulin secretion, insulin resistance and energy expenditure. Remarkably, insulin signalling in osteoblasts is a positive regulator of osteocalcin production and activation via its ability to indirectly enhance bone resorption by osteoclasts. In contrast, leptin is a potent inhibitor of osteocalcin function through its effect on the sympathetic tone. Hence, osteocalcin is part of a complex signalling network between bone and the organs more classically associated with the regulation of energy homeostasis, such as the pancreas and adipose tissue. This review summarises the molecular and cellular bases of the present knowledge on osteocalcin biology and discusses the potential relevance of osteocalcin to human metabolism and pathology.

Topics: Animals; Bone Remodeling; Endocrine System; Energy Metabolism; Humans; Insulin Resistance; Leptin; Mice; Models, Animal; Osteocalcin

Recent findings suggest that the bone is an active regulator of energy and glucose metabolism. The purpose of this review is to summarize current evidence in humans.. Both cross-sectional and longitudinal studies support osteocalcin as an active regulator of carbohydrate metabolism in humans, being the muscular load of physical activity one of the possible links between the osteoblast and the insulin axis. This axis could also have been involved in the modulation of nonalcoholic steatohepatitis. The osteoblast-to-insulin axis seems to act paradoxically in patients with increased growth hormone (acromegaly) and during bone repair. Some possible evolutionary implications are suggested.. Osteocalcin may have a role in the regulation of systemic energy metabolism, given the common origin of the osteoblast with the two other cells implicated (adipocytes and muscle cells). Bioactivity of circulating human carboxylated and uncarboxylated osteocalcin should be characterized in depth, especially in those patients with increased concentrations (renal failure). Osteocalcin is one of the clues in the interaction between calcium and glucose metabolism, and the discovery of the osteocalcin receptor will aid in the study of these relationships.

Topics: Adipose Tissue; Animals; Biological Evolution; Bone and Bones; Carbohydrate Metabolism; Energy Metabolism; Humans; Insulin; Insulin Resistance; Kidney Diseases; Leptin; Liver; Motor Activity; Osteoblasts; Osteocalcin

Obesity is a highly prevalent health problem in Western countries that leads to many important diseases such as type 2 diabetes and metabolic syndrome being now considered an inflammatory chronic disease. Adipocytes are no longer considered passive cells storing fat since they are major producers of inflammatory cytokines during obesity. Adipocytes and macrophages share many biological properties including the synthesis of similar molecules regulating inflammation. Fatty acid levels are elevated in obesity and induce inflammatory pathways by yet a mostly unknown mechanism, leading to the development of insulin and leptin resistance. Recent studies suggest that these effects could be mediated through the activation of toll-like receptors (TLR). TLR signalling pathways might contribute to the development of obesity-associated insulin resistance, thus representing a connection between innate immunity and metabolism. Here, we summarize the recent evidence for the important role that TLRs play in adipose tissue, obesity and insulin resistance.

Topics: Adipocytes; Adipose Tissue; Animals; Cytokines; Diabetes Mellitus, Type 2; Humans; Inflammation; Insulin Resistance; Leptin; Macrophages; Metabolic Syndrome; Obesity; Signal Transduction; Toll-Like Receptors

Leptin and adiponectin are hormones secreted from adipocytes that have important roles in metabolism and energy homeostasis. This review evaluates the effects of leptin and adiponectin on β-cell function by analyzing and compiling results from human clinical trials and epidemiologic studies as well as in vitro and in vivo experiments. Leptin has been shown to inhibit ectopic fat accumulation and thereby prevent β-cell dysfunction and protect the β-cell from cytokine- and fatty acid-induced apoptosis. However, leptin suppresses insulin gene expression and secretion as well as glucose transport into the β-cell. Adiponectin stimulates insulin secretion by enhancing exocytosis of insulin granules and upregulating the expression of the insulin gene; however, this effect depends on the prevailing glucose concentration and status of insulin resistance. In addition, adiponectin has antiapoptotic properties in β-cells. Available evidence concerning the role of these adipokines on insulin secretion, insulin gene expression, and apoptosis is not always entirely consistent; and many fundamental questions remain to be answered by future studies.

Topics: Adiponectin; Animals; Apoptosis; Clinical Trials as Topic; Epidemiologic Studies; Gene Expression Regulation; Humans; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Leptin

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

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

Resistance to the hormones insulin and leptin are hallmarks in common for type 2 diabetes mellitus and obesity. Both conditions are associated with increased activity and expression of protein tyrosine phosphatase (PTP)1B. Therefore, inhibition of PTP1B activity or down-regulation of its expression should ameliorate insulin and leptin resistance, and may hold therapeutic utility in type 2 diabetes mellitus and obesity control. This background has motivated the fervent search for PTP1B inhibitors, carried out in the recent years. The purpose of this review is to provide the most recent advances in understanding the structural details of PTP1B molecule relevant to the interactions with inhibitors, and the progress towards compounds with enhanced membrane permeability, affinity, specificity, and potency on intracellular PTP1B; several inhibitors of benefit in type 2 diabetes mellitus and obesity control are presented and discussed.

Topics: Diabetes Mellitus, Type 2; Enzyme Inhibitors; Humans; Insulin Resistance; Leptin; Molecular Structure; Obesity; Protein Tyrosine Phosphatase, Non-Receptor Type 1

Fatty acids released from white adipose tissue (WAT) provide important energy substrates during fasting. However, uncontrolled fatty acid release from WAT during non-fasting states causes lipotoxicity and promotes inflammation and insulin resistance, which can lead to and worsen type 2 diabetes (DM2). WAT is also a source for insulin sensitizing fatty acids such as palmitoleate produced during de novo lipogenesis. Insulin and leptin are two major hormonal adiposity signals that control energy homeostasis through signaling in the central nervous system. Both hormones have been implicated to regulate both WAT lipolysis and de novo lipogenesis through the mediobasal hypothalamus (MBH) in an opposing fashion independent of their respective peripheral receptors. Here, we review the current literature on brain leptin and insulin action in regulating WAT metabolism and discuss potential mechanisms and neuro-anatomical substrates that could explain the opposing effects of central leptin and insulin. Finally, we discuss the role of impaired hypothalamic control of WAT metabolism in the pathogenesis of insulin resistance, metabolic inflexibility and type 2 diabetes.

Topics: Adipose Tissue, White; Homeostasis; Humans; Hypothalamus; Insulin; Insulin Resistance; Leptin; Obesity; Signal Transduction

The hormone leptin is secreted from white adipocytes, and serum levels of leptin correlate with adipose tissue mass. Leptin was first described as acting on the satiety centre in the hypothalamus through specific receptors (ob-R) to restrict food intake and enhance energy expenditure. Leptin plays a crucial role in the maintenance of body weight and glucose homeostasis hrough central and peripheral pathways, including regulation of insulin secretion by pancreatic b cells. Leptin may also directly affect the metabolism and function of peripheral tissues. Leptin has been implicated in causing peripheral insulin resistance by attenuating insulin action, and perhaps insulin signalling, in various insulin-responsive cell types. Research has demonstrated a significant relationship between leptin and insulin, but the mechanisms underlying the changes of leptin induced by insulin, and vice versa, remain to be studied in more detail. Recent data provides convincing evidence that leptin has beneficial effects on glucose homeostasis in mouse models of insulin-deficient type 1 diabetes mellitus. Our study suggests that leptin could be used as an adjunct of insulin therapy in insulin-deficient diabetes, thereby providing an insight into the therapeutic properties of leptin as an anti-diabetic agent. Safety evaluation should include a careful assessment of the effects of this combination therapy on the counterregulatory response to hypoglycaemia. The role of leptin in alpha-cell function has not been studied in detail. Extensive studies will be needed to determine the long-term safety and efficacy of this therapy.

Topics: Adipose Tissue, White; Animals; Carbohydrate Metabolism; Glucagon-Secreting Cells; Humans; Insulin; Insulin Resistance; Insulin Secretion; Leptin; Mice

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

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

The US Food and Drug Administration approved use of recombinant human growth hormone (GH) for the treatment of idiopathic short stature (ISS) in children; however, few studies have evaluated metabolic outcomes. This article addresses whether children with ISS treated with GH experience the same metabolic benefits as children with GH deficiency (GHD) treated with GH. A systematic review of all published studies of GH treatment in children with ISS that included data on metabolic outcomes identified five studies. No meta-analysis has been performed.Studies show a metabolic response to GH treatment in children with ISS similar to that observed in children with GHD; effects include a transient decrease in insulin sensitivity and a dose-dependent increase in insulin-like growth factor I. However, no increase in the risk of diabetes was found. Children with ISS seem to benefit from GH treatment in terms of height gain without any severe negative metabolic outcomes.

Topics: Adipose Tissue; Adolescent; Body Height; Child; Dwarfism; Dwarfism, Pituitary; Glucose; Growth Disorders; Human Growth Hormone; Humans; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Lipid Metabolism; Male; Recombinant Proteins

Obesity plays a major role in the development of type 2 diabetes mellitus, and it has long been accepted that weight loss plays a significant role in diabetes therapy. This weight loss has traditionally been accomplished through lifestyle changes including diet and exercise. What has only more recently gained acceptance is that bariatric surgery may have a role to play in diabetes therapy as well. This article discusses the pathophysiology of type 2 diabetes mellitus and obesity and provides a basic understanding of these diseases, which forms the basis for understanding the importance of weight loss in their treatment.

Topics: Animals; Bariatric Surgery; Body Mass Index; Comorbidity; Diabetes Mellitus, Type 2; Disease Progression; Energy Intake; Energy Metabolism; Humans; Insulin Resistance; Leptin; Obesity; Risk Factors; Weight Loss

Orexin-A (hypocretin-1) and orexin-B (hypocretin-2) are hypothalamic neuropeptides that play key roles in the regulation of wakefulness, feeding, reward, autonomic functions and energy homeostasis. To control these functions indispensable for survival, orexin-expressing neurones integrate peripheral metabolic signals, interact with many types of neurones in the brain and modulate their activities via the activation of orexin-1 receptor or orexin-2 receptor. In addition, a new functional role of orexin is emerging in the regulation of insulin and leptin sensitivities responsible for whole-body glucose metabolism. Recent evidence indicates that orexin efficiently protects against the development of peripheral insulin resistance induced by ageing or high-fat feeding in mice. In particular, the orexin receptor-2 signalling appears to confer resistance to diet-induced obesity and insulin insensitivity by improving leptin sensitivity. In fact, the expression of orexin gene is known to be down-regulated by hyperglycaemia in the rodent model of diabetes, such as ob/ob and db/db mice. Moreover, the levels of orexin receptor-2 mRNA have been shown to decline in the brain of mice along with ageing. These suggest that hyperglycaemia due to insulin insensitivity during ageing or by habitual consumption of a high-fat diet leads to the reduction in orexin expression in the hypothalamus, thereby further exacerbating peripheral insulin resistance. Therefore, orexin receptor controlling hypothalamic insulin/leptin actions may be a new target for possible future treatment of hyperglycaemia in patients with type 2 diabetes.

Topics: Aging; Animals; Diet; Energy Intake; Energy Metabolism; Glucose; Homeostasis; Humans; Hypothalamus; Insulin; Insulin Resistance; Intracellular Signaling Peptides and Proteins; Leptin; Neurons; Neuropeptides; Neurotransmitter Agents; Obesity; Orexin Receptors; Orexins; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; RNA, Messenger; Signal Transduction; Thermogenesis

Obesity is characterized by increased storage of fatty acids in an expanded adipose tissue mass and is closely associated with the development of insulin resistance in peripheral tissues such as skeletal muscle and the liver. In addition to being the largest source of fuel in the body, adipose tissue and resident macrophages are also the source of a number of secreted proteins. Cloning of the obese gene and the identification of its product, leptin, was one of the first discoveries of an adipocyte-derived signaling molecule and established an important role for adipose tissue as an endocrine organ. Since then, leptin has been found to have a profound role in the regulation of whole-body metabolism by stimulating energy expenditure, inhibiting food intake and restoring euglycemia, however, in most cases of obesity leptin resistance limits its biological efficacy. In contrast to leptin, adiponectin secretion is often diminished in obesity. Adiponectin acts to increase insulin sensitivity, fatty acid oxidation, as well as energy expenditure and reduces the production of glucose by the liver. Resistin and retinol binding protein-4 are less well described. Their expression levels are positively correlated with adiposity and they are both implicated in the development of insulin resistance. More recently it has been acknowledged that macrophages are an important part of the secretory function of adipose tissue and the main source of inflammatory cyokines, such as TNFalpha and IL-6. An increase in circulating levels of these macrophage-derived factors in obesity leads to a chronic low-grade inflammatory state that has been linked to the development of insulin resistance and diabetes. These proteins commonly known as adipokines are central to the dynamic control of energy metabolism, communicating the nutrient status of the organism with the tissues responsible for controlling both energy intake and expenditure as well as insulin sensitivity.

Topics: Adiponectin; Adipose Tissue; Animals; Endocrine Glands; Energy Metabolism; Humans; Insulin Resistance; Interleukin-6; Leptin; Macrophages; Obesity; Protein Conformation; Resistin; Retinol-Binding Proteins, Plasma; Signal Transduction; Tumor Necrosis Factor-alpha

Determining the effect of hypothalamic inflammatory signals on energy balance presents a paradox. On the one hand, a large body of work has identified inflammatory signaling in the hypothalamus as an essential mediator of the sickness response--the anorexia, cachexia, fever, inactivity, lethargy, anhedonia and adipsia that are triggered by systemic inflammatory stimuli and promote negative energy balance. On the other hand, numerous recent studies implicate inflammatory activation within the hypothalamus as a key factor whereby high-fat diets--and saturated fats in particular--cause central leptin and insulin resistance and thereby promote the defense of elevated body weight. This paradox will likely remain unresolved until several issues have been addressed. Firstly, the hypothalamus--unlike many peripheral inflamed tissues--is an extremely heterogeneous tissue comprised of astrocytes, oligodendrocytes, microglia, endothelial cells, ependymal cells as well as numerous neuronal subgroups. Determining exactly which cells activate defined inflammatory signals in response to a particular stimulus--i.e. sepsis vs. nutrient excess--may yield critical clues. Secondly, for the sake of simplicity many studies evaluate inflammation as an on/off phenomenon. More realistically, inflammatory signaling occurs as a cascade or cycle that changes and progresses over time. Accordingly, even within the same cell type, the low-grade, chronic signal induced by nutrient excess may invoke a different cascade of signals than a strong, acute signal such as sepsis. In addition, because tolerance can develop to certain inflammatory mediators, physiological outcomes may not correlate with early biochemical markers. Lastly, the neuroanatomical location, magnitude, and duration of the inflammatory stimulus can undoubtedly influence the net CNS response. Rigorously evaluating the progression of the inflammatory signaling cascade within specific hypothalamic cell types is a key next step towards resolving the paradox surrounding the effect of inflammatory signaling on energy homeostasis.

Topics: Animals; Dietary Fats; Eating; Energy Metabolism; Homeostasis; Humans; Hypothalamus; Inflammation; Insulin Resistance; Leptin; Melanocortins; Obesity; Signal Transduction; Weight Gain

The worldwide pandemic of obesity is creating unique challenges for the diagnosis and treatment of asthma. A wealth of epidemiologic literature has established that whereas asthma can lead to obesity, obesity is a risk factor for asthma, but mechanisms are unclear. This review assesses the current understanding of the relationship between obesity and asthma.. Recent studies are developing a more sophisticated understanding of the possible inflammatory, immunologic, genetic, and mechanical mechanisms underlying the association between obesity and asthma. Obese asthma may be a unique phenotype of asthma, with a more difficult clinical course and altered response to asthma controller therapy. Adipokines such as leptin and adiponectin are thought to be important, but there is new interest in other inflammatory mechanisms related to visceral obesity, insulin resistance, and the metabolic syndrome.. There are still far more questions than answers as to how obesity might cause or worsen asthma. It is clear that weight gain and obesity are particularly troublesome in asthmatics, and clinicians should target these individuals for aggressive intervention. Randomized controlled trials are needed to determine the best treatment approaches for obese asthma, and prospective studies in which both obesity and asthma are well characterized are needed to better understand the underlying mechanisms.

Topics: Adipokines; Asthma; Humans; Insulin Resistance; Leptin; Obesity; Protein Kinase C-alpha

White adipose tissue is a mesenchymal tissue that begins developing in the fetus. Classically known for storing the body's fuel reserves, adipose tissue is now recognized as an endocrine organ. As such, the secretions from adipose tissue are known to affect several systems such as the vascular and immune systems and play major roles in metabolism. Numerous studies have shown nutrient or hormonal manipulations can greatly influence adipose tissue development. In addition, the associations between various disease states, such as insulin resistance and cardiovascular disease, and disregulation of adipose tissue seen in epidemiological and intervention studies are great. Evaluation of known adipokines suggests these factors secreted from adipose tissue play roles in several pathologies. As the identification of more adipokines and determination of their role in biological systems, and the interactions between adipocytes and other cells types continues, there is little doubt that we will gain a greater appreciation for a tissue once thought to simply store excess energy.

Topics: Adipogenesis; Adipokines; Adipose Tissue; Animals; Cardiovascular Diseases; Endocrine System; Gene Expression Regulation, Developmental; Growth Hormone; Humans; Insulin Resistance; Leptin; Mice; Mice, Knockout; Mice, Transgenic; Somatomedins

Leptin is a hormone secreted by adipose tissue in direct proportion to amount of body fat. The circulating leptin levels serve as a gauge of energy stores, thereby directing the regulation of energy homeostasis, neuroendocrine function, and metabolism. Persons with congenital deficiency are obese, and treatment with leptin results in dramatic weight loss through decreased food intake and possible increased energy expenditure. However, most obese persons are resistant to the weight-reducing effects of leptin. Recent studies suggest that leptin is physiologically more important as an indicator of energy deficiency, rather than energy excess, and may mediate adaptation by driving increased food intake and directing neuroendocrine function to converse energy, such as inducing hypothalamic hypogonadism to prevent fertilization. Current studies investigate the role of leptin in weight-loss management because persons who have recently lost weight have relative leptin deficiency that may drive them to regain weight. Leptin deficiency is also evident in patients with diet- or exercise-induced hypothalamic amenorrhea and lipoatrophy. Replacement of leptin in physiologic doses restores ovulatory menstruation in women with hypothalamic amenorrhea and improves metabolic dysfunction in patients with lipoatrophy, including lipoatrophy associated with HIV or highly active antiretroviral therapy. The applications of leptin continue to grow and will hopefully soon be used therapeutically.

Topics: Adipose Tissue; Amenorrhea; Animals; Atrophy; Energy Metabolism; Female; Humans; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Neurosecretory Systems; Obesity; Recombinant Proteins; Weight Loss

Insulin resistance is the main pathologic mechanism that links the constellation of clinical, metabolic and anthropometric traits with increased risk for cardiovascular disease and type II diabetes mellitus. These traits include hyperinsulinemia, impaired glucose intolerance, endothelial dysfunction, dyslipidemia, hypertension, and generalized and upper body fat redistribution. This cluster is often referred to as insulin resistance syndrome. The progression of insulin resistance to diabetes mellitus parallels the progression of endothelial dysfunction to atherosclerosis leading to cardiovascular disease and its complications. In fact, insulin resistance assessed by homeostasis model assessment (HOMA) has shown to be independently predictive of cardiovascular disease in several studies and one unit increase in insulin resistance is associated with a 5.4% increase in cardiovascular disease risk. This review article addresses the role of insulin resistance as a main causal factor in the development of metabolic syndrome and endothelial dysfunction, and its relationship with cardiovascular disease. In addition to this, we review the type of lifestyle modification and pharmacotherapy that could possibly ameliorate the effect of insulin resistance and reverse the disturbances in insulin, glucose and lipid metabolism.

Topics: Adiponectin; Animals; Atherosclerosis; Blood Glucose; Blood Pressure; Endothelium, Vascular; Humans; Hypoglycemic Agents; Inflammation; Insulin; Insulin Resistance; Leptin; Lipids; Metabolic Syndrome; Risk Factors; Risk Reduction Behavior

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

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

In order to explore the pathogenesis of non-alcoholic fatty liver disease (NAFLD), and to find the best evidence for clinical practice, recent literature about the pathogenesis and treatment of NAFLD was analyzed, and it was found that the generation of reactive oxygen species (ROS) is the most important factor in development of NAFLD. Based on insulin resistance (IR), generation of ROS is a central link in the course of "two hits". Other factors, such as leptin resistance, caspase-3, Fas and its ligand, peripheral natural killer T cells, cyclooxygenase-2, metabolic nuclear receptors, hepatic deposition of iron, ferritin, haptoglobin, retinol binding protein 4, imbalance of intestinal flora, mitochondrial dysfunction and endoplasmic reticulum stress, also contribute to the progress of NAFLD. In the treatment of NAFLD, beside the conventionally used methods such as IR improvement, antioxidation and lipid metabolism improvement, other medicines such as nuclear metabolism ligands or activators, iron-chelating agents and syndrome differentiation treatment in traditional Chinese medicine also have good efficacy.

Topics: Antioxidants; Fatty Liver; Humans; Insulin Resistance; Leptin; Lipid Metabolism; Medicine, Chinese Traditional; Non-alcoholic Fatty Liver Disease

Metabolic syndrome (MetS) is a constellation of metabolic derangements and underlying factors that significantly increases the risk for developing type 2 diabetes and cardiovascular diseases. MetS is a low-grade inflammatory condition, with systemic inflammation and inflammation of central abdominal fat as contributors. Systemic inflammation in MetS is thought to involve C-reactive protein and some proinflammatory cytokines; the nuclear factor-kappaB pathway also is believed to play a role. Inflammation of central adipose tissue leads to adipokine production, followed by secretion of adipokines into the general circulation to contribute to the overall inflammatory condition. The molecular mechanisms that contribute to this inflammation are still somewhat unclear, but several serine/threonine kinases are known to be involved. Dietary components may also contribute to central adiposity and the inflammation seen in MetS.

Topics: Abdominal Fat; Adipokines; Adiponectin; Adiposity; C-Reactive Protein; Cytokines; Diet; Humans; Inflammation; Insulin Resistance; Interleukins; Leptin; Life Style; Metabolic Syndrome; NF-kappa B; Nutritional Status; Oxidative Stress; Risk Factors; Serine; Threonine; Tumor Necrosis Factor-alpha

The relationship between obesity and hypertension is well established both in children and adults. The mechanisms through which obesity directly causes hypertension are still an area of research. Activation of the sympathetic nervous system has been considered to have an important function in the pathogenesis of obesity-related hypertension. The arterial-pressure control mechanism of diuresis and natriuresis, according to the principle of infinite feedback gain, seems to be shifted toward higher blood-pressure levels in obese individuals. During the early phases of obesity, primary sodium retention exists as a result of increase in renal tubular reabsorption. Extracellular-fluid volume is expanded and the kidney-fluid apparatus is resetted to a hypertensive level, consistent with a model of hypertension because of volume overload. Plasma renin activity, angiotensinogen, angiotensin II and aldosterone values display significant increase during obesity. Insulin resistance and inflammation may promote an altered profile of vascular function and consequently hypertension. Leptin and other neuropeptides are possible links between obesity and the development of hypertension. Obesity should be considered as a chronic medical condition, which is likely to require long-term treatment. Understanding of the mechanisms associated with obesity-related hypertension is essential for successful treatment strategies.

Topics: Blood Pressure; Humans; Hypertension; Insulin Resistance; Leptin; Natriuresis; Obesity; Sympathetic Nervous System

In several investigations on mountaineers under moderate hypoxia, at altitudes between 2,500 m and 4,500 m, weight loss occurs, fat levels in the serum and insulin resistance (in diabetic mountaineers) are reduced. Animal studies with different time dosage regimens of hypoxia in animal cages revealed different and partly confusing results regarding fat metabolism under hypoxia.. Hypothesis for the change in glucose and fat metabolism include a HIF promoted higher leptin rate under hypoxia and an increased glucose transport in peripheral organs.. This short review discusses some of the different investigations in this topic. In a second part it is shown how studies of metabolism in yeast cells with an upregulated glycolysis in the cell itself under hypoxic conditions could help to better understand metabolic changes under hypoxia.

Topics: Adaptation, Physiological; Blood Glucose; Energy Metabolism; Glycolysis; Humans; Hypoxia; Insulin Resistance; Leptin; Lipids; Models, Biological; Up-Regulation; Weight Loss; Yeasts

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

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

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

Obesity has been recognized as an important risk factor for many serious medical conditions. The association of obesity with an increased risk of many cancers is of enormous economic importance to the health industry.The metabolic syndrome and visceral obesity have an increasing prevelance and incidence in the general population.The actual prevelance of the metabolic syndrome is 24% in US population and between 24,6% and 30.9% in Europe. Recent evidence from epidemiologic and basic research studies, as well as clinical and intervention studies, supports the emerging hypothesis that metabolic syndrome may be an important etiologic factor for the onset of cancer. In addition, increased body weight has recently been shown to be associated with an increased risk of cancers at multiple specific sites. The close interaction between cancer cells and adipocytes is an intriguing issue in tumor biology. In nowdays, several metabolic markers are implicated in the development and progression of several malignancies. This review describes the emerging data concerning the role of metabolic markes in tumor cell growth and relates them to their future clinical prospects.

Topics: Adiponectin; Animals; Fatty Acids, Nonesterified; Ghrelin; Humans; Insulin Resistance; Leptin; Metabolic Syndrome; Neoplasms; Obesity

The frequency of obesity has been increasing worldwide for 20 years. Many epidemiological studies support a correlation between obesity and increased risk of cancer, particularly digestive cancers in both genders, and gynaecological cancer in women. Currently, about 5% of cancers could be directly related to overweight. Carcinogenesis mechanisms induced by obesity involve insulin resistance, adipokine and angiogenic factor secretions, and inflammation. Experimental and clinical evidence suggest that insulin resistance plays a major role in carcinogenesis. Insulin and non-protein banded IGF-1, whose levels are increased in type 2 diabetes, stimulate cellular growth and inhibit apoptosis. Abnormalities in adipokine secretion by the central adipose tissue play a role at different stages of obesity-induced carcinogenesis. Excess of leptin and PAI-1, associated with a decrease in adiponectin secretion in obese people, contributes to carcinogenesis through cellular growth and angiogenesis stimulation. Remodelling of the extracellular matrix due to metalloproteinase stimulation by PAI-1 is also able to promote cell migration. Obesity not only increases cancer frequency, but is also liable to modify the prognosis and the response to antiangiogenic therapy of digestive cancers. This data suggests the need for clinicians to take into account overweight in cancer risk evaluation and to consider obesity and metabolic disorders as confounding factors in designing therapeutic studies.

Topics: Adipokines; Adipose Tissue; Biological Factors; Body Mass Index; Diabetes Complications; Diabetes Mellitus, Type 2; Evidence-Based Medicine; France; Gastrointestinal Neoplasms; Global Health; Humans; Incidence; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Metalloproteases; Obesity; Plasminogen Activator Inhibitor 1; Prevalence; Prognosis; Risk Assessment; Risk Factors; Serine Proteinase Inhibitors

Obstructive sleep apnea (OSA) is a chronic disease characterized by repetitive partial or complete closure of the upper airway during sleep. OSA tends to be associated with components of metabolic syndrome sharing a common ground of metabolic changes with metabolic syndrome itself. Recent studies showed that subjects with OSA were 6-9 times more likely to have metabolic syndrome than subjects without OSA. Intermittent hypoxia and sleep fragmentation in OSA can initiate intermediary mechanisms (oxidative stress, neurohumoral changes, inflammation) leading to the components of metabolic syndrome. OSA has been suggested to be a novel risk factor, inside the metabolic syndrome, contributing to increased cardiovascular risk. Several studies report that continuous positive airway pressure (CPAP) treatment can reverse pathophysiological changes in OSA, increasing insulin sensitivity and reducing blood pressure. Recent evidences show that CPAP treatment reduces the risk of cardiovascular events and mortality in subjects with OSA. Some subjects with metabolic syndrome can be affected by undiagnosed OSA: CPAP treatment could significantly reduce cardiovascular risk in this subgroup of patients.

Topics: Age Factors; Aged; Blood Glucose; Cardiovascular Diseases; Clinical Trials as Topic; Continuous Positive Airway Pressure; Death, Sudden, Cardiac; Diabetes Mellitus, Type 2; Glucose Tolerance Test; Humans; Hypertension; Insulin Resistance; Leptin; MEDLINE; Metabolic Syndrome; Obesity; Randomized Controlled Trials as Topic; Risk Factors; Sleep Apnea, Obstructive; Stroke

Classically, sleep has been considered to serve an essential restorative function for the brain. However, there are an increasing number of studies linking decreased sleep quantity and/or quality in humans to an increased obesity and diabetes risk. Reductions in sleep quantity or quality lead to an increase in hunger and appetite, which chronically could predispose an individual to obesity. Carefully controlled studies have shown that two nights of insufficient sleep is causally linked to a decrease in disposition index, the most commonly used predictor of an individual's diabetes risk, and impairments in glucose tolerance and insulin sensitivity. Thus, sleep appears to play a critical role in modulating energy metabolism in peripheral tissues. Here we will discuss recent work implicating adipose tissue as a potential direct target of disruption of sleep quality, and explore the potential mechanistic links between sleep, adipose tissue and the global control of energy metabolism in humans.

Topics: Adipocytes; Animals; Humans; Insulin Resistance; Leptin; Lipid Metabolism; Sleep; Sleep Wake Disorders; Sympathetic Nervous System

Insulin and leptin play complementary roles in regulating the consumption, uptake, oxidation and storage of nutrients. Chronic consumption of diets that contain a high proportion of calories from saturated fat induces a progressive deterioration in function of both hormones. Certain rat lines and strains of mice are particularly sensitive to the obesogenic and diabetogenic effects of high fat diets, and have been used extensively to study the developmental progression of insulin and leptin resistance in relation to the increasing adiposity that is characteristic of their response to these diets. Some aspects of the diminished efficacy of each hormone are secondary to increased adiposity but a consensus is emerging to support the view that direct effects of dietary components or their metabolites, independent of the resulting obesity, play important roles in development of insulin and leptin resistance. In this minireview, we will examine the implications of crosstalk between leptin and insulin signaling during the development of diet-induced obesity, emphasizing potential interactions between pathways that occur among target sites, and exploring how these interactions may influence the progression of obesity and diabetes.

Topics: Adiposity; Animals; Dietary Fats; Energy Intake; Humans; Insulin; Insulin Resistance; Leptin; Mice; Obesity; Rats; Signal Transduction

Recent studies consistently support a hypoxia response in the adipose tissue in obese animals. The observations have led to the formation of an exciting concept, adipose tissue hypoxia (ATH), in the understanding of major disorders associated with obesity. ATH may provide cellular mechanisms for chronic inflammation, macrophage infiltration, adiponectin reduction, leptin elevation, adipocyte death, endoplasmic reticulum stress and mitochondrial dysfunction in white adipose tissue in obesity. The concept suggests that inhibition of adipogenesis and triglyceride synthesis by hypoxia may be a new mechanism for elevated free fatty acids in the circulation in obesity. ATH may represent a unified cellular mechanism for a variety of metabolic disorders and insulin resistance in patients with metabolic syndrome. It suggests a new mechanism of pathogenesis of insulin resistance and inflammation in obstructive sleep apnea. In addition, it may help us to understand the beneficial effects of caloric restriction, physical exercise and angiotensin II inhibitors in the improvement of insulin sensitivity. In this review article, literatures are reviewed to summarize the evidence and possible cellular mechanisms of ATH. The directions and road blocks in the future studies are analyzed.

Topics: Adiponectin; Adipose Tissue; Animals; Humans; Hypoxia; Inflammation; Insulin Resistance; Leptin; Mice; Neovascularization, Physiologic; Obesity; Signal Transduction

Obesity is a major risk factor for hypertension. Adipose tissue releases numerous substances that act on the pathophysiologic mechanisms of blood pressure. Management of obese patients with high blood pressure includes weight loss efforts, but antihypertensive treatment is most often necessary. Beta-blockers, alone or with thiazide diuretics, increase the risk of diabetes in hypertensive patients. Treatment against hypertension must include a renin-angiotensin system blocker, with a calcium channel blocker or a thiazide diuretic, if necessary.

Topics: Adiponectin; Adipose Tissue; Antihypertensive Agents; Blood Pressure; Combined Modality Therapy; Humans; Hypertension; Insulin Resistance; Leptin; Obesity; Sympathetic Nervous System; Weight Loss

The prevalence of obesity among children in the United States represents a pool of latent morbidity. Though the prevalence of obesity has increased in both boys and girls, the causes and consequences differ between the sexes. Thus, interventions proposed to treat and prevent childhood obesity will need to account for these differences.. This review examines gender differences in the presentation of obesity in children and describes environmental, hormonal, and genetic factors that contribute to observed gender differences.. A search of peer-reviewed, published literature was performed with PubMed for articles published from January 1974 through October 2008. Search terms used were obesity, sex, gender, hormones, family environment, body composition, adiposity, and genes. Studies of children aged 0 to 18 years were included, and only articles published in English were reviewed for consideration. Articles that illustrated gender differences in either the presentation or underlying mechanisms of obesity in children were reviewed for content, and their bibliographies were used to identify other relevant literature.. Gender differences in childhood obesity have been understudied partially because of how we define the categories of overweight and obesity. Close examination of studies revealed that gender differences were common, both before and during puberty. Boys and girls differ in body composition, patterns of weight gain, hormone biology, and the susceptibility to certain social, ethnic, genetic, and environmental factors.. Our understanding of how gender differences in pediatric populations relate to the pathogenesis of obesity and the subsequent development of associated comorbid states is critical to developing and implementing both therapeutic and preventive interventions.

Topics: Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Family Health; Female; Genetic Predisposition to Disease; Hormones; Humans; Insulin; Insulin Resistance; Leptin; Male; Obesity; Proteins; Receptor, Melanocortin, Type 4; Receptors, Leptin; Sex Factors; Social Environment

Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of common hepatic disorders in western countries, with multiple consequences and its incidence is paralleling the increasing numbers of overweight and obese individuals worldwide. The pathogenesis of NAFLD is thought to be related mainly with insulin resistance (IR) syndrome and oxidative stress; the latter resulting from mitochondrial fatty acids (FFAs) oxidation, nuclear factor-kappaB (NFkappaB)-dependent inflammatory cytokine expression and adipocytokines may promote hepatocellular damage, inflammation, fibrosis and progressive liver disease. Adipocytokines and other recognized cytokines produced partially by inflammatory cells infiltrating adipose tissue, play an important role in the pathogenesis of IR and NAFLD, through complex and interactive paracrine and endocrine mechanisms. Some adipocytokines, including adiponectin and leptin decrease IR, while others, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and resistin enhance IR. The multi-hit hypothesis provides a model that summarizes the complex factors and interactions leading from adipocytokines, FFAs metabolism and IR to NAFLD. This review outlines the pathways involved in adipocytokines, IR and NAFLD sequence; the first part describes the impaired IR pathway leading to NAFLD and the second part the mechanisms by which adipocytokines influence IR and NAFLD development and progression. Understanding these complex mechanisms has evoked new therapeutic approaches, which may provide promising results to date.

Topics: Adipokines; Adiponectin; Fatty Acids, Nonesterified; Fatty Liver; Humans; Insulin; Insulin Resistance; Leptin; Oxidative Stress; Signal Transduction; Tumor Necrosis Factor-alpha

Adipose tissue cells express and secrete numerous proteins influencing the signal transduction pathways of insulin receptor by auto-, para- and endocrine manner. Several cytokines, tumor necrosis factor-alpha and its soluble receptor forms, sTNFR1 and sTNFR2, resistin, retinol-binding protein 4, plasminogen activator inhibitor, lipocain 1 inhibit the signalization of insulin receptor causing insulin resistance in target tissues, mainly in adipose, liver and muscle, brain, endothelial as well as in pancreatic beta-cells. However, many other proteins produced by the fat tissue, such as adiponectin, visfatin, vaspin, apelin, omentin and chemerin enhance the signal transmission of the receptor. Recently discovered common mechanisms leading to insulin and cytokine resistance in obesity and type 2 diabetes mellitus, e.g. protein family of suppressor of cytokine signaling (SOCS) are also discussed.

Topics: Adipokines; Animals; Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Leptin; Lipocalin 1; Mutation; Obesity; Plasminogen Inactivators; Receptor, Insulin; Resistin; Retinol-Binding Proteins, Plasma; Signal Transduction; Transcription, Genetic; Tumor Necrosis Factor-alpha

Obesity is the major cause of type 2 diabetes. In the mid 1990s interest in adipose tissue was revived by the discovery of leptin. The association of obesity and diabetes emphasizes their shared physiopathological features. At the end of the 1990s, ghrelin, a potent gastric orexigenic factor, was found to be involved in obesity. Leptin and ghrelin have opposite actions in several tissues including the regulation of feeding in the brain.. To survey the role of leptin and ghrelin in glucose metabolism. We summarize the current state of research and discuss the roles of ghrelin and leptin in glucose homeostases and the potential application of drugs targeting leptin and ghrelin signalling to prevent and treat diabetes.. A pressing challenge is to determine how leptin, ghrelin and other adipokines or gastric factors are involved in metabolic disorders. Answering these questions will require the development of new pharmacological tools that target specific adipokine systems. Hopefully, new therapeutic targets will be identified.

Topics: Adult; Animals; Child; Diabetes Mellitus, Type 2; Drug Delivery Systems; Drug Evaluation, Preclinical; Energy Metabolism; Female; Ghrelin; Glucose; Humans; Hypoglycemic Agents; Insulin Resistance; Islets of Langerhans; Leptin; Mice; Mice, Knockout; Obesity; Receptors, Ghrelin; Receptors, Leptin

Obesity, especially visceral adiposity, is associated with morbidity and mortality through endocrine and mechanical processes. Clinical manifestations due to effects of obesity on the cardiovascular, respiratory, gastrointestinal, musculoskeletal, immune, and integumentary systems have been described. Further studies are needed to understand the pathologic processes underlying these clinical manifestations to improve disease prevention.

Topics: Adipocytes; Adiponectin; Adiposity; Cardiovascular Diseases; Energy Metabolism; Exercise; Gastrointestinal Diseases; Humans; Insulin Resistance; Intra-Abdominal Fat; Leptin; Musculoskeletal Diseases; Neoplasms; Obesity; Respiratory Tract Diseases

Worldwide, the prevalence of overweight and obesity and associated complications is increasing. Cardiovascular complications are the most important factor determining survival and influencing clinical management. However, obesity is also associated with an increased risk of metabolic syndrome, type 2 diabetes, cancer and other diseases. The development of complications depends on the amount of body fat and its endocrine function. The hormones (leptin, adiponectin, resistin) and cytokines (TNF alpha, IL-6, PAI-1) produced by the adipose tissue are the link between obesity and obesity-related complications. The present article discusses the structure, function and clinical significance of adipokines.

Topics: Adipocytes, White; Adipokines; Adiponectin; Humans; Insulin Resistance; Leptin; Obesity; Resistin; Structure-Activity Relationship

Studies of the role of immune system activation in the pathogenesis of obesity and its concomitant diseases have been conducted for some years. Numerous recent studies revealed an association between increased immune activation in obesity and the development of insulin resistance. On the other hand there is the hypothesis that immune activation in obesity is a homeostatic mechanism to protect the organism from reaching the point at which the over-accumulation of fat decreases the possibility to move. The aim of the present study was to review the current literature on immune activation in obesity and the participation of adipokines produced by adipose tissue in the development of insulin resistance. Attention is drawn to the similarities in function and gene expression of adipocytes and macrophages.

Topics: Adipocytes; Adipokines; Adipose Tissue; Animals; Gene Expression; Humans; Inflammation; Insulin Resistance; Interleukin-6; Leptin; Macrophages; Obesity; Resistin; Tumor Necrosis Factor-alpha

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

Obesity is the most serious long-term health risk currently facing America's adolescents. Weight gain during adolescence carries a higher risk for adult obesity and the metabolic syndrome. This review highlights early adolescence as a particularly high-risk time for weight gain due to the synergy of naturally occurring metabolic changes along with increasing behavioral risk factors. One of the first potential health effects of abnormal weight gain during this period is earlier puberty, usually manifested as thelarche. The obesity epidemic is clearly implicated in the national trend toward earlier thelarche, although the data are not as strong in relation to menarche. Leptin activation of the hypothalamic-pituitary axis, combined with insulin resistance, and increased adiposity may result in the higher estrogen levels that are linked to breast development. Young adolescents also experience a sharp decline in their level of physical activity, worsening nutritional habits, and other important psychosocial and developmental risk factors that may contribute to obesity and estrogen-dependent disease in later life, including polycystic ovary syndrome and breast cancer. Unfortunately, the very psychosocial factors that contribute to abnormal weight gain during early adolescence make prevention and treatment in this population particularly challenging. Therefore, intervening prior to pubertal onset becomes even more important given the risk factors present once puberty begins.

Topics: Adolescent; Adult; Breast Neoplasms; Estrogens; Female; Humans; Hypothalamo-Hypophyseal System; Insulin Resistance; Leptin; Metabolic Syndrome; Obesity; Polycystic Ovary Syndrome; Puberty; Risk Factors; Weight Gain

The metabolic syndrome is a common and complex disorder combining obesity, dyslipidemia, hypertension, and insulin resistance. It is a primary risk factor for diabetes and cardiovascular disease. We showed for the first time that the metabolic syndrome is associated with a higher fraction of oxidized LDL and thus with higher levels of circulating oxidized LDL. Hyperinsulinemia and impaired glycaemic control, independent of lipid levels, were associated with increased in vivo LDL oxidation, as reflected by the higher prevalence of high oxidized LDL. High levels of oxidized LDL were associated with increased risk of future myocardial infarction, even after adjustment for LDL-cholesterol and other established cardiovascular risk factors. This association is in agreement with the finding that accumulation of oxidized LDL, which activates/induces subsets of smooth muscle cells and macrophages to gelatinase production, was associated with upstream localization of a vulnerable plaque phenotype. Dyslipidemia and insulin resistance in obese LDL receptor-deficient mice were associated with increased oxidative stress and impaired HDL-associated antioxidant defence associated with accelerated atherosclerosis due to increased macrophage infiltration and accumulation of oxidized LDL in the aorta. The accumulation of oxidized LDL was partly due to an impaired HDL-associated antioxidant defence due to a decrease in PON. Our data in this experimental model are thus the more relevant because a decrease in PON activity was found to be associated with a defective metabolism of oxidized phospholipids by HDL from patients with type 2 diabetes. Weight loss in leptin-deficient, obese, and insulin-resistant mice was associated with expressional changes of key genes regulating adipocyte differentiation, glucose transport and insulin sensitivity, lipid metabolism, oxidative stress and inflammation, most of which are under the transcriptional control of PPARs. We established an important relationship between PPAR-gamma and SOD1 for the prevention of the oxidation of LDL in the arterial wall. For example we showed that rosuvastatin decreased the oxidized LDL accumulation by increasing the expression of PPAR-gamma and SOD1. In addition, we established a relation between increased PPAR-alpha expression in the adipose tissue and a change in the gene expression pattern, which explains the decrease of free fatty acids, triglycerides and the increase in insulin sensitivity. We demonstrated

Topics: Animals; Cardiovascular Diseases; Comorbidity; Humans; Inflammation; Insulin Resistance; Leptin; Lipid Metabolism; Lipoproteins, LDL; Metabolic Syndrome; Mice; Obesity; Oxidation-Reduction; Oxidative Stress; Risk Factors; Weight Loss

It has been suggested that sympathetic hyperactivity is found in patients with metabolic syndrome (MS) by measuring turnover rate of catecholamines and/or muscle sympathetic nerve firing rate. Increased leptin associated with MS stimulates sympathetic outflow from the hypothalamus, which may be one of causes of sympathetic hyperactivity. Insulin increased in association with insulin resistant in MS increases sodium reabsorption in the kidney leading to sodium retention. Increased intra-cranial sodium ions are known to augment sympathetic nervous system activity via stimulation of epithelial sodium channels, mineralocorticoid receptors, the renin-angiotensin-aldosterone system and endogenous digitalislike factors in the brain. This mechanism may be true in patients with essential hypertension, particularly in those who are sensitive to sodium loading.

Topics: Brain; Catecholamines; Humans; Hypertension; Insulin Resistance; Kidney; Leptin; Metabolic Syndrome; Receptors, Mineralocorticoid; Renin-Angiotensin System; Sodium; Sodium Channels; Sympathetic Nervous System

Hypertension and obesity are major components of the cardiometabolic syndrome and are both on the rise worldwide, with enormous consequences on global health and the economy. The relationship between hypertension and obesity is multifaceted; the etiology is complex and it is not well elucidated. This article, reviews the current knowledge on obesity-related hypertension. Further understanding of the underlying mechanisms of this epidemic will be important in devising future treatment avenues.

Topics: Adipocytes; Adiponectin; Animals; Humans; Hypertension; Insulin Resistance; Kidney; Leptin; Obesity; Renin-Angiotensin System; Sleep Apnea, Obstructive; Sympathetic Nervous System

Dysfunction of specific hypothalamic neurons is regarded as an important mechanism predisposing to the development of obesity. Recent studies have revealed that the consumption of fat-rich foods can activate an inflammatory response in the hypothalamus, which disturbs the anorexigenic and thermogenic signals generated by the hormones leptin and insulin, leading in turn to anomalous body mass control. Depending on diet composition, cytokines are expressed in the hypothalamus, contributing to the activation of intracellular inflammatory signal transduction. At least 4 distinct signaling pathways have been identified and the molecular mechanisms leading to the impairment of the leptin and insulin actions have been determined. Here, we present the mechanisms involved in diet-induced resistance to leptin and insulin action in the hypothalamus and discuss some of the potential applications of this knowledge in the therapeutics of obesity.

Topics: Animals; Body Weight; Cytokines; Dietary Fats; Encephalitis; Humans; Hypothalamus; Insulin; Insulin Resistance; Insulin Secretion; Leptin; Obesity; Signal Transduction

Adipose tissue is no longer considered to be an inert tissue of which function is to store fat. It actively secretes a number of biologic active compounds that are involved in the regulation of many processes like food intake, energy expenditure, metabolism homeostasis, immunity and blood pressure homeostasis. General metabolism alteration in patients with chronic kidney disease has a profound impact on biology of adipocytes. Chronic renal failure is a pathological condition, of which two major hallmarks are chronic inflammation and insulin resistance. In uraemic patients, adipose tissue became an important source of molecules that are responsible, at least in part, for the metabolic disturbances seen in these patients. Some of these molecules act as pro-inflammatory agents contributing to the maintenance and enhancement of the chronic inflammatory response. These pro-inflammatory molecules, along with other molecules secreted by the adipose tissue, have a central position in the aetiology of uraemia-associated insulin resistance. In this review, we intend to summarize some aspects of the biology of adipokines in uraemia, with emphasis on the link between these molecules and insulin resistance.

Topics: Adiponectin; Adipose Tissue; Humans; Insulin Resistance; Leptin; Nicotinamide Phosphoribosyltransferase; Resistin; Uremia

Despite the early recognition of the strong association between obstructive sleep apnoea (OSA) and obesity, and OSA and cardiovascular problems, sleep apnoea has been treated as a "local abnormality" of the respiratory track rather than as a "systemic illness". In 1997, we first reported that the pro-inflammatory cytokines interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNFalpha) were elevated in patients with disorders of excessive daytime sleepiness (EDS) and proposed that these cytokines were mediators of daytime sleepiness. In subsequent studies, it was shown that IL-6, TNFalpha, and insulin levels were elevated in sleep apnoea independently of obesity and that visceral fat was the primary parameter linked with sleep apnoea. Further studies showed that women with the polycystic ovary syndrome (PCOS) were much more likely than controls to have sleep-disordered breathing (SDB) and daytime sleepiness, suggesting a pathogenetic role of insulin resistance in OSA. Additional accumulated evidence that supports the role of obesity and the associated metabolic aberrations in the pathogenesis of sleep apnoea and related symptoms include: obesity without sleep apnoea is associated with daytime sleepiness; the protective role of gonadal hormones as suggested by the increased prevalence of sleep apnoea in post-menopausal women and the significantly reduced risk for OSA in women on hormonal therapy; partial effects of continuous positive airway pressure (CPAP) in obese patients with apnoea on hypercytokinemia, insulin resistance indices, and visceral fat; and that the prevalence of the metabolic syndrome in the U.S. population from the Third National Health and Nutrition Examination Survey (1988-1994) parallels the prevalence of symptomatic sleep apnoea in general random samples. Furthermore, the beneficial effect of a cytokine antagonist on EDS and apnoea in obese, male apnoeics and that of exercise and weight loss on SDB and EDS in general random or clinical samples, supports the hypothesis that cytokines and insulin resistance are mediators of EDS and sleep apnoea in humans. Finally, our recent finding that in obese, hypothalamic CRH neuron is hypoactive, provides additional evidence on the potential central neural mechanisms for depressed ventilation and consequent development of sleep apnoea in obese individuals. In conclusion, accumulating evidence provides support to our thesis that obesity via inflammation, insulin resistance, visceral adiposity, and

Topics: Adiposity; Female; Humans; Inflammation; Insulin Resistance; Intra-Abdominal Fat; Leptin; Male; Metabolic Syndrome; Models, Biological; Obesity; Polycystic Ovary Syndrome; Sleep Apnea Syndromes

Nonalcoholic fatty liver disease (NAFLD) spans a spectrum from simple steatosis to nonalcoholic steatohepatitis (NASH) to cirrhosis. Simple steatosis is the substrate upon which the more serious entities in the spectrum develop; it is the first "hit" in the multistep pathogenesis of NASH, which is considered the hepatic manifestation of the metabolic syndrome. Demonstration of the existence of regulatable fatty acid transport mechanisms has contributed to clarifying the role of fatty acid disposition in obesity, the various components of NAFLD, and the metabolic syndrome. Hepatic steatosis is closely linked to obesity. This linkage is based on the fact that obesity results in marked enlargement of the intraabdominal visceral fat depots. The eventual development of insulin resistance leads to continuous lipolysis within these depots, releasing fatty acids into the portal circulation, where they are rapidly translocated to the liver and reassembled into triglycerides. Reactive oxygen species, generated in the liver from oxidation of fatty acids, are precipitating factors in the cascade of events leading from simple steatosis to NASH. Dysregulation of fatty acid disposition, with ectopic lipid accumulation in other tissues, is a major contributing factor to other components of the metabolic syndrome. Bariatric surgery is an effective treatment for severe obesity, but its role in the management of the various forms of fatty liver disease is unclear. Our review of the literature that includes both initial and follow-up liver biopsies suggests that most obese patients with simple steatosis and NASH who undergo bariatric surgery will achieve improvement in hepatic histology, but that occasional patients, especially those who lose weight very rapidly, may show worsening of either fibrosis or steatohepatitis.

Topics: Abdominal Fat; Adipocytes; Animals; Bariatric Surgery; Comorbidity; Diabetes Mellitus, Type 2; Fatty Acids; Fatty Liver; Gastrointestinal Hormones; Humans; Insulin Resistance; Leptin; Lipolysis; Liver; Metabolic Syndrome; Obesity; Obesity, Morbid

The metabolic syndrome represents a major public health burden because of its high prevalence in the general population and its association with cardiovascular disease and type 2 diabetes. Accumulated evidence based on biochemical, neurophysiologic, and indirect measurements of autonomic activity indicate that visceral obesity and the metabolic syndrome are associated with enhanced sympathetic neural drive and vagal impairment. The mechanisms linking metabolic syndrome with sympathetic activation are complex and not completely understood, and cause-effect relationships need further clarification from prospective trials. Components of the metabolic syndrome that may directly or indirectly enhance sympathetic drive include hyperinsulinemia, leptin, nonesterified fatty acids, proinflammatory cytokines, angiotensinogen, baroreflex impairment, and obstructive sleep apnea. beta-Adrenoceptor polymorphisms have also been associated with adrenoceptor desensitization, increased adiposity, insulin resistance, and enhanced sympathetic activity. Because chronic sympathetic activation contributes to hypertension and its target-organ damage, sympathoinhibition remains an important goal in the therapeutic management of the metabolic syndrome.

Topics: Adipokines; Cytokines; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Humans; Hyperinsulinism; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Obesity; Risk Assessment; Sensitivity and Specificity; Sleep Apnea, Obstructive; Sympathetic Nervous System

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

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

The liver plays a pivotal role in the regulation of glucose metabolism because it is the key organ that maintains glucose levels during fasting. An emerging body of literature has demonstrated the important role of the hypothalamus in controlling hepatic glucose production (HGP). The hypothalamus senses circulating nutrients and hormones, conveying the energy status to the central nervous system, which, in turn, controls HGP in part by way of the autonomic nervous system. Overfeeding results in the failure of the hypothalamus to sense circulating nutrients and hormones, and in a loss of the central control of HGP.

Topics: Animals; Eating; Food; Glucose; Humans; Hypothalamus; Insulin; Insulin Resistance; Leptin; Liver; Models, Biological

Recently more and more evidences have emerged about the oncogenic effect of type 2 diabetes and metabolic syndrome. Among these evidences epidemiological data are in first line. There is a causal relationship according to gender, ethnicity and geographic situation between different tumors and type 2 diabetes/metabolic syndrome as well. Supposed pathomechanisms are obesity, cytokines, secreted excessively in adipose tissue, permanent and postprandial hyperglycemia, hyperinsulinism and insulin resistance, other growth factors, like proinsulin, insulin like growth factor-1, reactive oxygen species, angiogenesis, inflammation, and the multiple effects of inflammatory cytokines. It proved to be evident that both peroxisome-proliferator-activated receptors and the regulatory ubiquitin proteasome system have significant role in insulin sensitivity and in co-ordinating cell proliferation and angiogenesis. These mechanisms in metabolic syndrome are risk factors towards atherosclerosis and cancer diseases as well. This newly emerged knowledge may open new pathways in treating and preventing the above-mentioned pathologic processes.

Topics: Adiponectin; Adipose Tissue; Animals; Cell Proliferation; Cytokines; Diabetes Mellitus, Type 2; Humans; Hyperglycemia; Hyperinsulinism; Inflammation; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Metabolic Syndrome; Neoplasms; Neovascularization, Pathologic; Obesity; Peroxisome Proliferator-Activated Receptors; Reactive Oxygen Species; Risk Factors; Ubiquitins; Vascular Endothelial Growth Factor A

Recent work shows a high prevalence of low testosterone and inappropriately low LH and FSH concentrations in type 2 diabetes. This syndrome of hypogonadotrophic hypogonadism (HH) is associated with obesity, and other features of the metabolic syndrome (obesity and overweight, hypertension and hyperlipidemia) in patients with type 2 diabetes. However, the duration of diabetes or HbA1c were not related to HH. Furthermore, recent data show that HH is also observed frequently in patients with the metabolic syndrome without diabetes but is not associated with type 1 diabetes. Thus, HH appears be related to the two major conditions associated with insulin resistance: type 2 diabetes and the metabolic syndrome. CRP concentrations have been shown to be elevated in patients with HH and are inversely related to plasma testosterone concentrations. This inverse relationship between plasma free testosterone and CRP concentrations in patients with type 2 diabetes suggests that inflammation may play an important role in the pathogenesis of this syndrome. This is of interest since inflammatory mechanisms may have a cardinal role in the pathogenesis of insulin resistance. It is relevant that in the mouse, deletion of the insulin receptor in neurons leads to HH in addition to a state of systemic insulin resistance. It has also been shown that insulin facilitates the secretion of gonadotrophin releasing hormone (GnRH) from neuronal cell cultures. Thus, HH may be the result of insulin resistance at the level of the GnRH secreting neuron. Low testosterone concentrations in type 2 diabetic men have also been related to a significantly lower hematocrit and thus to an increased frequency of mild anemia. Low testosterone concentrations are also related to an increase in total and regional adiposity, and to lower bone density. This review discusses these issues and attempts to make the syndrome relevant as a clinical entity. Clinical trials are required to determine whether testosterone replacement alleviates symptoms related to sexual dysfunction, and features of the metabolic syndrome, insulin resistance and inflammation.

Topics: Animals; Atherosclerosis; Bone Density; Cross-Sectional Studies; Diabetes Complications; Diabetes Mellitus, Type 2; Hematocrit; Humans; Hypogonadism; Inflammation Mediators; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Models, Biological; Obesity; Prostatic Neoplasms; Sexual Dysfunction, Physiological; Testosterone

Over the past 30 years, a sharp rise in the prevalence of overweight and obesity has been noted in both children and adults. Health consequences include biomechanical, biochemical and psychosocial factors, with broad implications toward central adiposity and a number of conditions with which it relates. Substantial new information has surfaced within the last decade that alters previous concepts regarding the role of adipose tissue in health and in disease. This literature review explores the role that white adipose tissue (WAT) plays within a cascade of endocrine interfaces that have significant health consequences. WAT is now known to be an active participant in regulating physiological and pathological processes, including immunity and inflammation and to play a primary role in the development of a triad of hormonal imbalance (leptin resistance, adrenaline resistance, insulin resistance). Particular focus is placed on leptin hormone and its potential influences on inflammation and a host of other metabolic disturbances.

Topics: Adipose Tissue, White; Adult; Child; Diet Therapy; Female; Hormones; Humans; Inflammation; Insulin Resistance; Leptin; Male; Obesity; Waist Circumference

The adipocyte-derived hormone, leptin, signals the status of body energy stores to the central nervous system to regulate appetite and energy expenditure. A specific long-form leptin receptor (LepRb), a type I cytokine receptor, mediates leptin action on LepRb-expressing neurons in the brain. Leptin binding to LepRb activates the associated Janus kinase-2 (Jak2) tyrosine kinase to promote the phosphorylation of Jak2 and three residues on LepRb; each of these sites mediates a distinct aspect of downstream LepRb signaling, with differing physiologic functions. Tyr(1138) --> STAT3 signaling suppresses feeding, but is not required for a number of other leptin actions. Tyr(985) binds SH2-containing tyrosine phosphatase-2 and suppressor of cytokine signaling-3 and primarily mediates the attenuation of LepRb signaling in vivo. The role for Tyr(1077), the major regulator of signal transducer and activator of transcription-5 (STAT5) during leptin signaling, in the physiologic response to leptin remains unclear, although the obese phenotype of animals deleted for STAT5 in the brain suggests the potential importance of this signaling pathway. Leptin also modulates a number of other signaling pathways in the brain, including PI 3-kinase, mammalian target of rapamycin and AMP-dependent protein kinase; the pathways by which leptin controls these signals remain unclear, however, and may involve some indirect mechanisms. Important issues regarding leptin action and LepRb signaling in the future include not only the more thorough analysis of intracellular signaling pathways, but the neural substrate by which leptin acts, as most major populations of LepRb neurons remain poorly studied.

Topics: Animals; Homeostasis; Humans; Hypothalamus; Insulin Resistance; Leptin; Mice; Receptors, Cell Surface; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor; STAT5 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins

It has been long known that the frequency of overweight and obese people is higher among depressed and bipolar patients than in the general population. The marked alteration of body weight (and appetite) is one of the most frequent of the 9 symptoms of major depressive episode, and these symptoms occur during recurrent episodes of depression with a remarkably high consequence. According to studies with representative adult population samples, in case of obesity (BMI over 30) unipolar or bipolar depression is significantly more frequently (20-45%) observable. Since in case of depressed patients appetite and body weight reduction is observable during the acute phase, the more frequent obesity in case of depressed patients is related (primarily) not only to depressive episodes, but rather to lifestyle factors, to diabetes mellitus also more frequently occurring in depressed patients, to comorbid bulimia, and probably to genetic-biological factors (as well as to pharmacotherapy in case of medicated patients). At the same time, according to certain studies, circadian symptoms of depression give rise to such metabolic processes in the body which eventually lead to obesity and insulin resistance. According to studies in unipolar and bipolar patients, 57-68% of patients is overweight or obese, and the rate of metabolic syndrome was found to be between 25-49% in bipolar patients. The rate of metabolic syndrome is further increased by pharmacotherapy. Low total and HDL cholesterol level increases the risk for depression and suicide and recent studies suggest that omega-3-fatty acids possess antidepressive efficacy. Certain lifestyle factors relevant to healthy metabolism (calorie reduction in food intake, regular exercise) may be protective factors related to depression as well. The depression- and possibly suicide-provoking effect of sibutramine and rimonabant used in the pharmacotherapy of obesity is one of the greatest recent challenges for professionals and patients alike.

Topics: Anti-Obesity Agents; Antidepressive Agents; Appetite Depressants; Appetite Regulation; Bipolar Disorder; Circadian Rhythm; Cyclobutanes; Depression; Depressive Disorder, Major; Dietary Carbohydrates; Energy Intake; Ghrelin; Humans; Hypothalamo-Hypophyseal System; Insulin Resistance; Leptin; Obesity; Piperidines; Pituitary-Adrenal System; Pyrazoles; Rimonabant; Seasonal Affective Disorder; Sleep Wake Disorders; Surveys and Questionnaires; Weight Gain; Weight Loss

White adipose tissue was believed to be just an energy-storage organ, but it is now recognized to be an active participant in energy homoeostasis and physiological functions such as immunity and inflammation. Macrophages are components of adipose tissue and actively participate in its activities. Adipose tissue is known to express and secrete a variety of products known as 'adipokines', including leptin, adiponectin, resistin and visfatin, as well as cytokines and chemokines such as tumor necrosis factor-alpha, interleukin-6 and monocyte chemoattractant protein-1. The release of adipokines by either adipocytes or adipose tissue-infiltrated macrophages leads to a chronic subinflammatory state that could play a central role in the development of insulin resistance and type 2 diabetes, and the increased risk of cardiovascular disease associated with obesity.

Topics: Adipokines; Adiponectin; Endoplasmic Reticulum; Humans; Inflammation; Insulin Resistance; Interleukin-6; Leptin; Nicotinamide Phosphoribosyltransferase; Obesity; Plasminogen Activator Inhibitor 1; Resistin; Serum Amyloid A Protein; Tumor Necrosis Factor-alpha

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

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

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

Catch-up growth early in life (after fetal, neonatal or infantile growth retardation) is a major risk factor for later obesity, type-2 diabetes and cardiovascular diseases. These risks are generally interpreted alongside teleological arguments that environmental exposures which hinder growth early in life lead to programming of 'thrifty mechanisms' that are adaptive during the period of limited nutrient supply (or growth constraint), but which increase risks for diseases during improved nutrition and catch-up growth later in life. This paper addresses this notion of 'thrifty mechanisms' in the light of evidence that catch-up growth is characterized by a disproportionately higher rate of fat gain relative to lean tissue gain, and that such preferential catch-up fat is in part driven by energy conservation mechanisms operating via suppressed thermogenesis. It provides a molecular-physiological framework which integrates emerging insights into mechanisms by which this thrifty 'catch-up fat' phenotype cross-links with insulin and leptin resistance.

Topics: Adipose Tissue; Animals; Body Fat Distribution; Glucose; Humans; Infant; Infant, Low Birth Weight; Infant, Newborn; Infant, Small for Gestational Age; Insulin Resistance; Leptin; Metabolic Diseases; Muscle, Skeletal; Obesity; Signal Transduction; Thermogenesis

Increasing evidence supports the role of adipose tissue in the development of a systemic inflammatory state, which contributes to obesity-associated vasculopathy and cardiovascular risk. In addition to storing calories as triglycerides, adipocytes secrete a large variety of proteins, including cytokines, chemokines, and -hormone-like factors (eg, leptin, adiponectin, resistin). This production of pro chemokines by adipose tissue is of particular interest, because their local secretion by perivascular adipose depots may provide a new mechanistic link between obesity and its associated vascular complications. Insulin resistance, in subjects with or without diabetes, is frequently associated with obesity, particularly with an excess of intra-abdominal fat. Recently, the endocannabinoid system, among others, has been shown to be involved in the pathophysiology of visceral obesity and global cardiometabolic risk, as represented by the overall risk of developing type 2 diabetes or cardiovascular diseases.

Topics: Abdominal Fat; Adiponectin; C-Reactive Protein; Cardiovascular Diseases; Humans; Inflammation; Insulin Resistance; Leptin; Metabolic Syndrome; Resistin; Risk Factors

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

Estimates of people suffering from overweight (one billion) and obesity (300 million) are increasing. The accumulation of triglycerides in the liver, in the absence of excess alcohol intake, has been described in the early sixties. It was not until 1980, however, that Ludwig et al named this condition nonalcoholic steatohepatitis (NASH). Subsequently, nonalcoholic fatty liver disease (NAFLD) has been used as a general name for conditions ranging from simple steatosis through steatohepatitis to end-stage liver disease (cirrhosis). Many studies have demonstrated the significant correlation with obesity and insulin resistance. Other studies have revealed a significant correlation between hepatic steatosis, cardiovascular disease and increased intima-media thickness. WHO estimated that at least two million patients will develop cirrhosis due to hepatic steatosis in the years to come. Longitudinal cohort studies have demonstrated that those patients with cirrhosis have a similar risk to develop hepatocellular carcinoma as those with other causes of cirrhosis. Taken all together, NAFLD has become the third most important indication for liver transplantation. Therefore, training programmes in internal medicine, gastroenterology and hepatology should stress the importance of diagnosing this entity and treat properly those at risk for developing complications of portal hypertension and concomitant cardiovascular disease. This review will focus on the clinical characteristics, pathophysiology, imaging techniques and the readily available therapeutic options.

Topics: Adipocytes; Fatigue; Fatty Acids, Nonesterified; Fatty Liver; Humans; Insulin Resistance; Leptin; Lipids; Liver; Liver Failure; Pain; Reference Values

After an initial attempt by the WHO to define metabolic syndrome (MS) on a pathophysiologically oriented approach requiring the assessment of insulin resistance markers, the NCEP-ATPIII and more recently the IDF proposed more clinically oriented criteria to help, toward a preventive medicine goal, to identify patients who are likely to have features of the MS and be at increased risk of type 2 diabetes and cardio vascular disease. The notion of MS is built around abnormalities of the metabolism of lipids and carbon hydrates, a rise of blood pressure, and visceral obesity of abdominal localization. These parameters report only partially on mechanisms leading to the development of the MS. The physiopathology of MS is partially understood even today and likely results from the combination of environmental, genetic and epigenetic factors. Abdominal visceral obesity, a state of low-grade chronic inflammation and insulin resistance are the main processes susceptible to explain the various constituents of this syndrome.

Topics: Environment; Exercise; Humans; Hypertension; Inflammation; Insulin Resistance; Leptin; Metabolic Syndrome; Models, Biological; Nutritional Status; Psoriasis

The incidence and prevalence of obesity and the metabolic syndrome have risen markedly in the past decade, representing a serious cardiovascular health hazard with significant morbidity and mortality. The etiology of the metabolic syndrome and its various pathogenic mechanisms are incompletely defined and under intense investigation. Contemporary research suggests that the adipocyte-derived hormone leptin may be an important factor linking obesity, the metabolic syndrome, and cardiovascular disorders. Although recent evidence indicates that under normal conditions leptin may be an important factor in regulating pressure and volume, during situations of chronic hyperleptinemia and leptin resistance, this hormone may function pathophysiologically for the development of hypertension and cardiac and renal diseases. Future research will determine if reduction of circulating leptin and/or blockade of its peripheral actions can confer cardiovascular and renal protection in hyperleptinemic patients with obesity and the metabolic syndrome.

Topics: Appetite Regulation; Blood Pressure; Cardiovascular Diseases; Heart; Humans; Hypertension; Insulin Resistance; Kidney; Leptin; Metabolic Syndrome; Obesity; Receptors, Leptin; Risk Factors; Sympathetic Nervous System

The clustering of cardiovascular risk factors associated with abdominal obesity is well established. Although currently lacking a universal definition, the metabolic syndrome describes a constellation of metabolic abnormalities, including abdominal obesity, and was originally introduced to characterize a population at high cardiovascular risk. Adipose tissue is a dynamic endocrine organ that secretes several inflammatory and immune mediators known as adipokines. Dysregulation of adipokine secretion, free fatty acid toxicity, and the site-specific differences in abdominal (visceral) versus subcutaneous fat support abdominal obesity as a causal factor mediating the insulin resistance, increased risk of diabetes, and cardiovascular disease in the metabolic syndrome.

Topics: Adipokines; Adiponectin; Adiposity; Cardiovascular Diseases; Fatty Acids, Nonesterified; Humans; Insulin Resistance; Intra-Abdominal Fat; Leptin; Metabolic Syndrome; Obesity; Renin-Angiotensin System; Risk Factors; Subcutaneous Fat, Abdominal

Recently the definition, the pathophysiology and even the clinical utility of metabolic syndrome (MS) have been discussed. The risk induced by each component of the metabolic syndrome is higher than the risk induced by MS alone. MS alone is, in fact, a weaker predictor of cardiovascular disease than diabetes. New criteria to define the metabolic syndrome have been proposed, as adipokines, CRP and PAI-1. IGFBP-1 is related to hyperinsulinemia/insulin resistance and to the risk of diabetes and fatal ischemic heart disease development. IGF/IGFBP system could be a link between insulin resistance and cardiovascular disease. RBP-4 can attenuate insulin signalling in skeletal muscle and induce hepatic gluconeogenesis. The belief that insulin-resistance is the main cause of MS could change in favour of the adipose tissue dysfunction. The most common cause of a reduced capacity of the adipose tissue to store fats is the increased dietary intake, also present in lipodistrophy, type 1 diabetes mellitus and polycystic ovarian syndrome. The adipose tissue production of adipokines and cytokines (such as IL-6, TNF-alpha and TGF-beta) and the excessive lipid flux towards muscles, heart and liver (Ectopic fat storage syndrome) contribute to the MS genesis and to an increased cardiovascular risk. The comprehension of adipose tissue dysfunction mechanisms offers new possibilities of prevention and therapy.

Topics: Adiponectin; Adipose Tissue; C-Reactive Protein; Humans; Insulin Resistance; Insulin-Like Growth Factor Binding Proteins; Interleukin-6; Leptin; Metabolic Syndrome; Plasminogen Activator Inhibitor 1; Retinoblastoma Protein; Terminology as Topic

Currently, a high carbohydrate/low fat diet is recommended for patients with hypertension; however, the potentially important role that the composition of dietary fat and carbohydrate plays in hypertension and the development of pathological left ventricular hypertrophy (LVH) has not been well characterized. Recent studies demonstrate that LVH can also be triggered by activation of insulin signaling pathways, altered adipokine levels, or the activity of peroxisome proliferator-activated receptors (PPARs), suggesting that metabolic alterations play a role in the pathophysiology of LVH. Hypertensive patients with high plasma insulin or metabolic syndrome have a greater occurrence of LVH, which could be due to insulin activation of the serine-threonine kinase Akt and its downstream targets in the heart, resulting in cellular hypertrophy. PPARs also activate cardiac gene expression and growth and are stimulated by fatty acids and consumption of a high fat diet. Dietary intake of fats and carbohydrate and the resultant effects of plasma insulin, adipokine, and lipid concentrations may affect cardiomyocyte size and function, particularly in the setting of chronic hypertension. This review discusses potential mechanisms by which dietary carbohydrates and fats ca affect cardiac growth, metabolism, and function, mainly in the context of pressure overload-induced LVH.

Topics: Adiponectin; Animals; Blood Glucose; Dietary Carbohydrates; Dietary Fats; Humans; Hypertension; Hypertrophy, Left Ventricular; Insulin Resistance; Leptin; Lipid Metabolism; Models, Animal

Examination of individuals with 'extreme phenotypes' has revealed some rare monogenic disorders that were previously unknown. This identification can shed light on physiological pathways that are also important in normal physiology and how their impairment leads to more common, milder, multigenic forms of the disease. Ultimately, this is a potential route to treatment of both disease types. This approach is discussed in relation to Type 2 diabetes, arising from both insufficient insulin production and insulin resistance.

Topics: Diabetes Mellitus, Type 2; Genetic Predisposition to Disease; Humans; Insulin; Insulin Resistance; Leptin; Metabolic Diseases; Models, Biological; Obesity; Phenotype; PPAR gamma; Receptor, Melanocortin, Type 4

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

Obesity is associated with significant morbidity and mortality and is increasing in prevalence worldwide. Associated conditions include insulin resistance (IR), diabetes, hypertension and dyslipidaemia; a clustering of these has recently been termed as metabolic syndrome. Weight gain is a major predictor of the metabolic syndrome with waist circumference being a more sensitive indicator than body mass index as it reflects both abdominal subcutaneous adipose tissue and visceral adipose tissue (VAT). VAT has more metabolic activity and secretes a number of hormones and pro-inflammatory cytokines which are linked with the metabolic abnormalities listed above. Central obesity also increases the risk of obstructive sleep apnoea syndrome (OSAS), where the sleep disordered breathing may also independently lead to/or exacerbate IR, diabetes and cardiovascular risk. The contribution of OSAS to the metabolic syndrome has been under-recognized. The putative mechanisms by which OSAS causes or exacerbates these other abnormalities are discussed. We propose that activation of nuclear factor kappa B by stress hypoxia and/or by increased adipokines and free fatty acids released by excess adipose tissue is the final common inflammatory pathway linking obesity, OSAS and the metabolic syndrome both individually and, in many cases, synergistically.

Topics: Adiponectin; Diabetes Mellitus, Type 2; Humans; Inflammation; Insulin Resistance; Leptin; Metabolic Syndrome; NF-kappa B; Obesity; Risk Factors; Sleep Apnea Syndromes

The prevalence of obesity, especially among the young, is dramatically increasing in the United States. Obesity is associated with accelerated atherosclerosis and increased rates of cardiovascular death. There are many plausible mechanisms by which an increase in adipose tissue could adversely affect the vessel wall. These include the changes in blood pressure, glucose level, lipid/lipoprotein metabolism, and systemic inflammation. In addition, factors secreted by adipose tissue may directly influence vessel wall homeostasis by influencing the function of endothelial cells, arterial smooth muscle cells, and macrophages in the vessel wall. There is general agreement that central, as opposed to peripheral, adipose tissue confers the most cardio-metabolic risk. Although the basis of this differential risk has not been not established, the pattern of gene expression and secretory products in visceral fat would be predicted to be more atherogenic compared with that in subcutaneous peripheral fat. Numerous studies have shown the beneficial effects of weight loss on markers of cardiovascular risk but fewer have demonstrated improvement in direct measures of large vessel disease. The unfolding role of adipose tissue as an important metabolic and secretory organ provides new opportunities for developing more effective approaches for preventing obesity and its atherosclerotic complications.

Topics: Adiponectin; Adipose Tissue; Atherosclerosis; Endothelium, Vascular; Humans; Insulin Resistance; Leptin; Obesity; Prevalence; Prognosis; Risk Factors; United States

Topics: Adiponectin; Angiotensin II Type 1 Receptor Blockers; Antioxidants; Drug Design; Fatty Acids, Nonesterified; Fatty Liver; Humans; Hypolipidemic Agents; Insulin Resistance; Leptin; Metabolic Syndrome; Receptors, Adiponectin; Receptors, Cell Surface; Tumor Necrosis Factor-alpha

Several endocrine changes have been described in the obesity state. The corticotropic axis is hyperresponsive and there is enhancement of hormonal clearance, but cortisol levels are within the normal range. It is important to characterize a pseudo-Cushing in obesity. Leptin seems to be a permissive hormone for the beginning of puberty. In adults, gonadotropines are normal, and hyperandrogenism and hyperestrogenism are found. In women, insulin resistance has a central role in polycystic ovarian syndrome (POS), which is associated to ovarian hyperandrogenemia. In obese subjects, growth hormone (GH) is generally low and IGF1 is normal. Thyroid function is commonly normal in obese subjects.

Topics: Adrenocorticotropic Hormone; Endocrine Glands; Gonadotropins, Pituitary; Growth Hormone; Hormones; Humans; Hypothalamo-Hypophyseal System; Insulin Resistance; Leptin; Obesity; Thyrotropin

The unparalleled global rates of obesity and type 2 diabetes, together with the associated cardiovascular morbidity and mortality, are referred to as the "diabesity pandemic". Changes in lifestyle occurring worldwide, including the increased consumption of high-caloric foods and reduced exercise, are regarded as the main causal factors. Central obesity and insulin resistance have emerged as important linking components. Understanding the aetiology of the cluster of pathologies that leads to the increased risk is instrumental in the development of preventive and therapeutic strategies. Historically, skeletal muscle, adipose tissue and liver were regarded as key insulin target organs involved in insulin-mediated regulation of peripheral carbohydrate, lipid and protein metabolism. The consequences of impaired insulin action in these organs were deemed to explain the functional and structural abnormalities associated with insulin resistance. The discovery of insulin receptors in the central nervous system, the detection of insulin in the cerebrospinal fluid after peripheral insulin administration and the well-documented effects of intracerebroventricularly injected insulin on energy homeostasis, have identified the brain as an important target for insulin action. In addition to its critical role as a peripheral signal integrating the complex network of hypothalamic neuropeptides and neurotransmitters that influence parameters of energy balance, central nervous insulin signalling is also implicated in the regulation of peripheral glucose metabolism. This review summarizes the evidence of insulin action in the brain as part of the multifaceted circuit involved in the central regulation of energy and glucose homeostasis, and discuss the role of impaired central nervous insulin signalling as a pathogenic factor in the obesity and type 2 diabetes epidemic.

Topics: Animals; Brain; Diabetes Mellitus, Type 2; Disease Outbreaks; Energy Intake; Energy Metabolism; Glucose; Humans; Insulin; Insulin Resistance; Leptin; Life Style; Obesity; Physical Exertion; Receptor, Insulin; Signal Transduction

The increasing national prevalence of obesity is a major public health concern and a substantial burden on the health care resources of Canada. In addition to the direct health impact of obesity, this condition is a well-established risk factor for the development of various prevalent comorbidities including type 2 diabetes, hypertension, and cardiovascular disease. Historically, adipose tissue has been regarded primarily as an organ for energy storage. However, the discovery of leptin in the mid 1990's revolutionized our understanding of this tissue and has focused attention on the endocrine function of adipose tissue as a source of secreted bioactive peptides. These compounds, collectively termed adipokines, regulate a number of biological functions including appetite and energy balance, insulin sensitivity, lipid metabolism, blood pressure, and inflammation. The physiological importance of adipokines has led to the hypothesis that changes in the synthesis and secretion of these compounds in the obese are a causative factor contributing to the development of obesity and obesity-related diseases in these individuals. Following from this it has been proposed that pharmacologic manipulation of adipokine levels may provide novel effective therapeutic strategies to treat and prevent obesity, type 2 diabetes, and cardiovascular disease.

Topics: Adiponectin; Adipose Tissue; Angiotensin II; Animals; Cardiovascular Diseases; Complement Activation; Complement C3a; Complement Factor D; Cytokines; Diabetes Mellitus, Type 2; Fibrinolysis; Humans; Inflammation; Insulin Resistance; Interleukin-6; Leptin; Nicotinamide Phosphoribosyltransferase; Obesity; Plasminogen Activator Inhibitor 1; Renin-Angiotensin System; Resistin; Retinol-Binding Proteins; Retinol-Binding Proteins, Plasma; Risk Factors; Tumor Necrosis Factor-alpha

Leptin, which is produced by adipocytes, is known to be an important regulator of food intake and energy storage. Disturbance of thyroid function is associated with marked changes in both body weight and energy expenditure, and it has therefore been the subject of much research to study the mutual roles of leptin and thyroid hormones in this respect. Despite intensive research in this field, results are still not very clear. The aim of this review has been to update the current state of knowledge of leptin related to thyroid pathophysiology.

Topics: Animals; Humans; Hypothalamo-Hypophyseal System; Insulin Resistance; Leptin; Pituitary-Adrenal System; Protein Binding; Receptors, Leptin; Thyroid Gland; Thyroid Hormones

Growing evidence suggests that food intake, energy expenditure and endogenous glucose production are regulated by hypothalamic areas that respond to a variety of peripheral signals. Therefore, in response to a reduction in energy stores or circulating nutrients, the brain initiates responses in order to promote positive energy balance to restore and maintain energy and glucose homeostasis. In contrast, in times of nutrient abundance and excess energy storage, key hypothalamic areas activate responses to promote negative energy balance (i.e. reduced food intake and increased energy expenditure) and decreased nutrient availability (reduced endogenous glucose production). Accordingly, impaired responses or 'resistance' to afferent input from these hormonal or nutrient-related signals would be predicted to favour weight gain and insulin resistance and may contribute to the development of obesity and type 2 diabetes.

Topics: Animals; Diabetes Mellitus, Type 2; Eating; Energy Metabolism; Feedback, Physiological; Glucose; Homeostasis; Humans; Hypothalamus; Insulin Resistance; Leptin; Liver; Obesity; Signal Transduction; Weight Gain

The metabolic syndrome is a long-term process, explained by the interaction of genetic and environmental factors, that starts early in life and is involved in the pathophysiology of a large percentage of cases with type 2 diabetes and atherosclerosis. A number of clinical studies have demonstrated the importance of fat distribution and especially the contribution of visceral fat accumulation to the development of metabolic disorders. Visceral adipose tissue can be studied through different imaging techniques. The accumulation of visceral adipose tissue, as opposed to subcutaneous fat, increases the risk of developing metabolic disease and cardiovascular diseases (CVD). Visceral adipocytes secrete a variety of cytokines known as adipocytokines suggesting that adipose tissue is an endocrine organ that may affect the function of other organs. Weight loss, particularly a reduction in waist circumference, improves insulin sensitivity, lipid profile, and serum adipocytokines, reducing the risk of developing chronic disease and CVD. Waist circumference is a required component of metabolic syndrome under the International Diabetes Federation (IDF) criteria, rather than an optional component as used by other previous classifications. Studies have shown that using a lower waist circumference threshold within the context of metabolic syndrome increases the prevalence, but decreases the risk of mortality and type 2 diabetes. It is possible that waist circumference acts as a marker for other risk factors. These findings reinforce the notion that reductions in visceral adipose tissue should be a primary aim of strategies designed to reduce health risks associated with metabolic syndrome.

Topics: Abdominal Fat; Adiponectin; Adipose Tissue; Animals; Homocysteine; Humans; Insulin Resistance; Intra-Abdominal Fat; Leptin; Metabolic Syndrome; Waist-Hip Ratio

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

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

Abdominal adiposity, overweightness and obesity are frequently present in patients with polycystic ovary syndrome (PCOS). A large body of evidence suggests that abdominal adiposity and the resulting insulin resistance contribute to ovarian and, possibly, adrenal hyperandrogenism. However, androgen excess itself might also contribute to abdominal fat deposition in hyperandrogenic women. Recent genomic and proteomic analyses of visceral fat from PCOS patients have detected differences in gene expression and protein content compared with those of non-hyperandrogenic women. Here we review the existing evidence for a vicious circle whereby androgen excess favoring the abdominal deposition of fat further facilitates androgen secretion by the ovaries and adrenals in PCOS patients.

Topics: Abdominal Fat; Adiposity; Female; Humans; Hyperandrogenism; Hyperinsulinism; Insulin Resistance; Leptin; Models, Biological; Polycystic Ovary Syndrome

The fact that fat issue is an endocrine gland secreting several hormones participating in the pathogenesis of type 2 diabetes mellitus (DM2) is universally recognized. Fat issue secretes leptin, tumor necrosis factor alpha, resistin, adiponectin, interleukin-6, free fatty acids, visfatin, omentin, perilipin, and other substances that influence the condition of insulinoresistance, one of the main factors responsible for DM2. Subcutaneous fat and visceral depot fat tissue differ in the spectrum of hormones they produce; the list of these hormones is presented in the article. The presence of abdominal or visceral obesity is combined with significant insulinoresistance, which, in its turn, increases the risk of vascular complications of diabetes. The article also cover the participation of other mechanisms - insulin secretion defect, oxidation stress, low secretion of glucagon-like peptide 1, apoptosis, an increased quantity of amyloid and the fl-cell pull in the pancreatic island--in DM2 pathogenesis. The authors present data on the secretion of leptin, resistin, adiponectin, and tumor necrosis factor a, as well as the condition of the functional activity of beta-cells and the degree of insulinoresistance in 30 DM2 patients receiving dietotherapy.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Diabetes Mellitus, Type 2; Disease Progression; Humans; Insulin Resistance; Interleukin-6; Leptin; Obesity; Tumor Necrosis Factor-alpha

Topics: Exercise; Fatty Liver; Humans; Insulin Resistance; Leptin; Life Style; Lipid Metabolism; Liver

A cluster of risk factors associated with obesity defines the metabolic syndrome and identifies cardiometabolic risk. Accumulation of fat in the visceral depot is a more reliable predictor of cardiovascular disease than is total body mass or body mass index. The recent discovery of the endocannabinoid-CB1 receptor system and its impact on the regulation of energy metabolism represents a significant advance that will help target visceral fat and its metabolic implications. As a highly active endocrine organ, visceral fat secretes many bioactive molecules, known as adipokines. Dysregulation of these adipokines contributes to the pathogenesis of the obesity-associated metabolic syndrome, resulting in insulin resistance, type 2 diabetes, hypertension, hyperlipidemia, and vascular disease. Even modest weight reduction leads to reduced cardiometabolic risk by affecting the individual components comprising the metabolic syndrome.

Topics: Adiponectin; Anti-Obesity Agents; Blood Coagulation; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diet; Dyslipidemias; Exercise; Fatty Acids; Humans; Hypertension; Inflammation Mediators; Insulin Resistance; Intra-Abdominal Fat; Leptin; Life Style; Metabolic Syndrome; Obesity; Practice Guidelines as Topic; Risk Factors; Weight Loss

The global epidemic of obesity and type-2 diabetes mellitus (T2DM) has highlighted the need for new therapeutic approaches. The association of insulin resistance with these disorders and the knowledge that insulin receptor signaling is mediated by tyrosine (Tyr) phosphorylation have generated great interest in the regulation of the balance between Tyr phosphorylation and dephosphorylation. Several protein Tyr phosphatases (PTPs) have been implicated in the regulation of insulin action, with the most convincing data for PTP1B. Murine models targeting PTP1B, PTP1B(-/-)mice, demonstrate enhanced insulin sensitivity without the weight gain seen with other insulin sensitizers such as peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, probably due to a second action of PTP1B as a negative regulator of leptin signaling. Despite intensive efforts and recent progress, a safe, selective and efficacious PTP1B inhibitor has yet to be identified.

Topics: Animals; Diabetes Mellitus, Type 2; Drug Design; Humans; Insulin; Insulin Resistance; Leptin; Obesity; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Protein Tyrosine Phosphatase, Non-Receptor Type 2; Receptor-Like Protein Tyrosine Phosphatases, Class 2; Receptor, Insulin; Signal Transduction; Structure-Activity Relationship; Substrate Specificity

Unique genetic traits appear to play a role in the increased rates of hypertension (HTN), glucose dysregulation/diabetes (T2DM), and obesity in persons of African descent. Indeed, with increasing rates of westernization/urbanization and concomitant increases in obesity and T2DM, a similar predisposition to the cardiometabolic syndrome and cardiovascular disease (CVD) can be seen in Africans compared with persons of African descent, with CVD reaching epidemic proportions in many areas of Africa. In addition, the complex relationships of metabolic abnormalities that are unique to individuals of African descent have also been demonstrated in Africans. These include: (1) a dissociation of HTN to insulin resistance; (2) relative favorable lipid profile in the setting of increasing rates of CVD; (3) low levels of visceral adiposity in the setting of obesity and insulin resistance; and (4) a dissociation of insulin sensitivity and adiponectin when compared with Caucasians. Although not well understood, these unique relationships suggest that conventional parameters for CVD do not apply to Africans of persons of African descent.

Topics: Adiponectin; Africa; Diabetes Mellitus, Type 2; Dyslipidemias; Genetic Predisposition to Disease; Humans; Hypertension; Insulin Resistance; Leptin; Life Style; Metabolic Syndrome; Obesity; Risk Factors

Insulin resistance is one of the reasons of increasing carbohydrate metabolism disturbances with aging. Mechanisms of these changes had been partially elucidated. Decreasing of physical activity with increasing of total and abdominal fat are especially important pathogenetic mechanisms. Changes in glucose transporter 4 (GLUT-4) level in skeletal muscles and serum level of insulin like growth factor 1 (IGF-1) could be mechanisms independent of fat tissue. Other mechanisms which could be associated with insulin resistance in aging are related to leptin and adiponectin serum level or changes in mitochondrial energy metabolism and level of advanced glucose end products in diet.

Topics: Adiponectin; Aging; Carbohydrate Metabolism; Energy Metabolism; Glucose Transporter Type 4; Humans; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Muscle, Skeletal

Millions of people worldwide suffer from type 2 diabetes mellitus. There are two major factors that play a role in its pathogenesis: insulin resistance and impaired secretion of insulin by beta-cells. Impaired insulin action is closely linked to the phenomenon of obesity. The adipose tissue releases free fatty acids but also hormones and cytokines such as leptin, adiponectin, resistin, TNF-alpha and others. All those particles modify insulin action. This review article summarizes contemporary opinions on the role of obesity in the generation of resistance to insulin and subsequently impaired glucose tolerance as well as overt type 2 diabetes mellitus.

Topics: Adiponectin; Adipose Tissue; Blood Glucose; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Metabolic Syndrome; Obesity; Resistin; Tumor Necrosis Factor-alpha

An interactive network comprised of neuropeptide Y (NPY) and cohorts is obligatory in the hypothalamic integration of appetite and energy expenditure on a minute-to-minute basis. High or low abundance of NPY and cognate receptors dysregulates the homeostatic milieu engendering hyperphagia, decreased energy expenditure, obesity and attendant metabolic syndrome cluster of dyslipidemia, glucose intolerance, insulin resistance and hyperinsulinemia, risk factors for type II diabetes and cardiovascular diseases. Increasing the supply of the endogenous repressor hormone leptin locally in the hypothalamus with the aid of leptin gene therapy, blocked age-related and dietary obesities, and the sequential development of dyslipidemia, hyperglycemia, and insulin resistance. Thus, sustained repression of NPY signaling with increased leptin selectively in the hypothalamus can avert environmental obesity and the risks of metabolic diseases.

Topics: Animals; Dyslipidemias; Genetic Therapy; Humans; Hypothalamus; Insulin Resistance; Leptin; Metabolic Syndrome; Neuropeptide Y; Obesity

Several adipose-derived cytokines (adipokines) have been suggested to act as a link between accumulated fat mass and altered insulin sensitivity. Resistin and tumour necrosis factor-alpha (TNF-alpha) have been implicated in impairing insulin sensitivity in rodents; conversely, two other adipokines, leptin and adiponectin, increase insulin sensitivity in lean and obese rodents. Currently, there is considerable focus on the concept that lipid accumulation in skeletal muscle leads to the development of insulin resistance. Adiponectin and leptin have each been demonstrated to increase rates of fatty acid (FA) oxidation and decrease muscle lipid content, which may in part be the underlying mechanism to their insulin sensitizing effect. These effects on FA metabolism appear to be mediated in part through the activation of AMP-activated protein kinase. Evidence derived from animal and human studies suggests that the ability of leptin and adiponectin to stimulate FA oxidation in muscle is impaired in the obese condition. Thus, leptin and adiponectin resistance may be an initiating factor in the accumulation of intramuscular lipids, such as diacylglycerol and ceramide, and the ensuing development of insulin resistance. Lifestyle factors such as diet and exercise are able to restore the sensitivity of muscle to leptin. The actual physiological roles of resistin and TNF-alpha in altering muscle lipid metabolism are more controversial, but each has been shown to directly impair insulin signalling and consequently, insulin stimulated glucose uptake in muscle. However, the possibility that resistin and TNF-alpha reduces insulin sensitivity in muscle by directly impairing FA metabolism in this tissue leading to lipid accumulation, has been virtually unexamined. Thus, the contribution of various adipokines to the development of insulin resistance is complex and not fully understood. Finally, the effects of these adipokines on metabolism and insulin sensitivity are generally studied in isolation, making it difficult to predict the interactive effects and the net impact on insulin sensitivity.

Topics: Adiponectin; Animals; Fatty Acids; Glucose; Humans; Insulin; Insulin Resistance; Leptin; Muscle, Skeletal; Obesity; Oxidation-Reduction; Peptide Hormones; Rats; Receptors, Cell Surface; Resistin; Tumor Necrosis Factor-alpha

To survey the latest state of knowledge concerning the regulation of regional adipocytes and their role in the development of insulin resistance and type 2 diabetes.. Data from the English-language literature on regional adipocytes, including abdominal, intramyocellular, intrahepatic and intra-islet fat as well as the adipokines and their relations to insulin resistance and type 2 diabetes, were reviewed.. It is not the total amount of fat but the fat that resides within skeletal muscle cell (intramyocellular fat), hepatocytes and intra-abdominally (visceral fat), via systemic and local secretion of several adipokines, that influences insulin resistance. Among the adipokines that relate to insulin resistance, adiponectin and leptin appear to have clinical relevance to human insulin resistance and others may also contribute, but their role is still inconclusive. The intra-islet fat also adversely affects beta-cell function and number (beta-cell apoptosis), eventually leading to deterioration of glucose tolerance. The abnormal location of fat observed in patients with type 2 diabetes and their relatives is conceivably partly the results of the genetically determined, impaired mitochondrial fatty acid oxidative capacity. Restriction or elimination of the fat load by weight control, regular exercise and thiazolidinediones has been shown to improve insulin resistance and beta-cell function and to delay the development of type 2 diabetes.. These data support the plausibility of an essential role of regional adipose tissue in the development of insulin resistance and type 2 diabetes.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Leptin; Lipids; Muscle Cells

It now appears that, in most obese patients, obesity is associated with a low-grade inflammation of white adipose tissue (WAT) resulting from chronic activation of the innate immune system and which can subsequently lead to insulin resistance, impaired glucose tolerance and even diabetes. WAT is the physiological site of energy storage as lipids. In addition, it has been more recently recognized as an active participant in numerous physiological and pathophysiological processes. In obesity, WAT is characterized by an increased production and secretion of a wide range of inflammatory molecules including TNF-alpha and interleukin-6 (IL-6), which may have local effects on WAT physiology but also systemic effects on other organs. Recent data indicate that obese WAT is infiltrated by macrophages, which may be a major source of locally-produced pro-inflammatory cytokines. Interestingly, weight loss is associated with a reduction in the macrophage infiltration of WAT and an improvement of the inflammatory profile of gene expression. Several factors derived not only from adipocytes but also from infiltrated macrophages probably contribute to the pathogenesis of insulin resistance. Most of them are overproduced during obesity, including leptin, TNF-alpha, IL-6 and resistin. Conversely, expression and plasma levels of adiponectin, an insulin-sensitising effector, are down-regulated during obesity. Leptin could modulate TNF-alpha production and macrophage activation. TNF-alpha is overproduced in adipose tissue of several rodent models of obesity and has an important role in the pathogenesis of insulin resistance in these species. However, its actual involvement in glucose metabolism disorders in humans remains controversial. IL-6 production by human adipose tissue increases during obesity. It may induce hepatic CRP synthesis and may promote the onset of cardiovascular complications. Both TNF-alpha and IL-6 can alter insulin sensitivity by triggering different key steps in the insulin signalling pathway. In rodents, resistin can induce insulin resistance, while its implication in the control of insulin sensitivity is still a matter of debate in humans. Adiponectin is highly expressed in WAT, and circulating adiponectin levels are decreased in subjects with obesity-related insulin resistance, type 2 diabetes and coronary heart disease. Adiponectin inhibits liver neoglucogenesis and promotes fatty acid oxidation in skeletal muscle. In addition, adiponectin counteracts

Topics: Adiponectin; Adipose Tissue; Diabetes Mellitus, Type 2; Humans; Inflammation; Insulin Resistance; Interleukin-6; Leptin; Lipid Metabolism; Macrophages; Obesity; Resistin; Signal Transduction; Tumor Necrosis Factor-alpha

Topics: Adipocytes; Adiponectin; Animals; Diet, Atherogenic; Energy Metabolism; Exercise; Humans; Insulin Resistance; Leptin; Life Style; Metabolic Syndrome; Obesity; Tumor Necrosis Factor-alpha

Leptin is an adipocyte-secreted hormone which plays a key role in energy homeostasis. Recent advances in leptin physiology have revealed that the main role of this hormone in humans is to signal energy availability in energy-deficient states. Interventional studies in leptin deficient children and observational studies in normal girls and boys support a role for leptin as a permissive factor for the initiation of puberty in children. Moreover, recent "proof of concept" studies involving leptin administration to humans further support its critical role in regulating energy homeostasis, neuroendocrine and immune function as well as insulin resistance in states of energy/caloric deprivation. Leptin's potential role in the therapy of several disease states, including hypothalamic amenorrhea, anorexia nervosa and syndromes of insulin resistance is under intensive investigation.

Topics: Adolescent; Child; Energy Metabolism; Female; Homeostasis; Humans; Immunity; Infant, Newborn; Insulin Resistance; Leptin; Male; Mutation; Neurosecretory Systems; Obesity; Puberty

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

The worldwide increase in the prevalence of obesity is becoming one of the most important clinical-epidemiological phenomena of the present days. Environmental factors such as changes in life-style and feeding behavior associated with poorly characterized genetic determinants are though to play the most important roles in the pathogenesis of this disease. During the last ten years, since the discovery of leptin, great advances were obtained in the characterization of the hypothalamic mechanisms involved in the control of food intake and thermogenesis. Such advances are unveiling a complex and integrated system and are opening a wide perspective for the finding of novel therapeutic targets for the treatment of this harming condition. This review will present some of the most recent findings in this field. It will be focused on the actions of leptin and insulin in the hypothalamus and will explore the hypothesis that hypothalamic resistance to the action of these hormones may play a role in the development of obesity and may act as a molecular link between obesity, type 2 diabetes mellitus and other clinical conditions on which insulin resistance plays an important pathogenetic role.

Topics: Diabetes Mellitus, Type 2; Eating; Humans; Hypothalamus; Insulin Resistance; Leptin; Life Style; Obesity; Thermogenesis; Transcription, Genetic

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

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

Endothelial dysfunction is associated with several vascular conditions as atherosclerosis, hypertension, hyperlipidemia and diabetes mellitus. In all these conditions insulin resistance (IR) is present. Cytokines are low molecular weight proteins with several endocrine and metabolic functions that participate of inflammation and immune response. Several of these cytokines are independent risk factors for cerebrovascular and coronary artery disease. The major sources of cytokines (adipokines) are the visceral and subcutaneous adipose tissues. Thus, increased adipose tissue mass is associated with alteration in adipokine production as over expression of tumor necrosis factor alpha, interleukin 6, plasminogen activator inhibitor 1, and under expression of adiponectin in adipocite tissue. The pro-inflammatory status associated with these changes provides a potential link between IR and endothelial dysfunction, the early stage in the atherosclerotic process, in obese individuals, and type 2 diabetic patients. Reduction of adipose tissue mass through weight reduction in association with exercise reduces TNF-alpha, IL-6, and PAI-1, increases adiponectin, and is associated with improved insulin sensitivity and endothelial function. This review will focus on the evidence for regulation of endothelial function by insulin and the adypokines such as adyponectin, leptin, resistin, IL-6 and TNF-alpha. Interaction between insulin signaling and adypokines will be discussed, as well as the concept that aberrant adypokine secretion in IR and/or obesity impairs endothelial function and contributes further to reduce insulin sensitivity.

Topics: Adiponectin; Cardiovascular Diseases; Cytokines; Endothelium, Vascular; Fatty Acids; Humans; Hypertension; Inflammation; Insulin Resistance; Leptin

Recent progress in adipocyte biology delineates that adipocytes not only store excess energy, but also respond to metabolic signals by secreting proteins that exert local, central, and peripheral effects. Among these adipokines are free fatty acids, plasminogen activator inhibitor-1, angiotensinogen, TNFa, leptin and adiponectin. Dysregulation of production of these adipokines and/or imbalance of their actions lead to a wide array of liver and systemic pathophysiology related to NASH such as 1) development of systemic and hepatic insulin resistance, 2) progression from benign fatty liver to steatohepatitis and 3) activation of hepatic fibrogenesis. This review deals with the emerging concept of the adipokine interrelationship with the liver.

Topics: Adipocytes; Adiponectin; Angiotensinogen; Animals; Fatty Liver; Fibrosis; Humans; Insulin Resistance; Leptin; Liver; Plasminogen Activator Inhibitor 1; Tumor Necrosis Factor-alpha

Obese women are characterized by similar comorbidities to men, particularly type 2 diabetes mellitus and cardiovascular diseases. Moreover, they also develop some specific problems, including fertility-related disorders and some hormone-dependent forms of cancer. The relationship between excess body fat and reproductive disturbances appears to be stronger for early-onset obesity. Early onset of obesity, particularly during adolescence, favours the development of menses irregularities, chronic oligo-anovulation and infertility in adulthood. Moreover, obesity in women can increase the risk of miscarriage and impair the outcome of assisted reproductive technologies. The main factor implicated in the association between obesity and fertility-related disorders is insulin excess, which accompanies insulin resistance. Hyperinsulinaemia may be directly responsible for the development of androgen excess, through its effects in reducing sex hormone-binding globulin synthesis and circulating concentrations, and in stimulating ovarian androgen production rates. Androgen excess, in turn, represents one of the major factors leading to altered ovarian physiology and associated ovulatory disturbances. Obesity-associated hyperleptinaemia may represent an additional factor involved in anovulation, not only through the induction of insulin resistance, but also through a direct impairment of ovarian function.

Topics: Androgens; Animals; Female; Humans; Hyperinsulinism; Infertility, Female; Insulin Resistance; Leptin; Metabolic Syndrome; Obesity; Polycystic Ovary Syndrome; Reproduction

Enhanced chronic systemic inflammation and reduced insulin sensitivity are often associated in patients with chronic renal failure, contributing to cardiovascular morbidity and mortality in these patients. Adipose tissue produces several hormones (adipocytokines including leptin, resistin, tumor necrosis factor-alpha, and adiponectin) that modulate both systemic inflammatory response and insulin action. High leptin, resistin, and tumor necrosis factor-alpha and low adiponectin are associated with proinflammatory conditions, whereas opposite patterns are commonly observed in the presence of increased insulin sensitivity, low inflammation, and reduced cardiovascular risk. Oxidative stress has also been shown recently to modulate adipocytokine production, resulting in a proinflammatory profile. Increments of plasma concentrations of both proinflammatory and anti-inflammatory adipocytokines have been reported in chronic renal failure, possibly caused by both passive accumulation from reduced renal excretion and metabolic abnormalities induced by uremia. The potential role of altered adipose tissue adipocytokine production in the onset of renal failure-associated inflammatory and metabolic derangements remains largely to be elucidated and is discussed in the current report.

Topics: Adiponectin; Adipose Tissue; Cytokines; Ghrelin; Humans; Inflammation; Insulin Resistance; Kidney Failure, Chronic; Leptin; Nutritional Physiological Phenomena; Oxidative Stress; Peptide Hormones; Uremia

The polycystic ovary syndrome (PCOS) is one of the most common causes of infertility due to anovulation in women. The clinical features of PCOS are heterogeneous and may change throughout the lifespan, starting from adolescence to postmenopausal age. This is largely dependent on the influence of obesity and metabolic alterations, including an insulin-resistant state and the metabolic syndrome, which consistently affect most women with PCOS. Obesity does in fact have profound effects on both the pathophysiology and the clinical manifestation of PCOS, by different mechanisms leading to androgen excess and increased free androgen availability and to alterations of granulosa cell function and follicle development. Notably, simple obesity per se represents a functional hyperandrogenic state. These mechanisms involve early hormonal and metabolic factors during intrauterine life, leptin, insulin and the insulin growth factor system and, potentially, the endocannabinoid system. Compared with normal weight women with PCOS, those with obesity are characterised by a worsened hyperandrogenic and metabolic state, poorer menses and ovulatory performance and, ultimately, poorer pregnancy rates. The importance of obesity in the pathogenesis of PCOS is emphasised by the efficacy of lifestyle intervention and weight loss, not only on metabolic alterations but also on hyperandrogenism, ovulation and fertility. The increasing prevalence of obesity among adolescent and young women with PCOS may partly depend on the increasing worldwide epidemic of obesity, although this hypothesis should be supported by long-term prospective epidemiological trials. This may have great relevance in preventive medicine and offer the opportunity to expand our still limited knowledge of the genetic and environmental background favouring the development of the PCOS.

Topics: Adipose Tissue; Adult; Cannabinoid Receptor Modulators; Female; Humans; Hyperandrogenism; Infertility, Female; Insulin Resistance; Leptin; Male; Menstruation Disturbances; Obesity; Phenotype; Polycystic Ovary Syndrome; Pregnancy; Prenatal Exposure Delayed Effects

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Humans; Hypertension; Insulin Resistance; Leptin; Life Style; Metabolic Syndrome; Obesity; Sympathetic Nervous System

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

The blood-brain barrier (BBB) prevents the unrestricted movement of peptides and proteins between the brain and blood. However, some peptides and regulatory proteins can cross the BBB by saturable and non-saturable mechanisms. Leptin and insulin each cross the BBB by their own transporters. Impaired transport of leptin occurs in obesity and accounts for peripheral resistance; that is, the condition wherein an obese animal loses weight when given leptin directly into the brain but not when given leptin peripherally. Leptin transport is also inhibited in starvation and by hypertriglyceridemia. Since hypertriglyceridemia occurs in both starvation and obesity, we have postulated that the peripheral resistance induced by hypertriglyceridemia may have evolved as an adaptive mechanism in response to starvation. Insulin transport is also regulated. For example, treatment of mice with lipopolysaccharide (LPS) increases insulin transport across the BBB by about threefold. Since many of the actions of CNS insulin oppose those of peripheral insulin and since LPS releases proinflammatory cytokines, enhanced transport of insulin across the BBB could be a mechanism which promotes insulin resistance in sepsis. The brain endothelial cells which comprise the BBB secrete many substances including cytokines. Such secretion can be stimulated from one side of the BBB with release into the other side. For example, it appears that adiponectin can inhibit release of interleukin-6 from brain endothelial cells. Overall, the BBB represents an important interface in mediating gut-brain axes.

Topics: Adiponectin; Animals; Biological Transport; Blood-Brain Barrier; Digestive System Physiological Phenomena; Humans; Hypertriglyceridemia; Insulin; Insulin Resistance; Leptin; Starvation

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: Diagnosis, Differential; Diet Therapy; Exercise Therapy; Humans; Hyperglycemia; Hyperinsulinism; Immunosuppression Therapy; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Plasma Exchange; Receptor, Insulin; Syndrome

Topics: Adult; Animals; Child; Diabetes Mellitus, Lipoatrophic; Female; GTP-Binding Protein gamma Subunits; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Lamin Type A; Leptin; Male; Mutation; Prognosis

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

To review the potential role of leptin, hyperleptinaemia and leptin resistance in the cardiovascular and endocrine complications of metabolic syndrome.. Review of literature listed in Medline.. Hyperleptinaemia is common in obesity and reflects increased adiposity and leptin resistance. Nevertheless, leptin resistance may not be complete as several actions of leptin, such as cardiovascular sympatho-activation, might be preserved in obese subjects known to be resistant to the metabolic effects of leptin (i.e. selective leptin resistance). Notably, the renal and sympathetic actions of leptin may play an important role in the pathogenesis of hypertension related to obesity and metabolic syndrome. Furthermore, the lipotoxic effect of leptin resistance may cause insulin resistance and beta cell dysfunction, increasing the risk of type 2 diabetes. Leptin has also been shown to possess proliferative, pro-inflammatory, pro-thrombotic, and pro-oxidative actions.. Hyperleptinaemia and leptin resistance may contribute to hypertension, impaired glucose metabolism, and pro-atherogenic state in obesity and metabolic syndrome.

Topics: Animals; Atherosclerosis; Blood Pressure; Diabetes Mellitus, Type 2; Drug Resistance; Humans; Hypertension; Insulin Resistance; Leptin; Metabolic Syndrome; Obesity

Topics: Adipose Tissue; Animals; Atherosclerosis; Chemokines; Humans; Insulin Resistance; Interleukin 1 Receptor Antagonist Protein; Leptin

The incidence of type 1 and type 2 diabetes mellitus in the pediatric population has increased over the past decade. The practitioner is often faced with the challenge of differentiating between type 1 and type 2 diabetes at the time of initial diagnosis because of the overlap of clinical and laboratory characteristics between these two entities. Adipokines are proteins secreted by the adipose tissue. Leptin and adiponectin are two adipokines that have been extensively studied in vitro, in animal studies, and in human subjects with type 1 and type 2 diabetes. Leptin and adiponectin play a significant role in the regulation of lipid and carbohydrate metabolism. Adiponectin increases insulin sensitivity in both the liver and skeletal muscle. Leptin decreases appetite, increases energy expenditure, suppresses insulin synthesis and secretion and increases insulin sensitivity. Changes in the secretion or sensitivity to leptin and adiponectin may contribute to the development of type 1 and type 2 diabetes. Adiponectin is higher in adult and pediatric patients with type 1 diabetes compared to those with type 2 diabetes. Data regarding leptin levels are contradictory. Most studies report decreased serum leptin at the time of diagnosis in type 1 diabetes compared to type 2 diabetes subjects and non-diabetic controls. This paper will review basic research and clinical evidence supporting the role of adiponectin and leptin in the development of type 1 and type 2 diabetes and discuss their potential use as tools in the differential diagnosis of pediatric diabetes.

Topics: Adiponectin; Child; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Diagnostic Techniques, Endocrine; Humans; Immune System; Insulin Resistance; Leptin; Metabolic Networks and Pathways; Models, Biological; Obesity

Topics: Adipocytes; Adiponectin; Adipose Tissue; Animals; Body Mass Index; Humans; Insulin Resistance; Leptin; Motor Activity; Obesity; Resistin

Topics: Adipose Tissue; Humans; Insulin Resistance; Leptin; Metabolic Syndrome; Tumor Necrosis Factor-alpha

Topics: Animals; Brain; Hypothalamus; Insulin; Insulin Resistance; Leptin; Metabolic Syndrome; Mice

Topics: Adolescent; Adult; Aged; C-Peptide; Child; Coronary Disease; Diabetes Complications; Glucose; Humans; Insulin; Insulin Resistance; Leptin; Middle Aged; Obesity; Potassium; Risk Factors; Vascular Resistance

From an evolutionary perspective, Darwinian selection has favored insulin-resistant individuals, ie, those with a trait ensuring brain functioning in situations of extreme fuel deprivation. The ability to mount a powerful inflammatory response to infection was another survival advantage in our ancestors, and we now have solid evidence showing that these 2 traits, insulin resistance and inflammation (as measured by serum C-reactive protein [CRP]), are associated in modern human beings. In an analysis of 192 nondiabetic hemodialysis patients, leptin and adiponectin were related in an opposite fashion with insulin sensitivity in end-stage renal disease (ESRD) and interacted in determining insulin resistance in these patients. The risk of insulin resistance was about 6 times higher in ESRD patients with an unfavorable combination of the 2 adipokines (high leptin and low adiponectin) than in those with a favorable combination (low leptin and high adiponectin). Low adiponectin but not high leptin predicted incident cardiovascular events in this cohort. Neither leptin nor adiponectin were associated with CRP in a cross-sectional analysis, but they were linked in an opposite fashion to CRP in a longitudinal study in 21 patients with acute inflammation secondary to infection. High sympathetic activity predicts adverse cardiovascular outcomes in ESRD. Of note, we found that the risk for cardiovascular events is more than 3 times higher in patients with high sympathetic activity and low adiponectin than in those with high adiponectin and low sympathetic activity. The adipocyte hormones leptin and adiponectin are associated in an opposite fashion to insulin sensitivity and inflammation in ESRD patients. Relatively lower plasma adiponectin levels are associated with a higher rate of incident cardiovascular events. Finally, low adiponectin and high norepinephrine seem to be interacting factors in the dismal cardiovascular outcomes with ESRD.

Topics: Adiponectin; Adipose Tissue; Body Composition; C-Reactive Protein; Cardiovascular Diseases; Cytokines; Energy Metabolism; Humans; Inflammation; Insulin Resistance; Kidney Failure, Chronic; Leptin; Renal Dialysis; Risk Factors

Obstructive sleep apnea syndrome (OSAS) is usually associated with conditions known to increase insulin resistance and cardiovascular risk, such as hypertension, obesity, and diabetes. Thus, investigating whether obstructive sleep apnea itself is an independent risk factor for increased insulin resistance and whether continuous positive airway pressure treatment (CPAP) might improve insulin sensitivity brings up considerable methodological problems. Even if insulin sensitivity improves, it is hard to distinguish between an effect of CPAP treatment, e.g. in the reduction of nocturnal sympathetic activity caused by the sleep disturbance, and concomitant factors, such as weight loss. Two recent investigations were able to prove that OSAS is an independent risk factor for insulin resistance: one study in a statistical approach, the other by demonstrating a significant improvement of insulin sensitivity already two days after onset of CPAP therapy, thus clearly ruling out such confounding factors as changes in lifestyle or weight loss. However, it is still not clear if this improvement in insulin sensitivity is accompanied by an improvement in the usually elevated cardiovascular risk of patients with OSAS. Since a decrease in elevated markers of subclinical inflammation--nowadays regarded as the main culprit of cardiovascular complications and atherosclerosis--such as Interleukin-6 and C-reactive protein has been reported during CPAP therapy, and since an improvement in left ventricular function and a decrease in blood pressure were also reported under CPAP treatment, there are several good reasons to assume an improvement in metabolical function in OSAS patients due to CPAP treatment.

Topics: Continuous Positive Airway Pressure; Humans; Insulin Resistance; Leptin; Models, Biological; Obesity; Sleep Apnea, Obstructive

Fatty tissue synthesizes and secretes a wide range of products that may be directly involved in the pathogenesis of the complications associated with obesity. These so-called adipokines may trigger or sustain a chronic inflammatory process. By manipulating the secretory function of fat cells, it might in future be possible to prevent the development of the metabolic and cardiovascular complications of obesity. Current data already suggest that weight reduction and certain substances with an anti-inflammatory action reduce the risk for the metabolic and cardiovascular complications of obesity. To date, however, the evidence available is only indirect, and is insufficient to definitively establish causal relationships between certain secretory products of adipocytes and the comorbidities of adiposity. Further clinical studies are needed.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Animals; Coronary Disease; Diabetes Mellitus, Type 2; Humans; Hypertension; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Interleukin-6; Leptin; Metabolic Syndrome; Obesity; Plasminogen Inactivators; Risk Factors; Thromboembolism; Weight Loss

The metabolic syndrome currently reaches epidemic proportions in the Western industrialized world. Its hallmarks obesity, type 2 diabetes mellitus, and atherosclerosis are closely associated, and we are just beginning to understand the reasons for this relationship: adipose tissue-derived proteohormones (adipocytokines), under normal weight conditions, guarantee homeostasis of glucose and lipid metabolism, but their dysregulated production in the obese state promotes insulin resistance, inflammation, as well as atherosclerotic events. This review will focus on the current understanding of the adipocytokines' molecular role in metabolism and metabolic disease.

Topics: Adipocytes; Adiponectin; Adult; Cytokines; Developed Countries; Homeostasis; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Metabolic Syndrome; Obesity; Prevalence

Topics: Adipocytes; Adiponectin; Animals; Arteriosclerosis; Endothelium, Vascular; Energy Metabolism; Humans; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Life Style; Mitogen-Activated Protein Kinases; Obesity; Phosphatidylinositol 3-Kinases; Receptor, Insulin; Risk Factors; Signal Transduction

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

Topics: Adipose Tissue; Biomarkers; Blood Glucose; Cardiovascular Diseases; Cholesterol, HDL; Humans; Insulin Resistance; Leptin; Lipid Metabolism; Metabolic Syndrome; Obesity; Practice Guidelines as Topic; Risk; Triglycerides; Viscera

Impaired insulin sensitivity and endothelial dysfunction are important markers in the development of restenosis after coronary stenting. In addition, new markers of inflammation and endothelium activation, such as increased leptin levels, also have to considered. Many studies have shown that hyperinsulinemia and insulin resistance increase neointimal index measured six months after coronary stenting, and that insulin-sensitizers have beneficial effects by decreasing the rate of restenosis. The role of endothelial dysfunction in the process of restenosis is a fascinating problem. The pathobiology of restenosis in stented arteries is largely related to neointimal hyperplasia, which is dependent upon several factors, such as a reduction in nitric oxide activity that determines endothelial dysfunction and oxidative stress. Abnormal endothelium-dependent vasodilation (related to decreased nitric oxide production in the insulin-resistant state) might be explained by alterations in intracellular signaling and increased endothelin-1 production. Leptin is a hormone related to both fat metabolism and insulin resistance that has been recognized as an independent predictor of coronary restenosis. Chronic hyperleptinemia can reduce the synthesis of nitric oxide owing to the increased oxidative stress in endothelial cells. As a result, the goal in prevention of in-stent restenosis is to develop drugs that are able to act both as insulin- and endothelium-sensitizers.

Topics: Animals; Coronary Restenosis; Endothelium, Vascular; Humans; Insulin Resistance; Leptin

This review examines the relationship between obesity and prostate cancer, with an update of recent research in this field.. A recent report of the Cancer Prevention Study II showed a direct relationship between increasing body mass index and prostate cancer mortality. However, the US Health Professionals Followup Study reported an inverse association between obesity and the risk of developing prostate cancer in men under 60 years of age or in those with a family history of prostate cancer. These studies illustrate the contradictory evidence linking obesity to prostate cancer risk and mortality. Body mass does not appear to affect the performance of prostate-specific antigen as a diagnostic test, and on prostate biopsy a lower body mass is associated with a higher cancer detection rate and a higher cancer volume as measured by core length involvement. In two recent radical prostatectomy series, obesity was associated with worse pathological features and higher biochemical recurrence rates. The higher risk of recurrence persisted in patients with organ-confined disease and negative surgical margins, implying that this risk is not related to surgical technique. Several potential biological mechanisms have been proposed to explain this link including hormonal alterations, hyperinsulinemia, glucose intolerance, and elevated insulin-like growth factor and leptin levels.. Recent literature provides evidence that obesity may promote the development of a more aggressive form of prostate cancer, resulting in higher recurrence rates after primary therapy and higher cancer mortality rates overall. The mechanism to explain the association between obesity and prostate cancer is unclear.

Topics: Body Mass Index; Comorbidity; Humans; Insulin Resistance; Leptin; Male; Neoplasm Recurrence, Local; Obesity; Prostatectomy; Prostatic Neoplasms; Risk Assessment

Topics: Active Transport, Cell Nucleus; Animals; Appetite; DNA-Binding Proteins; Humans; Hypothalamus; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Intracellular Signaling Peptides and Proteins; Leptin; Phosphatidylinositol 3-Kinases; Phosphatidylinositol Phosphates; Phosphoproteins; Receptor, Insulin; Signal Transduction; STAT3 Transcription Factor; Trans-Activators

White adipose tissue is no longer considered an inert tissue mainly devoted to energy storage but is emerging as an active participant in regulating physiologic and pathologic processes, including immunity and inflammation. Macrophages are components of adipose tissue and actively participate in its activities. Furthermore, cross-talk between lymphocytes and adipocytes can lead to immune regulation. Adipose tissue produces and releases a variety of proinflammatory and anti-inflammatory factors, including the adipokines leptin, adiponectin, resistin, and visfatin, as well as cytokines and chemokines, such as TNF-alpha, IL-6, monocyte chemoattractant protein 1, and others. Proinflammatory molecules produced by adipose tissue have been implicated as active participants in the development of insulin resistance and the increased risk of cardiovascular disease associated with obesity. In contrast, reduced leptin levels might predispose to increased susceptibility to infection caused by reduced T-cell responses in malnourished individuals. Altered adipokine levels have been observed in a variety of inflammatory conditions, although their pathogenic role has not been completely clarified.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Animals; Autoimmune Diseases; Complement Factor D; Cytokines; Hormones, Ectopic; Humans; Inflammation; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Macrophages; Nicotinamide Phosphoribosyltransferase; Obesity; Resistin; Serine Endopeptidases

Risks of chronic metabolic acidosis in patients with chronic kidney disease. Metabolic acidosis is associated with chronic renal failure (CRF). Often, maintenance dialysis therapies are not able to reverse this condition. The major systemic consequences of chronic metabolic acidosis are increased protein catabolism, decreased protein synthesis, and a negative protein balance that improves after bicarbonate supplementation. Metabolic acidosis also induces insulin resistance and a decrease in the elevated serum leptin levels associated with CRF. These three factors may promote protein catabolism in maintenance dialysis patients. Available data suggest that metabolic acidosis is both catabolic and anti-anabolic. Several clinical studies have shown that correction of metabolic acidosis in maintenance dialysis patients is associated with modest improvements in nutritional status. Preliminary evidence indicates that metabolic acidosis may play a role in beta2-microglobulin accumulation, as well as the hypertriglyceridemia seen in renal failure. Interventional studies for metabolic acidosis have yielded inconsistent results in CRF and maintenance hemodialysis patients. In chronic peritoneal dialysis patients, the mitigation of acidemia appears more consistently to improve nutritional status and reduce hospitalizations. Large-scale, prospective, randomized interventional studies are needed to ascertain the potential benefits of correcting acidemia in maintenance hemodialysis patients. To avoid adverse events, an aggressive management approach is necessary to correct metabolic acidosis. Clinicians should attempt to adhere to the National Kidney Foundation Kidney Disease Outcome Quality Initiative (K/DOQI) guidelines for maintenance dialysis patients. The guidelines recommend maintenance of serum bicarbonate levels at 22 mEq/L or greater.

Topics: Acidosis; Amino Acids, Branched-Chain; Animals; Firefly Luciferin; Humans; Hydrocortisone; Hyperparathyroidism, Secondary; Insulin Resistance; Kidney Failure, Chronic; Leptin; Luciferases; Nutritional Status; Rats

The role of adipocytes as protein secreting cells has been known for almost 15 years. Most of these proteins have known biological activity and are called adipokines. However, only a few of the adipokines have been shown to regulate insulin sensitivity. The latter effects are direct or indirect. The adipokines regulating insulin sensitivity are tumor necrosis factor alpha, adiponectin, interleukin-6, resistin and leptin. This review examines the mechanism how these adipokines influence insulin sensitivity, how the adipocyte production of the adipokines is regulated and if genetic variance in the genes encoding for adipokines is important for the development of type 2 diabetes mellitus.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Animals; Cytokines; Diabetes Mellitus, Type 2; Genetic Variation; Hormones, Ectopic; Humans; Inflammation; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Interleukin-6; Leptin; Models, Biological; Nicotinamide Phosphoribosyltransferase; Resistin; Tumor Necrosis Factor-alpha

For many years adipose tissue was viewed as the site where excess energy was stored, in the form of triglycerides (TGs), and where that energy, when needed elsewhere in the body, was released in the form of fatty acids (FAs). Recently, it has become clear that when the regulation of the storage and release of energy by adipose tissue is impaired, plasma FA levels become elevated and excessive metabolism of FA, including storage of TGs, occurs in nonadipose tissues. Most recently, work by several laboratories has made it clear that in addition to FA, adipose tissue communicates with the rest of the body by synthesizing and releasing a host of secreted molecules, collectively designated as adipokines. Several recent reviews have described how these molecules, along with FA, significantly effect total body glucose metabolism and insulin sensitivity. Relatively little attention has been paid to the effects of adipokines on lipid metabolism. In this review, we will describe, in detail, the effects of molecules secreted by adipose tissue, including FA, leptin, adiponectin, resistin, TNF-alpha, IL-6, and apolipoproteins, on lipid homeostasis in several nonadipose tissues, including liver, skeletal muscle, and pancreatic beta cells.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Animals; Apolipoproteins; Fatty Acids; Homeostasis; Hormones, Ectopic; Humans; Insulin; Insulin Resistance; Insulin Secretion; Intercellular Signaling Peptides and Proteins; Interleukin-6; Islets of Langerhans; Leptin; Lipid Metabolism; Lipoproteins, VLDL; Liver; Resistin; Tumor Necrosis Factor-alpha

None of the synonyms of nonalcoholic fatty liver disease (NAFLD) include clinical correlates nor do they mention insulin resistance, a recognized determinant of the etiopathogenesis and natural history of NAFLD.. The literature concerning the pathogenesis and definition of NAFLD is reviewed.. The reasons why NAFLD should be renamed are: (a) clinically meaningful hepatic steatosis could be present at less than 5% triglyceride hepatic content; (b) steatosis is usually no longer observed in the most advanced forms of NAFLD ('cryptogenic cirrhosis'); (c) the concurrence of metabolic derangements could be more important than alcohol in the pathogenesis of alcoholic liver disease; (d) a concurrent metabolic etiology might worsen the course of chronic HCV and autoimmune hepatitis; (e) in NAFLD the liver is a target organ of the metabolic syndrome, a systemic subclinical inflammatory state.. The introduction of a positive criterion also mentioned in its definition would benefit the diagnosis of NAFLD and of steatohepatitis observed in the setting of other liver diseases, help to estimate the risk of its progression and aid the treatment of metabolic (fatty) liver disorders. There is a compelling need for an experts' agreement on a new definition of insulin resistance/metabolic-related liver disease.

Topics: Chronic Disease; Diagnosis, Differential; Disease Progression; Fatty Liver; Humans; Insulin Resistance; Leptin; Risk Factors; Terminology as Topic

Insulin resistance is frequently accompanied by obesity and both obesity and type 2 diabetes are associated with a mild chronic inflammation. Elevated levels of various cytokines, such as TNF-alpha and IL-6, are typically found in the adipose tissue in these conditions. It has been suggested that many cytokines produced in the adipose tissue are derived from infiltrated inflammatory cells. However, the adipose tissue itself has proven to be an important endocrine organ, secreting several hormones and cytokines, usually referred to as adipokines. Peroxisome proliferator-activated receptor (PPAR)gamma is essential for adipocyte proliferation and differentiation. In recent years, PPARgamma and its ligands, the thiazolidinediones (TZD), have achieved great attention due to their insulin sensitizing and anti-inflammatory properties. Treatment with TZDs result in improved insulin signaling and adipocyte differentiation, increased adipose tissue influx of free fatty acids and inhibition of cytokine expression and action. As a result, PPARgamma plays a central role in maintaining a functional and differentiated adipose tissue.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Animals; Cell Differentiation; Hormones, Ectopic; Humans; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Interleukin-6; Leptin; Ligands; PPAR gamma; Resistin; Signal Transduction; Thiazolidinediones; Tumor Necrosis Factor-alpha

Since obesity is becoming increasingly prevalent worldwide, much effort is being devoted to understanding its pathogenesis and treatment. In recent years, several candidate genes have been proposed as therapeutic targets. However, stearoyl-CoA desaturase 1 (SCD1) is of special significance, because it is the major gene target of leptin-a central mediator of energy homeostasis. There is evidence that SCD1 deficiency activates metabolic pathways that promote beta-oxidation and decrease lipogenesis in liver and skeletal muscles. One mechanism is via increased activation of AMP-activated protein kinase. SCD1 mutation results also in global changes in expression of genes involved in lipid metabolism. SCD1 deficient mice have increased energy expenditure, reduced body adiposity, and are resistant to diet-induced obesity. In this review, we examine data from our laboratory and others suggesting that SCD1 is an important component in the regulation of body metabolism.

Topics: Animals; Arteriosclerosis; Energy Metabolism; Fatty Liver; Humans; Insulin Resistance; Leptin; Liver; Metabolic Diseases; Muscle, Skeletal; Obesity; Oxidation-Reduction; Stearoyl-CoA Desaturase; Thermogenesis

The fat mass participates in the regulation of glucose and insulin metabolism through the release of adipocytokines in a mechanism called the adipoinsular axis. Putative adipocytokines include leptin, adiponectin and resistin. Obesity plays an important role in the pathogenesis of insulin resistance and type 2 diabetes mellitus (T2DM). Bariatric surgery for morbidly obese patients leads to rapid and prolonged improvement in insulin resistance and T2DM in the vast majority of patients. We have previously proposed that the rapid improvement in insulin resistance observed following bariatric surgery is mediated by changes in incretin levels of the entero-insular axis and that long-term improvement is modulated by fat mass loss and changes in adipocytokine levels of the adipoinsular axis. In this review, we examine the information that supports a role of leptin, adiponectin and resistin in the development of insulin resistance and T2DM. Increasing levels of leptin and decreasing levels of adiponectin correlate with worsening insulin resistance in obese individuals. We also explore the relationship between changes in adipocytokines following bariatric surgery and long-term improvement in insulin resistance and T2DM. Leptin levels drop and adiponectin levels rise following laparoscopic adjustable gastric banding, gastric bypass and biliopancreatic diversion. These changes correlate with weight loss and improvement in insulin. Although resistin may play an important role in explaining insulin resistance, animal and human studies currently show conflicting results.

Topics: Adiponectin; Animals; Gastric Bypass; Hormones, Ectopic; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Obesity, Morbid; Resistin

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

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

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

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

Topics: Adipocytes; Adiponectin; Adipose Tissue; Animals; Antibodies; Humans; Insulin Resistance; Leptin; Mice; Mice, Obese; Obesity; Resistin; Species Specificity; Tumor Necrosis Factor-alpha

Insulin resistance has been implicated as one possible factor that links visceral obesity to unfavourable metabolic and cardiovascular consequences. However, the mechanism whereby adipose tissue causes alterations in insulin action remains unclear. White adipose tissue is secreting several hormones, particularly leptin and adiponectin, and a variety of other protein signals: the adipocytokines. They include proteins involved in the regulation of energy balance, lipid and glucose metabolism as well as angiogenesis, vascular and blood pressure regulation. Visceral obesity and inflammation within white adipose tissue may be a crucial step contributing to the emergence of insulin resistance, type 2 diabetes and atherosclerosis. A growing list of adipocytokines involved in inflammation (IL-1beta, IL-6, IL-8, IL-10, TNF-alpha, TGF-beta,) and the acute-phase response (serum amyloid A, PAI-1) have been found to be increased in the metabolic syndrome. It is, however, unclear as to the extent adipose tissue contributes quantitatively to the elevated circulating levels of these factors in obesity and how they may affect the insulin-dependent tissues. This review describes the role of the currently known adipocytokines and hormones released by adipose tissue in generating the insulin resistance state and the chronic inflammatory profile which frequently goes together with visceral obesity.

Topics: Adiponectin; Adipose Tissue; Complement C3a; Humans; Insulin Resistance; Interleukin-6; Leptin; Models, Biological; Peptides; Resistin; Tumor Necrosis Factor-alpha

Obesity is associated with a diverse set of metabolic disorders, and has reproductive consequences that are complex and not well understood. The adipose tissue-produced leptin has dominated the literature with regards to female fertility complications, but it is pertinent to explore the likely role of other adipokines--adiponectin and resistin--as our understanding of their biological functions emerge. Leptin influences the developing embryo, the functioning of the ovary and the endometrium, interacts with the release and activity of gonadotrophins and the hormones that control their synthesis. In this review such biological actions and potential roles of the adipokines leptin, adiponectin and resistin are explored in relation to female fertility and the complexity of the obese metabolic state.

Topics: Adiponectin; Adipose Tissue; Animals; Blood Glucose; Female; Humans; Infertility, Female; Insulin; Insulin Resistance; Leptin; Mice; Mice, Knockout; Models, Animal; Obesity; Pregnancy; Resistin

There is increasing evidence that visceral adipose tissue is a causative risk factor for fatty liver and nonalcoholic steatohepatitis. Adipose tissue-derived secretory proteins are collectively named adipocytokines. Obesity and mainly visceral fat accumulation impair adipocyte function and adipocytokine secretion and the altered release of these proteins contributes to hypertension, impaired fibrinolysis and insulin resistance. This review summarizes recent findings on the role of the adipocytokines adiponectin, leptin and resistin in the context of hepatic insulin resistance, fatty liver and liver fibrosis. Elevated levels of resistin antagonize hepatic insulin action and raise plasma glucose levels. Leptin exerts insulin-sensitizing effects, but obesity has been linked to leptin resistance and low levels of circulating leptin receptor, indicating that high levels of leptin cannot mediate its beneficial effects. Adiponectin improves insulin sensitivity; however, low circulating adiponectin is found in the obese state. Adiponectin is an anti-inflammatory protein, whereas leptin augments inflammation and fibrogenesis. Disturbed adipocytokine secretion might, therefore, promote hepatic steatosis and the development of nonalcoholic steatohepatitis. The beneficial effects of the therapeutic approaches so far tested in the treatment of fatty liver disease and fibrosis might be due to the modulation of these adipocytokines.

Topics: Adipocytes; Adipose Tissue; Cytokines; Fatty Liver; Glucose; Humans; Insulin; Insulin Resistance; Leptin; Liver Cirrhosis; Obesity; Viscera

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

Topics: Abnormalities, Multiple; Child; Drug Resistance; Endocrine System Diseases; Energy Metabolism; Ghrelin; Homeostasis; Hormones; Humans; Hypothalamus, Middle; Insulin; Insulin Resistance; Leptin; Obesity; Peptide Fragments; Peptide Hormones; Peptide YY; Sympathetic Nervous System; Vagus Nerve

In this work, I stand out the rich endocrine role of adipocytes, that together with its function of lipidic deposit and regulating of metabolism, this confers them a central place in physiology and pathology.

Topics: Adipocytes; Adiponectin; Adolescent; Adult; Aged; Animals; Child; Diabetes Mellitus, Type 2; Female; Humans; Hypothalamus; Infant, Newborn; Insulin Resistance; Interleukins; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Middle Aged; Obesity; Osteoporosis; Osteoporosis, Postmenopausal; Puberty; Rats; Tumor Necrosis Factor-alpha

The insulin resistance (metabolic) syndrome (IRS), also known as syndrome X, is characterized by a clustering of factors associated with cardiovascular risk (obesity, impaired glucose metabolism, hypertension, and dyslipidemia). As reported from the third National Health and Nutrition Examination survey, the IRS is present in approximately 24% of adults in the United States and is strongly associated with coronary heart disease, stroke, type 2 diabetes, and all-cause mortality. Of equal importance, it is now clear that the origins of the IRS extend back into childhood (the IRS is found in approximately 4-10% of children and adolescents) and that the high prevalence of adult IRS is strongly linked to the development of cardiovascular risk during childhood and tracking of the components of the IRS into adulthood. The goal of this review is to present a summary of the currently available information on the IRS in the pre-adult age group with reference to adult studies only when necessary for clarification. The review will specifically summarize insulin resistance in childhood; the important influence of obesity and, in particular, visceral fat, on insulin resistance and the IRS; differences between ethnic groups; relations to adipocytokines, inflammatory factors and oxidative stress; relations of hypertension and lipids to insulin resistance; familial factors; endocrine complications; and potential therapeutic effects from diet and physical activity. Despite the lesser amount of basic and clinical information on childhood IRS in comparison to information available from adult studies, there can now be little doubt that the adverse associations among risk factors comprising the IRS begin in childhood. The challenge is to identify etiologic relations and develop intervention strategies designed to reduce the increasing prevalence of type 2 diabetes and cardiovascular disease.

Topics: Adolescent; C-Reactive Protein; Child; Humans; Hypertension; Insulin Resistance; Intra-Abdominal Fat; Leptin; Lipoproteins, VLDL; Metabolic Syndrome; Obesity; Oxidative Stress; Risk Factors

In the recent years we have begun to appreciate that adipose tissue is more than just a passive repository for excess energy. It is a highly active endocrine organ secreting a range of bioactive peptides with both local and distant action collectively called 'adipokines' or 'adipose tissue hormones'. They include leptin, adiponectin, resistin, acylation-stimulating protein (ASP), plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor alpha (TNFalpha), interleukin 6, and angiotensinogen. Some of these are specific fat-related hormones that are involved in regulating energy homeostasis, carbohydrate and lipid metabolism, vascular homeostasis and immune response. Moreover, the tissue is implicated in the metabolism of some steroid hormones. Disturbances in adipokine production may have potential repercussions in the pathophysiology of obesity, insulin resistance, and dyslipidemia. Reversal or alleviation of these changes seem to be a promising target for management of the mentioned disorders. The objective of this review is to summarise the most important aspects of biology, actions and regulation of these hormones with a special emphasis on the most recent literature.

Topics: Acylation; Acyltransferases; Adipocytes; Adiponectin; Angiotensinogen; Humans; Hydrocortisone; Insulin Resistance; Interleukin-6; Leptin; Obesity; Plasminogen Activator Inhibitor 1; Resistin; Tumor Necrosis Factor-alpha

Normal metabolic balance is maintained by a complex homeostatic system involving multiple tissues and organs. Acquired or inherited defects associated to environmental factors in any part of this system can lead to metabolic disorders such as the syndrome X which is presently a frequent syndrome in industrialized countries. It is characterized by a cluster of risk factors of atherosclerosis including insulin resistance, hyperinsulinemia, impaired glucose tolerance or type 2 diabetes, hypertension, dyslipidemia, and coagulation abnormalities. Its pathophysiology is likely to involve insulin resistance at the level of both skeletal muscle and visceral adipose tissue and altered fluxes of metabolic substrates between these tissues that in turn impair liver metabolism. Therapeutic intervention favours at present diet and exercise prescriptions. In addition, if necessary, specific treatment of the metabolic disorders is required. In the treatment of insulin resistance, new promising drugs are likely to be used in the next future. In this regard, adipose tissue, once thought to function primarily as a passive depot for the storage of excess lipid, is now understood to play a much more active role in metabolic regulation, secreting a variety of metabolic hormones and actively functioning to prevent deleterious lipid accumulation in other tissues and to modulate the insulin resistance. Here, we review new advances in our understanding of mechanisms leading to insulin resistance and type 2 diabetes from the perspective of the role and interactions of recently identified adipocyte-specific chemical messengers, the adipocytokines, such as adiponectin, tumor necrosis factor-alpha, interleukin 6, and resistin.

Topics: Adiponectin; Adipose Tissue; Animals; Diabetes Mellitus, Type 2; Energy Metabolism; Humans; Incidence; Insect Hormones; Insulin Resistance; Leptin; Mice; Obesity; Oligopeptides; Pyrrolidonecarboxylic Acid; Resistin

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

Obesity is a common problem in much of the western world today in that is linked directly with several disease processes, notably, hypertension. It is becoming clear that the adipocyte is not merely an inert organ for storage of energy but that it also secretes a host of factors that interact with each other and may result in elevated blood pressure. Of particular importance is the putative role of leptin in the causation of hypertension via an activation of the sympathetic nervous system and a direct effect on the kidneys, resulting in increased sodium reabsorption leading to hypertension. Obesity per se may have structural effects on the kidneys that may perpetuate hypertension, leading to an increased incidence of end-stage renal disease that results in further hypertension. Adipose tissue may elaborate angiotensin from its own local renin-angiotensin system. The distribution of body fat is considered important in the genesis of the obesity-hypertension syndrome, with a predominantly central distribution being particularly ominous. Weight loss is the cornerstone in the management of the obesity-hypertension syndrome. It may be achieved with diet, exercise, medications, and a combination of these measures. Anti-obesity medications that are currently undergoing clinical trials may play a promising role in the management of obesity and may also result in lowering of blood pressure. Antihypertensives are considered important components in the holistic approach to the management of this complex problem.

Topics: Adipose Tissue; Aldosterone; Animals; Body Mass Index; Humans; Hypertension; Inflammation; Insulin Resistance; Kidney; Leptin; Metabolic Syndrome; Neuropeptides; Obesity; Renin-Angiotensin System; Sympathetic Nervous System; Thrombosis

Our understanding of the effects of leptin have stemmed mainly from animal studies, which continue to leave important clues of its roles in physiology, metabolism, neuroscience, and cell signaling. Since its discovery, leptin has been linked to various pathways, either directly at its primary site of action in the hypothalamus, or indirectly via downstream effector pathways such as in adipocytes and muscle. Leptin's importance is exemplified by the lack of redundant backup mechanisms, since leptin-deficient mice are obese, diabetic, and sterile. Investigations uncovering the pleiotropic actions of leptin were unfolded mainly from rodent models. Thus, this chapter focuses on these studies and, more specifically, on those findings recently brought forward by transgenic mice overexpressing leptin. The vast amount of biology that has been ascribed to leptin encompasses effects on food intake, insulin sensitivity, adiposity, thermogenesis, reproduction, immunity, and bone regulation. Mechanisms underlying leptin's action revolve essentially around neural pathways but also encompass to a lesser extent peripheral mechanisms. The roles of leptin along these axes are reviewed, with particular emphasis on pathways and phenotypes generated by transgenic hyperleptinemia. An evolutionary significance of hyperleptinemia in association with development of leptin resistance is suggested as a protective armament against some of the detrimental effects caused by hyperleptinemia in transgenic mice overexpressing leptin.

Topics: Adipose Tissue; alpha-MSH; Animals; Blood Glucose; Body Composition; Body Temperature Regulation; Eating; Gene Expression; Insulin Resistance; Leptin; Mice; Mice, Transgenic; Models, Animal; Reproduction; Sympathetic Nervous System

Caloric restriction in animal models delays many age-related pathological conditions. Ageing rats have characteristically increased body weight, fat mass and a specific body fat distribution. This report will focus on the potential cause-effect relationship between increased fat mass and accelerated ageing. In humans, increased fat mass (obesity), and in particular increases in abdominal obesity as a result of deposition of visceral fat, are associated with the metabolic syndrome of ageing. This syndrome is associated with hyperinsulinaemia, dyslipidaemia, type 2 diabetes mellitus, atherosclerosis, hypercoagulability and hypertension. Fat tissue, however, plays a major role by secreting multiple metabolically active factors, which are potentially responsible for the development of insulin resistance. This article will review various experimental models (in animals) used to prevent insulin resistance of ageing by decreasing fat mass, and in particular, decreasing visceral fat. We suggest that this decrease in fat mass and its beneficial repercussions observed in ageing animal models may apply also to human ageing and its related pathology.

Topics: Adipose Tissue; Aging; Animals; Body Composition; Energy Intake; Insulin; Insulin Resistance; Leptin; Models, Animal; Rats; Viscera

It is now recognized that the white adipose tIssue (WAT) produces a variety of bioactive peptIdes, collectively termed "adipokines". Alteration of WAT mass in obesity or lipoatrophy, affects the production of most adipose secreted factors. Since both conditions are associated with multiple metabolic disorders and increased risk of cardiovascular diseases, the Idea has emerged that WAT could be instrumental in these complications, by virtue of its secreted factors. Several adipokines are increased in the obese state and have been implicated in hypertension (angiotensinogen), impaired fibrinolysis (PAI-1) and insulin resistance (ASP, TNFalpha, IL-6, resistin). Conversely, leptin and adiponectin both exert an insulin-sensitizing effect, at least in part, by favoring tIssue fatty-acId oxIdation through activation of AMP-activated kinase. In obesity, insulin resistance has been linked to leptin resistance and decreased plasma adiponectin. In lipoatrophic mice, where leptin and adiponectin circulating levels are low, administration of the two adipokines synergistically reverses insulin resistance. Leptin and adiponectin also have distinct properties: leptin, as a long-term integrative signal of energy store and adiponectin, as a potent anti-atherogenic agent. The thiazolIdinedione anti-diabetic drugs increase endogenous adiponectin production in rodents and humans, supporting the Idea that the development of new drugs targeting adipokines might represent a promising therapeutic approach to protect obese patients from insulin resistance and atherosclerosis.

Topics: Adiponectin; Adipose Tissue; Animals; Fibrinolysis; Hormones, Ectopic; Humans; Hypertension; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Interleukin-6; Leptin; Plasminogen Activator Inhibitor 1; Proteins; Resistin; Tumor Necrosis Factor-alpha

The role of insulin resistance in non-alcoholic fatty liver disease is suggested by laboratory data (hyperinsulinemia and decreased sensitivity to endogenous and exogenous insulin). The clinical association with features of the metabolic syndrome, particularly in the most aggressive stages of the disease, further confirms a causative role. Fat accumulation in the liver may stem either from genetic defects, primarily responsible for insulin resistance, or excessive calorie intake and visceral obesity, and is mediated by adipocytokines (leptin, adiponectin, tumour necrosis factor-alpha). Progression of fatty liver to steatohepatitis may be the result of an imbalance between pro-inflammatory and anti-inflammatory cytokines, triggering the formation of reactive oxygen species and intrahepatic lipid peroxidation. This process may also be promoted or accelerated by pro-oxidant xenobiotics or environmental factors. Insulin resistance provides a target for specific treatment of non-alcoholic fatty liver, and insulin-sensitising agents (metformin or thiazolidinediones) as well as lifestyle changes to reduce visceral adiposity are the most promising therapeutic options. Future trials need to be performed in order to test the long-term effectiveness of these treatments on the basis of clinically relevant histological outcomes.

Topics: Adipose Tissue; Fatty Liver; Humans; Hypoglycemic Agents; Insulin Resistance; Interleukin-6; Leptin; Models, Biological; Thiazolidinediones; Tumor Necrosis Factor-alpha

Adipose tissue (AT) is not considered anymore as a passive depot for storing excess energy in the form of triglycerides but as an active organ secreting several hormones or adipokines. With the exception of adiponectin the serum levels of adipokines are increased in obesity. Leptin regulates food intake, reproductive and immune system. Adiponectin decreases insulin resistance and has antiinflammatory properties. On the contrary, resisting, tumor necrosis factor and Interleukin-6 are diabetogenic and induce inflammatory reactions. It is believed that atherosclerosis is due to the inflammation induced by oxydized LDL-cholesterol in vessels. Abdominal obesity is associated with increased incidence of metabolic disorders and insulin resistance. The role of adipokines in these disorders is described as well as their role in the antidiabetic effect of thiazo-linedinediones. AT contains also enzymes responsible for the aromatization of androstenedione into estrone, which could explain an increase of breast and uterus cancer in obese people.

Topics: Adiponectin; Adipose Tissue; Cytokines; Fatty Acids; Hormones; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Interleukin-6; Leptin; Obesity; Protein Biosynthesis; Thiazolidinediones; Tumor Necrosis Factor-alpha

Topics: Antihypertensive Agents; Body Mass Index; Catecholamines; Diet, Reducing; Exercise Therapy; Humans; Hypertension; Insulin Resistance; Leptin; Life Style; Obesity; Reference Standards; Risk Factors

Topics: Adipocytes; Animals; Arteriosclerosis; Cell Differentiation; Humans; Hypertension; Insulin Resistance; Leptin; Ligands; Lipid Metabolism; Macrophage Activation; Metabolic Syndrome; Neovascularization, Pathologic; Receptors, Cytoplasmic and Nuclear; Thiazolidinediones; Transcription Factors; Vascular Endothelial Growth Factor A

Leptin was originally discovered as an adipocyte-derived hormone involved in the central control of body weight and energy homeostasis. It is now clear that leptin is a pleiotropic cytokine, with activities on many peripheral cell types. These findings may help explain the surprising role of leptin in pathophysiological processes. Recent evidence suggests that leptin contributes to atherosclerosis and to the increased risk of cardiovascular disease in obese people. Leptin also appears to be involved in T-cell-dependent immunity and possibly in the development and maintenance of certain autoimmune diseases. Here, we review the role of leptin in cardiovascular and autoimmune diseases, and also briefly address the potential therapeutic use of leptin antagonists.

Topics: Adipocytes; Arteriosclerosis; Autoimmune Diseases; Cardiovascular Diseases; Humans; Immunity, Cellular; Insulin Resistance; Leptin; Receptors, Leptin; Receptors, Mitogen; Signal Transduction

The adipocytokines are biologically active polypeptides that are produced either exclusively or substantially by the adipocytes, and act by endocrine, paracrine, and autocrine mechanisms. Most have been associated with obesity, hyperinsulinaemia, type 2 diabetes, and chronic vascular disease; in addition, six adipocytokines--vascular endothelial growth factor, hepatocyte growth factor, leptin, tumour necrosis factor-alpha, heparin-binding epidermal growth factor-like growth factor, and interleukin-6--promote angiogenesis while one, adiponectin, is inhibitory. Obesity and insulin resistance have both been identified as risk factors for breast cancer and are associated with late-stage disease and poor prognosis. Angiogenesis is essential for breast cancer development and progression, and so it is plausible that obesity-related increases in adipocytokine production and a reduction in adiponectin may adversely affect breast cancer outcome by their angiogenesis-related activities. There is also experimental evidence that some adipocytokines can act directly on breast cancer cells to stimulate their proliferation and invasive capacity. Thus, adipocytokines may provide a biological mechanism by which obesity and insulin resistance are causally associated with breast cancer risk and poor prognosis. Both experimental and clinical studies are needed to develop this concept, and particularly in oestrogen-independent breast cancers where preventive and therapeutic options are limited.

Topics: Adipocytes; Adiponectin; Animals; Body Composition; Breast Neoplasms; Cytokines; Female; Humans; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Obesity; Prognosis; Proteins; Risk Factors

Topics: Adiponectin; Adipose Tissue; Cytokines; Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Interleukin-6; Leptin; Proteins; Tumor Necrosis Factor-alpha

From the perspective of a muscle physiologist, adipose tissue has long been perceived predominantly as a fuel reservoir that provides muscle and other tissues with NEFA when exogenous nutrients are insufficient for their energy needs. Recently, studies have established that adipose tissue is also an endocrine organ. Among the hormones it releases are adiponectin and leptin, both of which can activate AMP-activated protein kinase and increase fatty acid oxidation in skeletal muscle and probably other tissues. Deficiencies of leptin or leptin receptor, adiponectin and IL-6 are associated with obesity, insulin resistance and a propensity to type 2 diabetes. In addition, a lack of adiponectin has been linked to atherosclerosis. Whether this pathology reflects a deficient activation of AMP-activated protein kinase in peripheral tissues remains to be determined. Finally, recent studies have suggested that skeletal muscle may also function as an endocrine organ when it releases the cytokine IL-6 into the circulation during sustained exercise. Interestingly, one of the apparent effects of IL-6 is to stimulate lipolysis, causing the release of NEFA from the adipocyte. Thus, hormonal communications exist between the adipocyte and muscle that could enable them to talk to each other. The physiological relevance of this cross talk clearly warrants further study.

Topics: Adiponectin; Adipose Tissue; Energy Metabolism; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Interleukin-6; Leptin; Lipid Metabolism; Lipolysis; Muscle, Skeletal

Topics: Fatty Liver; Female; Hepatitis; Humans; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Obesity; Oxidative Stress; Risk Factors; Tumor Necrosis Factor-alpha

Topics: Adipose Tissue; Adult; Aged; Aging; Androgens; Body Composition; Cholesterol; Growth Hormone; Humans; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Middle Aged; Triglycerides

Liver fibrosis is the consequence of chronic or repeated liver injury caused by hepatotoxic agents like alcohol and viruses, as well as immune and congenital metabolic disorders. Nonalcoholic fatty liver disease (NAFLD), caused by obesity and abnormal lipid metabolism, may be the latest known cause of liver fibrosis and cirrhosis. Furthermore, NAFLD with obesity can provide a terrain in which alcoholic and viral liver diseases, such as chronic hepatitis C, are prone to cause liver cirrhosis. Insulin, insulin-like growth factor (IGF)-1, peroxisome proliferator-activated receptors (PPARs), leptin, adiponectin, and preadipocyte factor-1/delta-like1 (Pref-1/dlk1) are hormones, growth factors, nuclear receptors, and cytokines that are actively involved in lipid metabolism. They share common target cells important in liver fibrosis, i.e., hepatic stellate cells (HSCs). Activation of HSCs is known to initiate and perpetuate liver fibrosis. Insulin and IGF-1 stimulate HSC activation and collagen production in vitro. However, IGF-1 alleviates liver fibrosis in vivo. Ligands of PPARy inhibit HSC activation and collagen synthesis in vivo and in vitro, and are helpful in decreasing liver fibrosis. But ligands of PPARbeta enhance proliferation of HSCs. Leptin is profibrogenic, and liver fibrosis is decreased in leptin- or leptin receptor-deficient mice. Adiponectin is, on the contrary, anti-fibrogenic. Extensive liver fibrosis may develop in adiponectin-knockout mice and is alleviated by administration of recombinant adiponectin. Pref-1/dlkl is implicated in fibrogenesis of the liver through its modulation of HSCs. The use of such biologically active molecules in lipid metabolism as ligands of PPARgamma and adiponectin might not help slim down a patient on the whole, but can potentially be used to halt the progression of liver fibrosis. Weight reduction, a strategy for controlling obesity and metabolic syndromes, may also be a tool for decreasing NAFLD and alleviating liver cirrhosis.

Topics: Adiponectin; Calcium-Binding Proteins; Humans; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Liver Cirrhosis; Membrane Proteins; Obesity; Peroxisome Proliferator-Activated Receptors; Peroxisomes; Repressor Proteins; Somatomedins

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

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

It is generally accepted that obesity is associated with many other multiple-risk factor syndromes such as hypertension, hyperlipidemia, type 2 diabetes mellitus, and periodontal disease. The number of obese people is increasing rapidly in both western and eastern countries. Adipocytes in the adipose tissues of obese people produce large quantities of biologically active molecules such as leptin, an important molecule regulating energy expenditure and body weight. Therefore, adipocyte-derived active molecules, named adipocytokines, are candidate molecules accounting for the close association between obesity and other multiple-risk factor syndromes. The proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) is produced by adipocytes, and its blood concentration is elevated in obese patients and declines with weight loss. Studies have demonstrated that TNF-alpha suppresses insulin action via its specific receptor; hence, it exacerbates insulin resistance. In addition to adipocytes, monocytes/macrophages produce large quantities of TNF-alpha. Thus, TNF-alpha, produced from monocytic cells due to inflammatory diseases, may have an additive influence on insulin sensitivity to adipocyte-derived TNF-alpha. Here, we hypothesized that 1) TNF-alpha produced by the adipose tissues of obese patients acts as a risk factor for periodontal inflammation, and 2) TNF-alpha produced due to periodontal inflammation may be an additional important factor influencing insulin sensitivity in both obese and type 2 diabetic patients. We believe that this interaction is a possible mechanism accounting for a 2-way relationship between type 2 diabetes and periodontal disease.

Topics: Adipocytes; Cytokinins; Diabetes Mellitus, Type 2; Humans; Inflammation Mediators; Insulin Resistance; Leptin; Macrophages; Monocytes; Obesity; Periodontal Diseases; Periodontitis; Risk Factors; Syndrome; Tumor Necrosis Factor-alpha

Topics: Adipocytes; Adipose Tissue; Diabetes Mellitus, Type 2; Energy Metabolism; Hormones, Ectopic; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Obesity; Receptors, Cell Surface; Receptors, Cytokine; Resistin

Topics: Antioxidants; Body Weight; Fatty Liver; Humans; Insulin Resistance; Leptin; Lipids; Liver

Globally, the prevalence of obesity is escalating, and insulin resistance resulting from increased (predominantly visceral) adipose tissue mass has been identified as a key factor that could drive parallel rises in type 2 diabetes mellitus (T2DM) prevalence. Correlations between these global epidemics have encouraged investigation into potential molecular links between the related impairments in lipid and glucose homeostasis. This article reviews factors released from adipose tissue that could contribute to the development of insulin resistance and beta-cell dysfunction, including tumour necrosis factor alpha (TNF-alpha), free fatty acids (FFAs), adiponectin, resistin and leptin. It also considers whether agonists of the peroxisome proliferator-activated receptor gamma, which is abundant in adipose tissue, might have an important impact on factors associated with adipocyte metabolism. For example, the thiazolidinediones, a class of oral anti-diabetic agents that reduce insulin resistance and improve beta-cell function, might mediate these effects by regulating adipocyte-derived factors, in particular TNF-alpha and FFAs.

Topics: Adipocytes; Animals; Humans; Hypoglycemic Agents; Insulin Resistance; Islets of Langerhans; Leptin; Obesity; Receptors, Cytoplasmic and Nuclear; Species Specificity; Thiazolidinediones; Transcription Factors

The renin-angiotensin system (RAS) and the endothelin system have been implicated in the pathogenesis of human cardiovascular and renal diseases, and inhibition of the RAS markedly improves morbidity and survival. Obesity in humans is associated with an increased risk for the development of hypertension, atherosclerosis and focal-segmental glomerulosclerosis, however the exact mechanisms underlying these pathologies in obese individuals are not known. This article discusses the clinical importance of obesity and the current evidence for local activation of the renin-angiotensin system and its interactions with the endothelin system in obesity and the cardiovascular pathologies associated with it.

Topics: Adipocytes; Adiponectin; Angiotensin II; Animals; Endothelin-1; Endothelium, Vascular; Hormones, Ectopic; Humans; Hypertension; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Kidney; Leptin; Mice; Nerve Growth Factor; Obesity; Proteins; Rats; Renin-Angiotensin System; Resistin

Obesity, which has reached epidemic prevalence, is now recognized as an independent risk factor for increasing blood pressure. The complex mechanisms of obesity-related hypertension are unclear, but several studies have provided evidence of a hypertensive shift in pressure natriuresis. Excess sympathetic outflow to the kidneys and changes in renal structure and function may both affect the renal pressure relationship. Other factors that may contribute to altered natriuresis include hyperinsulinemia, hyperleptinemia and activation of the renin-angiotensin system. Disruption of the renal alpha2 adrenoceptors or leptin receptor implicated in natriuresis control may also be an additive risk for the increase in tubular reabsorption in obesity hypertension.. Recent advances have highlighted the importance of two adipocyte-derived hormones - leptin and angiotensinogen - in obesity hypertension. Leptin has direct central effects that increase sympathetic outflow to the kidney and the new concept of selective leptin resistance, suggests the maintenance of leptin-induced sympathetic activation in obesity, despite resistance to leptin metabolic effects. On the other hand, a recent study showed that angiotensinogen produced in the adipocyte is also relevant to blood pressure control.. The article reviews the factors implicated in the disruption of blood pressure control in obesity. Further investigation on the time course of the disease would reveal the relative importance of each of the factors that influence the risk of hypertension in obese individuals.

Topics: Humans; Hypertension; Insulin; Insulin Resistance; Leptin; Obesity; Renin-Angiotensin System; Risk Factors; Sympathetic Nervous System

The obesity epidemic is driving metabolic (insulin resistance) syndrome-related health problems including an approximately threefold increased coronary heart disease risk. Sympathetic hyperfunction may participate in the pathogenesis and complications of the metabolic syndrome including higher blood pressure, a more active renin-angiotensin system, insulin resistance, faster heart rates, and excess cardiovascular disease including sudden death. Possible factors augmenting sympathetic activation in the metabolic syndrome include alterations of insulin, leptin, nonesterified fatty acids (NEFAs), cytokines, tri-iodothyronine, eicosanoids, sleep apnea, nitric oxide, endorphins, and neuropeptide Y. Of note, high plasma NEFAs are a risk factor for hypertension and sudden death. In short-term human studies, NEFAs can raise blood pressure, heart rate, and a(1)-adrenoceptor vasoreactivity, while reducing baroreflex sensitivity, endothelium-dependent vasodilatation, and vascular compliance. Efforts to further identify the mechanisms and consequences of sympathetic dysfunction in the metabolic syndrome may provide insights for therapeutic advances to ameliorate the excess cardiovascular risk and adverse outcomes.

Topics: Cardiovascular Diseases; Fatty Acids, Nonesterified; Humans; Hypertension; Insulin Resistance; Leptin; Metabolic Syndrome; Muscle, Skeletal; Obesity; Risk Factors; Sleep Apnea Syndromes; Sympathetic Nervous System

Many studies have demonstrated that excess of visceral fat has deleterious effects on insulin action. Mainly, it has been shown to be associated with a decrease in hepatic and peripheral insulin sensitivity, which results in a clinical condition also known as insulin resistance. This report describes a novel experimental method that we employed in order to analyze the particular effects of visceral fat on insulin activity. By extracting visceral fat we were able to distinguish the specific role that it plays in insulin action, and to analyze its effects on the gene expression of a variety of fat-derived peptides, which may be considered to be (at least partially) mediators in the development of the metabolic syndrome and possibly diabetes mellitus.

Topics: Adipose Tissue; Animals; Humans; Insulin; Insulin Resistance; Leptin; Models, Animal; Obesity; Rats; Skin; Viscera

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

Diabetes mellitus and hypertension are often associated with each other, and both are risk factors for cardiovascular diseases. Insulin resistance has been noted as an etiology for diabetes, hypertension and atherosclerosis. Insulin resistance often accompanied hyperinsulinemia and it is thought to elevate blood pressure through stimulation of the sympathetic nervous system and renin-angiotensin system, promotion of sodium retention in the renal tubules, and proliferation of vascular smooth muscle cells via insulin-like growth factor. Also high blood glucose may impair vascular endothelial cells and produce oxidant stress. To prevent the occurrence of hypertension in diabetes patients, improving insulin resistance have to be considered, and primary care such as reducing body weight, salt and alcohol restriction, exercise and non-smoking are important.

Topics: Arteriosclerosis; Diabetes Mellitus, Type 2; Endothelium, Vascular; Humans; Hyperinsulinism; Hypertension; Insulin Resistance; Leptin; Life Style; Oxidative Stress; Primary Prevention; Renin-Angiotensin System; Sympathetic Nervous System

The obesity crisis in the United States has been associated with an alarming increase in the prevalence of the metabolic syndrome (MSX) disease cluster. Here we review evidence that the MSX reflects a failure of a system of intracellular lipid homeostasis that prevents lipotoxicity in the organs of overnourished individuals by confining the lipid overload to cells specifically designed to store large quantities of surplus calories, the white adipocytes. Normally, early in obesity, adipocytes increase leptin and adiponectin secretion, hormones that enhance oxidation of surplus liquids in nonadipose tissues by activating AMP-activated protein kinase and reducing the activity and expression of lipogenic enzymes. These events combine to lower malonyl coenzyme A. Deficiency of and/or unresponsiveness to leptin prevents these protective events and results in ectopic accumulation of lipids. Increased de novo ceramide formation is probably the most damaging lipid and is a cause of lipoapoptosis, abetted by a decline in tissue Bcl-2. Pancreatic beta-cells and myocardiocytes are cellular victims of the process, leading to non-insulin-dependent diabetes and lipotoxic cardiomyopathy. The MSX is particularly prevalent in visceral obesity, probably because visceral adipocytes make less leptin than sc adipocytes. Cushing's syndrome, the lipodystrophy associated with protease inhibitor therapy of AIDS, polycystic ovarian disease, as well as diet-induced visceral obesity, all have a high waist/hip ratio, and all exhibit MSX. Increased lipid content in the heart and skeletal muscle organs of such patients is now under study.

Topics: Body Mass Index; Dietary Fats; Humans; Insulin Resistance; Leptin; Metabolic Syndrome; Obesity

Approximately two-thirds of the US population are overweight, which means that insulin resistance is probably the most common metabolic abnormality in the USA. I propose three novel concepts concerning the causes and consequences of insulin resistance that challenge current thinking. First, there is the evidence that resistance to insulin-stimulated glucose metabolism is not a primary event in obesity, but is secondary to lipid accumulation resulting from full responsiveness to insulin-stimulated lipogenic activity. Second, resistance to insulin-stimulated glucose metabolism, now considered detrimental to health, might be a protective mechanism that reduces lipid-induced damage to tissue by excluding glucose from cells, thus decreasing glucose-derived lipogenesis. Third, I suggest that lipid-induced insulin resistance and the accompanying metabolic syndrome are secondary to leptin resistance, resulting in breakdown in the normal partitioning of surplus lipids in the adipocyte compartment.

Topics: Adipose Tissue; Animals; Blood Glucose; Humans; Insulin Resistance; Leptin; Lipid Metabolism; Metabolic Syndrome; Obesity; Rats

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

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

Leptin is the first of a group of adipocyte-secreted hormones to be used clinically to treat hypoleptinemic states. In children with congenital leptin deficiency and extreme obesity, leptin induces satiety and a dramatic loss of weight. In hypoleptinemic patients with extreme insulin resistance and lipodystrophy, leptin ameliorates insulin resistance, hyperglycemia, hyperinsulinemia, dyslipidemia and hepatic steatosis. In both these leptin-deficient states, leptin therapy restores gonadotrophin secretion, as well as luteinizing hormone and thyroid-stimulating hormone pulsitility.

Topics: Animals; Humans; Hypothalamo-Hypophyseal System; Insulin Resistance; Leptin; Lipodystrophy; Obesity; Pituitary-Adrenal System; Satiation; Weight Loss

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

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

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

Obesity and arterial hypertension are important public health problems. Both overweight and hypertension predispose to cardiovascular diseases, such as myocardial infarction, stroke and renal failure. Moreover, overweight clearly predisposes to hypertension, and thus to an increased prevalence of cardiovascular diseases. This in turn favors inactivity and further weight gain, leading to an exacerbation of cardiovascular disorders. Obesity, hypertension and cardiovascular diseases thus contribute to three corners of a vicious triangle. It is within this conceptual framework that this paper reviews the pathogenesis of obesity-related hypertension, which is highly complex. Many factors act together to promote vasoconstriction and sodium retention. Leptin, free fatty acids and insulin, whose levels are increased in obesity, may act synergistically to stimulate sympathetic activity and vasoconstriction. In addition, obesity-induced insulin resistance and endothelial dysfunction may operate as amplifiers of the vasoconstrictor response. Finally, increased renal tubular reabsorption of sodium may also occur, caused by an increased renal sympathetic nerve activity, the direct effect of insulin, hyperactivity of the renin-angiotensin system and possibly by an alteration of intrarenal physical forces. All together, these factors will lead to sustained hypertension. Because the prevalence of obesity was steadily increasing in the last decades, leading to an increased prevalence of hypertension and cardiovascular disorders, obesity and hypertension will most likely become the health challenges of the twenty-first century.

Topics: Adult; Aged; Fatty Acids, Nonesterified; Humans; Hypertension; Insulin Resistance; Kidney; Leptin; Middle Aged; Obesity; Sodium; Sympathetic Nervous System; Tumor Necrosis Factor-alpha; Weight Gain

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; Aquaporins; Glucose Intolerance; Humans; Hyperlipidemias; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Lipid Metabolism; Obesity; Proteins; Syndrome; Viscera

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

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

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

During pregnancy, a number of maternal metabolic changes occur early and continue throughout pregnancy which help optimize the transfer of nutrients to the fetus. During normal pregnancy, there are a decrease in insulin sensibility which is physiological, progressive and reverse. For glucose tolerance to be maintained in pregnancy it is necessary for maternal insulin secretion to increase sufficiently to counteract the fall in insulin sensitivity. The metabolic characteristic of women with gestational diabetes is insufficient insulin secretion to counteract the pregnancy related fall in insulin sensitivity. There are a lot of factors that could explain the mechanism of insulin secretion and insulin sensitivity during normal pregnancy and gestational diabetes mellitus. Although glucose tolerance normalizes shortly after pregnancy with gestational diabetes in the majority of women, the risk of developing overt diabetes, especially type 2 diabetes is markedly increased. The mechanisms which could explain gestational diabetes are the same as type 2 diabetes mellitus. We could speculate that these two diseases are identical for alterations in carbohydrate metabolism, but at different stages.

Topics: Diabetes, Gestational; Female; Humans; Insulin; Insulin Resistance; Insulin Secretion; Leptin; Pregnancy

The debate on metformin use in polycystic ovary syndrome (PCOS) has mainly focused on its treatment for infertility in ovulation induction and menstrual cyclicity. Here we will summarize the data supporting the effect of metformin on improving hyperandrogenaemia and hyperinsulinaemia in PCOS patients. We propose that metformin benefits PCOS patients undergoing gonadotrophin therapy and IVF as well as ovulation induction. We also advocate the use of insulin sensitizing drugs to reduce miscarriage rates, and risks associated with coronary artery disease, gestational diabetes and obesity.

Topics: Androgens; Cardiovascular Diseases; Female; Fertilization in Vitro; Gonadotropins; Humans; Hypoglycemic Agents; Infertility, Female; Insulin; Insulin Resistance; Leptin; Menstrual Cycle; Metformin; Ovulation Induction; Plasminogen Activator Inhibitor 1; Polycystic Ovary Syndrome

Non-alcoholic steatohepatitis (NASH) is a disease of emerging identity and importance. It is frequently associated with obesity, especially visceral fat, and is intimately related to fatty liver and markers of the insulin resistance syndrome. Both the prevalence and the severity of liver steatosis are related to body mass index, waist circumference, hyperinsulinaemia, hypertriglyceridaemia and impaired glucose tolerance or type 2 diabetes. The identification of obese patients who may progress from steatosis to NASH and from NASH to fibrosis/cirrhosis is an important clinical challenge. Substantial weight loss is accompanied by a marked attenuation of insulin resistance and related metabolic syndrome and, concomitantly, by a remarkable regression of liver steatosis in most patients, although increased inflammation may be detected in some subjects. Thus, NASH may be considered as another disease of affluence, as is the insulin resistance syndrome, and perhaps being part of it, especially in obese patients.

Topics: Cytokines; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Fatty Liver; Humans; Insulin Resistance; Leptin; Obesity; Oxidative Stress; Prognosis; Weight Loss

Many genetic manipulations have created models of obesity, leanness or resistance to dietary obesity in mice, often providing insights into molecular mechanisms that affect energy balance, and new targets for anti-obesity drugs. Since many genes can affect energy balance in mice, polymorphisms in many genes may also contribute to obesity in humans, and there may be many causes of primary leptin resistance. Secondary leptin resistance (due to high leptin levels) can be investigated by combining the ob mutation with other obesity genes. Some transgenic mice have failed to display the expected phenotype, or have even been obese when leanness was expected. Compensatory changes in the expression of other genes during development, or opposing influences of the gene on energy balance, especially in global knockout mice, may offer explanations for such findings. Obesity has been separated from insulin resistance in some transgenic strains, providing new insights into the mechanisms that usually link these phenotypes. It has also been shown that in some transgenic mice, obesity develops without hyperphagia, or leanness without hypophagia, demonstrating that generalised physiological explanations for obesity in individual humans may be inappropriate. Possibly the most important transgenic model of obesity so far created is the Type 1 11beta-hydroxysteroid dehydrogenase over-expressing mouse, since this models the metabolic syndrome in humans. The perspectives into obesity offered by transgenic mouse models should assist clinical researchers in the design and interpretation of their studies in human obesity.

Topics: Adipose Tissue; Animals; Animals, Genetically Modified; Drug Resistance; Energy Metabolism; Glucocorticoids; Hypothalamus; Insulin Resistance; Leptin; Neuropeptides; Obesity

Abnormalities in coagulation and haemostasis represent a well-known link between obesity and thrombosis (both arterial and venous). Several studies have shown that obese patients have higher plasma concentrations of all pro-thrombotic factors (fibrinogen, vonWillebrand factor (vWF), and factor VII), as compared to non-obese controls, with a positive association with central fat. Similarly, plasma concentrations of plasminogen activator inhibitor-1 (PAI-1) have been shown to be higher in obese patients as compared to non-obese controls and to be directly correlated with visceral fat. Furthermore, obesity is characterized by higher plasma concentrations of anti-thrombotic factors, such as tissue-type plasminogen activator (t-PA) and protein C, as compared to non-obese controls, the increase in these factors being likely to represent a protective response partly counteracting the increase in pro-thrombotic factors. The issue of whether adipose tissue contributes directly to plasma PAI-1, its products stimulating other cells to produce PAI-1, or whether it primarily contributes indirectly has not yet been resolved. It has been proposed that the secretion of interleukin-6 (IL-6) by adipose tissue, combined with the actions of adipose tissue-expressed TNF-alpha in obesity, could underlie the association of insulin resistance with endothelial dysfunction, coagulopathy, and coronary heart disease. The role of leptin in impairing haemostasis and promoting thrombosis has been recently reported. Finally, some hormonal abnormalities (androgen, F, catecholamines) associated with the accumulation of body fat may contribute to the impairment of coagulative pathway in obesity. As to intervention strategies, dietary (i.e., low-fat high-fiber diet) and lifestyle (i.e., physical activity) measures have been demonstrated to be effective in improving the obesity-associated pro-thrombotic risk profile.

Topics: Adipose Tissue; Blood Coagulation Disorders; Endocrine Glands; Fibrinolysis; Hemostasis; Humans; Insulin Resistance; Leptin; Obesity; Plasminogen Activator Inhibitor 1; Polymorphism, Genetic; Thrombosis

Topics: Adipocytes; Adipose Tissue; Animals; Female; Genetic Predisposition to Disease; Humans; India; Insulin Resistance; Leptin; Male; Mice; Mice, Obese; Molecular Biology; Obesity; Research; Risk Assessment; Sensitivity and Specificity

Beta 3-adrenergic receptors are expressed mainly in adipose tissues and play an important role in lipolysis and thermogenesis. Chronic administration of beta 3-adrenergic receptor agonists into obese rodents reduce the size of adipocytes by the breakdown of triglyceride and ameliorate insulin resistance associated with the normalization of the expression of adipocytokines, such as leptin and tumor necrosis factor-alpha. However, acute administration of the drugs induce remarkable insulin secretion, the mechanism of which is still unclear. Although the effect of beta 3-adrenergic receptor agonists may be different between rodents and human, these drugs are promising as anti-obese or anti-diabetic agents, and several clinical studies are underway.

Topics: Acetates; Adipocytes; Adrenergic beta-3 Receptor Agonists; Adrenergic beta-Agonists; Animals; Anti-Obesity Agents; Drug Design; Humans; Hypoglycemic Agents; Indoles; Insulin; Insulin Resistance; Insulin Secretion; Leptin; Receptors, Adrenergic, beta-3

Skeletal muscle contains the majority of the body's glycogen stores and a similar amount of readily accessible energy as intramyocellular triglyceride (imTG). While a number of factors have been considered to contribute to the pathogenesis of insulin resistance (IR) in obesity and type 2 diabetes mellitus (DM), this review will focus on the potential role of skeletal muscle triglyceride content. In obesity and type 2 DM, there is an increased content of lipid within and around muscle fibers. Changes in muscle in fuel partitioning of lipid, between oxidation and storage of fat calories, almost certainly contribute to accumulation of imTG and to the pathogenesis of both obesity and type 2 DM. In metabolic health, skeletal muscle physiology is characterized by the capacity to utilize either lipid or carbohydrate fuels, and to effectively transition between these fuels. We will review recent findings that indicate that in type 2 DM and obesity, skeletal muscle manifests inflexibility in the transition between lipid and carbohydrate fuels. This inflexibility in fuel selection by skeletal muscle appears to be related to the accumulation of imTG and is an important aspect of IR of skeletal muscle in obesity and type 2 DM.

Topics: Adipose Tissue; Diabetes Mellitus, Type 2; Glycogen; Humans; Insulin Resistance; Leptin; Muscle, Skeletal; Obesity; Triglycerides

Different types of lean mice have been produced by genetic manipulation. Leanness can result from deficiency of stored energy or a lack of adipocytes to store the lipid. Mice lacking functional adipocytes are usually insulin resistant and have fatty livers, and elevated circulating triglyceride levels. Insulin resistance may result from the lack of adipocyte hormones (such as leptin) and increased metabolite (such as triglyceride) levels in nonadipose tissue. Mice with depleted adipocyte triglyceride levels typically are insulin sensitive and have normal or low liver and circulating triglycerides. Mechanisms to produce depleted adipocytes include increased energy expenditure by peripheral tissues, peripheral mechanisms to decrease food intake, and altered central regulation of these processes.

Topics: Adipocytes; Animals; Body Weight; Energy Metabolism; Fatty Liver; Insulin; Insulin Resistance; Leptin; Mice; Thinness; Triglycerides

Preeclampsia, a common complications of pregnancy, is associated with an increase in the concentration of leptin in the maternal blood, which precedes the clinical onset of the disease. This review addresses the potential sources of leptin and considers the possible consequences, although at present these are entirely conjectural. The placenta is likely to contribute to the rise in leptin, and placental hypoxia and inflammatory mediators may be important stimuli. The possible protective and damaging sequelae of an increase in the maternal leptin concentrations may range from beneficial stimulation of fetal growth to an increase in blood pressure through stimulation of sympathetic activity. Further research is needed to determine if the rise in leptin plays a role in preeclampsia or whether it is a secondary and unrelated bystander.

Topics: Embryonic and Fetal Development; Female; Fetal Blood; Humans; Insulin Resistance; Leptin; Placenta; Pre-Eclampsia; Pregnancy

The development of type 2 diabetes is linked to insulin resistance coupled with a failure of pancreatic beta-cells to compensate by adequate insulin secretion.. Here, we review studies obtained from genetically engineered mice that provide novel insights into the pathophysiology of insulin resistance.. Knockout models with monogenic impairment in insulin action have highlighted the potential role for insulin signalling molecules in insulin resistance at a tissue-specific level. Polygenic models have strengthened the idea that minor defects in insulin secretion and insulin action, when combined, can lead to diabetes, emphasizing the importance of interactions of different genetic loci in the production of diabetes. Knockout models with tissue-specific alterations in glucose or lipid metabolism have dissected the individual contributions of insulin-responsive organs to glucose homeostasis. They have demonstrated the central role of fat as an endocrine tissue in the maintenance of insulin sensitivity and the development of insulin resistance. Finally, these models have shown the potential role of impaired insulin action in pancreatic beta-cells and brain in the development of insulin deficiency and obesity.

Topics: Adipose Tissue; Animals; Brain; Diabetes Mellitus, Type 2; Glucose; Humans; Insulin Resistance; Islets of Langerhans; Leptin; Lipid Metabolism; Liver; Mice; Mice, Knockout; Models, Animal; Muscle, Skeletal; Obesity; Receptor, Insulin; Receptors, Somatomedin; Research Design

There is now compelling evidence that, in addition to signaling to the central nervous system (CNS), leptin also exerts its metabolic effects acting directly on peripheral tissues. It has been demonstrated by in vivo and in vitro studies, that leptin increases glucose and fatty acid metabolism in skeletal muscle. These direct leptin effects are supported by the presence of the long form of the leptin receptor, considered to be capable of performing intracellular signaling, in peripheral tissues, including skeletal muscle. The exposure of soleus muscle to supra-physiological leptin concentrations stimulate the activity of both the pyruvate-dehydrogenase (PDH) complex and Krebs cycle. This could be due to a direct stimulation of PDH and krebs cycle by leptin or a consequence of an indirect effect of this hormone activating the mitochondrial uncoupling process. In addition, in soleus and extensor digitorum longus (EDL) muscles, leptin and insulin had opposite effects on lipid metabolism, with leptin favoring lipid oxidation and insulin favoring lipid storage as triglycerides (TG). The leptin effects on free fatty acid (FFA) oxidation were more pronounced in soleus than in EDL. The differences in response of soleus compared with that of EDL was probably due to differences in fiber type composition and metabolic characteristics. It has been demonstrated that leptin reduces the TG content of skeletal. When tissue TG content is severely depleted by hyperleptinemia in normal rats, there is a dramatic increase in insulin sensitivity. This lipopenic effect of leptin may protect from the development of insulin resistance and diabetes in animals. In humans, obesity is also associated with an increase in insulin resistance and the development of Type II diabetes, however, contrary to rats and mice, there is abundance of leptin, indicating a state of resistance to this hormone in humans. Future studies are necessary to investigate the reasons why lean subjects seem to respond properly to endogenous leptin while obese ones don't. The understanding of the putative direct leptin signaling pathway in skeletal muscle could be an important step towards the utilization of leptin or a leptin receptor agonist as therapeutic tools to treat obesity and its related metabolic disorders.

Topics: Animals; Carrier Proteins; Fatty Acids; Glucose; Humans; Insulin; Insulin Resistance; Leptin; Muscle, Skeletal; Obesity; Receptors, Cell Surface; Receptors, Leptin; Triglycerides

An established fact in the polycystic ovarian syndrome (POS) is an abnormal ovarian steroidogenesis. Though this suggest an intrinsic ovarian defect, the syndrome could also be influenced by factors outside the ovaries. Although of unknown etiology, the POS is one of the most frequent endocrine disorders in the gynecologic practice. The disorder is characterized by ultrasound findings of enlarged polycystic ovaries, hyperandrogenism, menstrual disorders, obesity and including the appearance of infertility. There are a series of mechanisms involved in the extraovarian androgen increase in patients with POS. Among these mechanisms are implicated those of central and peripheral origin, genetic factors and adrenocortical dysfunction. In the same way, the alterations produced could imply genetic, molecular biological, biochemical, physiological and endocrinological factors. Sometimes all these factors could interact at the same time. The high serum androgen level could stop the pituitary gonadotropin production, either as a direct mechanism or as a result of its peripheral conversion. The increased androgens also explain the manifestations of clinical acne, hirsutism, and the detention in follicular ovarian maturation. All these manifestations are related with the menstrual disorders, anovulation, and infertility that these patients develop. The characteristics of the extraovarian POS include the 17-hydroxyprogesterone elevation in response to the ACTH test and the dexamethasone suppression of adrenal androgens. It is possible to improve the ovarian function in some patients with POS. This could be achieved with clomiphene citrate associated with glucocorticoids to induce ovulation.

Topics: 11-beta-Hydroxysteroid Dehydrogenases; 17-alpha-Hydroxyprogesterone; 3-Hydroxysteroid Dehydrogenases; Adrenal Cortex; Adrenal Hyperplasia, Congenital; Adrenocortical Hyperfunction; Adrenocorticotropic Hormone; Adult; Androgens; Catecholamines; Clomiphene; Corticotropin-Releasing Hormone; Cortisone; Dexamethasone; Female; Glucocorticoids; Gonadal Steroid Hormones; Humans; Hydroxysteroid Dehydrogenases; Hyperinsulinism; Hyperprolactinemia; Hypothalamo-Hypophyseal System; Infant, Newborn; Infertility, Female; Insulin Resistance; Leptin; Mineralocorticoids; Obesity; Ovary; Ovulation Induction; Pituitary-Adrenal System; Polycystic Ovary Syndrome; Pseudopregnancy; Steroid 11-beta-Hydroxylase; Steroid 17-alpha-Hydroxylase; Steroids; Sterol Esterase; Stress, Psychological

Insulin resistance and hyperinsulinemia have been observed in essential hypertension. The selective impairment of glucose metabolism in skeletal muscle may accompanied hyperinsulinemia and raise blood pressure through sympathetic nervous system and/or renin-angiotensin system activation, renal sodium retention, proliferation of vascular smooth muscle and leptin. Recently, molecular techniques have applied for investigating the mechanisms of insulin resistance. The mutation of insulin receptor gene, changes of muscle fiber composition and muscle blood flow, abnormalities of insulin signal transduction, and TNF-alpha are considered as involvement of insulin resistance in the skeletal muscle. While further study will be necessary to clarify the mechanisms of insulin resistance and hypertension.

Topics: Animals; Cell Division; Glucose; Humans; Hyperinsulinism; Hypertension; Insulin Resistance; Leptin; Muscle, Skeletal; Muscle, Smooth, Vascular; Receptor, IGF Type 1; Receptor, Insulin; Renin-Angiotensin System; Signal Transduction; Sodium-Potassium-Exchanging ATPase; Sympathetic Nervous System; Syndrome; Tumor Necrosis Factor-alpha

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

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

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

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

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

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

Obesity and related metabolic disorders are prevalent health issues in modern society and are commonly attributed to lifestyle and dietary factors. However, the mechanisms by which environmental factors modulate the physiological systems that control weight regulation and the aetiology of metabolic disorders, which manifest in adult life, may have their roots before birth. The 'fetal origins' or 'fetal programming' paradigm is based on the observation that environmental changes can reset the developmental path during intrauterine development leading to obesity and cardiovascular and metabolic disorders later in life. The pathogenesis is not based on genetic defects but on altered genetic expression as a consequence of an adaptation to environmental changes during fetal development. While many endocrine systems can be affected by fetal programming recent experimental studies suggest that leptin and insulin resistance are critical endocrine defects in the pathogenesis of programming-induced obesity and metabolic disorders. However, it remains to be determined whether postnatal obesity is a consequence of programming of appetite regulation and whether hyperphagia is the main underlying cause of the increased adiposity and the development of metabolic disorders.

Topics: Animals; Appetite; Endocrine Glands; Female; Fetus; Humans; Insulin Resistance; Leptin; Obesity; Pregnancy; Prenatal Exposure Delayed Effects

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

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

Topics: Animals; Diabetes Mellitus, Experimental; Insulin Resistance; Leptin; Lipodystrophy; Mice

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

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

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

The immune system is closely integrated with the neuroendocrine system, and infection-induced increases in cytokines such as IL-1, IL-6 and TNF have numerous effects on the central nervous system. These include stimulation of the hypothalamus-pituitary-adrenal (HPA) axis, as well as of leptin production. The increase in leptin causes loss of appetite, which may be deleterious for children who are living under conditions of poverty, have frequent infections and are often already undernourished. These cytokines may also be involved in problems of obesity, since they activate the HPA-axis and since TNF is produced by fat cells and can cause insulin resistance. The immune system originally developed for hunter-gatherers may not be well adapted to the pathology of poverty or that of excess.

Topics: Adaptation, Physiological; Adult; Bacterial Infections; Child; Cytokines; Humans; Hypothalamo-Hypophyseal System; Immune System; Immune Tolerance; Infant, Newborn; Insulin; Insulin Resistance; Leptin; Neurotransmitter Agents; Nutrition Disorders; Nutritional Physiological Phenomena; Obesity; Pituitary-Adrenal System; Poverty; Risk Factors; Virus Diseases

Topics: Animals; Gene Expression Regulation; Hexosamines; Humans; Insulin Resistance; Leptin; Nutritional Physiological Phenomena; Obesity; Satiation

Topics: Adipocytes; Adipose Tissue; Adult; Humans; Insulin Resistance; Leptin; Middle Aged; Obesity; Tumor Necrosis Factor-alpha

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

The obesity-like effects produced by the chronic intracerebroventricular (i.c.v.) neuropeptide Y (NPY) infusion in normal rats require the presence of glucocorticoids, as none of them occurs when NPY is similarly infused in adrenalectomized rats. NPY effects are present again when i.c.v. NPY is infused together with i.c.v. dexamethasone in adrenalectomized animals. The inhibitory effect of leptin on food intake and body weight observed when the hormone is i.c.v. administered to normal rats is markedly enhanced and longer lasting when the same dose of leptin is i.c.v. administered to adrenalectomized rats. Glucocorticoid administration to adrenalectomized rats dose-dependently reduces, then abolishes, this potent effect of leptin. Thus, glucocorticoids limit leptin-induced effects. The chronic i.c.v. infusion of glucocorticoids (dexamethasone) to normal rats produces an obesity syndrome with its several abnormalities. This appears to be due to glucocorticoid-elicited increases in hypothalamic NPY levels together with decreases in those of CRH. Thus, the status of the hypothalamo-pituitary-adrenal axis and related glucocorticoid output is a relevant facet of body weight homeostasis. It may be a deleterious environmental factor responsible for the development of obesity, insulin as well as leptin resistance, and type 2 diabetes.

Topics: Animals; Body Weight; Central Nervous System; Glucocorticoids; Homeostasis; Insulin Resistance; Leptin; Neuropeptide Y; Obesity; Peripheral Nervous System; Rats

Atherosclerosis starts in childhood, and is accelerated in some individuals. A cluster of clinical and biochemical factors constitute the risk profile for many of them, perhaps most important being metabolic insulin resistance syndrome. Insulin resistance and its components for children and adolescents, especially obesity and dyslipidemia, are generators of hypertension, glucose intolerance and complications of atherosclerosis in adulthood. Some individuals are genetically predisposed, particularly those with the family history of such disorders. For many subjects, there is 'tracking' of metabolic and lifestyle factors from early age to adulthood. Several new risk factors of atherosclerosis (e.g. level of lipoprotein (a), procoagulant state, hyperhomocysteinemia, low birth weight and adverse in-utero environment, and possibly inflammatory markers) are current and potentially future areas of research concerning children and young individuals. Definition of and research on new and hitherto not investigated factors and formulation of strategies to neutralize the known factors are of paramount importance for primary prevention of atherosclerosis. Simple and effective measures for prevention include increasing awareness of the diseases, maintenance of ideal body weight, regular physical exercise, avoidance of smoking and chewing of tobacco, eating a balanced diet, and early periodic monitoring of blood pressure and metabolic status. These measures, starting from childhood, should be applied to all and in particular to the susceptible offspring, predisposed individuals, and populations.

Topics: Adolescent; Adult; Age Factors; Arteriosclerosis; Birth Weight; Blood Coagulation Factors; Child; Child, Preschool; Coronary Disease; Diabetes Complications; Exercise; Female; Homocysteine; Humans; Hypertension; Infant; Infant, Newborn; Insulin Resistance; Leptin; Life Style; Lipids; Lipoprotein(a); Male; Middle Aged; Obesity; Primary Prevention; Risk Factors; Sex Factors; Smoking

Adipose tissue is not simply a storage depot. Adipocytes secrete hormones, growth factors and cytokines, such as leptin and TNF-alpha, as well as proteins that are related to the immune system and vascular functions. Through this network of endocrine, paracrine, and autocrine signals fat cells participate in the regulation of energy homeostasis, host defense and reproduction, and may also contribute to the development of pathological states, such as insulin resistance. Adipose tissue is confined to distinct depots. In Cushing's disease or following treatment of AIDS, certain adipose depots enlarge whereas others shrink, suggesting the existence of site-specific differences in fat cell function. Increases in adipocyte number occur via replication of preadipocytes, a process that is not restricted to infancy but occurs throughout life. In contrast to still widely-held beliefs, mature fat cells can be eliminated by dedifferentiation or apoptosis. PPAR-gamma, a transcription factor that is activated by fatty acids and prostaglandins, plays a central role in adipose conversion of preadipocytes and appears to participate in controlling the size of mature fat cells as well.

Topics: Adipocytes; Adipose Tissue; Apoptosis; Cell Differentiation; Diet, Reducing; Energy Metabolism; Fatty Acids; Humans; Insulin Resistance; Leptin; Lipid Metabolism; Obesity; Receptors, Cytoplasmic and Nuclear; Syndrome; Transcription Factors

Aging is associated with a redistribution of both fat and lean tissue within the body. Intra-abdominal fat (IAF) accumulates more rapidly than total fat while the loss of lean body mass is mostly due to sarcopenia. Increase of visceral fat plays a major role in the pathogenesis of insulin resistance, which leads to type II diabetes and also to cardiovascular diseases. This review is focussed on the relationships that exist between the accumulation of IAF and insulin resistance during aging. The various methods available for assessing IAF are briefly reviewed; imaging techniques are the only reference methods, and their availability is limited. Insulin resistance that appears with aging is caused by accumulation of IAF, rather than by aging per se. Studies done in type II diabetic patients suggest that the metabolic link between increased IAF and insulin resistance could well be the increased availability and/or oxidation of free fatty acids. Physical inactivity certainly enhances both IAF accumulation and, more directly, insulin resistance. Independent and significant effects of menopause or of sarcopenia on insulin resistance remain to be established. The influence of hormonal changes, reduced fatty acid utilization, and resistance to leptin on IAF accumulation are also discussed. Although it is difficult to determine the independent influence of each of these factors, IAF accumulation seems to be a central and important determinant of cardiovascular risk. The last part of this review is devoted to protein metabolism and focused on the preservation of protein metabolism in the liver during aging.

Topics: Adipose Tissue; Aging; Body Composition; Humans; Insulin Resistance; Leptin; Lipid Metabolism; Liver; Obesity; Proteins

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

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

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

Human obesity is the result of both environmental and genetic factors. In this manuscript, we briefly review the metabolic factors predicting body weight gain in Pima Indians, a population prone to obesity. The metabolic predictors of weight gain are: 1) a low metabolic rate, 2) low levels of physical activity, 3) low rates of fat oxidation, 4) insulin sensitivity, 5) low sympathetic nervous system activity, and 6) low plasma leptin concentrations. In contrast, obesity is associated with high metabolic rate, high fat oxidation, low insulin sensitivity and high plasma leptin concentration. This observation emphasizes the need to conduct prospective studies to obtain a better understanding of the etiology of obesity. In addition, genetic studies will help to identify new pathways involved in the pathophysiology of obesity.

Topics: Basal Metabolism; Dietary Fats; Energy Metabolism; Exercise; Female; Humans; Insulin Resistance; Leptin; Male; Obesity; Oxidation-Reduction; Proteins; Sympathetic Nervous System; Weight Gain

It is now believed that the GLUT-4 receptor, tumor necrosis factor-alpha (TNF-alpha), essential fatty acids (EFAs) and their metabolites and daf-genes have an important role in the development of obesity and non-insulin dependent diabetes mellitus (NIDDM). The protein encoded by daf-2 is 35% identical to the human insulin receptor, daf-7 codes a transforming growth factor-beta (TGF-beta) type signal and daf-16 can enhance superoxide dismutase (SOD) expression. EFAs and their metabolites can alter the cell membrane fluidity and enhance the expression of GLUT-4 and insulin receptors. EFAs can suppress TNF-alpha production and secretion, a mechanism that may have relevance to the role of these fatty acids in the pathogenesis of insulin resistance, obesity and NIDDM. Melatonin has anti-oxidant actions similar to daf-16, TGF-beta and SOD. Based on this evidence, it is proposed that GLUT-4, TNF-alpha, EFAs, daf-genes, melatonin and leptin interact with each other in ways which may have relevance to the development or abrogation of insulin resistance, obesity, NIDDM, complications due to NIDDM, longevity and ageing.

Topics: Caenorhabditis elegans Proteins; Diabetes Mellitus, Type 2; Fatty Acids, Essential; Glucose; Glucose Transporter Type 4; Homeostasis; Humans; Insulin Resistance; Leptin; Melatonin; Models, Biological; Monosaccharide Transport Proteins; Multigene Family; Muscle Proteins; Proteins; Receptor, Insulin; Tumor Necrosis Factor-alpha

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

Tumor necrosis factor-alpha (TNF alpha) is a multifunctional cytokine which exerts a myriad of biological actions in different tissues and species. Many of these actions can perturb the normal regulation of energy metabolism. In adipose tissue, in particular, TNF alpha has been demonstrated to regulate or interfere with adipocyte metabolism at numerous sites including transcriptional regulation, glucose and fatty acid metabolism and hormone receptor signaling. The implications of these perturbations in disease states and the current understanding of the molecular mechanisms utilised by TNF alpha are discussed herein.

Topics: Adipocytes; Animals; Apoptosis; Cell Differentiation; Humans; Insulin Resistance; Leptin; Ligands; Lipid Metabolism; Plasminogen Activator Inhibitor 1; Protein Biosynthesis; Receptors, Tumor Necrosis Factor; Tumor Necrosis Factor-alpha

The additional energy requirements of pregnancy are needed for increases in maternal (breast, uterus and adipose) and feto-placental tissue accrued during pregnancy as well as the additional running cost of pregnancy for example increased cardiac output. Based on prospective longitudinal studies, the additional energy requirements of pregnancy range from > 500 MJ in Swedish women to net savings of approximately 50 MJ in women in The Gambia with their usual nutritional intake. In addition to the wide variation in estimated energy expenditure among various ethnic populations, there is as much as a 10-20 fold range in the total energy cost of pregnancy and lactation within relatively homogenous populations. The estimates of energy intake in these studies, however, are generally less than the estimates of total energy expenditure. The discrepancy between energy intake and energy expenditure during pregnancy is most probably due to several factors including decreased maternal activity, unreliable reporting of energy intake and possibly increased metabolic efficiency of basal metabolic rate, thermic effect of foods and physical activity. Based on recent studies, variations in maternal pregravid glucose insulin sensitivity may account for part of the observed variability associated with maternal metabolic adaptations during pregnancy. Decreases in insulin sensitivity have a significant inverse correlation with accretion of adipose tissue in early pregnancy. Likewise, there is a significant inverse correlation between decreases in basal oxygen consumption with increases in endogenous glucose production. The mechanism for these changes remain speculative. Additionally, although serum leptin concentrations increase 66% in early pregnancy and are correlated with maternal fat mass and basal energy expenditure, the increases in serum leptin occur prior to any significant increases in body fat or basal metabolic rate suggesting that pregnancy represents another leptin resistant state. Based on these data, specific recommendations for acceptable carbohydrate and fat intake during pregnancy and lactation are not possible for every woman at this time. Additional prospective studies, evaluating long-term maternal and neonatal outcome are needed before more meaningful nutritional recommendations can be proposed.

Topics: Adipose Tissue; Body Composition; Dietary Carbohydrates; Dietary Fats; Energy Intake; Energy Metabolism; Female; Humans; Insulin Resistance; Lactation; Leptin; Longitudinal Studies; Nutritional Requirements; Pregnancy; Proteins

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

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

Topics: Diabetes Mellitus, Type 2; Gene Expression Regulation; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Leptin; Obesity; Proteins

It has been increasingly recognised in recent years that type 2 (non-insulin-dependent) diabetes is part of a cluster of cardiovascular risk factors known as the metabolic syndrome, but also endorsed with such names as the deadly quartet, syndrome X and the insulin resistance syndrome. Atherosclerosis is the most common complication of type 2 diabetes among Europeans, and coronary artery, cerebrovascular and peripheral vascular disease are 2 to 5 times more common in people with this condition than in those without diabetes. These observations indicate that the treatment of type 2 diabetes requires agents that do more than simply lower blood glucose levels, and a therapy with both antihyperglycaemic effects and beneficial effects on dyslipidaemia, hypertension, obesity, hyperinsulinaemia and insulin resistance is likely to be most useful. In this respect, metformin has an important and established role: this drug has been shown to lower blood glucose and triglyceride levels, and to assist with weight reduction and to reduce hyperinsulinaemia and insulin resistance. Studies in the Israeli sand rat, Psammomys obesus, have indicated hyperinsulinaemia/insulin resistance to be the initial and underlying metabolic disorder in obesity and type 2 diabetes. Thus, the well established effect of metformin in reducing insulin resistance makes this drug an excellent candidate for the prevention of progression of impaired glucose tolerance to type 2 diabetes, and for the reduction of mortality associated with cardiovascular disease.

Topics: Animals; Blood Glucose; Cardiovascular Diseases; Chromans; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Humans; Hyperinsulinism; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Male; Metformin; Rats; Risk Factors; Thiazoles; Thiazolidinediones; Troglitazone

Obesity and Type 2 diabetes are now major public health issues in developed nations and have reached epidemic proportions in many developing nations, as well as disadvantaged groups in developed countries, e.g., Mexican-Americans, African-Americans, and Australian Aborigines. These groups all show hyperinsulinemia and insulin resistance, which have been demonstrated to be future predictors of Type 2 diabetes and have also been suggested as key factors in the etiology of the Metabolic Syndrome. It is now increasingly recognized that Type 2 diabetes is part of a cluster of cardiovascular disease (CVD) risk factors comprising the Metabolic Syndrome. This group is at very high risk of atherosclerosis because each of the risk factors in the Metabolic Syndrome cluster in its own right is an important CVD risk factor. They also contribute cumulatively to atherosclerosis. A key strategy in reducing macrovascular disease lies in the better understanding of the Metabolic Syndrome--glucose intolerance, hypertension, hyperlipidemia, and central obesity. Although it has been suggested that hyperinsulinemia/insulin resistance is the central etiological factor for the Metabolic Syndrome, epidemiological data do not support the idea that this can account for all of the cluster abnormalities. We have animal and human data suggesting that hyperleptinemia rather than, or synergistically with, hyperinsulinemia may play a central role in the genesis of the CVD risk factor cluster that constitutes the syndrome. Studies in Psammomys obesus (the Israeli sand rat) suggest hyperinsulinemia/insulin resistance is an early metabolic lesion in the development of obesity and Type 2 diabetes. This animal also develops other features of the Metabolic Syndrome, making it an excellent model to investigate etiology. Psammomys, when placed on an ad libitum laboratory diet, develops hyperinsulinemia, insulin resistance, impaired glucose tolerance, diabetes, and dyslipidemia. It also develops hyperleptinemia and leptin insensitivity, and hyperleptinemia is correlated with insulin resistance independent of changes in body weight. It is likely that a similar sequence occurs in the transition from the prediabetic state to Type 2 diabetes in humans. More recently, other potential players in the etiology of the Metabolic Syndrome have been suggested including endothelial dysfunction and acetylation-stimulating protein (ASP). It has been suggested that endothelial dysfunction may be an antecedent fo

Topics: Acetylation; Animals; Diabetes Mellitus, Type 2; Endothelium, Vascular; Humans; Hyperinsulinism; Insulin Resistance; Leptin; Obesity; Risk Factors

Increased fat mass (FM), and in particular a specific increase in visceral fat (VF), may account for the age-associated decrease in insulin action and the development of Syndrome X. Utilizing chronic caloric restriction (CR) with aging in a rodent model, we dissociated the effects of VF and FM, and demonstrated that the decrease in VF accumulation was sufficient to prevent the marked decrease in hepatic insulin action. This suggests that the typical increase in VF with aging, rather than aging per se, determines hepatic insulin resistance. To directly assess the role of VF, we studied rats after surgical removal of VF or sham operation. Surgical extraction of VF (which accounts for approximately 10% of total fat) improved hepatic insulin action by more than twofold. We studied the role of fat-derived peptides in the regulation of body composition and insulin action. While VF extraction resulted in decreased gene expression for leptin and TNF-alpha in the subcutaneous adipose, administration of leptin selectively decreased visceral fat (approximately 60%), and enhanced the action of insulin on inhibiting hepatic glucose production (approximately 80%). Thus, the cause-effect relationship between the age-related increase in VF and the decrease in hepatic insulin action may involve the failure of leptin to "cross talk" with other fat depots to regulate fat distribution.

Topics: Adipose Tissue; Aging; Animals; Body Constitution; Glucose; Humans; Insulin; Insulin Resistance; Leptin; Liver; Rats; Viscera

The combination of obesity with arterial hypertension is frequent finding in clinical practice. In 70% of the males and 61% of the females the high blood pressure is directly connected with obesity. The assumed mechanisms by which obesity leads to arterial hypertension are: insuline resistance; genetic factors (hypothesis for the sparing gene); correlations leptin-neuropeptide Y; fatty tissue as origin of local pressor and depressor humoral factors. The arterial hypertension in obesity is salt-sensible, associated with increased intraglomerular pressure, microalbuminuria and increased risk for cardiovascular complications. The reduction of the body weight is the principal nonmedical mean for treatment of the arterial hypertension. Of the antihypertensive drugs those which are neutral with respect to the carbohydrat and fat metabolism are preferred inhibitors of the converting enzyme, calcium antagonists, selective alpha-1 blockers, central alpha-2 agonist.

Topics: Adipose Tissue; Cardiovascular Diseases; Humans; Hypertension; Insulin Resistance; Leptin; Obesity; Risk Factors

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

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

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

Obesity gains increasing prevalence world-wide. Multifactorially caused it presents itself in numerous heterogeneous phenotypes with a wide spectrum of clinical symptoms. The full-blown female obesity syndrome is initiated already in childhood, associated with ovarian hyperandrogenaemia (polycystic ovary syndrome) in the reproductive phase, and characterised by increasing co-morbidity (cancer; metabolic syndrome; arteriosclerosis) in the postmenopausal state leading to shortened longevity. Due to the complexity of psychic, somatic and endocrine-metabolic disturbances a causal break-through in the treatment of the disease could not be achieved yet, but the enhanced basal understanding and recently investigated pharmaceutical principles might enable to improve the therapeutical approaches.

Topics: Adolescent; Adult; Aged; Arteriosclerosis; Child; Combined Modality Therapy; Female; Gene Expression; Humans; Insulin Resistance; Leptin; Middle Aged; Neoplasms; Obesity; Polycystic Ovary Syndrome; Pregnancy; Proteins; Risk Factors

Obesity is associated with an increased incidence of insulin resistance, dyslipoproteinemia, and hypercoagulability. In a more recently established hypothesis of body weight control and regulation of metabolism, the adipocyte secretes leptin and locally expresses TNF-alpha, the latter being responsible for the expression of metabolic cardiovascular risk factors. TNF-a mRNA expression and TNF-alpha protein are greatly increased in adipose tissue from obese animals and humans. Elevated TNF-alpha expression induces insulin resistance by downregulating the tyrosine kinase activity of the insulin receptor and decreasing the expression of GLUT-4 glucose transporters. TNF-alpha also reduces lipoprotein lipase activity in white adipocytes, stimulates hepatic lipolysis, and increases plasminogen activator inhibitor-1 content in adipocytes. Moreover, adipocytes secrete leptin, a molecule with a secondary cytokine structure whose concentrations correlate with the amount of fat tissue. Increased leptin levels downregulate appetite and increase sympathetic activity and thermogenesis in the hypothalamus. Diet-induced weight loss reduces adipose TNF-alpha expression and serum leptin levels and is associated with improved insulin sensitivity and lipid metabolism. Although exercise has also been shown to reduce leptin levels, an influence on TNF-a expression in adipocytes or muscle cells has not yet been demonstrated.

Topics: Animals; Arteriosclerosis; Coronary Disease; Diet; Exercise; Humans; Insulin Resistance; Leptin; Obesity; Proteins; Risk Factors; Tumor Necrosis Factor-alpha; Weight Loss

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

This review considers recent findings and ideas on the impact of dietary carbohydrates on insulin sensitivity in the context of the prevention of diabetes and cardiovascular disease. We assess the evidence for benefits in insulin sensitivity following high starch as distinct from high sucrose intakes when the diet is low in fat. We consider relationships between obesity, leptin and carbohydrate intake. We conclude that reducing the rate of carbohydrate digestion in the small bowel may be the key stage at which to intervene to reduce insulinaemia and so prevent downregulation of insulin receptors and insulin resistance.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Humans; Insulin Resistance; Leptin; Obesity; Rats; Starch

Topics: Animals; Carrier Proteins; Diabetes Mellitus, Type 2; Genetic Predisposition to Disease; Genome; Humans; Insulin Resistance; Ion Channels; Leptin; Membrane Proteins; Mice; Mice, Mutant Strains; Mitochondrial Proteins; Obesity; Receptors, Adrenergic, beta-2; Receptors, Cell Surface; Receptors, Leptin; Tumor Necrosis Factor-alpha; Uncoupling Protein 1

Leptin, the product of the ob gene, controls appetite through the hypothalamus and may affect many other tissues because of the widespread distribution of its receptors. Leptin is synthesized by white adipose tissue (WAT) under conditions of high energy availability and insulin stimulus. Glucocorticoids enhance this synthesis and catecholamines hamper leptin production. Leptin diminishes insulin secretion by the pancreatic beta cells and induces insulin resistance. In fact leptin hampers insulin action on WAT itself in a negative feedback loop. The evidence acquired in studies on diabetics, starvation, refeeding and insulin and glucose clamps supports this interpretation, which may also explain part of the difficulties encountered by the current postulate that links leptin to WAT mass size signalling to the brain. Leptin may be, essentially, a counter-regulatory hormone limiting the insulin drive to store energy in the form of fat, its effects reaching from a decrease in food intake to lower insulin secretion and increased resistance to insulin and lower glucose uptake and fat synthesis by WAT.

Topics: Adipose Tissue; Animals; Choroid Plexus; Energy Metabolism; Feedback; Glucose; Hormones; Humans; Insulin; Insulin Resistance; Leptin; Obesity; Proteins; Starvation

Topics: Animals; Carrier Proteins; Diabetes Mellitus, Type 2; DNA, Mitochondrial; Genotype; Humans; Insulin; Insulin Resistance; Insulin Secretion; Leptin; Mutation; Obesity; Proteins; Receptors, Adrenergic, beta; Receptors, Cell Surface; Receptors, Leptin; Risk

Leptin 167 an amino acid product of the recently discovered obesity gene "ob-gene", is a tissue hormone of adipose tissue. It is a hormonal satiety signal or a signal for terminating food intake. Its level rise after a meal or after administration. Rats with a mutation of the ob-gene have zero or very low leptin levels, are hyperphagic, obese and sterile, develop diabetes as a result of overeating. Administration of recombinant leptin arrests hyperphagia, the body weight declines and sexual function improve partly, in particular in males. It seems that leptin controls not only the function of the hypothalamic satiety centre but also the output of GnRh and other liberins as well as thermoregulation, muscular and sexual activity and thus energy expenditure. In the majority of obese rats and human the leptin levels are significantly higher compared with asthenic individuals, proportionate to the percentage of body fat and BMI. Obesity promotes also insulin resistance and penetration of the H-phenomenon into the phenotype. In the insulin resistance syndrome (5H-X) it may thus be assumed that there is a parallel leptin and insulin resistance, probably of the postreceptor type, and even a causal association, as the "db" gene is identical with the gene for leptin receptors.

Topics: Animals; Humans; Insulin Resistance; Leptin; Obesity; Proteins

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

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

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

Leptin is the product of OB gene. This 16 kDa protein is produced by mature adipocytes and is secreted in plasma. Its plasma levels are strongly correlated with adipose mass in rodents as well as in humans. Leptin inhibits food intake, reduces body weight and stimulates energy expenditure. It has been suggested that leptin could be the link between obesity and diabetes. Recent experiments in rodents have shown that leptin expression in adipocytes is also regulated at short-term by hormones and nutrients. Leptin expression increases after food intake and decreases during fasting and diabetes. Insulin and glucocorticoids increase leptin expression, whereas catecholamines, via beta-adrenergic receptors and cAMP, and long-chain fatty acids (and thiazolidinediones), via PPARy, inhibit leptin expression. Leptin is a cytokine that binds to transmembrane receptors similar to the receptors of cytokine family (type IL-6), and transmit their information inside the cell, after dimerisation. A short-form of leptin receptor (with a cytoplasmic domain of 34 amino residues) has been identified in the choroid plexus. This type of receptor should be used for leptin transport across the blood-brain barrier. Then leptin binds to a long-form of leptin receptor in the hypothalamus (with a cytoplasmic domain of 302 amino residues) and decreases the production of neuropeptide Y, a neuromediator of food intake. The long-form of leptin receptor, transmits its information via the Janus Kinases (JAK) who subsequently phosphorylate transcription factors of the STAT family. Intermediary forms of leptin receptor have been identified in other tissues: liver, heart, skeletal muscles, endocrine pancreas. The role of leptin receptors in these tissues remains obscure, but is of considerable interest. Recent studies have shown that leptin inhibits insulin secretion and have anti-insulin effects on liver and adipose tissue. If these effects are confirmed, leptin could play a role similar to TNF alpha and could participate in the insulin-resistance of obesity and type II diabetes.

Topics: Adipose Tissue; Animals; Energy Metabolism; Gene Expression; Genetic Linkage; Humans; Insulin Resistance; Leptin; Mice; Mice, Obese; Obesity; Proteins

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

The ability to store substantial amounts of energy as lipid in adipose tissue has allowed development of a variety of strategies in wild animals to meet the considerable metabolic challenge of lactation. The ability to use adipose tissue energy has also been critical for development of the exceptional rates of milk production achieved in the dairy cow. Lactation thus results in profound changes in adipose tissue metabolism, the molecular bases of which are beginning to be resolved in domestic ruminants and laboratory rodents. In addition to its role as an energy store, adipose tissue has a variety of other functions (e.g., modulation of mammary development, appetite, immune system function), some of which are important for lactation.

Topics: Adaptation, Physiological; Adipose Tissue; Animals; Animals, Suckling; Appetite; Cattle; Circadian Rhythm; Energy Metabolism; Female; Fertility; Humans; Insulin; Insulin Resistance; Lactation; Leptin; Lipid Metabolism; Lipolysis; Lymphatic System; Mammals; Mammary Glands, Animal; Mice; Phosphatidylinositol 3-Kinases; Rats; Sheep; Signal Transduction; Species Specificity

Topics: Adaptor Proteins, Signal Transducing; Adipose Tissue; Agouti Signaling Protein; Animals; Carboxypeptidase H; Carboxypeptidases; Carrier Proteins; CCAAT-Enhancer-Binding Proteins; Cell Differentiation; DNA-Binding Proteins; Feeding Behavior; Gene Expression Regulation; Homeostasis; Hormones; Humans; Hypothalamus; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Mice; Mice, Mutant Strains; Models, Biological; Neuropeptide Y; Nuclear Proteins; Obesity; Proteins; Receptors, Adrenergic, beta; Receptors, Adrenergic, beta-3; Receptors, Cell Surface; Receptors, Cytoplasmic and Nuclear; Receptors, Leptin; Sterol Regulatory Element Binding Protein 1; Transcription Factors

We investigated whether Lactobacillus plantarum strain LMT1-48, isolated from Korean fermented foods and newborn feces, is a suitable probiotic supplement to treat overweight subjects.. In this randomized, double-blind, placebo-controlled clinical trial, 100 volunteers with a body mass index of 25 to 30 kg/m2 were assigned randomly (1:1) to receive 2×1010 colony forming units of LMT1-48 or to a placebo treatment group. Body composition was measured by dual-energy X-ray absorptiometry, and abdominal visceral fat area (VFA) and subcutaneous fat area were measured by computed tomography scanning. Changes in body fat, VFA, anthropometric parameters, and biomarkers were compared between the two treatment groups (ClinicalTrials.gov number: NCT03759743).. After 12 weeks of treatment, the body weight decreased significantly from 76.6±9.4 to 75.7±9.2 kg in the LMT1-48 group but did not change in the placebo group (P=0.022 between groups). A similar pattern was found in abdominal VFA between the two groups (P=0.041). Serum insulin levels, the corresponding homeostasis model assessment of insulin resistance, and leptin levels decreased in the LMT1-48 group but increased in the placebo group (all P<0.05). Decrease in body weight and body mass index by treatment with LMT1-48 was correlated with increase in Lactobacillus levels significantly. LMT1-48 also increased Oscillibacter levels significantly, which were negatively correlated with triglyceride and alanine transaminase levels.. Administration of LMT1-48 decreased body weight, abdominal VFA, insulin resistance, and leptin levels in these subjects with overweight, suggesting its anti-obesogenic therapeutic potential.

Topics: Adipose Tissue; Body Weight; Humans; Insulin Resistance; Lactobacillus plantarum; Leptin; Overweight

Introduction: rs822393 is related to dietary intervention responses. The aim of our study was to analyze the metabolic effects of 2 hypocaloric diets with a different fat profile during 3 months according to the genetic variant rs822393. Methods: a population of 361 obese patients were randomly allocated to one of two diets; Diet P (enriched in polyunsaturated fatty acids) vs. Diet M (enriched in monounsaturated fatty acids). Adiposity and biochemical parameters were determined. rs822393 was assessed by real-time PCR, with a dominant model analysis (CC vs CT+TT). Results: genotype distribution was: 221 CC (61.2 %), 115 CT (31.9 %) and 25 TT (6.9 %). Basal and post-intervention HDL cholesterol, adiponectin levels and adiponectin/leptin ratio were lower in T-allele than non-T-allele carriers. After both diets, BMI, weight, fat mass, waist circumference, systolic blood pressure, insulin levels, HOMA-IR, leptin, total cholesterol and LDL-cholesterol improved significantly in both genotype groups. After Diet P, HDL-cholesterol (delta: 5.6 ± 1.1 mg/dl vs. 2.7 ± 0.9 mg/dl; p = 0.01), serum adiponectin (20.1 ± 2.9 ng/dl vs. 6.8 ± 3.0 ng/dl; p = 0.02) and adiponectin/leptin ratio (0.57 ± 0.1 units vs. 0.20 ± 0.08 units; p = 0.03) improved in non-T allele carriers. The same improvements were observed after Diet M: HDL-cholesterol (delta: 5.5 ± 0.8 mg/dl vs. 3.1 ± 0.9 mg/dl; p = 0.03), serum adiponectin (19.5 ± 2.9 ng/dl vs. 4.5 ± 2.8 ng/dl; p = 0.01), and adiponectin/leptin ratio (0.54 ± 0.1 units vs. 0.15 ± 0.08 units; p = 0.03). These parameters remained unchanged in T-allele carriers. Conclusion: after two different hypocaloric diets, obese subjects with the T allele of rs822393 did not improve their adiponectin levels, ratio adiponectin/leptin, and HDL-cholesterol, despite loss of weight.. Introducción: el polimorfismo rs822393 está relacionado con las respuestas a las intervenciones dietéticas. El objetivo de nuestro estudio fue analizar los efectos metabólicos de 2 dietas hipocalóricas con diferente perfil graso durante 3 meses según la variante genética rs822393. Métodos: una muestra de 361 pacientes obesos se asignó aleatoriamente a una de dos dietas: dieta P (enriquecida en ácidos grasos poliinsaturados) y dieta M (enriquecida en ácidos grasos monoinsaturados). Se determinaron parámetros de adiposidad y bioquímicos; rs822393 se evaluó mediante PCR en tiempo real, con un análisis de modelo dominante (CC frente a CT+TT). Resultados la distribución del genotipo fue: 221 CC (61,2 %), 115 CT (31,9 %) y 25 TT (6,9 %). El colesterol HDL basal y posterior a la intervención, los niveles de adiponectina y la relación adiponectina/leptina fueron más bajos en los portadores del alelo T que en los no portadores del alelo T. Tras la intervención con ambas dietas, el IMC, el peso, la masa grasa, la circunferencia de la cintura, la presión arterial sistólica, los niveles de insulina, el HOMA-IR, la leptina, el colesterol total y el colesterol LDL mejoraron significativamente en ambos grupos de genotipo. Después de la dieta P: HDL-colesterol (delta: 5,6 ± 1,1 mg/dl vs. 2,7 ± 0,9 mg/dl; p = 0,01), adiponectina sérica (20,1 ± 2,9 ng/dl vs. 6,8 ± 3,0 ng/dl; p = 0,02) y la relación adiponectina/leptina (0,57 ± 0,1 unidades frente a 0,20 ± 0,08 unidades; p = 0,03) mejoraron en los no portadores del alelo T. Se observaron los mismos resultados después de la dieta M: HDL-colesterol (delta: 5,5 ± 0,8 mg/dl frente a 3,1 ± 0,9 mg/dl; p = 0,03), adiponectina sérica (19,5 ± 2,9 ng/dl frente a 4,5 ± 2,8 ng /dl; p = 0,01) y relación adiponectina/leptina (0,54 ± 0,1 unidades vs. 0,15 ± 0,08 unidades; p = 0,03). Estos parámetros permanecieron sin cambios en los portadores del alelo T. Conclusión: tras las dos dietas hipocalóricas diferentes, los sujetos obesos con el alelo T de rs822393 no mejoraron los niveles de adiponectina, ratio adiponectina/leptina y colesterol HDL, a pesar de la pérdida de peso.

Topics: Adiponectin; Cholesterol, HDL; Diet, Reducing; Humans; Insulin Resistance; Leptin; Obesity

Appetite disturbance is a common problem in obesity and depression. The beneficial effects of polyphenols in promoting satiety have been shown. This study aimed to investigate the effects of sumac supplementation along with calorie restricted diet (CRD) on appetite in overweight and obese women with depression.. In this trial, 60 overweight and obese women with depression were randomly assigned to receive a CRD plus 3 g/day of either sumac or placebo for 12 weeks. The appetite score, serum levels of leptin, neuropeptide Y (NPY), insulin, fasting blood sugar (FBS), homeostasis model assessment of insulin resistance (HOMA-IR), and quantitative insulin sensitivity check index (QUICKI) were assessed at baseline and at the end of the study.. Sumac supplementation significantly reduced the appetite score (p = 0.02), serum levels of leptin (p = 0.03), NPY (p = 0.01), insulin (p = 0.03), FBS (p = 0.03), and HOMA-IR (p = 0.02) compared to the placebo group. QUICKI increased significantly in the sumac group compared to the placebo group (p = 0.009).. Sumac along with a CRD may have some beneficial effects on appetite through possible modulatory effects on leptin resistance, insulin sensitivity, and NPY levels in overweight and obese women with depression.

Topics: Appetite; Blood Glucose; Depression; Dietary Supplements; Double-Blind Method; Female; Humans; Insulin; Insulin Resistance; Leptin; Obesity; Overweight; Powders; Rhus

This study investigated the effects of 12 weeks of high-intensity functional training (HIFT) combined with spinach-derived thylakoid supplementation on some selected Adipokines and insulin resistance in males with obesity.. There were significant interactions (p<0.001 for all) between exercise and time for adiponectin (ES:0.48), leptin (ES:0.46), resistin (ES:0.3), omentin (ES:0.65), vaspin (ES:0.46), visfatin (ES:0.62), apelin (ES:0.42), RBP4 (ES:0.63), chemrin (0.36) and semaphorin3c (ES: 0.5). Plasma levels of semaphorin3c were significantly correlated (p<0.05) with body weight (r= 0.57), BMI (r= 0.43), FFM (r= -0.612), FAT (r= 0.768), VO. Our findings indicate that 12 weeks of HIFT supplemented with spinach-derived thylakoid reduced levels of leptin, resistin, vaspin, visfatin, apelin, RBP4, chemrin, semaphorin3c and insulin resistance while increasing adiponectin and omentin levels in men with obesity.

Topics: Adipokines; Adiponectin; Adult; Apelin; Dietary Supplements; Glucose; High-Intensity Interval Training; Humans; Insulin; Insulin Resistance; Leptin; Lipids; Male; Nicotinamide Phosphoribosyltransferase; Obesity; Resistin; Spinacia oleracea; Thylakoids; Young Adult

Deficiency in the adipose-derived hormone leptin or leptin receptor signaling causes class 3 obesity in individuals with genetic loss-of-function mutations in leptin or its receptor LEPR and metabolic and liver disease in individuals with hypoleptinemia secondary to lipoatrophy such as in individuals with generalized lipodystrophy. Therapies that restore leptin-LEPR signaling may resolve these metabolic sequelae. We developed a fully human monoclonal antibody (mAb), REGN4461 (mibavademab), that activates the human LEPR in the absence or presence of leptin. In obese leptin knockout mice, REGN4461 normalized body weight, food intake, blood glucose, and insulin sensitivity. In a mouse model of generalized lipodystrophy, REGN4461 alleviated hyperphagia, hyperglycemia, insulin resistance, dyslipidemia, and hepatic steatosis. In a phase 1, randomized, double-blind, placebo-controlled two-part study, REGN4461 was well tolerated with an acceptable safety profile. Treatment of individuals with overweight or obesity with REGN4461 decreased body weight over 12 weeks in those with low circulating leptin concentrations (<8 ng/ml) but had no effect on body weight in individuals with higher baseline leptin. Furthermore, compassionate-use treatment of a single patient with atypical partial lipodystrophy and a history of undetectable leptin concentrations associated with neutralizing antibodies to metreleptin was associated with noteable improvements in circulating triglycerides and hepatic steatosis. Collectively, these translational data unveil an agonist LEPR mAb that may provide clinical benefit in disorders associated with relatively low leptin concentrations.

Topics: Animals; Antibodies; Body Weight; Compassionate Use Trials; Humans; Insulin Resistance; Leptin; Lipodystrophy, Congenital Generalized; Mice; Obesity; Receptors, Leptin

Evidence is emerging that interdaily meal pattern variability potentially affects response such as thermic effect of food (TEF), macronutrient metabolism, and appetite.. To investigate the effect of irregular meal pattern on TEF, glucose, insulin, lipid profile, and appetite regulation in women who are overweight or with obesity and confirmed insulin resistance.. In a randomized crossover trial, 9 women [mean ± SD BMI (in kg/m2): 33.3 ± 3.1] with confirmed insulin resistance consumed a regular (14 d; 6 meals/d) and an irregular (14 d; 3-9 meals/d) meal pattern separated by a 14-d washout interval. Identical foods were provided during the interventions, and at the start and end of each meal pattern, participants attended the laboratory after an overnight fast. Energy expenditure, glucose, insulin, lipids, adiponectin, leptin, glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and ghrelin were measured at baseline and for 3 h after consumption of a test drink, after which an ad libitum test meal was offered. Subjective appetite ratings were recorded before and after the test drink, after the ad libitum meal, and during the intervention. Continuous interstitial glucose monitoring was undertaken for 7 consecutive days during each intervention.. TEF (over 3 h) was significantly lower postirregular intervention compared with postregular (97.7 ± 19.2 kJ*3 h in postregular visit and 76.7 ± 35.2 kJ*3 h in postirregular visit, paired t test, P = 0.048). Differences in HOMA-IR between the 2 interventions (3.3 ± 1.7 and 3.6 ± 1.6 in postregular and postirregular meal pattern, respectively) were not significant. Net incremental AUC for GLP-1 concentrations (over 3 h) for the postregular meal pattern were higher (864.9 ± 456.1 pmol/L*3 h) than the postirregular meal pattern (487.6 ± 271.7 pmol/L*3 h, paired t test, P = 0.005).. Following a 14-d period of an irregular meal pattern, TEF was significantly less than following a regular meal pattern, potentially compromising weight management if sustained long term. This study was registered at www.clinicaltrials.gov as NCT02582606.

Topics: Adiponectin; Adolescent; Adult; Appetite; Blood Glucose; Blood Glucose Self-Monitoring; Energy Metabolism; Feeding Behavior; Female; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Leptin; Lipids; Meals; Middle Aged; Obesity; Overweight; Peptide YY; Thermogenesis; Young Adult

Topics: Adiponectin; Adolescent; Adult; Aged; Blood Glucose; Body Mass Index; Breast Neoplasms; Cancer Survivors; Dietary Supplements; Female; Humans; Insulin; Insulin Resistance; Leptin; Middle Aged; Neuropeptide Y; Obesity; Young Adult

High carbohydrate, lower fat (HCLF) diets are recommended to reduce cardiometabolic disease (CMD) but low carbohydrate high fat (LCHF) diets can be just as effective. The effect of LCHF on novel insulin resistance biomarkers and the metabolome has not been fully explored. The aim of this study was to investigate the impact of an ad libitum 8-week LCHF diet compared with a HCLF diet on CMD markers, the metabolome, and insulin resistance markers. n = 16 adults were randomly assigned to either LCHF (n = 8, <50 g CHO p/day) or HCLF diet (n = 8) for 8 weeks. At weeks 0, 4 and 8, participants provided fasted blood samples, measures of body composition, blood pressure and dietary intake. Samples were analysed for markers of cardiometabolic disease and underwent non-targeted metabolomic profiling. Both a LCHF and HCLF diet significantly (p < 0.01) improved fasting insulin, HOMA IR, rQUICKI and leptin/adiponectin ratio (p < 0.05) levels. Metabolomic profiling detected 3489 metabolites with 78 metabolites being differentially regulated, for example, an upregulation in lipid metabolites following the LCHF diet may indicate an increase in lipid transport and oxidation, improving insulin sensitivity. In conclusion, both diets may reduce type 2 diabetes risk albeit, a LCHF diet may enhance insulin sensitivity by increasing lipid oxidation.

Topics: Adiponectin; Adult; Biomarkers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diet, Carbohydrate-Restricted; Dietary Carbohydrates; Dietary Fats; Glucose; Humans; Insulin; Insulin Resistance; Leptin; Lipids; Metabolome

Topics: Adult; Blood Glucose; Diet, Mediterranean; Fasting; Female; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Overweight; Pilot Projects; Weight Loss

Topics: Adolescent; Adult; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Exercise; Fibronectins; Humans; Insulin; Insulin Resistance; Leptin; Male; Obesity; Resistance Training; Young Adult

The global obesity epidemic continues to rise worldwide. In this context, unraveling new interconnections between biological systems involved in obesity etiology is highly relevant. Dysregulation of the endocannabinoidome (eCBome) is associated with metabolic complications in obesity. This study aims at deciphering new associations between circulating endogenous bioactive lipids belonging to the eCBome and metabolic parameters in a population of overweight or obese individuals with metabolic syndrome. To this aim, we combined different multivariate exploratory analysis methods: canonical correlation analysis and principal component analysis, revealed associations between eCBome subsets, and metabolic parameters such as leptin, lipopolysaccharide-binding protein, and non-esterified fatty acids (NEFA). Subsequent construction of predictive regression models according to the linear combination of selected endocannabinoids demonstrates good prediction performance for NEFA. Descriptive approaches reveal the importance of specific circulating endocannabinoids and key related congeners to explain variance in the metabolic parameters in our cohort. Analysis of quartiles confirmed that these bioactive lipids were significantly higher in individuals characterized by important levels for aforementioned metabolic variables. In conclusion, by proposing a methodology for the exploration of large-scale data, our study offers additional evidence of the existence of an interplay between eCBome related-entities and metabolic parameters known to be altered in obesity.

Topics: Acute-Phase Proteins; Adult; Carrier Proteins; Endocannabinoids; Fatty Acids; Female; Humans; Insulin Resistance; Leptin; Male; Membrane Glycoproteins; Obesity

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

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

Insulin resistance early after acute myocardial infarction is associated with increased heart failure and mortality. OMEGA-REMODEL was a prospective double-blind 1:1 randomized control trial of patients with AMI. We reported that 6-month treatment with omega-3 fatty acid (O-3FA) 4 g/day attenuated cardiac remodeling accompanied by reduction in inflammation. We hypothesized that insulin resistance modifies the therapeutic effect of O-3FA on post-MI cardiac remodeling. The OMEGA-REMODEL study group was dichotomized according to cohort- and gender-specific median cutoff value of leptin-to-adiponectin ratio (LAR) at baseline (LAR-Hi vs LAR-Lo). Mixed model regression analyses were used to evaluate effect modification of O-3FA on reduction of left ventricular end-systolic volume index (LVESVI) by LAR status. Baseline LAR was evaluated on 325 patients (59 ± 11 years, 81% male). A total of 168 patients were categorized in LAR-Lo, and 157 in LAR-Hi. O-3FA treatment resulted in significant LVESVI reduction in patients with LAR-Lo but not with LAR-Hi (p = 0.0002 vs 0.66, respectively). Mixed model regression analysis showed significant modification of LAR on O-3FA's treatment effect in attenuating LVESVI (p = 0.021). In conclusion, this post-hoc efficacy analysis suggests that LAR status significantly modified O-3FA's treatment effect in attenuating cardiac remodeling. During the convalescent phase of acute infarct healing, patients with lower insulin resistance estimated by LAR appear to derive more therapeutic response from O-3FA toward improvement of LVESVI.

Topics: Adiponectin; Aged; C-Peptide; Double-Blind Method; Fatty Acids, Omega-3; Female; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Myocardial Infarction; Prognosis; Proinsulin; Stroke Volume; Treatment Outcome; Ventricular Remodeling

Women with PCOS are linked to insulin resistance, inflammation, and vitamin D (VD) deficiency. The study endeavors to comprehend the differential impact of insulin sensitizers vs. anti-androgen on serum leptin levels among women with PCOS rendered vitamin D replete with high VD oral supplement. This was open-labeled randomized study that screened 180 eligible women presenting to Endocrine clinic with oligomenorrhea or features of hyperandrogenism. Ninety-nine women who furnished written informed consent and fulfilled the Rotterdam 2003 criteria for diagnosis of PCOS were randomized into 3 drug treatment arms to receive either spironolactone (50 mg/d; n=30), metformin (1000 mg/d; n=30) or pioglitazone (30 mg/d; n=30). These women were also administered oral VD (4000 IU/day) in addition to the allocated drug for a period of 6 months. Detailed history, clinical examination, and laboratory evaluation was carried out at baseline and 6 months after intervention. Number of menstrual cycles/year increased while as Ferriman-Gallwey score, blood glucose, HOMA-IR, and plasma insulin levels significantly decreased in all the three arms with better outcomes in spironolactone and pioglitazone arms (p<0.05). Similarly, serum leptin levels superiorly improved in spironolactone and pioglitazone group. Pioglitazone group showed better efficacy in lowering serum total testosterone (p<0.05). Co-supplementation of high dosage VD with spironolactone or pioglitazone are more effective in reducing plasma leptin levels than metformin, and thus might prove to be better therapeutic strategies for women with PCOS.

Topics: Adult; Blood Glucose; Female; Humans; Insulin; Insulin Resistance; Leptin; Metformin; Pioglitazone; Polycystic Ovary Syndrome; Spironolactone; Testosterone; Vitamin D; Young Adult

Growing evidence suggests that leptin is critical for glycemic control. Impaired leptin signaling may also contribute to low adiponectin expression in obese individuals. We assessed the association of leptin and adiponectin with incident type 2 diabetes (T2D), their interactions with sex and obesity status, and mediation by insulin resistance.. We included study participants from the Jackson Heart Study, a prospective cohort of adult African Americans in Jackson, Mississippi, that were free of T2D at the baseline Exam 1. Incident T2D was defined as new cases at Exam 2 or Exam 3. We created separate Cox regression models (hazard ratios per log-transformed ng/mL of leptin and adiponectin) with and without insulin resistance, HOMA-IR. Mediation by insulin resistance was analyzed. Several interactions were assessed, including by sex, HbA1c, and obesity.. Among our 3363 participants (mean age 53 years, 63% women), 584 developed incident T2D. Leptin was directly associated with incident T2D when modeled without HOMA-IR (HR = 1.29, 95% CI = 1.05-1.58). This direct association between leptin and T2D was significant among men (HR = 1.33, 95% CI = 1.05-1.69), but nonsignificant among women (HR = 1.24, 95% CI = 0.94-1.64); statistical interaction with sex was nonsignificant (p = 0.65). The associations in all participants and in men were nullified by HOMA-IR (HR = 0.99, 95% CI = 0.80-1.22; HR = 1.00, 95% CI = 0.78-1.28, respectively), indicating mediation through insulin resistance (proportion mediated: 1.04), and were not observed in abdominally obese participants. Adiponectin was inversely associated with T2D even after adjustment for HOMA-IR in women (HR = 0.68, 95% CI = 0.55-0.84), but not in men (HR = 0.80, 95% CI = 0.62-1.04). The inverse association was present only among abdominally obese participants, and persisted after adjustment for HOMA-IR.. Among African Americans in the Jackson Heart Study the association of leptin with incident type 2 diabetes was mediated by insulin resistance. This association was present only among abdominally non-obese participants. Differences by sex appeared: men showed a significant association mediated by insulin resistance. Among abdominally obese participants, adiponectin was inversely associated with incident T2D even after adjustment for HOMA-IR. Our results should inform future clinical trials that aim to reduce the burden of type 2 diabetes through the modification of serum levels of leptin and adiponectin.

Topics: Adiponectin; Adult; Aged; Aged, 80 and over; Biomarkers; Black or African American; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Humans; Incidence; Insulin Resistance; Leptin; Longitudinal Studies; Male; Middle Aged; Obesity; Prognosis; Prospective Studies; Risk Factors; United States; Young Adult

Our study aim was to assess how the macronutrient intake during total parenteral nutrition (TPN) modulates plasma total free fatty acids (FFAs) levels and individual fatty acids in critically ill patients.. Adult patients aged 18-80, admitted to the intensive care unit (ICU), who were indicated for TPN, with an expected duration of more than three days, were included in the study. Isoenergetic and isonitrogenous TPN solutions were given with a major non-protein energy source, which was glucose (group G) or glucose and lipid emulsions (Smof lipid; group L). Blood samples were collected on days 0, 1, 3, 6, 9, 14, and 28.. A significant decrease (. Decreased plasma FFA in critically ill patients who receive TPN may result from increased insulin sensitivity with a better effect in group G, owing to higher insulin and glucose dosing and no lipid emulsions. It is advisable to include a lipid emulsion at the latest from three weeks of TPN to prevent essential fatty acid deficiency.

Topics: Aged; alpha-Tocopherol; Critical Illness; Emulsions; Fatty Acids, Essential; Fatty Acids, Nonesterified; Female; Glucose; Humans; Insulin Resistance; Intensive Care Units; Leptin; Lipids; Male; Middle Aged; Parenteral Nutrition, Total; Prospective Studies

To compare endocrine responses to intermittent vs continuous enteral nutrition provision during short-term bed rest.. Intermittent enteral nutrition attenuates the progressive rise in plasma leptin and insulinemia seen with continuous feeding during bed rest, suggesting that continuous feeding increases insulin requirements to maintain euglycemia. This raises the possibility that hepatic insulin sensitivity is impaired to a greater extent with continuous versus intermittent feeding during bed rest. To attenuate endocrine and metabolic changes with enteral feeding, an intermittent feeding strategy may, therefore, be preferable to continuous provision of nutrition. This trial was registered on clinicaltrials.gov as NCT02521025.

Topics: Adult; Bed Rest; Blood Glucose; Enteral Nutrition; Female; Glucagon-Like Peptide 1; Glucose; Humans; Insulin; Insulin Resistance; Leptin; Male; Rest

The effect of nonnutritive sweeteners on appetite is controversial. Some studies have found changes in certain appetite control hormones with sucralose intake that may be through interaction with sweet taste receptors located in the intestine.. The aim of this study was to evaluate whether sucralose consumption could produce changes in fasting plasma concentrations of appetite-regulating hormones, including glucagon-like peptide 1, ghrelin, peptide tyrosine tyrosine, and leptin, and secondarily in insulin resistance.. A 2-week parallel randomized clinical trial with an additional visit conducted 1 week after dosing termination.. Sixty healthy, normal-weight individuals, without habitual consumption of nonnutritive sweeteners were recruited from July 2015 to March 2017 in Mexico City.. Daily sucralose consumption at 15% of the acceptable daily intake by using commercial sachets added to food. The control group followed the same protocol without an intervention.. Fasting concentrations of appetite regulating hormones before and after the intervention. Fasting glucose and insulin concentrations were measured to assess insulin resistance as a secondary outcome.. Basal and final concentrations were compared using Wilcoxon matched-pairs test and Mann-Whitney U test for analysis between groups. Repeated measures analysis of variance was used to evaluate changes in the homeostasis model assessment of insulin resistance.. Sucralose was not associated with changes in any of the hormones measured. One week postintervention, an incremental change (P=0.04) in the homeostasis model assessment of insulin resistance was found in the intervention group.. Sucralose intake is not associated with changes in fasting concentrations of glucagon-like peptide 1, ghrelin, peptide tyrosine tyrosine, or leptin. An increase in the homeostasis model assessment of insulin resistance observed only at 1 week postdosing is of unknown clinical significance, if any.

Topics: Adult; Appetite; Blood Glucose; Diet; Dipeptides; Fasting; Female; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Leptin; Male; Mexico; Sucrose

The worldwide obesity epidemic is a major health problem driven by the modern food environment. Recently, it has been shown that smell perception plays a key role in eating behavior and is altered in obesity. However, the underlying mechanisms of this phenomenon are not well understood yet. Since the olfactory system is closely linked to the endocrine system, we hypothesized that hormonal shifts in obesity might explain this relationship. In a within-subject, repeated-measures design, we investigated sensitivity to a food and a non-food odor in the hungry and sated state in 75 young healthy (26 normal weight, 25 overweight, and 24 obese) participants (37 women). To determine metabolic health status and hormonal reactivity in response to food intake, we assessed pre- and postprandial levels of insulin, leptin, glucose, and ghrelin. Odor sensitivity did not directly depend on body weight status/body mass index (BMI) or hunger state. However, we could establish a strong negative mediating effect of insulin resistance on the relationship between BMI/waist-hip ratio and olfactory sensitivity for the food odor. These findings indicate an impact of metabolic health status on sensitivity to food odors. Our results contribute to a better understanding of the mechanisms behind altered smell perception in obesity.

Topics: Adolescent; Adult; Blood Glucose; Body Weight; Eating; Feeding Behavior; Female; Food; Ghrelin; Humans; Hunger; Insulin; Insulin Resistance; Leptin; Male; Obesity; Odorants; Olfactory Perception; Overweight; Postprandial Period; Satiation; Sensory Thresholds; Young Adult

To comparatively investigate the differential effect of second-line tumour necrosis factor inhibitors (TNFis) versus other biological agents on cardiovascular disease (CVD) risk-associated biomarkers in patients with rheumatoid arthritis (RA).. We evaluated the serum levels of lipoprotein-associated apoproteins ApoA1 and ApoB100 and lipoprotein(a) (Lp(a)) and the leptin/adiponectin ratio (LAR) as an insulin resistance proxy in patients with RA from the Rotation Or Change (ROC) trial treated with either a second-line TNFi or another biologic (tocilizumab (TCZ), rituximab or abatacept) at baseline and week 24. We compared the changes in biomarker levels in each group and according to the EULAR response.. Of the 300 patients enrolled in the ROC trial, 203 were included in the study, including 96 in the second-line TNFi group and 107 in the other biological group. The measured biomarkers did not deteriorate between baseline and week 24 regardless of the group. A greater improvement in the LAR was noted in the other biological group (median (IQR) -0.12 ng/µg (-0.58 to 0.31) vs 0.04 (-0.19 to 0.43), p=0.033), and a greater improvement in the Lp(a) level was observed following treatment with TCZ than with a TNFi (-0.05 g/L (-0.11 to -0.01) vs -0.01 g/L (-0.02 to 0.01), p<0.001). When considering the patients' responses to treatment, improved biomarkers were mainly observed in the EULAR responders in each treatment group.. TNFis and non-TNFis were neutral on improved CVD risk-associated biomarkers in patients with RA insufficiently controlled by TNFis. TCZ could be associated with a better improvement concerning Lp(a) and LAR than TNFis. This improvement could be related to a good therapeutic response, thereby supporting the need of good control of RA.. ClinicalTrials.gov Identifier NCT01000441, registered on 22 October 2009.

Topics: Abatacept; Adiponectin; Aged; Antibodies, Monoclonal, Humanized; Apolipoprotein A-I; Apolipoprotein B-100; Arthritis, Rheumatoid; Biological Factors; Biomarkers; Cardiovascular Diseases; Female; Humans; Insulin Resistance; Leptin; Lipoprotein(a); Male; Middle Aged; Risk Factors; Rituximab; Tumor Necrosis Factor Inhibitors

Menopause, which occurs following a declined ovarian activity and reduced estrogen levels, can lead to long-term changes in lipid and glycemic profiles and increases the risk of cardiovascular disease and osteoporosis. Cornelian cherry (Cornus mas) is rich in phytochemicals and antioxidants, which appears to be useful in reducing the postmenopausal complications. This interventional, double-blinded, randomized clinical trial carried out on 84 menopaused women aged 45-60 years old. They were randomly divided into two groups. The treatment group received three capsules of 300 mg of Cornus mas extract (CME), and control group received three capsules of 300 mg of starch powder per day for 8 weeks. Then, BMI, waist circumference, glycemic indices, lipid profile, serum apoproteinase, apoprotein B100, fibrinogen, and leptin were measured. The dietary intakes were evaluated using 24-hr dietary recall questionnaire. The consumption of CME in comparison with the control group resulted in a significant reduction in weight, body mass index, waist circumference, LDL to HDL ratio, total cholesterol to HDL ratio, and fibrinogen. There was also a significant increase in HDL and ApoA1 levels in the treatment group. Furthermore, there was a significant decrease in BMI, waist circumference, fasting insulin, and insulin resistance index after 8 weeks of using CME. Summing up the results, it can be concluded that CME can have possible effects on decreasing BMI, waist circumference, and improving some aspects of lipid profile and glycemic indices in postmenopausal women.

Topics: Antioxidants; Blood Glucose; Body Mass Index; Body Weight; Cornus; Female; Fruit; Humans; Insulin; Insulin Resistance; Leptin; Lipid Metabolism; Lipids; Middle Aged; Plant Extracts; Postmenopause

Greater body weight has been associated impairments in neurocognition and greater dementia risk, although the mechanisms linking weight and neurocognition have yet to be adequately delineated.. To examine metabolic mechanisms underlying the association between obesity and neurocognition.. We conducted a secondary analysis of weight, neurocognition, and the potentially mediating role of metabolic and inflammatory biomarkers among 160 participants from the ENLIGHTEN trial of vascular cognitive impairment, no dementia (CIND). Neurocognition was assessed using a 45-minute assessment battery assessing Executive Function, Verbal and Visual Memory. We considered three metabolic biomarkers: insulin resistance (homeostatic model assessment [HOMA-IR]), plasma leptin, and insulin-like growth factor (IGF-1). Inflammation was assessed using C-reactive protein. Multiple regression analyses were used.. Participants included 160 sedentary older adults with CIND. Participants tended to be overweight or obese (mean BMI = 32.5 [SD = 4.8]). Women exhibited higher BMI (p = 0.043), CRP (p < 0.001), and leptin (p < 0.001) compared with men. Higher BMI levels were associated with worse performance on measures of Executive Function (β= -0.16, p = 0.024) and Verbal Memory (β= -0.16, p = 0.030), but not Visual Memory (β= 0.05, p = 0.500). Worse metabolic biomarker profiles also were associated with lower Executive Function (β= -0.12, p = 0.050). Mediation analyses suggested leptin was a plausible candidate as a mediator between BMI and Executive Function.. In overweight and obese adults with vascular CIND, the association between greater weight and poorer executive function may be mediated by higher leptin resistance.

Topics: Aged; Biomarkers; Body Mass Index; C-Reactive Protein; Cognition; Dementia, Vascular; Executive Function; Female; Humans; Inflammation; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Male; Memory; Middle Aged; Neuropsychological Tests; Obesity

We sought to determine whether prenatal supplementation with the omega-3 fatty acids eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) would increase markers of insulin sensitivity in maternal or cord blood compared with placebo supplementation. A secondary aim was to evaluate the association of serum EPA and DHA fractions with adiponectin, leptin and the adiponectin:leptin ratio (ALR). We hypothesized that omega-3 fatty acid supplementation would increase markers of insulin sensitivity in maternal and umbilical cord plasma.. We analyzed stored plasma samples collected from a prior 3-arm prospective, double-blinded, randomized controlled trial in which 126 women with singleton pregnancies between 12- and 20-weeks' gestation were randomized to receive: 1) an EPA-rich fish oil supplement, 2) a DHA-rich fish oil supplement, or 3) a soy oil placebo. Maternal venous blood samples were collected at 12-20 weeks gestation (before supplementation) and at 34-36 weeks gestation. At delivery, cord blood was collected. Samples were analyzed using sandwich enzyme-linked immunosorbent assay kits to quantify leptin and adiponectin levels which were utilized to calculate the ALR, a proxy measure for insulin sensitivity.. We found no difference in adiponectin, leptin, and the ALR between the treatment and placebo groups at baseline, after supplementation, or in umbilical cord blood. In regression analyses, higher maternal serum DHA fraction was associated with increased ALR before (p = 0.01) and after (p = 0.04) DHA supplementation. There was no association of EPA fraction with any measure of insulin sensitivity. Cord blood DHA fraction was significantly associated with cord plasma leptin (p = 0.02). Early pregnancy BMI was significantly associated with maternal leptin levels at baseline and in late pregnancy (p < 0.001) and was inversely associated with the ALR (p < 0.001). The ALR decreased significantly between the early and late pregnancy visits (p < 0.001). Pregnancy weight gain was inversely associated with the ALR (P. < 0.02).. EPA- and DHA- rich fish oil supplementation had no effect on plasma markers of insulin sensitivity. However, maternal serum DHA fraction was significantly associated with markers of insulin sensitivity.. https://clinicaltrials.gov/, registration number NCT00711971, 7/7/2008.

Topics: Adiponectin; Adult; Dietary Supplements; Docosahexaenoic Acids; Double-Blind Method; Eicosapentaenoic Acid; Female; Fetal Blood; Humans; Insulin Resistance; Leptin; Pregnancy; Prenatal Care; Prospective Studies; Young Adult

The present study examined the effect of a 12-week combined resistance and aerobic exercise training program on cardiometabolic biomarkers and red blood cell (RBC) hemorheological function in 20 obese older men (mean age: 68.8 ± 0.9 years). Subjects were randomly divided into two groups (exercise intervention [EXP;

Topics: Aged; Biomarkers; Blood Glucose; Body Composition; Cardiovascular Diseases; Erythrocytes; Exercise; Exercise Therapy; Hemorheology; Humans; Insulin; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Obesity

Alpha-lipoic acid (ALA) is a short chain fatty acid and is known as a universal antioxidant. The aim of the current clinical trial study was to explore the effects of ALA supplementation on maternal circulating values of adiponectin (A), leptin (L); and A/L, L/A, adiponectin/homeostatic model assessment for insulin resistance (A/H), and malondialdehyde/total antioxidant capacity (MDA/TAC) ratios in pregnant women with gestational diabetes mellitus (GDM). Sixty women diagnosed as GDM during 24 and 28 weeks of pregnancy were randomly divided into drug (n = 30) and placebo (n = 30) groups. They consumed ALA (100 mg) and cellulose acetate (100 mg) respectively for 8 weeks, per day. The biochemical variables were evaluated before and after the trial. Maternal fasting serum values of glucose (p < .001), HOMA-IR (p < .001), MDA/TAC (p < .001), and L/A (p = .008) were decreased while values of adiponectin (p = .011), A/L (p = .001), and A/H (p < .001) were increased in the drug group after the intervention. In summary, current study had shown that after daily supplementation with 100 mg of ALA for 8 weeks in women with GDM, maternal circulating values of adiponectin, A/L, and A/H were increased while values of L/A and MDA/TAC were decreased.

Topics: Adiponectin; Adult; Antioxidants; Blood Glucose; Diabetes, Gestational; Dietary Supplements; Double-Blind Method; Female; Humans; Insulin Resistance; Leptin; Malondialdehyde; Oxidative Stress; Pregnancy; Thioctic Acid; Treatment Outcome

To evaluate the effects of metreleptin in patients with partial lipodystrophy (PL).. Patients aged ≥ 6 months with PL, circulating leptin < 12.0 ng/mL, and diabetes mellitus, insulin resistance, or hypertriglyceridemia received metreleptin doses (once or twice daily) titrated to a mean of 0.124 mg/kg/day. Changes from baseline to month 12 in glycated hemoglobin (HbA1c) and fasting serum triglycerides (TGs; co-primary endpoints), fasting plasma glucose (FPG), and liver volume were evaluated. Additional assessments included the proportions of patients achieving target decreases in HbA1c or fasting TGs at month 12, long-term treatment effects, and treatment-emergent adverse events (TEAEs).. Significant (p < 0.05) reductions in HbA1c (-0.6%), fasting TGs (-20.8%), FPG (-1.2 mmol/L), and liver volume (-13.4%) were observed in the overall PL population at month 12. In a subgroup of patients with baseline HbA1c ≥ 6.5% or TGs ≥ 5.65 mmol/L, significant (p < 0.05) reductions were seen in HbA1c (-0.9%), fasting TGs (-37.4%), FPG (-1.9 mmol/L), and liver volume (-12.4%). In this subgroup, 67.9% of patients had a ≥ 1% decrease in HbA1c or ≥ 30% decrease in fasting TGs, and 42.9% had a ≥ 2% decrease in HbA1c or ≥ 40% decrease in fasting TGs. Long-term treatment in this subgroup led to significant (p < 0.05) reductions at months 12, 24, and 36 in HbA1c, fasting TGs, and FPG. Metreleptin was well tolerated with no unexpected safety signals. The most common TEAEs were abdominal pain, hypoglycemia, and nausea.. In patients with PL, treatment with metreleptin was well tolerated and resulted in improvements in glycemic control, hypertriglyceridemia, and liver volume.

Topics: Adolescent; Adult; Blood Glucose; Child; Female; Glycated Hemoglobin; Humans; Hypertriglyceridemia; Insulin Resistance; Leptin; Lipodystrophy, Familial Partial; Male; Middle Aged; Prospective Studies; Treatment Outcome; Young Adult

Some adiponectin gene (ADIPOQ) single-nucleotide polymorphisms (SNPs) have been related to basal and adiponectin levels and metabolic parameters. The aim of this study was to evaluate the effect of the genetic variant rs1501299 ADIPOQ gene on biochemical changes after weight loss secondary to a high-protein and low-carbohydrate diet versus a standard severe hypocaloric diet over 9 mo as the primary endpoint.. A white population of 270 obese patients was enrolled in a randomized clinical trial with two hypocaloric diets (high-protein and low carbohydrate diet [HP] versus standard diet [S]) over 9 mo of intervention. The statistical analysis was performed for the combined GT and TT as a group (T-allele carriers) and GG as second group (non-T-allele carriers). Before and after 12 wk on each hypocaloric diet, an anthropometric evaluation, an assessment of nutritional intake, and a biochemical analysis were realized.. With both dietary interventions, body weight, body mass index (BMI), fat mass, waist circumference, systolic blood pressure, and leptin levels decreased. In non-T-allele carriers after both diets, the decrease in total cholesterol levels -12.3 ± 2.2 mg/dL (T-allele carriers -6.9 ± 2.1 mg/dL; P = 0.01 diet HP) and 12.2 ± 3.1 mg/dL (T-allele carriers -4.7 ± 1.2 mg/dL; P = 0.02 after diet S), low-density lipoprotein cholesterol -13.2 ± 2.7 mg/dL (T-allele carriers -6.1 ± 2.1 mg/dL; P = 0.02 after diet HP) and -9.3 ± 1.8 mg/dL (T-allele carriers -4.8 ± 2.9 mg/dL; P = 0.01 after diet S), triacylglycerol levels -12.7 ± 6.1 mg/dL (T-allele carriers -6 ± 2.9 mg/dL; P = 0.01 after diet HP) and -16.3 ± 7.2 mg/dL (T-allele carriers -5.3 ± 1.4 mg/dL; P = 0.03 after diet S), insulin levels -5 ± 1.1 mUI/L (in T-allele -1.7 ± 0.9 mUI/L; P = 0.02 after diet HP) and -3.2 1.1 mUI/L (T-allele carriers -0.7 ± 0.7 mUI/L; P = 0.02 after diet S), and homeostatic model assessment of insulin resistance levels -0.4 ± 0.2 units (T-allele group -0.1 ± 0.1; P = 0.04 after diet HP) and -0.7 ± 0.1 units (T-allele carriers -0.1 ± 0.5 mg/dL; P = 0.01 after diet S) was higher than T-allele carriers. Only no T-allele carriers showed an increase in adiponectin levels after both diets.. After two different hypocaloric diets during 9 mo of intervention, the GG genotype of an ADIPOQ gene variant (rs1501299) is related to better improvement in adiponectin levels, insulin resistance, and lipid profile than T-allele carriers.

Topics: Adiponectin; Adult; Alleles; Anthropometry; Body Mass Index; Body Weight; Diet, Carbohydrate-Restricted; Diet, High-Protein; Diet, Reducing; Female; Genetic Loci; Genotype; Humans; Insulin Resistance; Leptin; Lipids; Male; Middle Aged; Obesity; Polymorphism, Single Nucleotide; Treatment Outcome; Waist Circumference

Though most of the observational studies have shown that metformin can reduce serum thyroid stimulating hormone (TSH) level in patients of hypothyroidism with diabetes or polycystic ovarian disease, randomised controlled trials are sparse. The primary objective of this study was to evaluate the effect of metformin on thyroid function tests (TSH, free T4, and free T3) in patients with subclinical hypothyroidism (SCH).. In this open label, parallel arm, randomised controlled trial, 60 patients of SCH (TSH 5.5-10 mIU/L) were randomised to either metformin group (1500 mg/day) or control group.. A total of 46 patients (23 in each group) completed the study and no significant difference in serum TSH, free T4 or free T3 was found in between the 2 groups. Neither there was any significant change in serum TSH, free T4 or free T3 (pre and post 6 months) within the individual groups. However, the rate of normalisation of serum TSH in patients with negative thyroid antibody was significantly higher than patients with positive thyroid antibody (71.4% vs. 18.8%; P = 0.026) in metformin group in post hoc analysis. Fasting plasma glucose, serum high-density lipoprotein and indices of insulin sensitivity significantly improved in metformin group. Four patients (17%) had mild gastrointestinal adverse effects in the metformin group.. We did not find any significant change in thyroid function test in patients with SCH with metformin therapy.

Topics: Adiponectin; Adult; Blood Glucose; Cholesterol; Female; Humans; Hypothyroidism; Insulin Resistance; Leptin; Male; Metformin; Middle Aged; Prolactin; Thyroid Function Tests; Thyrotropin; Thyroxine; Triiodothyronine

The prevalence of obesity and its related metabolic syndrome (MetS) has shown an upsurge in recent years due to modified lifestyle patterns. The present study was designed to investigate the impact of a nutritionally balanced conventional meal replacement diet with modified macromolecular composition (rich in soy/pea protein and soluble fibers) and caloric restriction on Taiwanese obese subjects. Obese subjects (BMI > 27; n = 50, male 23, female 27) were recruited and requested to replace two meals per day (breakfast and lunch or dinner) with the balanced nutritional meal replacement diet (equal to 240 kcal) for 8 weeks with one regular meal and make sure that the daily target calorie limit (caloric restriction) was less than 1500 kcal day-1 for men and 1200 kcal day-1 for women. After eight weeks of intervention with a calorie-restricted balanced partial meal replacement diet, the levels of body weight, body fat, and waist circumference were significantly reduced by 4.1 kg, 2.38%, and 5.06 cm, respectively. The levels of serum total cholesterol (TC), triglycerides (TG) and low-density lipoprotein cholesterol (LDL-c) were significantly decreased (p < 0.05) with a significant increase (p < 0.05) in high-density lipoprotein cholesterol (HDL-c) levels after 8 weeks of intervention with the meal replacement diet. Moreover, the levels of insulin, homeostatic model assessment-insulin resistance (HOMA-IR), leptin, thiobarbituric acid reactive substances (TBARS) and cardiovascular risk factors were significantly attenuated (p < 0.05). To conclude, the present intervention with meal replacement and caloric restriction on obese subjects could concomitantly decrease the body weight and glycemic and cardiovascular risk factors and thereby lower the risk of various metabolic disorders.

Topics: Adult; Aged; Aged, 80 and over; Body Mass Index; Caloric Restriction; Cholesterol; Cholesterol, LDL; Diet, Reducing; Energy Intake; Female; Humans; Insulin; Insulin Resistance; Leptin; Male; Meals; Middle Aged; Obesity; Young Adult

Studies have reported contradictory findings regarding the effect of a mixture of 2 conjugated linoleic acid (CLA) isomers on body weight and some serum indices. This study aims to investigate the effect of daily supplementation of these 2 isomers on body composition and serum leptin and insulin levels in obese adults.. This randomized, double-blind clinical trial was performed on 54 adults with class I obesity. The subjects were randomly assigned into 2 groups of 27 and were followed for 3 months so that a total of 3000 mg of CLA supplement and placebo were administered in 3 daily doses in the intervention and control groups, respectively. Body composition indices as well as fasting serum levels of insulin and leptin were also measured. The paired t-test was used for evaluating within-group effects from baseline. The independent t-test was used to compare between-group differences for variables with normal distribution.. Although body weight and body mass index (BMI) were not significantly decreased during intervention in groups, but the body fat mass (BFM) (P=0.034), body fat percentage (P=0.022) and trunk fat (P=0.027) decreased significantly during intervention with CLA. The fasting plasma sugar (P=0.042) and Homeostatic model assessment for insulin resistance (HOMA/IR) (P=0.044) in the intervention group declined during 12 weeks of intervention. Serum leptin was associated with a significant decrease during the intervention period (P=0.039).. CLA supplementation could reduce body fat and serum leptin. Hence, it could be taken into account as a factor for weight loss but not to control or prevent diabetes.

Topics: Adipose Tissue; Adult; Body Composition; Dietary Supplements; Double-Blind Method; Female; Humans; Insulin; Insulin Resistance; Leptin; Linoleic Acids, Conjugated; Male; Obesity; Weight Loss

To investigate the effects of a low- versus high-intensity aerobic training on biomarkers of inflammation and endothelial dysfunction in adolescents with obesity.. Sixty-two adolescents with obesity [age = 15 (14) y, body mass index = 34.87 (4.22) kg·m. HIT reduced neutrophils [from 4.4 (1.9) to 3.6 (1.3) µL. Both HIT and LIT improved the inflammatory profile. The study, however, indicated that the number of biomarkers and the magnitude of changes were higher in the HIT compared with LIT.

Topics: Adolescent; Biomarkers; Body Mass Index; Cardiorespiratory Fitness; Exercise Therapy; Female; High-Intensity Interval Training; Humans; Inflammation; Insulin Resistance; Intercellular Adhesion Molecule-1; Interleukin-6; Leptin; Male; Monocytes; Neutrophils; Oxygen Consumption; Pediatric Obesity; Peroxidase; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

Bariatric surgery (BS) promotes carotid intima-media thickness (C-IMT) regression as early as 6 months post-surgery. To verify whether C-IMT regression occurs even earlier, we aimed at the effect of Roux-en-Y gastric bypass (RYGBP) and biliopancreatic diversion (BPD) on C-IMT 1-2 months and 12 months post-surgery.. Prospective trial. BS was performed on 109 patients either with (RYGBP = 42; BDP = 40) or without type 2 diabetes (RYGBP = 27). Healthy volunteers served as control group.. baseline, 1-2 months, 12 months post-surgery.. changes (∆) in C-IMT, weight, body mass index, fat mass, waist and neck circumferences, blood pressure, HbA1c, glucose, insulin, insulin sensitivity [HOMA-IR; OGIS, from meal tolerance test], lipids, C-reactive protein, leptin, adiponectin, MCP-1.. All surgery subgroups had similar levels of ∆-C-IMT. C-IMT in the pooled surgery group reduced from [mean (95% confidence interval)] 0.81 (0.77-0.84) mm to 0.66 (0.63-0.69) mm, p < 0.001 [-17.1 (-20.4 to -13.8)%] at 1-2 months, and to 0.63 (0.59-0.66) mm, p < 0.001 [-21.8 (-25.3 to -18.4)%] at 12 months post-surgery. ∆-C-IMT 1-2 months and 12 months post-surgery correlated to baseline C-IMT, and with ∆-leptin at 1-2 months, but not at 12 months post-surgery. In linear regression analysis, ∆-leptin and baseline C-IMT were predictors of ∆-C-IMT 1-2 months post-surgery.. A remarkable C-IMT regression occurred as early as 1-2 months after BS in obese patients either with or without type 2 diabetes, which was associated to the early reduction in leptin, (at least partially) independent of weight loss. Whether this is a causative or correlative association needs further investigation.

Topics: Adult; Bariatric Surgery; Body Mass Index; Carotid Arteries; Carotid Intima-Media Thickness; Diabetes Mellitus, Type 2; Female; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Obesity, Morbid; Time Factors; Tunica Intima; Weight Loss; Young Adult

The aim of this study was to investigate the plasma adipokine responses to high-intensity interval training (HIT) in overweight/obese women. Twelve women (age 21.7 ± 3.8 years) completed a 19 days of HIT comprising six session of 4-6 repeats of a Wingate test (0.065 kg load/kg). Plasma adipokine levels were measured before exercise, and at 5 and 90 min after exercise on the first and the last training days. Adiponectin was higher at 5 min than 90 min post-exercise (11.7 ± 7.3 and 10.5 ± 5.8 ng/ml; p = .01) in the first exercise day. Leptin decreased 5 min after exercise (23.6 ± 13.2 vs. baseline 27.8 ± 14.4 ng/ml; p < .01) and remained depressed following 90 min (p < .01). The changes in adiponectin and leptin concentrations were similar on the first and last exercise days. No consistent effect was found on resistin concentration. Future studies are required to disclose the functional consequences of these alterations in plasma adipokine levels.

Topics: Adiponectin; Adiposity; Adult; Body Mass Index; Electric Impedance; Female; High-Intensity Interval Training; Humans; Insulin Resistance; Kinetics; Leptin; Obesity; Overweight; Oxygen Consumption; Reproducibility of Results; Resistin; Turkey; Young Adult

Hypogonadism frequently occurs in male patients with type 2 diabetes (T2DM) and is linked to insulin resistance and inflammation. Testosterone levels rise acutely in obese patients following bariatric surgery, though long-term changes have not been investigated in a randomized controlled trial. This study evaluated obese men with T2DM randomized to either bariatric surgery or medical therapy. Testosterone, gonadotropins, body composition, insulin sensitivity, and inflammatory markers were evaluated in 32 patients at baseline and at 5 years. Surgical patients had 47.4% increase in free testosterone compared to medical therapy patients who had 2.2% decrease (P = 0.013). Increase in free testosterone correlated with reduction in body weight, high-sensitivity C-reactive protein (hsCRP), and leptin levels. Prolonged improvements in testosterone levels after bariatric surgery in T2DM are found to be related to reduction in body weight and adipogenic inflammation.

Topics: Adult; Bariatric Surgery; Blood Glucose; Body Composition; C-Reactive Protein; Diabetes Mellitus, Type 2; Follow-Up Studies; Humans; Hypogonadism; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Testosterone

The nature of the link (causal vs non-causal) between low 1,25-OH vitamin D and insulin resistance (IR) in patients with chronic kidney disease (CKD) remains elusive. We have now made a post hoc analysis of the effect of vitamin D receptor activation by paricalcitol on IR in the complete dataset of a double-blind, randomized, placebo controlled trial, the Paricalcitol and ENdothelial fuNction in chronic kidneY disease (PENNY).. Eighty-eight patients with stage 3-4 CKD were randomized (1:1) to receive 2 μg/day paricalcitol or matching placebo for 12 weeks. IR was measured by five IR indices: the homeostasis model assessment of insulin resistance (HOMA-IR), the quantitative insulin sensitivity check index (QUICKI), the McAuley index, the HOMA corrected for adiponectin (HOMA-AD) and the Leptin-adiponectin ratio (LAR). As compared to placebo, paricalcitol produced the expected small rise in serum calcium (+0.07 mmol/L, P = 0.01) and phosphate (+0.08 mmol/L, P = 0.034) and the expected parathyroid hormone suppression (-96 pg/ml, P < 0.001). However, the drug largely failed to affect the five indices of IR which remained unchanged both in the active and the placebo arm (paricalcitol vs placebo, P ranging from 0.25 to 0.62) and no effect modification of paricalcitol on IR by vitamin D or other parameters was registered.. Paricalcitol treatment for 12 weeks does not improve IR in patients with stage 3-4 CKD. Low vitamin D receptor activation is not a causal factor for IR in the CKD population.

Topics: Adiponectin; Aged; Biomarkers; Blood Glucose; Double-Blind Method; Ergocalciferols; Female; Humans; Insulin; Insulin Resistance; Italy; Leptin; Male; Middle Aged; Receptors, Calcitriol; Renal Insufficiency, Chronic; Time Factors; Treatment Outcome

The purpose of this study was to investigate the pleiotropic effects of 12 weeks of supervised exercise training at maximal fat oxidation (FATmax) intensity on body composition, lipid profile, glycemic control, insulin sensitivity and serum adipokine levels in older women with type 2 diabetes. Thirty-one women with type 2 diabetes, aged 60 to 69 years, were randomly allocated into exercise and control groups. Body composition, lipid profile, blood glucose, insulin resistance and serum leptin and adiponectin concentrations were measured before and after the intervention. Exercise group (n=16) walked at individualized FATmax intensities for 1 h/day for 3 days/week over 12 weeks. No dietary intervention was introduced during the experimental period. Maximal fat oxidation rate was 0.37±0.10 g/min, and occurred at 37.3±7.3% of the estimated VO

Topics: Adiponectin; Adipose Tissue; Aged; Blood Glucose; Body Composition; Diabetes Mellitus, Type 2; Diet; Female; Humans; Insulin Resistance; Leptin; Middle Aged; Oxidation-Reduction; Oxygen Consumption; Patient Compliance; Physical Conditioning, Human

Recombinant leptin (metreleptin) ameliorates hyperphagia and metabolic abnormalities in leptin-deficient humans with lipodystrophy. We aimed to determine whether metreleptin improves glucose and lipid metabolism in humans when food intake is held constant.. Patients with lipodystrophy were hospitalized for 19 days, with food intake held constant by a controlled diet in an inpatient metabolic ward. In a nonrandomized, crossover design, patients previously treated with metreleptin (n = 8) were continued on metreleptin for 5 days and then taken off metreleptin for the next 14 days (withdrawal cohort). This order was reversed in metreleptin-naive patients (n = 14), who were reevaluated after 6 months of metreleptin treatment on an ad libitum diet (initiation cohort). Outcome measurements included insulin sensitivity by hyperinsulinemic-euglycemic clamp, fasting glucose and triglyceride levels, lipolysis measured using isotopic tracers, and liver fat by magnetic resonance spectroscopy.. With food intake constant, peripheral insulin sensitivity decreased by 41% after stopping metreleptin for 14 days (withdrawal cohort) and increased by 32% after treatment with metreleptin for 14 days (initiation cohort). In the initiation cohort only, metreleptin decreased fasting glucose by 11% and triglycerides by 41% and increased hepatic insulin sensitivity. Liver fat decreased from 21.8% to 18.7%. In the initiation cohort, changes in lipolysis were not independent of food intake, but after 6 months of metreleptin treatment on an ad libitum diet, lipolysis decreased by 30% (palmitate turnover) to 35% (glycerol turnover).. Using lipodystrophy as a human model of leptin deficiency and replacement, we show that metreleptin improves insulin sensitivity and decreases hepatic and circulating triglycerides and that these improvements are independent of its effects on food intake.. ClinicalTrials.gov NCT01778556FUNDING. This research was supported by the intramural research program of the NIDDK.

Topics: Adolescent; Adult; Aged; Cross-Over Studies; Eating; Female; Humans; Insulin Resistance; Leptin; Lipodystrophy; Liver; Male; Middle Aged; Triglycerides

Exercise training is recommended for improving health and protecting against the development of metabolic and cardiovascular pathologies. Combined resistance and aerobic exercise training (CRAE) has been shown to provide unique benefits in older adults with cardiovascular diseases.. We sought to determine the beneficial effects of CRAE in adolescent girls who are obese and hyperinsulinemic.. Forty adolescent girls who are obese (age 14.7 ± 1 years; BMI 30 ± 2) were randomly assigned to a "no exercise" (CON n = 20) or combined exercise group (EX n = 20). The EX group performed resistance and aerobic exercise for 12 weeks, 5 times per week. Exercise intensity was increased gradually, from 40 to 70% of heart rate reserve (HRR), every 4 weeks. The brachial-ankle pulse wave velocity (BaPWV), blood pressure (BP), heart rate (HR), blood leptin, adiponectin levels, and body composition were measured before and after the 12-week intervention.. We observed that CRAE effectively reduced the body fat percentage, body weight, and waist circumference in the EX group (p < 0.05). After 12 weeks of training, subjects in the CRAE group maintained appropriate leptin and adiponectin levels and showed positive improvements of blood insulin, glucose, and insulin resistance parameters relative to baseline and to the CON group (p < 0.05).. CRAE is a useful therapeutic method to alleviate metabolic risk factors in adolescent girls who are obese and hyperinsulinemic.

Topics: Adiponectin; Adiposity; Adolescent; Blood Glucose; Blood Pressure; Female; Heart Rate; Humans; Insulin; Insulin Resistance; Leptin; Obesity; Resistance Training

The aim of this study was to conduct a randomized clinical trial to assess the effects of 16 weeks of combined training on body composition, lipid profile, adiponectin, C-reactive protein (CRP), and leptin levels in people living with HIV/AIDS (PLWHA).. Fifty-eight HIV-infected individuals were randomized into a training group (T) or a control group (C). Combined training consisted of aerobic and resistance exercises performed at the same training session, applied at a frequency of three times a week for a total of 16 weeks. Waist circumference, body mass, body fat percentage (%fat), fat mass, lipid profile, adiponectin, CRP, and leptin levels were measured pre- and post-training in both groups.. Sixteen weeks of combined training decreased (P < 0.05) body fat in different body segments in PLWHA. Lipodystrophic PLWHA experienced greater reduction in body fat in the android region than non-lipodystrophic PLWHA after combined training. Lipid profile and circulating levels of adiponectin, leptin, and CRP remained unchanged.. Sixteen weeks of combined training was effective to reduce body fat in different body segments, without altering plasma lipid and cytokine levels.

Topics: Adiponectin; Adipose Tissue; Body Composition; Body Mass Index; C-Reactive Protein; Exercise; Exercise Therapy; HIV; HIV Infections; Humans; Insulin Resistance; Leptin; Lipodystrophy; Resistance Training; Waist Circumference

Chemerin has been suggested as a potential link between obesity and associated comorbidities in humans. Therefore, we studied the relationships between chemerin, parameters of fat mass, and Metabolic Syndrome (MetS) in obese children before and after weight reduction.. We determined chemerin, bioactive leptin (bioLep), BMI-SDS, waist circumference (WC), body fat based on skinfold measurements and bioimpedance analyses, lipids, transaminases, insulin resistance index HOMA, and blood pressure in 88 obese children participating in a lifestyle intervention at baseline and 1 year later. Furthermore, we determined chemerin concentrations in 23 normal-weight children.. Obese children demonstrated significantly (p < 0.001) higher chemerin concentrations compared to normal-weight children (96.2 ± 23.0 versus 63.1 ± 12.4 ng/ml). The chemerin concentrations were not related to age or gender. Prepubertal children had higher (p = 0.024) chemerin concentrations than pubertal children (71.0 ± 13.4 versus 58.0 ± 8.9 ng/ml). Weight loss was associated with a decrease of chemerin (-14.0 ± 22.0 ng/ml; p < 0.001) and an improvement of all parameters of the MetS. Chemerin was significantly related to BMI-SDS, WC, and bioLep in cross-sectional and longitudinal analyses. Chemerin and its changes were significantly related to insulin, HDL-cholesterol, triglycerides and their changes in multiple linear regression analyses adjusted to age, gender, pubertal stage, leptin and BMI.. Since chemerin was related to parameters of central fat mass and MetS both in cross-sectional and longitudinal analyses these findings suggest an impact of chemerin on factors of the MetS in obese children.

Topics: Biomarkers; Blood Glucose; Body Mass Index; Chemokines; Child; Cross-Sectional Studies; Female; Humans; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Longitudinal Studies; Male; Metabolic Syndrome; Pediatric Obesity; Treatment Outcome; Triglycerides; Waist Circumference; Weight Loss; Weight Reduction Programs

Chemically-interesterified (CIE) fats are

Topics: Adiposity; Adult; Apolipoprotein A-I; Apolipoprotein B-100; Blood Glucose; Body Mass Index; Cholesterol; Diet; Dietary Fats; Double-Blind Method; Fatty Acids; Female; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Overweight; Palm Oil; Patient Compliance; Snacks; Stearic Acids; Triglycerides; Weight Gain; Young Adult

Appetite and gastrointestinal hormones (GIHs) participate in energy homeostasis, feeding behavior and regulation of body weight. We demonstrated previously the superior effect of a hypocaloric diet regimen with lower meal frequency (B2) on body weight, hepatic fat content, insulin sensitivity and feelings of hunger compared to the same diet divided into six smaller meals a day (A6). Studies with isoenergetic diet regimens indicate that lower meal frequency should also have an effect on fasting and postprandial responses of GIHs. The aim of this secondary analysis was to explore the effect of two hypocaloric diet regimens on fasting levels of appetite and GIHs and on their postprandial responses after a standard meal. It was hypothesized that lower meal frequency in a reduced-energy regimen leading to greater body weight reduction and reduced hunger would be associated with decreased plasma concentrations of GIHs: gastric inhibitory peptide (GIP), glucagon-like peptide-1(GLP-1), peptide YY(PYY), pancreatic polypeptide (PP) and leptin and increased plasma concentration of ghrelin. The postprandial response of satiety hormones (GLP-1, PYY and PP) and postprandial suppression of ghrelin will be improved.. In a randomized crossover study, 54 patients suffering from type 2 diabetes (T2D) underwent both regimens. The concentrations of GLP-1, GIP, PP, PYY, amylin, leptin and ghrelin were determined using multiplex immunoanalyses.. Fasting leptin and GIP decreased in response to both regimens with no difference between the treatments (p = 0.37 and p = 0.83, respectively). Fasting ghrelin decreased in A6 and increased in B2 (with difference between regimens p = 0.023). Fasting PP increased in B2with no significant difference between regimens (p = 0.17). Neither GLP-1 nor PYY did change in either regimen. The decrease in body weight correlated negatively with changes in fasting ghrelin (r = -0.4, p<0.043) and the postprandial reduction of ghrelin correlated positively with its fasting level (r = 0.9, p<0.001). The postprandial responses of GIHs and appetite hormones were similar after both diet regimens.. Both hypocaloric diet regimens reduced fasting leptin and GIP and postprandial response of GIP comparably. The postprandial responses of GIHs and appetite hormones were similar after both diet regimens. Eating only breakfast and lunch increased fasting plasma ghrelin more than the same caloric restriction split into six meals. The changes in fasting ghrelin correlated negatively with the decrease in body weight. These results suggest that for type 2 diabetic patients on a hypocaloric diet, eating larger breakfast and lunch may be more efficient than six smaller meals during the day.

Topics: Adult; Aged; Body Weight; Caloric Restriction; Cross-Over Studies; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Humans; Hunger; Insulin Resistance; Leptin; Male; Meals; Middle Aged; Pancreatic Polypeptide; Peptide YY; Time Factors; Treatment Outcome

Emerging evidence suggests that helminths might confer protection against the development of type 2 diabetes. We aimed to assess the role of adipokines in mediating the effect of helminths on insulin resistance. Serum samples were obtained from a randomized-controlled trial of anthelmintic treatment in an area endemic for soil-transmitted helminths (STH), Flores Island, Indonesia. In STH-infected subjects, anthelmintic treatment significantly increased the ratio of leptin to adiponectin (treatment effect factor (95% confidence interval (CI)), P-value for interaction: 1.20 (1.06-1.35), P=0.010), which largely stemmed from a significant reduction in adiponectin (0.91 (0.85-0.98), P=0.020) and a trend for an increase in leptin level (1.10 (1.00-1.21), P=0.119). No significant effect on resistin level was observed. This increase in leptin to adiponectin ratio seemed to contribute to the observed effect of deworming on increased insulin resistance (IR) as adjustment for leptin to adiponectin ratio attenuated the effect on IR from 1.07 (1.01-1.14, P=0.023) to 1.05 (0.99-1.11, P=0.075). Anthelmintic treatment in STH-infected subjects increases leptin to adiponectin ratio which may in small part contribute to the modest increase in IR. Further studies will be needed to assess the effect of the changes in adipokine levels on the host immune response and metabolism.

Topics: Adiponectin; Adult; Albendazole; Anthelmintics; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Helminthiasis; Humans; Indonesia; Insulin Resistance; Leptin; Male; Middle Aged; Placebos

Dietary calorie restriction and exercise promote weight loss and may have additive effects for improving insulin sensitivity, independent of weight loss. It is not known if these effects are attributable to changes in circulating cytokines. We evaluated the hypothesis that modest, matched weight loss induced by calorie restriction and exercise have additive effects on circulating cytokines and these changes correlate with improvements in insulin sensitivity. Overweight and sedentary women and men (n = 52, 45-65 years) were randomized to undergo 7 % weight loss by using 3-6 months of calorie restriction, exercise, or a combination of both calorie restriction and exercise. Concentrations of cytokines and hormones were measured in fasting and oral glucose tolerance test blood samples. Insulin sensitivity was estimated based on oral glucose tolerance test for glucose and insulin. With all groups combined, fasting leptin (p < 0.0001) and high molecular weight adiponectin (p = 0.04) decreased and pentraxin-3 increased (p < 0.0001), in a manner that correlated with improvements in insulin sensitivity (all p ≤ 0.0002). These changes, combined with decreases in glucose-dependent insulinotropic polypeptide from the oral glucose tolerance test, explained 63 % of the variance (p < 0.0001) in insulin sensitivity improvements. Exercise and calorie restriction had additive effects on leptin, with a similar trend for high molecular weight adiponectin. Monocyte chemoattractant protein-1 and C-reactive protein concentrations did not change. Calorie restriction and exercise had opposite effects on soluble tumor necrosis factor receptor-1. Modest weight loss in overweight adults decreases serum leptin and high molecular weight adiponectin, and increases pentraxin-3 concentrations in a manner that correlates with increased insulin sensitivity. Exercise has additive effects to those induced by calorie restriction for reductions in leptin and possibly adiponectin. These changes may contribute to the additive effects of calorie restriction and exercise for improving insulin sensitivity.

Topics: Adiponectin; Aged; Biomarkers; Body Mass Index; C-Reactive Protein; Caloric Restriction; Combined Modality Therapy; Cytokines; Diabetes Mellitus, Type 2; Exercise; Female; Follow-Up Studies; Gastric Inhibitory Polypeptide; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Missouri; Overweight; Peptide Fragments; Risk; Serum Amyloid P-Component; Weight Loss

Sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) cause weight loss and metabolic improvement, but results of published studies are contradictory.. The aim of this study was to compare the effects of SG and RYGB on ghrelin, leptin, and glucose homeostasis in a randomized controlled trial.. University hospital, Poland.. Seventy-two morbidly obese patients were randomly selected to undergo either SG (n = 36) or RYGB (n = 36). Fasting ghrelin, leptin, glucose, insulin, C-peptide, glucagon, glycated hemoglobin, and homeostasis model assessment of insulin resistance were assessed preoperatively and at 1, 6, and 12 months postoperatively. No differences were found in anthropometric and biochemical parameters between the study groups at baseline.. Sixty-nine (95.8%) patients completed the study. Percentage of excess weight loss at 12 months was 67.6±19.3% after SG and 64.2±18.5% after RYGB (P>.05). Fasting ghrelin levels decreased 1 month after SG (from 76.8 pmol/L to 35.3 pmol/L; P<.05) and remained reduced until 12 months (41.6 pmol/L; P<.05) but increased 12 months after RYGB from 74.6 pmol/L to 130.2 pmol/L (P<.05). Leptin, glucose, insulin, and C-peptide concentrations and glycated hemoglobin and homeostasis model assessment of insulin resistance values decreased significantly in both groups during 12 months.. RYGB and SG induce comparable weight loss and improvement in metabolism of glucose. Ghrelin levels decrease after SG and increase after RYGB, but this difference does not affect similar outcomes of these procedures during 1-year follow-up. The contribution of ghrelin to weight loss or metabolic benefits after bariatric surgery is not straightforward, but rather influenced by multiple factors.

Topics: Adolescent; Adult; Blood Glucose; C-Peptide; Female; Gastrectomy; Gastric Bypass; Ghrelin; Glucagon; Glycated Hemoglobin; Homeostasis; Humans; Insulin Resistance; Laparoscopy; Leptin; Male; Middle Aged; Obesity, Morbid; Operative Time; Prospective Studies; Weight Loss; Young Adult

Low-grade inflammation is associated with obesity and the metabolic syndrome (MetS). Preclinical evidence suggests that resveratrol (RSV) has beneficial metabolic and anti-inflammatory effects that could have therapeutic implications.. To investigate effects of long-term RSV treatment on inflammation and MetS.. A randomized, placebo-controlled, double-blind, parallel group clinical trial conducted at Aarhus University Hospital.. Middle-aged community-dwelling men (N = 74) with MetS, 66 of whom completed all visits (mean ± standard error of the mean): age, 49.5 ± 0.796 years; body mass index, 33.8 ± 0.44 kg/m2; waist circumference, 115 ± 1.14 cm.. Daily oral supplementation with 1000 mg RSV (RSVhigh), 150 mg RSV, or placebo for 16 weeks.. Plasma levels of high-sensitivity C-reactive protein (hs-CRP), circulating lipids, and inflammatory markers in circulation and adipose/muscle tissue biopsy specimens; glucose metabolism; and body composition including visceral fat and ectopic fat deposition.. RSV treatment did not lower circulating levels of hs-CRP, interleukin 6, or soluble urokinase plasminogen activator receptor in plasma, and inflammatory gene expression in adipose and muscle tissues also remained unchanged. RSV treatment had no effect on blood pressure, body composition, and lipid deposition in the liver or striated muscle. RSV treatment had no beneficial effect on glucose or lipid metabolism. RSVhigh treatment significantly increased total cholesterol (P < 0.002), low-density lipoprotein (LDL) cholesterol (P < 0.006), and fructosamine (P < 0.013) levels compared with placebo.. RSV treatment did not improve inflammatory status, glucose homeostasis, blood pressure, or hepatic lipid content in middle-aged men with MetS. On the contrary, RSVhigh significantly increased total cholesterol, LDL cholesterol, and fructosamine levels compared with placebo.

Topics: Absorptiometry, Photon; Adipose Tissue; Antioxidants; Blood Glucose; Blood Pressure; Blotting, Western; Body Composition; C-Reactive Protein; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Double-Blind Method; Fructosamine; Humans; Insulin; Insulin Resistance; Interleukin-6; Intra-Abdominal Fat; Leptin; Liver; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Metabolic Syndrome; Middle Aged; Muscle, Skeletal; Quadriceps Muscle; Real-Time Polymerase Chain Reaction; Receptors, Urokinase Plasminogen Activator; Resveratrol; Stilbenes; Triglycerides

High-amylose maize resistant starch type 2 (HAM-RS2) stimulates gut-derived satiety peptides and reduces adiposity in animals. Human studies have not supported these findings despite improvements in glucose homeostasis and insulin sensitivity after HAM-RS2 intake which can lower adiposity-related disease risk. The primary objective of this study was to evaluate the impact of HAM-RS2 consumption on blood glucose homeostasis in overweight, healthy adults. We also examined changes in biomarkers of satiety (glucagon-like peptide-1 [GLP-1], peptide YY [PYY], and leptin) and body composition determined by anthropometrics and dual-energy x-ray absorptiometry, dietary intake, and subjective satiety measured by a visual analogue scale following HAM-RS2 consumption.. Using a randomized-controlled, parallel-arm, double-blind design, 18 overweight, healthy adults consumed either muffins enriched with 30 g HAM-RS2 (n = 11) or 0 g HAM-RS2 (control; n = 7) daily for 6 weeks. The HAM-RS2 and control muffins were similar in total calories and available carbohydrate.. At baseline, total PYY concentrations were significantly higher 120 min following the consumption of study muffins in the HAM-RS2 group than control group (P = 0.043). Within the HAM-RS2 group, the area under the curve (AUC) glucose (P = 0.028), AUC leptin (P = 0.022), and postprandial 120-min leptin (P = 0.028) decreased independent of changes in body composition or overall energy intake at the end of 6 weeks. Fasting total PYY increased (P = 0.033) in the HAM-RS2 group, but changes in insulin or total GLP-1 were not observed. Mean overall change in subjective satiety score did not correlate with mean AUC biomarker changes suggesting the satiety peptides did not elicit a satiation response or change in overall total caloric intake. The metabolic response from HAM-RS2 occurred despite the habitual intake of a moderate-to-high-fat diet (mean range 34.5% to 39.4% of total calories).. Consuming 30 g HAM-RS2 daily for 6 weeks can improve glucose homeostasis, lower leptin concentrations, and increase fasting PYY in healthy overweight adults without impacting body composition and may aid in the prevention of chronic disease. However, between-group differences in biomarkers were not observed and future research is warranted before specific recommendations can be made.. None.

Topics: Absorptiometry, Photon; Adiposity; Adolescent; Adult; Biomarkers; Blood Glucose; Diet, High-Fat; Double-Blind Method; Female; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Overweight; Peptide YY; Postprandial Period; Satiation; Starch; Young Adult; Zea mays

The present randomized, double-blind, placebo-controlled study aimed to evaluate the effect of Zingiber officinale (ginger) consumption on some metabolic and clinical features of obesity.. Eighty eligible obese women (aged 18-45 years) were randomly assigned to either ginger or placebo groups (receiving 2 g/day of ginger powder or corn starch as two 1 g tablets) for 12 weeks. Body mass index (BMI) and body composition were assessed every 4 weeks, and serum levels of leptin, adiponectin, resistin, insulin and glucose were determined before and after intervention. The homeostasis model assessment of insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI) were also calculated.. Ginger consumption significantly decreased BMI, serum insulin and HOMA-IR index, along with increasing QUICKIs as compared to the placebo. Moreover, significant reductions in serum leptin, resistin and glucose were observed in both groups, especially in ginger group with nonsignificant differences between groups. The body composition and serum levels of adiponectin were not significantly changed in study groups.. In conclusion, our findings demonstrate a minor beneficial effect of 2 g ginger powder supplementation for 12 weeks on weight loss and some metabolic features of obesity. However, given the lack of data in this area, ongoing clinical trials are needed to further explore ginger's effectiveness.

Topics: Adipokines; Adiponectin; Adolescent; Adult; Blood Glucose; Body Composition; Body Mass Index; Body Weight; Diet; Double-Blind Method; Female; Humans; Insulin; Insulin Resistance; Leptin; Middle Aged; Obesity; Resistin; Young Adult; Zingiber officinale

Physical activity after prostate cancer diagnosis has been shown to reduce the risk of disease progression. Here, we aimed to evaluate the effect of a 2-year home-based endurance training intervention on body composition, biomarkers levels, and prostate-specific antigen (PSA) doubling time as a surrogate end-point for progressing disease.. Out-clinic patients with either biochemical recurrence following radical prostatectomy or patients managed on active surveillance were randomized to either 24 months (3 times/week) of home-based endurance training or usual care. Aerobic fitness, body composition, insulin sensitivity, and biomarkers were measured at 0, 6, and 24 months of intervention. PSA doubling time (PSADT) was calculated based on monthly PSA measurements.. Twenty-five patients were enrolled, and 19 patients completed the study. PSADT increased in the training group from 28 to 76 months (p < 0.05) during the first 6 months and was correlated with changes in VO2max (p < 0.01, r (2) = 0.41). The training group lost 3.6 ± 1.0 kg (p < 0.05) exclusively as fat mass, yet the changes in body composition were not associated with the increased PSADT. The training group showed significant improvements in plasma triglycerides, adiponectin, IGF-1, IGFBP-1, and fasting glucose levels, but no changes in insulin sensitivity (measured as Matsuda index), testosterone, cholesterols, fasting insulin, plasma TNF-alpha, IL-6, or leptin levels. The control group showed no changes in any of the evaluated parameters across the 2-year intervention.. In this small randomized controlled trial, we found that improvements in fitness levels correlated with increasing PSADT, suggesting a link between training and disease progression.

Topics: Adiponectin; Aged; Body Composition; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Disease Progression; Exercise Test; Exercise Therapy; Glucose Tolerance Test; Humans; Insulin Resistance; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor I; Interleukin-6; Leptin; Male; Middle Aged; Motor Activity; Neoplasm Recurrence, Local; Oxygen Consumption; Physical Endurance; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Risk; Treatment Outcome; Triglycerides; Tumor Necrosis Factor-alpha

One-third of men with type 2 diabetes have hypogonadotropic hypogonadism (HH). We conducted a randomized placebo-controlled trial to evaluate the effect of testosterone replacement on insulin resistance in men with type 2 diabetes and HH.. A total of 94 men with type 2 diabetes were recruited into the study; 50 men were eugonadal, while 44 men had HH. Insulin sensitivity was calculated from the glucose infusion rate (GIR) during hyperinsulinemic-euglycemic clamp. Lean body mass and fat mass were measured by DEXA and MRI. Subcutaneous fat samples were taken to assess insulin signaling genes. Men with HH were randomized to receive intramuscular testosterone (250 mg) or placebo (1 mL saline) every 2 weeks for 24 weeks.. Men with HH had higher subcutaneous and visceral fat mass than eugonadal men. GIR was 36% lower in men with HH. GIR increased by 32% after 24 weeks of testosterone therapy but did not change after placebo (P = 0.03 for comparison). There was a decrease in subcutaneous fat mass (-3.3 kg) and increase in lean mass (3.4 kg) after testosterone treatment (P < 0.01) compared with placebo. Visceral and hepatic fat did not change. The expression of insulin signaling genes (IR-β, IRS-1, AKT-2, and GLUT4) in adipose tissue was significantly lower in men with HH and was upregulated after testosterone treatment. Testosterone treatment also caused a significant fall in circulating concentrations of free fatty acids, C-reactive protein, interleukin-1β, tumor necrosis factor-α, and leptin (P < 0.05 for all).. Testosterone treatment in men with type 2 diabetes and HH increases insulin sensitivity, increases lean mass, and decreases subcutaneous fat.

Topics: Adult; Body Composition; C-Reactive Protein; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Hormone Replacement Therapy; Humans; Hypogonadism; Inflammation; Insulin; Insulin Resistance; Interleukin-1beta; Intra-Abdominal Fat; Leptin; Male; Middle Aged; Subcutaneous Fat; Testosterone; Tumor Necrosis Factor-alpha

The aim of this study was to compare the effects of 12 weeks of high-intensity interval training (HIIT) with the effects of 12 weeks of plyometric exercise combined with HIIT (P+HIIT) on anthropometric, biochemical, and physical fitness data in young obese females. Sixty-eight participants (age, 16.6 ± 1.3 y; body mass, 82.8 ± 5.0 kg; body fat, 39.4% ± 3.3%; body mass index z score, 2.9 ± 0.4) were assigned to 1 of 3 groups: HIIT (2 blocks per session of 6-8 bouts of 30-s runs at 100% velocity at peak oxygen uptake, with 30-s active recovery between bouts at 50%velocity at peak oxygen uptake (n = 23)); P+HIIT (2 blocks per session of 3 different 15-s plyometric exercises with 15-s passive recoveries, totaling 2 min for each plyometric exercise + the same HIIT program (n = 26)); or control (no exercise (n = 19)). Anthropometric (body mass, body mass index z score, body fat, lean body mass, and waist circumference), biochemical (plasma glucose, insulin, leptin and adiponectin concentrations, leptin/adiponectin ratio, and homeostasis model assessment of insulin resistance (HOMA-IR)), physical fitness (peak oxygen uptake, velocity at peak oxygen uptake, squat jump, and countermovement jump performances), and energy intake data were collected. Both training programs improved the anthropometric, biochemical, and physical fitness variables. However, the P+HIIT program induced greater improvements than did the HIIT program in lean body mass (+3.0% ± 1.7%), plasma glucose and leptin concentrations (-11.0% ± 4.7% and -23.8% ± 5.8%, respectively), plasma leptin/adiponectin ratio (-40.9% ± 10.9%), HOMA-IR (-37.3% ± 6.2%), and squat jump performance (22.2% ± 7.5%). Taken together, these findings suggest that adding plyometric exercises to a HIIT program may be more beneficial than HIIT alone in obese female adolescents.

Topics: Adiponectin; Adipose Tissue; Adolescent; Blood Glucose; Body Mass Index; Energy Intake; Female; Homeostasis; Humans; Insulin; Insulin Resistance; Leptin; Obesity; Oxygen Consumption; Physical Fitness; Plyometric Exercise; Waist Circumference

The objective of the present study was to investigate the effects of combined training without caloric restriction on inflammatory markers in overweight girls. Thirty-three girls (13-17 years) were assigned into overweight training (n = 17) or overweight control (n = 16) groups. Additionally, a normal-weight group (n = 15) was used as control for the baseline values. The combined training programme consisted of six resistance exercises (three sets of 6-10 repetitions at 60-70% 1 RM) followed by 30 min of aerobic exercise (walking/running) at 50-80% VO2peak, performed in the same 60 min session, 3 days/weeks, for 12 weeks. Body composition, dietary intake, aerobic fitness (VO2peak), muscular strength (1 RM), glycaemia, insulinemia, lipid profile and inflammatory markers (C-reactive protein, interleukin-6, tumour necrosis factor-alpha, interleukin-10, leptin, resistin and adiponectin) were measured before and after intervention. There was a significant decrease in body fat (P < 0.01) and increase in fat-free mass (P < 0.01), VO2peak (P < 0.01), 1 RM for leg press (P < 0.01) and bench press (P < 0.01) in the overweight training group. Concomitantly, this group presented significant decreases in serum concentrations of C-reactive protein (P < 0.05) and leptin (P < 0.05), as well as in insulin resistance (P < 0.05) after the experimental period. In conclusion, 12 weeks of combined training without caloric restriction reduced inflammatory markers associated with obesity in overweight girls.

Topics: Adipokines; Adipose Tissue; Adolescent; Biomarkers; Body Composition; Body Fluid Compartments; C-Reactive Protein; Caloric Restriction; Cytokines; Exercise; Female; Humans; Inflammation; Inflammation Mediators; Insulin Resistance; Leptin; Muscle Strength; Obesity; Overweight; Oxygen Consumption; Resistance Training

Obesity induces insulin resistance (IR), the key etiologic defect of type 2 diabetes mellitus (T2DM). Therefore, an incidence of obesity-induced diabetes is expected to decrease if obesity is controlled. Although Metformin is currently one of the main treatment options for T2DM in obese patients, resulting in an average of 5% weight loss, adequate weight control in all patients cannot be achieved with Metformin alone. Thus, additional therapies with a weight loss effect, such as acupuncture, may improve the effectiveness of Metformin.Subjective:We designed this randomized clinical trial (RCT) to compare the effects of Metformin monotherapy with that of Metformin and acupuncture combined therapy on weight loss and insulin sensitivity among overweight/obese T2DM patients, to understand whether acupuncture plus Metformin is a better approach than Metformin only on treating diabetes. To understand whether acupuncture can be an insulin sensitizer and, if so, its therapeutic mechanism.. Our results show that Metformin and acupuncture combined therapy significantly improves body weight, body mass index (BMI), fasting blood sugar (FBS), fasting insulin (FINS), homeostasis model assessment (HOMA) index, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), leptin, adiponectin, glucagon-like peptide-1 (GLP-1), resistin, serotonin, free fatty acids (FFAs), triglyceride (TG), low-density lipoprotein cholesterol (LDLc), high-density lipoprotein cholesterol (HDLc) and ceramides.. Consequently, Metformin and acupuncture combined therapy is more effective than Metformin only, proving that acupuncture is an insulin sensitizer and is able to improve insulin sensitivity possibly by reducing body weight and inflammation, while improving lipid metabolism and adipokines. As a result, electro-acupuncture (EA) might be useful in controlling the ongoing epidemics in obesity and T2DM.

Topics: Acupuncture Therapy; Adiponectin; Adult; Biomarkers; Body Mass Index; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Interleukin-6; Leptin; Male; Metformin; Obesity; Resistin; Serotonin; Triglycerides; Tumor Necrosis Factor-alpha; Weight Loss

Previous experimental studies have suggested curcumin as a safe phytochemical that can improve insulin resistance through effects on adiponectin and leptin. This study aimed to investigate the effect of curcumin on circulating adiponectin and leptin concentrations in patients with metabolic syndrome.. In this pilot, randomized, double-blind, placebo-controlled trial, subjects who met the criteria of metabolic syndrome according to the National Cholesterol Education Program Adult Treatment Panel III criteria were randomly assigned to curcumin (n = 59; 1000 mg/d) or a placebo (n = 58) for 8 wk. Serum adiponectin and leptin concentrations were determined before and after intervention. The pooled effect size for the impact of curcumin supplementation on serum adiponectin and leptin levels was also estimated using random-effects metaanalysis.. Eight-week supplementation with curcumin was associated with a significant increase in serum adiponectin levels (P < 0.001) and a reduction in serum leptin concentrations (P < 0.001). Serum leptin:adiponectin ratio was also improved by curcumin (P < 0.001). These beneficial effects of curcumin remained significant after adjustment for changes in serum lipids and glucose concentrations and baseline differences in body mass index and serum levels of glucose and glycated hemoglobin as potential confounders of treatment response. Metaanalysis suggested that curcumin supplementation can increase adiponectin levels by 76.78% (95% CI: 6.14-147.42; P = 0.0330), and reduce leptin by 26.49% (95% CI: -70.44 to 17.46), however this latter effect size did not reach statistical significance (P = 0.238).. Curcumin can improve serum levels of adiponectin and leptin in patients with metabolic syndrome. This trial was registered at the UMIN Clinical Trials Registry (http://www.umin.ac.jp/ctr/) under Trial No. UMIN000018339.

Topics: Adipokines; Adiponectin; Adult; Blood Glucose; Curcumin; Dietary Supplements; Double-Blind Method; Female; Humans; Insulin Resistance; Leptin; Lipids; Male; Metabolic Syndrome; Middle Aged; Pilot Projects

Non-alcoholic steatohepatitis (NASH) is a chronic liver disease that is capable of progressing to end-stage liver disease, but generally has a benign course. Non-alcoholic steatohepatitis (NASH) is a growing public health problem with no approved therapy. NASH projected to be the leading cause of liver transplantation in the United States by 2020. Obesity, non-insulin-dependent diabetes mellitus and hyperlipidaemia are the most common associations of the disease. Global prevalence of NASH is 10-24% amongst general population but increases to 25-75% in obese diabetic individuals.. There is an urgent need for efficient therapeutic options as there is still no approved medication. The aim of this study was to detect changes in biochemical parameters including insulin resistance, cytokines, blood lipid profile and liver enzymes following weight loss in patients with non-alcoholic steatohepatitis.. One hundred obese patients with NASH, their age between 35-50 years, body mass index (BMI) from 30 to 35 Kg/m(2) were included in the study in two subgroups; the first group (A) received moderate aerobic exercise training in addition to diet regimen , where the second group (B) received no treatment intervention.. The mean values of leptin, TNF-α, IL6, IL8, Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Homeostasis Model Assessment-Insulin Resistance- index (HOMA-IR), Total Cholesterol (TC), Low Density Lipoprotein Cholesterol (LDL-c) , Triglycerides (TG) and BMI were significantly decreased in group (A), where the mean value of Adiponectin and High Density Lipoprotein Cholesterol (HDL-c) were significantly increased, while there were no significant changes in group (B). Also, there was a significant difference between both groups at the end of the study.. Weight loss modulates insulin resistance, adiponectin, leptin, inflammatory cytokine levels and markers of hepatic function in patients with nonalcoholic steatohepatitis.

Topics: Alanine Transaminase; Aspartate Aminotransferases; Biomarkers; Body Mass Index; Diabetes Complications; Diet; Exercise; Female; Humans; Inflammation Mediators; Insulin Resistance; Interleukins; Leptin; Lipids; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Obesity; Single-Blind Method; Tumor Necrosis Factor-alpha; Weight Loss; Weight Reduction Programs

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

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

Insulin resistance (IR), a risk factor for cardiovascular disease and all-cause mortality, is prevalent among maintenance hemodialysis patients. Effects of omega-3 fatty acids on IR in hemodialysis patients have not been well understood. This study aimed to determine the effects of omega-3 fatty acids on IR and serum lipids of hemodialysis patients.. Fifty-four adult patients on hemodialysis were randomly assigned to receive either 1800 mg of omega-3 fatty acids or placebo daily for 4 months. Serum concentrations of glucose, triglyceride, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, C-reactive protein, insulin, leptin, and adiponectin were measured at baseline and after 4 months of the intervention. Insulin resistance was assessed using the homeostasis model assessment of insulin resistance and 2 adipokine-based measures of IR, including the leptin-adiponectin ratio and homeostasis model assessment corrected by adiponectin.. Mean differences of serum C-reactive protein, insulin, leptin, and adiponectin concentrations did not show significant difference between the two groups following 4 months of intervention. Fasting serum glucose and low-density lipoprotein cholesterol were not significantly influenced by omega-3 supplementation, either. Serum triglyceride, total cholesterol, and high-density lipoprotein cholesterol levels significantly decreased in the omega-3 group (P = .02, P = .03, and P < .001, respectively). None of the indirect indexes of IR showed significant changes at the end of the study in either the omega-3 or placebo group.. Supplemental use of omega-3 fatty acids showed some beneficial effects on lipid profile of hemodialysis patients without any improvement in IR.

Topics: Adiponectin; Adult; Aged; Blood Glucose; Blood Urea Nitrogen; C-Reactive Protein; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Dietary Supplements; Docosahexaenoic Acids; Eicosapentaenoic Acid; Female; Humans; Insulin; Insulin Resistance; Kidney Failure, Chronic; Leptin; Male; Middle Aged; Renal Dialysis; Single-Blind Method; Treatment Outcome; Triglycerides

Weight loss intervention is the principal non-pharmacological method for prevention and treatment of type 2 diabetes. However, little is known whether it influences insulin sensitivity directly or via its anti-inflammatory effect. The aim of this study was to assess the independent role of changes in inflammation status and weight loss on insulin sensitivity in this population.Overweight and obese nondiabetic participants without co-morbidities underwent a one-year weight loss intervention focused on caloric restriction and behavioral support. Markers of inflammation, body composition, anthropometric para-meters, and insulin sensitivity were recorded at baseline, 6, and 12 months. Insulin sensitivity was assessed with frequently sampled intravenous glucose tolerance test and Minimal Model. Twenty-eight participants (F: 15, M: 13, age 39±5 years, BMI 33.2±4.6 kg/m(2)) completed the study, achieving 9.4±6.9% weight loss, which was predominantly fat mass (7.7±5.6 kg, p<0.0001). Dietary intervention resulted in significant decrease in leptin, leptin-to-adiponectin ratio, hs-CRP, and IL-6 (all p<0.02), and improvement in HOMA-IR and Insulin Sensitivity Index (SI) (both p<0.001). In response to weight loss IL-1β, IL-2, leptin, and resistin were significantly associated with insulin, sensitivity, whereas sICAM-1 had only marginal additive effect. Moderate weight loss in otherwise healthy overweight and obese individuals resulted in an improvement in insulin sensitivity and in the overall inflammation state; the latter played only a minimal independent role in modulating insulin sensitivity.

Topics: Adult; Blood Glucose; Body Composition; Body Mass Index; C-Reactive Protein; Caloric Restriction; Diet; Female; Humans; Inflammation; Insulin Resistance; Interleukin-6; Leptin; Lipids; Male; Middle Aged; National Institutes of Health (U.S.); Obesity; Overweight; Prospective Studies; United States; Weight Loss

This study assessed the effect of a 12-week sports-based exercise intervention on glucose regulation, anthropometry and inflammatory markers associated with the prevalence of type 2 diabetes mellitus (T2DM) in Indigenous Australian men.. Twenty-six inactive Indigenous Australian men (48.6±6.6 years) were randomized into exercise (n=16) or control (n=10)conditions.. Training included ∼2-3 days/week for 12 weeks of sports and gym exercises in a group environment, whilst control participants maintained normal activity and dietary patterns. Pre- and post-intervention testing included: anthropometry, peak aerobic capacity, fasting blood chemistry of inflammatory cytokines, adiponectin, leptin, cholesterol, glucose, insulin and C-peptide. An oral glucose tolerance test measured glucose, insulin and C-peptide 30, 60, 90 and 120min post 75g glucose ingestion.. The exercise condition decreased insulin area under the curve (25±22%), increased estimated insulin sensitivity (35±62%) and decreased insulin resistance (9±35%; p<0.05), compared with control (p>0.05). The exercise condition decreased in body mass index, waist circumference and waist to hip ratio (p<0.05), compared to control (p>0.05). Leptin decreased in the exercise group, with no changes for adiponectin (p>0.05) or inflammatory markers (p>0.05) in either condition. Aerobic fitness variables showed significant increases in peak oxygen consumption for the exercise condition compared to no change in control (p>0.05).. Findings indicate positive clinical outcomes in metabolic, anthropometric and aerobic fitness variables. This study provides evidence for sport and group-based activities leading to improved clinical risk factors associated with T2DM development in clinically obese Indigenous Australian men.

Topics: Adiponectin; Adult; Australia; Body Mass Index; Cytokines; Diabetes Mellitus, Type 2; Exercise; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Native Hawaiian or Other Pacific Islander; Oxygen Consumption; Physical Conditioning, Human; Risk Factors; Sports; Waist Circumference; Waist-Hip Ratio; Young Adult

Osteocalcin has been proposed to be a novel link between bone and energy metabolism. Previous studies showed its relations to exercise, body fat and glucose metabolism, but their interrelationship remains inconslusive. We evaluated the changes in osteocalcin level following 8-week exercise programme and assessed how they are related to concomitant changes in body fat composition, insulin resistance and various adipocytokines in a single centre, randomized and prospective design.. A total of 39 young obese, otherwise healthy males were randomly assigned to control (n = 10) and exercise (n = 29) groups. Subjects in Exercise group were on 8-week supervised exercise training programme of four sessions per week. Body fat compositions were analysed using whole body bone mineral density, various metabolic parameters, osteocalcin and adipocytokines were assessed from fasting blood samples before and after 8-week exercise programme.. Body fat reduction following exercise significantly increased serum total (1·51 ± 0·36 vs 1·69 ± 0·39 mmol/l, P = 0·01, baseline vs postexercise) and undercarboxylated osteocalcin level (0·44 ± 0·14 vs 0·64 ± 0·26 mmol/l, P < 0·01), and the increase in osteocalcin was in negative correlations with changes in body weight, BMI and body fat percentage as well as HOMA-IR and leptin (all P < 0·05). The changes in osteocalcin and leptin were not independent predictors of changes in insulin resistance and osteocalcin, respectively.. In a physiological axis of bone-fat-energy metabolism, exercise-induced body fat reduction and improved insulin sensitivity were accompanied by an increase in serum osteocalcin and leptin levels, but other factors also seem to be involved in this interrelationship.

Topics: Adipokines; Adiposity; Adult; Body Mass Index; Cross-Sectional Studies; Energy Metabolism; Exercise; Humans; Insulin Resistance; Leptin; Male; Obesity; Osteocalcin; Prospective Studies; Young Adult

Gut hormones change with weight loss in adults but are not well studied in obese youth.. The primary aim was to evaluate how gut hormones and subjective appetite measure change with dietary weight loss in obese adolescents.. Participants were a subset of those taking part in the 'Eat Smart Study'. They were aged 10-17 years with body mass index (BMI) > 90th centile and were randomized to one of three groups: wait-listed control, structured reduced carbohydrate or structured low-fat dietary intervention for 12 weeks. Outcomes were fasting glucose, insulin, leptin, adiponectin, total amylin, acylated ghrelin, active glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide (GIP), pancreatic polypeptide (PP) and total peptide tyrosine-tyrosine. Pre- and postprandial subjective sensations of appetite were assessed using visual analogue scales.. Of 87 'Eat Smart' participants, 74 participated in this sub-study. The mean (standard deviation) BMI z-score was 2.1 (0.4) in the intervention groups at week 12 compared with 2.2 (0.4) in the control group. Fasting insulin (P = 0.05) and leptin (P = 0.03) levels decreased, while adiponectin levels increased (P = 0.05) in the intervention groups compared with control. The intervention groups were not significantly different from each other. A decrease in BMI z-score at week 12 was associated with decreased fasting insulin (P < 0.001), homeostatic model of assessment-insulin resistance (P < 0.001), leptin (P < 0.001), total amylin (P = 0.03), GIP (P = 0.01), PP (P = 0.02) and increased adiponectin (P < 0.001). There was no significant difference in appetite sensations.. Modest weight loss in obese adolescents leads to changes in some adipokines and gut hormones that may favour weight regain.

Topics: Adiponectin; Adolescent; Adult; Appetite; Body Mass Index; Body Weight; Fasting; Female; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Leptin; Male; Pediatric Obesity; Peptide YY; Postprandial Period; Weight Loss

To investigate the feasibility and safety of a 24-week exercise intervention, compared to control, in males with Barrett's oesophagus, and to estimate the effect of the intervention, compared to control, on risk factors associated with oesophageal adenocarcinoma development.. A randomized controlled trial of an exercise intervention (60 minutes moderate-intensity aerobic and resistance exercise five days/week over 24 weeks; one supervised and four unsupervised sessions) versus attention control (45 minutes stretching five days/week over 24 weeks; one supervised and four unsupervised sessions) in inactive, overweight/obese (25.0-34.9 kg/m2) males with Barrett's oesophagus, aged 18-70 years. Primary outcomes were obesity-associated hormones relevant to oesophageal adenocarcinoma risk (circulating concentrations of leptin, adiponectin, interleukin-6, tumour necrosis factor-alpha, C-reactive protein, and insulin resistance [HOMA]). Secondary outcomes included waist circumference, body composition, fitness, strength and gastro-oesophageal reflux symptoms. Outcomes were measured at baseline and 24-weeks. Intervention effects were analysed using generalised linear models, adjusting for baseline value.. Recruitment was difficult in this population with a total of 33 participants recruited (target sample size: n = 80); 97% retention at 24-weeks. Adherence to the exercise protocol was moderate. No serious adverse events were reported. A statistically significant intervention effect (exercise minus control) was observed for waist circumference (-4.5 [95% CI -7.5, -1.4] cm; p < 0.01). Effects on primary outcomes were not statistically significant.. This small, exploratory trial provides important information to inform future trial development including recruitment rates and estimates of effect sizes on outcomes related to oesophageal adenocarcinoma risk. Future trials should investigate a combined dietary and exercise intervention to achieve greater weight loss in this population and relax inclusion criteria to maximize recruitment.. Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12609000401257.

Topics: Adenocarcinoma; Adiponectin; Barrett Esophagus; C-Reactive Protein; Case-Control Studies; Esophageal Neoplasms; Exercise; Humans; Insulin Resistance; Interleukin-6; Leptin; Male; Middle Aged; Obesity; Overweight; Risk Factors; Tumor Necrosis Factor-alpha

The aim of this study was to investigate whether indicators of metabolic health fluctuate during the week in a group of children posing unhealthier physical activity, sedentary time, and sleep during weekends compared to weekdays.. A total of 807 eight- to eleven-year-old children had valid metabolic health markers from one, two, or three measurements contributing 2190 to 2240 observations of metabolic health markers. The weekly variation was tested using linear mixed models.. Homeostatic model assessment of insulin resistance (HOMAIR), triglycerides, leptin (all P < 0.001), and adiponectin (P = 0.03) decreased from Monday to Friday, whereas ghrelin increased (P < 0.001). HOMAIR , triglycerides, and leptin were 35%, 28%, and 33% higher on Mondays compared to Fridays, respectively, and ghrelin was 7% lower on Mondays compared to Fridays (all P < 0.001).. The large weekly variation in HOMAIR , triglycerides, and leptin was likely the result of unhealthier behaviors during weekends. These findings have public health relevance and raise methodological issues that should ideally be taken into account in future studies.

Topics: Adiponectin; Biomarkers; Child; Ghrelin; Health Behavior; Health Status; Homeostasis; Humans; Insulin Resistance; Leptin; Linear Models; Peptide Hormones; Sedentary Behavior; Sleep; Time Factors; Triglycerides

To evaluate the effect of Zhenggan Tang decoction on serum levels of leptin, adiponectin and insulin resistance on liver cirrhosis induced by chronic hepatitis B.. Sixty-six patients were recruited and randomly assigned either to a control group or to an intervention group, with 35 cases in the treatment and 31 in the control group respectively. Patients in the control group received inosine tablets and vitamin C treatment while patients in the treatment group were given Zhenggan Tang decoction additionally. After 3 months of treatment, the serum levels of leptin and adiponectin were detected and the index of insulin resistance calculated.. There were no significant difference between the serum levels of leptin, adiponectin and the index of insulin resistance seen in the control group before and after the treatment. Serum levels of leptin and adiponectin and the index of insulin resistance in treatment group were reduced significantly after the treatment (P < 0.05). There were significant difference in the serum levels of leptin and adiponectin between treat group and control group (P < 0.05).. Zhenggan Tang decoction seemed to have reduced the serum levels of leptin, adiponectin and the index of insulin resistance among cirrhotic patients that induced by chronic hepatitis B.

Topics: Adiponectin; Drugs, Chinese Herbal; Hepatitis B, Chronic; Humans; Insulin Resistance; Leptin; Liver Cirrhosis; Treatment Outcome

This study aimed to analyze the influence of H. pylori infection on insulin resistance and metabolic syndrome (MS) by multivariate analysis of a community-based cohort study. From January 2013 to February 2014,811 subjects were enrolled in a community-based cohort study from the northeastern region of Taiwan. All subjects received a demographic survey and blood tests, including an H. pylori antibody test, liver biochemistry tests, lipid profiles, sugar/insulin levels for Homeostatic model assessment (HOMA-IR index), and measurements of adipokines and inflammatory cytokines. A total of 264 men and 547 women were included in this study. The mean age was 59.2 ± 12.7 years. Subjects seropositive for H. pylori antibodies exhibited higher rates of hypertension, an increased incidence of a HOMA-IR index > 2.5 and a higher level of tumor necrosis factor-α than those without H. pylori antibodies. We found a significant difference in the presence of H. pylori antibodies between subjects with MS and those without MS (76.7% vs. 53.7%, p = 0.007) among subjects < 50 y/o. A HOMA-IR index >2.5, H. pylori antibody presence and leptin were predictors for MS in subjects < 50 y/o. The estimated odds ratio of MS for a subject with H. pylori antibodies was 3.717 (95% CI = 1.086-12.719) times that of a subject without H. pylori antibodies. In addition, no difference in H. pylori antibody status was detected for MS prediction in subjects that were ≧ 50 y/o (p = 0.861). In conclusion, subjects with H. pylori antibodies had a higher incidence of a HOMA-IR >2.5 than those without H pylori antibodies. For subjects aged < 50 y/o, the H. pylori antibody was a predictor for MS.

Topics: Age Factors; Aged; Antibodies, Bacterial; Case-Control Studies; Female; Helicobacter Infections; Helicobacter pylori; Humans; Hypertension; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Middle Aged; Taiwan

Being overweight or obese is associated with a greater risk of coronary heart disease and stroke compared with normal weight. The role of the specific adipose tissue-derived substances, called adipocytokines, in overweight- and obesity-related cardiovascular disease (CVD) is still unclear.. To investigate the associations of three adipose tissue-derived substances: adiponectin, leptin, and interleukin-6 with incident CVD in a longitudinal population-based study, including extensive adjustments for traditional and metabolic risk factors closely associated with overweight and obesity. C-reactive protein (CRP) was used as a proxy for interleukin-6.. Prospective population-based study of 6.502 participants, 51.9% women, aged 30-60 years, free of CVD at baseline, with a mean follow-up time of 11.4 years, equivalent to 74,123 person-years of follow-up. As outcome, we defined a composite outcome comprising of the first event of fatal and nonfatal coronary heart disease and fatal and nonfatal stroke.. During the follow-up period, 453 composite CV outcomes occurred among participants with complete datasets. In models, including gender, age, smoking status, systolic blood pressure, treatment for hypertension, diabetes, body mass index (BMI), total cholesterol, high-density-lipoprotein cholesterol, homeostasis model assessment of insulin resistance, estimated glomerular filtration rate, adiponectin, leptin, and CRP, neither adiponectin (hazard ratio [HR] with 95% confidence interval [CI]: 0.97 [0.87-1.08] per SD increase, P = 0.60) nor leptin (0.97 [0.85-1.12] per SD increase, P = 0.70) predicted the composite outcome, whereas CRP was significantly associated with the composite outcome (1.19 [1.07-1.35] per SD increase, P = 0.002). Furthermore, in mediation analysis, adjusted for age and sex, CRP decreased the BMI-associated CV risk by 43% (95%CI 29-72).. In this study, neither adiponectin nor leptin were independently associated with CVD, raising questions over their role in CVD. The finding that CRP was significantly associated with an increased risk of CVD and decreased the BMI-associated CVD risk substantially, could imply that interleukin-6-related pathways may play a role in mediating overweight- and obesity-related CVD.

Topics: Adipokines; Adult; Aged; Blood Pressure; C-Reactive Protein; Cardiovascular Diseases; Denmark; Early Medical Intervention; Female; Humans; Incidence; Insulin Resistance; Leptin; Longitudinal Studies; Male; Middle Aged; Obesity; Prognosis; Prospective Studies; Risk Factors

It has been found that the expression of fatty acid-binding protein 2 gene mRNA is under dietary control. The polymorphism Ala54Thr of this protein was associated with high insulin resistance.. The aim of our study was to investigate the influence of Thr54 polymorphism on metabolic response, weight loss and serum adipokine levels secondary to high-protein/low-carbohydrate vs. standard hypocaloric diets during 9 months.. A population of 193 obese subjects was analyzed in a randomized trial. A nutritional evaluation was performed at the beginning and at the end of a 9-month period in which subjects received 1 of 2 diets (diet HP: high-protein/low-carbohydrate vs. diet S: standard diet).. With both diets and in both genotype groups, body mass index, weight, fat mass, waist circumference, systolic blood pressure and leptin levels decreased. With both diets and only in wild genotype (diet HP vs. diet S), glucose (-6.2 ± 2.1 vs. -4.9 ± 2.0 mg/dl; p < 0.05), insulin levels (-5.0 ± 3.9 vs. -2.0 ± 2.1 UI/l; p < 0.05), homeostasis model assessment for insulin resistance (HOMA-R) (-1.1 ± 0.9 vs. -0.7 ± 1.0 units; p < 0.05) decreased. The improvement in these parameters was higher with diet HP than HS. With both diets and only in the wild genotype, total cholesterol and LDL-total cholesterol levels decreased.. Carriers of Thr54 allele have a different metabolic response after weight loss than wild type non-A carriers obese, with a lack of decrease of LDL-cholesterol, glucose, insulin levels and HOMA-R.

Topics: Adipokines; Adult; Blood Pressure; Body Mass Index; Body Weight; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Diet, Carbohydrate-Restricted; Diet, Reducing; Dietary Carbohydrates; Dietary Proteins; Fatty Acid-Binding Proteins; Female; Genotype; Genotyping Techniques; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Risk Factors; Waist Circumference; Weight Loss

Gender plays a role in the development of a number of cardiovascular and metabolic diseases and it has been suggested that females may be more insulin resistant in utero. We sought to assess the relationship between infant gender and insulin resistance in a large pregnancy cohort.. This is a secondary analysis of a cohort from the ROLO randomized control trial of low GI diet in pregnancy. Serum insulin, glucose and leptin were measured in early pregnancy and at 28 weeks. At delivery cord blood C-peptide and leptin were measured. A comparison of maternal factors, fetal biometry, insulin resistance and leptin was made between male and female offspring. A multivariate regression model was built to account for the possible effects of maternal BMI, birthweight and original study group assignment on findings.. A total of 582 women were included in this secondary analysis, of whom 304 (52.2%) gave birth to male and 278 (47.8%) gave birth to female infants. Compared to male infants at birth, female infants were significantly lighter, (3945 ± 436 vs. 4081± 549g, p<0.001), shorter in length (52.36 ± 2.3 vs. 53.05 ± 2.4cm, p<0.001) and with smaller head circumferences (35.36 ± 1.5 vs. 36.10 ± 1.1cm, p<0.001) than males. On multiple regression analysis, women pregnant with female fetuses were less insulin resistant in early pregnancy, i.e. had lower HOMA indices (B = -0.19, p = 0.01). Additionally female fetuses had higher concentrations of both cord blood leptin and C-peptide at birth when compared to male offspring (B = 0.38, p<0.001 and B = 0.31, p = 0.03 respectively).. These findings suggest gender is a risk factor for insulin resistance in-utero. Additionally, carrying a female fetus decreases the risk of insulin resistance in the mother, from as early as the first trimester.

Topics: Birth Weight; Body Mass Index; C-Peptide; Female; Fetal Blood; Fetal Development; Humans; Infant; Insulin Resistance; Leptin; Male; Pregnancy; Risk Factors; Sex Factors

Obesity is related to hormonal disorders that affect the reproductive system. Low-glycemic index (LGI) diets seem to exert a positive effect on weight loss and on metabolic changes that result from obesity.. We investigated the effects of a hypocaloric diet with an LGI and low glycemic load on anthropometric and metabolic variables, ghrelin and leptin concentrations, and the pregnancy rate in overweight and obese infertile women who were undergoing in vitro fertilization (IVF).. The study was a randomized block-design controlled trial in which we analyzed 26 overweight or obese infertile women. Patients were assigned to a hypocaloric LGI-diet group or a control group and followed the protocol for 12 wk. Body weight, body mass index (BMI), percentage of body fat, glucose, insulin, homeostasis model assessment of insulin resistance, serum lipids, reproductive hormones, leptin, acylated ghrelin, number of oocytes retrieved in the IVF cycle, and pregnancy rate were determined.. There were greater reductions in body mass, BMI, percentage of body fat, waist:hip ratio, and leptin in the LGI-diet group than in the control group (P < 0.05). Despite a change of 18% in mean values, there was no significant increase in acylated ghrelin concentrations in the LGI group compared with the control group (P = 0.215). The LGI-diet group had 85.4% more oocytes retrieved than did the control group (7.75 ± 1.44 and 4.18 ± 0.87, respectively; P = 0.039) in the IVF cycle. Three patients (21.4%) in the LGI group experienced a spontaneous pregnancy during the follow-up, which generated 3 live births.. The hypocaloric LGI diet promoted a decrease in BMI, percentage of body fat, and leptin concentrations, which improved oocyte development and pregnancy rate. These results support the clinical recommendation to advise overweight and obese women to lose weight through a balanced diet before being submitted for treatment with assisted reproduction technologies. A hypocaloric diet combined with LGI foods seems to be beneficial for these patients, but additional studies are required before this treatment is recommended. This trial was registered at clinicaltrials.gov as NCT02416960.

Topics: Adiposity; Adult; Body Mass Index; Brazil; Diet, Reducing; Female; Fertilization in Vitro; Follow-Up Studies; Ghrelin; Glycemic Index; Glycemic Load; Humans; Infertility, Female; Insulin Resistance; Leptin; Obesity; Overweight; Pregnancy; Pregnancy Rate; Risk; Waist-Hip Ratio; Weight Loss

Limited studies have shown that Coleus forskohlii extract may aid in weight management. This randomized, double blind placebo-controlled clinical study assessed the effects of supplementation with C. forskohlii extract on key markers of obesity and metabolic parameters in overweight and obese individuals. Thirty participants completed the trial and they were randomly assigned to receive either 250 mg of C. forskohlii extract (n = 15) or a placebo twice daily for 12 weeks. All participants were advised to follow a hypocaloric diet throughout the study. Body weight, body mass index (BMI), waist and hip circumference, and waist to hip ratio, were monitored fortnightly. Dietary intake was assessed at the baseline and weeks 4, 8 and 12. Appetite was assessed using visual analogue scales and blood samples were analyzed for plasma lipids, ghrelin, leptin, glucose and insulin at the baseline and end of the intervention. Significant reductions to waist and hip circumference (p = 0.02; p = 0.01, respectively) were recorded in both experimental and placebo groups after the 12 week intervention. Furthermore, high density lipoprotein-cholesterol (HDL-C) was significantly increased (p = 0.01) in both groups. The experimental group showed a favorable improvement in insulin concentration and insulin resistance (p = 0.001; 0.01 respectively) compared to the placebo group. These findings suggest that C. forskohlii extract in conjunction with a hypocaloric diet may be useful in the management of metabolic risk factors.

Topics: Adult; Aged; Appetite; Blood Glucose; Body Mass Index; Body Weight; Cholesterol, HDL; Diet, Reducing; Dietary Supplements; Dose-Response Relationship, Drug; Double-Blind Method; Energy Intake; Female; Ghrelin; Humans; Insulin; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Middle Aged; Obesity; Plant Extracts; Plectranthus; Risk Factors; Waist Circumference; Waist-Hip Ratio; Young Adult

To observe the effect of Qingre Yangyin Recipe (QRYYR) on sex hormones and insulin resistance (IR) in polycystic ovary syndrome (PCOS) patients.. Totally 90 PCOS patients were randomly assigned to the Chinese herbs group,the Western medicine group, the combined group, 30 in each group. Patients in the Chinese herbs group took QRYYR, one dose per day in two portions, once in the morning and once in the evening. Patients in the Western medicine group took Metformin 500 mg, twice per day for 3 consecutive months. Patients in the combined group took QRYYR and Metformin (the same as the former said two groups) in the 1st month, and took QRYYR for the following two months. Fasting blood glucose (FPG) and postprandial 2 h blood glucose (2 h GLU) were determined using hexokinase method before and after treatment. Fasting insulin (FINS), postprandial 2 h insulin (2 h INS), luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol (E2), progesterone (P), prolactin (PRL), and testosterone (T) were detected using chemiluminescent method. Leptin and adiponectin (APN) were determined using ELISA. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. Body weight and height were measured once before treatment and once after treatment to calculate body mass index (BMI). The total two-phase basal body temperature (BBT) actually obtained within 3 months was statistically collected to calculate the two-phase BBT rate. Scores for Chinese medical syndromes were compared between the two groups before and after treatment.. Compared with before treatment in the same group, BMI, FINS, 2 h INS, HOMA-IR, leptin, LH, PRL, T, and scores for Chinese medical syndromes obviously decreased, and APN levels increased (P < 0.05). FPG and 2 h FPG obviously decreased in the Western medicine group and the combined group (P < 0.05). E2 levels obviously decreased in the combined group with statistical difference (P < 0.05). Compared with the Chinese herbs group, the difference of BMI between pre-treatment and post-treatment was more in the combined group (P < 0.05). The difference of FPG,2 h GLU, 2 h INS, HOMA-IR, and APN between pre-treatment and post-treatment was more in the Chinese herbs group and the combined group (P < 0.05). Compared with the Western medicine group, the difference of PRL, T, and scores for Chinese medical syndromes was more in the Western medicine group and the combined group (P < 0.05); the difference of E2 and LH was even more in the combined group (P < 0.05). Compared with the combined group, the biphasic rate was obviously lowered in the Western medicine group (P < 0.05).. QRYYR could improve IR but with weaker power to that of Metformin. It also could decrease serum levels of LH, T, PRL, and scores for Chinese medical syndromes, with superior effect to that of Metformin. The effect in the combined group was better.

Topics: Adiponectin; Blood Glucose; Body Mass Index; Drugs, Chinese Herbal; Estradiol; Female; Follicle Stimulating Hormone; Gonadal Steroid Hormones; Humans; Insulin; Insulin Resistance; Leptin; Luteinizing Hormone; Metformin; Polycystic Ovary Syndrome; Progesterone; Prolactin; Testosterone

In obese males obstructive sleep apnoea (OSA) is associated with inflammation and insulin resistance; however, findings are confounded by adipose tissue, a hormone- and cytokine-secreting organ. Our goal was to examine whether in a relatively nonobese population, OSA is associated with sleepiness and inflammation/insulin resistance, and to assess the effects of a 2-month placebo-controlled continuous positive airway pressure (CPAP) use. 77 subjects, 38 middle-aged males and post-menopausal females with OSA and 39 male and female controls, were studied in the sleep laboratory for 4 nights. Measures of sleepiness (objective and subjective), performance, serial 24-h blood samples for interleukin (IL)-6, tumour necrosis factor receptor (TNFR)-1, leptin and adiponectin, and single samples for high-sensitivity C-reactive protein (hsCRP), fasting glucose and insulin levels were obtained. Apnoeic males were significantly sleepier and had significantly higher hsCRP, IL-6, leptin and insulin resistance than controls. Apnoeic females had significantly higher hsCRP; however, objective sleepiness, IL-6, TNFR-1, insulin resistance (Homeostatic Model Assessment index), leptin and adiponectin were similar to controls. CPAP improved subjective sleepiness, but no changes were observed in any of the biomarkers. In conclusion, OSA is associated with sleepiness, inflammation and insulin resistance, even in nonobese males, and this association is stronger in males than in females. Short-term CPAP does not improve the inflammatory/metabolic aberrations in OSA.

Topics: Adiponectin; Blood Glucose; Body Mass Index; C-Reactive Protein; Case-Control Studies; Continuous Positive Airway Pressure; Cross-Over Studies; Female; Humans; Inflammation; Insulin; Insulin Resistance; Interleukin-6; Leptin; Male; Middle Aged; Receptors, Tumor Necrosis Factor, Type I; Sex Factors; Sleep Apnea, Obstructive; Treatment Outcome

In order to compare the effects of leisure physical activity (LPA), aerobic training (AT) and aerobic plus resistance training (AT + RT) as part of a 6-month interdisciplinary therapy in body composition, insulin resistance and leptin concentrations in obese adolescents, 72 volunteers (n = 24 in each group) ages 15-19 years were evaluated. Delta (Δ) body mass (kg) and Δ BMI (kg/m(2)) was different between AT and LPA groups and in AT + RT group compared to both LPA and AT groups; Δ body fat mass (kg and %) was different only in AT + RT group compared to both LPA and AT; Δ body lean mass (%) was different only in AT + RT group; Δ body lean mass (kg) was negative only in AT and positive and different from AT in AT + RT group; ΔHOMA-IR did not differ among groups; Δ leptin (ng/ml) was negative and different from LPA for both AT and AT + RT groups. In conclusion, both AT and AT + RT promoted a reduction on leptin levels, however, the adolescents subjected to AT + RT presented better results in body composition than the AT group. These results highlight the importance of associating aerobic and resistance training with nutritional and psychological approaches in the treatment of obese adolescents.

Topics: Adolescent; Body Composition; Body Mass Index; Body Weight; Diet; Energy Intake; Female; Humans; Insulin Resistance; Leisure Activities; Leptin; Male; Motor Activity; Obesity; Patient Education as Topic; Physical Conditioning, Human; Resistance Training; Young Adult

Topics: Adult; Body Mass Index; Female; Gastric Balloon; Ghrelin; Growth Hormone; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Obesity, Morbid; Prospective Studies; Treatment Outcome; Weight Loss

The concentration of serum testosterone is mainly regulated by the testicular function, which is under control of the central hypothalamic-pituitary-gonadal axis. A certain amount of testosterone is converted into β-estradiol by adipose tissue. Obesity in men is often associated with decreased androgen levels. The aim of the present study was to examine the effect of caloric restriction on serum testosterone levels in obese men. Dietary intervention study was performed with a very low calorie diet (800 kcal/d) for 12 weeks. Thirteen obese human male subjects (median body mass index: 42.7 kg/m2) were included. Body composition was assessed by impedance analysis. Insulin sensitivity was estimated by leptin-to-adiponectin ratio (LAR). Testosterone (T), β-estradiol, albumin, sex hormone-binding globulin (SHBG), LH, and FSH serum concentrations were measured by enzyme immunoassays. Statistical analysis was performed on baseline and values after 3 months. Caloric restriction significantly increased total testosterone (6.97 nmol/l to 13.21 nmol/l; p=0.001) and SHBG (22.11 nmol/l to 42.12 nmol/l; p=0.001) concentrations in serum. This is caused by a significant improvement of the testicular function (LH/T: 0.36-0.20; p=0.005) and a significant reduction of the T/β-estradiol conversion rate (73.59-104.29; p=0.003). There was a significant negative correlation of improvement of testicular function and LAR (rs=-0.683 (p=0.042)). In obese men caloric restriction significantly increases the serum testosterone concentration. This is achieved by 2 distinct mechanisms, that is, improvement of testicular function and reduced conversion of testosterone to β-estradiol by aromatase activity of the adipose tissue.

Topics: Adiponectin; Adult; Caloric Restriction; Estradiol; Humans; Insulin Resistance; Leptin; Luteinizing Hormone; Male; Middle Aged; Obesity; Testis; Testosterone

We investigated the early effects of whole body vibration (WBV) added to hypocaloric diet on insulin-resistance and other parameters associated with glucose regulation in sedentary obese individuals. We randomly assigned 34 patients to WBV plus hypocaloric diet (WBV group) or diet alone (CON group) for 8 weeks. Fasting and post-load glucose, insulin, lipids, C-reactive protein, tumor necrosis factor-α, leptin, adiponectin were assessed. Insulin sensitivity index (ISI) was derived from oral-glucose-tolerance test. Body composition was evaluated with dual-energy X-ray absorptiometry. Both groups lost approximately 5% of weight, with greater reduction of body fat in WBV than in CON (-7.1±1.2 Kg vs. -5.3±1.0 Kg, p=0.003). Percent variation of ISI was more pronounced in WBV than in CON group (+35±4% vs. + 22±5%, p=0.002), accompanied by slight improvement in post-load glucose (-1.07±0.02 vs. - 0.12±0.01 mmol/l, p=0.031) but without changes in fasting levels. Adiponectin significantly increased in WBV group compared with CON (p=0.021 for comparison) whereas no differences in leptin and inflammatory markers were observed. In middle-aged sedentary obese subjects, WBV added to hypocaloric diet for 8 weeks improved body composition, insulin-resistance, glucose regulation and adiponectin levels to a greater extent compared with diet alone. Efficacy and feasibility of this approach in the long term need to be ascertained.

Topics: Adiponectin; Adult; Anthropometry; Blood Glucose; C-Reactive Protein; Diet, Reducing; Female; Humans; Insulin; Insulin Resistance; Leptin; Lipids; Male; Middle Aged; Obesity; Sedentary Behavior; Tumor Necrosis Factor-alpha; Vibration

Resistance training (RT) had a positive effect on musculoskeletal, cardiovascular, and type 2 diabetes disease. Knowing about the influence of different types of RT on the adipokines involved in the insulin regulation could be useful for the treatment of insulin resistance or diabetes. Therefore, the purpose of this study was to compare the effects of nonperiodized vs. periodized RT on plasma adiponectin, leptin and insulin resistance index in overweight men.. Thirty two sedentary overweight men (mean ± SD; age, 23.4 ± 0.6 years) were allocated to one of the following (n=8) groups: control group (CON), nonperiodized (NP), linear periodized (LP) and daily undulating periodized (DUP) training groups. Subjects in training groups performed RT protocols 3daysperweek for 8 weeks. Blood samples were taken before and 72 h after the training period and were analyzed for plasma adiponectin, leptin, glucose, and insulin.. Insulin resistance decreased in all training groups but significant differences were only found between DUP and CON groups (P<0.05). However, after 8 weeks of RT no significant changes were observed in plasma adiponectin and leptin concentrations. Body fat percent and waist to hip ratio (WHR) decreased significantly (P<0.05) following training, whereas, no significant changes were detected in body mass and BMI (P>0.05). The maximum strength (1RM) for bench press and leg press increased after RT in all training groups (P<0.05).. Short-term periodized RT protocols can be an efficient training strategy for improving insulin resistance and muscular strength in overweight men, while, they have no significant influence on adiponectin and leptin.

Topics: Adiponectin; Anthropometry; Diet; Energy Intake; Homeostasis; Humans; Insulin Resistance; Leptin; Male; Muscle Strength; Periodicity; Resistance Training; Time Factors; Young Adult

OBJECTIVE Leptin administration is known to directly modulate pancreatic β-cell function in leptin-deficient rodent models. However, human studies examining the effects of leptin administration on β-cell function are lacking. In this study, we examined the effects (16-20 weeks) of leptin replacement on β-cell function in patients with lipodystrophy. RESEARCH DESIGN AND METHODS In a prospective, open-label, currently ongoing study, we studied the effects of leptin replacement on β-cell function in 13 patients with congenital or acquired lipodystrophy. Insulin secretory rate (ISR) was calculated by C-peptide deconvolution from plasma glucose and C-peptide levels measured during oral glucose tolerance tests (OGTTs) performed at baseline and after 16-20 weeks of leptin replacement. β-Cell glucose sensitivity and rate sensitivity were assessed by mathematical modeling of OGTT. RESULTS There was a significant decrease in triglycerides, free fatty acids, and glycosylated hemoglobin levels (A1C) after leptin therapy. Patients with lipodystrophy have high fasting and glucose-stimulated ISR. However, leptin therapy had no significant effect on fasting ISR, total insulin secretion during OGTT, β-cell glucose sensitivity, rate sensitivity, or insulin clearance. CONCLUSIONS In contrast to the suppressive effects of leptin on β-cell function in rodents, 16-20-week treatment with leptin in lipodystrophy patients did not significantly affect insulin secretion or β-cell function in leptin-deficient individuals with lipodystrophy.

Topics: Adolescent; Adult; Child; Female; Glucose Tolerance Test; Hormone Replacement Therapy; Humans; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Leptin; Lipodystrophy; Male; Middle Aged; Young Adult

Although benefits have been attributed to the Mediterranean diet, its effect on glycaemic control has not been totally elucidated. The aim of this work was to compare the effect of two Mediterranean diets versus a low-fat diet on several parameters and indices related to glycaemic control in type 2 diabetic subjects.. A multicentric parallel trial was conducted on 191 participants (77 men and 114 women) of the PREDIMED study in order to compare three dietary interventions: two Mediterranean diets supplemented with virgin olive oil (n=67; body mass index (BMI)=29.4±2.9) or mixed nuts (n=74; BMI=30.1±3.1) and a low-fat diet (n=50; BMI=29.8±2.8). There were no drop-outs. Changes in body weight and waist circumference were determined. Insulin resistance was measured by HOMA-IR index, adiponectin/leptin and adiponectin/HOMA-R ratios after 1 year of follow-up.. Increased values of adiponectin/leptin ratio (P=0.043, P=0.001 and P<0.001 for low-fat, olive oil and nut diets, respectively) and adiponectin/HOMA-IR ratio (P=0.061, P=0.027 and P=0.069 for low-fat, olive oil and nut diets, respectively) and decreased values of waist circumference (P=0.003, P=0.001 and P=0.001 for low-fat, olive oil and nut diets, respectively) were observed in the three groups. In both Mediterranean diet groups, but not in the low-fat diet group, this was associated with a significant reduction in body weight (P=0.347, P=0.003 and P=0.021 for low-fat, olive oil and nut diets, respectively).. Mediterranean diets supplemented with virgin olive oil or nuts reduced total body weight and improved glucose metabolism to the same extent as the usually recommended low-fat diet.

Topics: Adipokines; Adiponectin; Aged; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Diet, Fat-Restricted; Diet, Mediterranean; Dietary Fats; Female; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Nuts; Obesity; Olive Oil; Plant Oils; Waist Circumference; Weight Loss

Adiponectin, an adipose tissue derived hormone, is known to have insulin-sensitizing, anti-inflammatory, and anti-atherogenic properties in the general population. Adiponectin secretion is suppressed by systemic inflammation, a highly prevalent condition in maintenance hemodialysis (MHD) patients. We evaluated whether short-term administration of interleukin 1 receptor antagonist (IL-1ra) improves adiponectin levels and insulin sensitivity in MHD patients.. Ad hoc analysis was performed on a pilot randomized placebo-controlled trial of the administration of IL-1ra in chronically inflamed MHD patients. Twenty-two patients were randomly assigned to receive 100 mg of IL-1ra or placebo (1:1) for 4 weeks, and 14 completed the trial. ANCOVA was used to compare percent change from baseline to 4 weeks. The primary outcome was percent change in adiponectin and the secondary outcomes were changes in leptin, homeostatic model assessment of insulin resistance (HOMA-IR) and the leptin-to-adiponectin ratio (LAR).. Patients' mean age was 49 ± 13 years, and 71 % were males. At baseline, the median values for adiponectin, leptin, LAR and HOMA-IR were 11.5 μg/ml [interquartile range (IQR) 9, 28.5], 17.8 ng/ml (3.9, 50.0), 2.20 (0.13, 3.98), and 2.8 (2.0, 3.6), respectively. IL-1ra administration resulted in a mean percent increase in serum adiponectin of 22 % vs. 14 % decrease in the placebo arm (p = 0.003). Leptin, LAR or HOMA-IR levels did not change in either arm.. Short-term administration of IL-1ra significantly increased adiponectin levels among prevalent MHD patients. The intervention did not impact insulin sensitivity parameters. Studies of longer duration and larger sample size are needed to further evaluate the potential effect of anti-inflammatory interventions on metabolic markers and insulin sensitivity in MHD patients.

Topics: Adiponectin; Adult; Aged; Anti-Inflammatory Agents; Biomarkers; Female; Humans; Inflammation; Insulin Resistance; Interleukin 1 Receptor Antagonist Protein; Leptin; Male; Middle Aged; Pilot Projects; Renal Dialysis; Renal Insufficiency, Chronic; Tennessee; Time Factors; Treatment Outcome; Up-Regulation

Several studies have identified relationships between weight loss and adipokine levels; however, none have looked at the combined effect of aerobic exercise training with the consumption of a low- or a high-glycemic diet. We examined the effects of 12 wk of aerobic exercise combined with either a low-glycemic index diet (∼40 U) plus exercise (LoGIX) or a high-glycemic index diet (∼80 U) diet plus exercise (HiGIX) on plasma leptin and adiponectin (total and high molecular weight [HMW]) in 27 older obese adults (age = 65 ± 0.5 yr, body mass index = 34.5 ± 0.7 kg·m).. Insulin sensitivity was calculated from an oral glucose tolerance test. Fasting HMW adiponectin and leptin were quantified from plasma samples obtained before the insulin sensitivity index obtained from the oral glucose tolerance test. Glucose and insulin measures were obtained before and every 30 min during the test. Dual-energy x-ray absorptiometry and computerized tomography were used to determine body composition and to quantify subcutaneous and visceral abdominal adiposity, respectively.. Fasting leptin was significantly decreased in both groups (LoGIX: preintervention = 33.8 ± 4.7, postintervention = 19.2 ± 4.5; HiGIX: preintervention = 27.9 ± 4.2, postintervention = 11.9 ± 2.2 ng·mL; P = 0.004), and HMW adiponectin was significantly increased (LoGIX: preintervention = 1606.9 ± 34.6, postintervention = 3502.3 ± 57; HiGIX: preintervention = 3704.8 ± 38.1, postintervention = 4284.3 ± 52.8 pg·mL; P = 0.003) after the 12-wk intervention. Total body fat was reduced after both interventions. Visceral fat mass was inversely correlated with HMW adiponectin, whereas subcutaneous fat correlated with leptin.. The data suggest that exercise training, independent of dietary glycemic index, favorably alters HMW adiponectin and leptin secretion and that a reduction in visceral fat mass is a key factor regulating HMW adiponectin in older obese persons.

Topics: Adiponectin; Adiposity; Aged; Diet, Carbohydrate-Restricted; Exercise Therapy; Female; Glycemic Index; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Molecular Weight; Obesity; Weight Loss

This is a secondary analysis of 621 women in ROLO study, a randomized control trial of low glycemic index (GI) diet in pregnancy to prevent the recurrence of macrosomia, which aims to assess the effect of the diet on maternal and fetal insulin resistance, leptin, and markers of inflammation. In early pregnancy and at 28 weeks, serum was analyzed for insulin, leptin, tumor necrosis factor α (TNF-α), and interleukin 6 (IL-6). At delivery, cord blood concentrations of leptin, TNF-α, IL-6, and C-peptide were recorded. We found no difference between those who did or did not receive low GI advice with respect to the concentrations of any marker in early pregnancy, at 28 weeks or in cord blood. Women in the intervention arm of the study did have a lower overall rise in insulin concentrations from early pregnancy to 28 weeks gestation, P = .04. Of the women in the intervention arm, 20% were in the highest quartile for insulin change (28-week insulin - insulin at booking) compared to 29% of controls (P = .02). In conclusion, a low GI diet in pregnancy has little effect on leptin and markers of inflammation although an attenuated response to the typical increase in insulin resistance seen in pregnancy with advancing gestation was seen in those who received the low GI advice.

Topics: Biomarkers; C-Peptide; Diet, Carbohydrate-Restricted; Female; Fetal Blood; Fetal Macrosomia; Gestational Age; Glycemic Index; Humans; Inflammation Mediators; Insulin Resistance; Interleukin-6; Leptin; Maternal Nutritional Physiological Phenomena; Nutritional Status; Pregnancy; Tumor Necrosis Factor-alpha

Fibre intake among North Americans is currently less than half the recommended amount. Consumers are interested in food products that could promote weight loss and improve health. Consequently, evaluation of unique fibre sources with potential gut-mediated benefits for metabolic health warrants investigation. Our objective is to assess the effects of yellow pea fibre supplementation on weight loss and gut microbiota in an overweight and obese adult population.. In a double blind, placebo controlled, parallel group study, overweight and obese (BMI = 25-38) adults will be randomized to either a 15 g/d yellow pea fibre supplemented group or isocaloric placebo group for 12 weeks (n = 30/group). The primary outcome measure is a change in body fat from baseline to 12 weeks. Secondary outcomes include glucose tolerance, appetite regulation, serum lipids and inflammatory markers. Anthropometric data (height, weight, BMI, and waist circumference) and food intake (by 3-day weighed food records) will be measured at baseline and every 4 weeks thereafter. Subjective ratings of appetite will be recorded by participants at home on a weekly basis using validated visual analogue scales. At week 0 and at the end of the study (week 12), an ad libitum lunch buffet protocol for objective food intake measures and dual-energy X-ray absorptiometry (DXA) scan for body composition will be completed. Participants will be instructed not to change their exercise habits during the 12 week study. Glucose and insulin will be measured during an oral glucose tolerance test at weeks 0 and 12. Levels of lipids and CRP will be measured and inflammatory markers (adiponectin, leptin, TNF-α, IL-6 and IL-8) in the serum will be quantified using Milliplex kits. Mechanisms related to changes in gut microbiota, serum and fecal water metabolomics will be assessed.. Globally the development of functional foods and functional food ingredients are critically needed to curb the rise in metabolic disease. This project will assess the potential of yellow pea fibre to improve weight control via gut-mediated changes in metabolic health in overweight and obese adults.. ClinicalTrials.gov (NCT01719900) Registered October 23, 2012.

Topics: Absorptiometry, Photon; Adiponectin; Adolescent; Adult; Aged; Appetite; Body Composition; Body Mass Index; C-Reactive Protein; Cholesterol, HDL; Cholesterol, LDL; Dietary Supplements; Double-Blind Method; Female; Glucose Tolerance Test; Humans; Insulin Resistance; Interleukin-6; Interleukin-8; Intestines; Leptin; Male; Microbiota; Middle Aged; Obesity; Overweight; Pisum sativum; Treatment Outcome; Triglycerides; Tumor Necrosis Factor-alpha; Weight Loss; Young Adult

We sought to determine: (1) if early weight regain between 1 and 2 years after Roux-en-Y gastric bypass (RYGB) is associated with worsened hepatic and peripheral insulin sensitivity, and (2) if preoperative levels of ghrelin and leptin are associated with early weight regain after RYGB.. Hepatic and peripheral insulin sensitivity and ghrelin and leptin plasma levels were assessed longitudinally in 45 subjects before RYGB and at 1 month, 6 months, 1 year, and 2 years postoperatively. Weight regain was defined as ≥5% increase in body weight between 1 and 2 years after RYGB.. Weight regain occurred in 33% of subjects, with an average increase in body weight of 10 ± 5% (8.5 ± 3.3 kg). Weight regain was not associated with worsening of peripheral or hepatic insulin sensitivity. Subjects with weight regain after RYGB had higher preoperative and postoperative levels of ghrelin compared to those who maintained or lost weight during this time. Conversely, the trajectories of leptin levels corresponded with the trajectories of fat mass in both groups.. Early weight regain after RYGB is not associated with a reversal of improvements in insulin sensitivity. Higher preoperative ghrelin levels might identify patients that are more susceptible to weight regain after RYGB.

Topics: Adult; Anastomosis, Roux-en-Y; Female; Ghrelin; Humans; Insulin Resistance; Leptin; Longitudinal Studies; Male; Middle Aged; Obesity; Postoperative Period; Recurrence; Weight Gain

The present study examined the effects of timed ingestion of supplemental protein (20-g servings of whey protein, 3×/day), added to the habitual diet of free-living overweight/obese adults and subsequently randomized to either whey protein only (P; n = 24), whey protein and resistance exercise (P + RT; n = 27), or a whey protein and multimode exercise training program [protein and resistance exercise, intervals, stretching/yoga/Pilates, endurance exercise (PRISE); n = 28]. Total and regional body composition and visceral adipose tissue (VAT) mass (dual-energy X-ray absorptiometry), insulin sensitivity [homeostasis model assessment-estimated insulin resistance (HOMA-IR)], plasma lipids and adipokines, and feelings of hunger and satiety (visual analog scales) were measured before and after the 16-wk intervention. All groups lost body weight, fat mass (FM), and abdominal fat; however, PRISE lost significantly (P < 0.01) more body weight (3.3 ± 0.7 vs. 1.1 ± 0.7 kg, P + RT) and FM (2.8 ± 0.7 vs. 0.9 ± 0.5 kg, P + RT) and gained (P < 0.05) a greater percentage of lean body mass (2 ± 0.5 vs. 0.9 ± 0.3 and 0.6 ± 0.4%, P + RT and P, respectively). Only P + RT (0.1 ± 0.04 kg) and PRISE (0.21 ± 0.07 kg) lost VAT mass (P < 0.05). Fasting glucose decreased only in P + RT (5.1 ± 2.5 mg/dl) and PRISE (15.3 ± 2.1 mg/dl), with the greatest decline occurring in PRISE (P < 0.05). Similarly, HOMA-IR improved (0.6 ± 0.3, 0.6 ± 0.4 units), and leptin decreased (4.7 ± 2.2, 4.7 ± 3.1 ng/dl), and adiponectin increased (3.8 ± 1.1, 2.4 ± 1.1 μg/ml) only in P + RT and PRISE, respectively, with no change in P. In conclusion, we find evidence to support exercise training and timed ingestion of whey protein added to the habitual diet of free-living overweight/obese adults, independent of caloric restriction on total and regional body fat distribution, insulin resistance, and adipokines.

Topics: Adipokines; Adiponectin; Adipose Tissue; Body Composition; Body Fat Distribution; Body Mass Index; Body Weight; Dietary Supplements; Eating; Exercise; Female; Humans; Hunger; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Milk Proteins; Obesity; Overweight; Physical Endurance; Satiety Response; Whey Proteins

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

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

There is an inverse relationship between triglycerides and high-density lipoprotein cholesterol (HDL-C) in insulin resistance, such that improvement in insulin resistance decreases triglycerides and increases HDL-C. Patients with lipodystrophy have extreme insulin resistance with high triglycerides and low HDL-C. Leptin replacement in lipodystrophy leads to a marked decrease in triglycerides (∼60%).. Our objective was to study the effects of metreleptin on triglycerides and HDL-C in lipodystrophy in contrast to changes in triglycerides and HDL-C in interventions for the obesity-associated metabolic syndrome.. This open-label nonrandomized study at the National Institutes of Health included 82 patients with various forms of lipodystrophy.. Metreleptin (0.06-0.24 mg/kg/d) was administered for 24 months in lipodystrophy.. Serum triglycerides and HDL-C were measured.. At baseline, lipodystrophy patients had low HDL-C (30 ± 1 mg/dL) and high triglycerides (961 ± 220 mg/dL) with an inverse relationship between the two (R = -0.37, P = .0006). There was no change in HDL-C with metreleptin despite major improvement in triglycerides, and individual changes in triglycerides only weakly predicted HDL-C change. On linear regression, in obesity, a decrease of 0.1 mg/dL in log(triglycerides) was associated with a 4.2 mg/dL rise in HDL-C, whereas in lipodystrophy, a decrease of 0.1 mg/dL in log(triglycerides) was associated with only a 0.6 mg/dL rise in HDL-C.. The normal reciprocal relationship between triglyceride and HDL-C change seen in response to interventions for the obesity-associated metabolic syndrome is quantitatively different from that seen in lipodystrophy in response to metreleptin. Further work is needed to understand HDL-C regulation in this condition.

Topics: Adolescent; Adult; Child; Cholesterol, HDL; Female; Humans; Insulin Resistance; Leptin; Lipid Metabolism; Lipodystrophy; Male; Metabolic Syndrome; Middle Aged; Obesity; Treatment Outcome; Triglycerides; Young Adult

Obesity, insulin resistance, and aging are closely associated and adipokines seem to have a crucial role in their pathophysiology. We aim to study the relationship between aging and chemerin, adiponectin, and leptin levels in type 2 diabetes mellitus (T2DM). Age correlated positively with chemerin and leptin and inversely with adiponectin. Body mass index (BMI) correlated positively with leptin (in males) and chemerin and inversely with adiponectin. The patients with ≥ 65 years (n = 34) showed significantly higher leptin and chemerin and lower adiponectin levels than middle-aged (38-64 years) patients (n = 39) and controls (n = 20). After statistical adjustment for length of disease, there was a loss of significance, between T2DM groups, for adiponectin and, in female, for leptin. In the older group, BMI correlated with adiponectin and with leptin, but not with chemerin. Adiponectin and leptin levels in elderly T2DM patients seem to be closely linked to obesity and to length of the disease. In elderly T2DM patients, chemerin concentrations are increased and seem to be independent of length of disease and BMI, suggesting that adipocyte dysfunction is enhanced with aging. The understanding of the glucose homeostasis impairment in the elderly is mandatory in order to achieve ways to improve their quality of life and longevity.

Topics: Adiponectin; Adult; Age Factors; Aged; Aged, 80 and over; Aging; Body Mass Index; Chemokines; Diabetes Complications; Diabetes Mellitus, Type 2; Female; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Male; Middle Aged; Obesity; Time Factors

Progressive midlife weight gain is associated with multiple adverse health outcomes and may represent an early manifestation of insulin resistance in a distinct subset of women. Emerging data implicate hyperinsulinema as a proximate cause of weight gain and support strategies that attenuate insulin secretion.. To assess a previously reported novel hypocaloric carbohydrate modified diet alone (D), and in combination with metformin (M) and metformin plus low-dose rosiglitazone (MR), in diverse women with midlife weight gain (defined as >20lbs since the twenties), normal glucose tolerance, and hyperinsulinemia.. 46 women, mean age 46.6±1.0, BMI 30.5±0.04 kg/m2, 54.5% white, 22.7% black, 15.9% Hispanic, at 2 university medical centers.. A dietary intervention designed to reduce insulin excursions was implemented in 4 weekly nutritional group workshops prior to randomization.. Change in 6-month fasting insulin. Pre-specified secondary outcomes were changes in body weight, HOMA-IR, metabolic syndrome (MS) measures, leptin, and adiponectin.. Six-month fasting insulin declined significantly in the M group: 12.5 to 8.0 µU/ml, p = .026. Mean 6-month weight decreased significantly and comparably in D, M, and MR groups: 4.7, 5.4, and 5.5% (p's.049, .002, and.032). HOMA-IR decreased in M and MR groups (2.5 to 1.6 and 1.9 to 1.3, p's = .054, .013). Additional improvement in MS measures included reduced waist circumference in D and MR groups and increased HDL in the D and M groups. Notably, mean fasting leptin did not decline in a subset of subjects with weight loss (26.15±2.01 ng/ml to 25.99±2.61 ng/ml, p = .907. Adiponectin increased significantly in the MR group (11.1±1.0 to 18.5±7.4, p<.001) Study medications were well tolerated.. These findings suggest that EMPOWIR's easily implemented dietary interventions, alone and in combination with pharmacotherapies that target hyperinsulinemia, merit additional investigation in larger, long-term studies.. ClinicalTrials.gov NCT00618072.

Topics: Blood Glucose; Body Mass Index; Body Weight; Diet, Carbohydrate-Restricted; Female; Follow-Up Studies; Humans; Hypoglycemic Agents; Insulin Resistance; Leptin; Metabolic Syndrome; Middle Aged; Patient Compliance; Risk Factors; Treatment Outcome

Fat redistribution, increased inflammation and insulin resistance are prevalent in non-diabetic subjects treated with maintenance dialysis. The aim of this study was to test whether pioglitazone, a powerful insulin sensitizer, alters body fat distribution and adipokine secretion in these subjects and whether it is associated with improved insulin sensitivity.. This was a double blind cross-over study with 16 weeks of pioglitazone 45 mg vs placebo involving 12 subjects.. At the end of each phase, body composition (anthropometric measurements, dual energy X-ray absorptometry (DEXA), abdominal CT), hepatic and muscle insulin sensitivity (2-step hyperinsulinemic euglycemic clamp with 2H2-glucose) were measured and fasting blood adipokines and cardiometabolic risk markers were monitored.. Four months treatment with pioglitazone had no effect on total body weight or total fat but decreased the visceral/sub-cutaneous adipose tissue ratio by 16% and decreased the leptin/adiponectin (L/A) ratio from 3.63 × 10(-3) to 0.76 × 10(-3). This was associated with a 20% increase in hepatic insulin sensitivity without changes in muscle insulin sensitivity, a 12% increase in HDL cholesterol and a 50% decrease in CRP.. Pioglitazone significantly changes the visceral-subcutaneous fat distribution and plasma L/A ratio in non diabetic subjects on maintenance dialysis. This was associated with improved hepatic insulin sensitivity and a reduction of cardio-metabolic risk markers. Whether these effects may improve the outcome of non diabetic end-stage renal disease subjects on maintenance dialysis still needs further evaluation.. ClinicalTrial.gov NCT01253928.

Topics: Adipokines; Adipose Tissue; Adult; Body Composition; Cross-Over Studies; Double-Blind Method; Fasting; Female; Glucose; Homeostasis; Humans; Insulin Resistance; Intra-Abdominal Fat; Kidney Failure, Chronic; Leptin; Liver; Male; Middle Aged; Pilot Projects; Pioglitazone; Renal Dialysis; Subcutaneous Fat; Thiazolidinediones

Previous studies have found that L-arginine induced beneficial effects over insulin resistance both in type 2 diabetes mellitus patients and healthy individuals. The aim of our study was to investigate whether an L-arginine enteral supplementation (20 g per day) in head and neck cancer patients could modify insulin resistance, leptin and adiponectin levels after surgery.. At surgery 82 patients were randomly allocated to two groups: group I received an enteral diet supplements with a high dose of arginine (20g per day) and group II received an enteral formula without arginine. At basal time and on postoperative day 10, the following parameters were recorded: glucose, c-reactive protein, insulin, HOMA (homeostasis model assessment), leptin and adiponectin.. Values of weight, body mass index, fat mass and fat free mass remained unchaged during the acute nutritional intervention in both groups. Insulin levels UI/L (-0.21+/-0.18) and HOMA units (-0.07+/-0.13) decreased in the arginine group. Adiponectin levels (+1.8+/-2.3ng/ml) increased in the arginine group.. Short-term enteral L-arginine therapy addeded to usual enteral nutrition of patients affected by head and neck cancer and surgery without diabetes mellitus type 2 is able to improve insulin resistance and adiponectin levels.. Introducción: Alguntos trabajos han encontrado que la L-arginina induce efectos beneficiosos sobre la resistencia a la insulina, tanto en pacientes con diabetes tipo 2 como en individuos sanos. El objetivo de nuestro estudio fue investigar si la suplementación enteral de L-arginina (20 g por día) en pacientes con cáncer de cabeza y cuello puede modificar la resistencia a la insulina, los niveles de leptina y adiponectina después de la cirugía. Material y métodos: Tras la cirugía 82 pacientes fueron asignados aleatoriamente a dos grupos: grupo I recibió un enterales suplementos de dieta con una dosis alta de arginina (20 g por día) y el grupo II recibió una fórmula enteral sin arginina. En el momento basal y el día 10 tras la cirugia, se registraron los siguientes parámetros: glucosa, proteína C reactiva, insulina, HOMA (Homeostasis Model Assessment), leptina y adiponectina. Resultados: Los valores de peso, índice de masa corporal, la masa grasa y la masa libre de grasa se mantuvieron sin cambios durante la intervención nutricional aguda en ambos grupos. Los niveles de insulina UI/L (-0,21 + / -0,18) y HOMA (-0,07 + / -0,13) disminuyeron en el grupo de arginina. Los niveles de adiponectina (1,8 + / -2.3ng/ml) aumentaron en el grupo de arginina. Conclusión: La nutrición enteral con L-arginina a corto plazo en los pacientes afectados por cáncer de cabeza y cuello y tras cirugía es capaz de mejorar la resistencia a la insulina y los niveles de adiponectina.

Topics: Adiponectin; Aged; Arginine; Dietary Supplements; Female; Head and Neck Neoplasms; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Postoperative Period; Single-Blind Method

The visceral fat is linked to insulin resistance, the metabolic syndrome, type 2 diabetes and an increased cardiovascular risk, but it is not clear whether it has a causative role.. Surgical resection of this fat depot is a research model to address this issue. Twenty premenopausal women with metabolic syndrome and grade III obesity were randomized to undergo Roux-en-Y gastric bypass (RYGBP) either alone or combined with omentectomy. Insulin sensitivity (IS; euglycemic-hyperinsulinemic clamp), acute insulin response to glucose (AIR; intravenous glucose tolerance test), disposition index (DI = AIR × IS measured by clamp), lipid profile, adipokine profile (leptin, adiponectin, resistin, visfatin, interleukin-6, TNF-α, MCP-1), ultra-sensitive C-reactive protein (CRP), body composition, and abdominal fat echography were assessed prior to surgery and 1, 6, and 12 months post-surgery.. Omentectomy was associated with greater weight loss at all time points. IS improved similarly in both groups. Omentectomy was associated to lower CRP after 12 months, but it did not influence adipokines and other metabolic parameters. Among non-diabetic subjects, omentectomy was associated with a preservation of baseline AIR after 12 months (as opposed to deterioration in the control group) and a greater DI after 6 and 12 months.. Although omentectomy did not enhance the effect of RYGBP on insulin sensitivity and adipokines, it was associated with a preservation of insulin secretion, a greater weight loss, and lower CRP.

Topics: Adiponectin; Adult; Biomarkers; Blood Glucose; Body Composition; C-Reactive Protein; Cardiovascular Diseases; Chemokine CCL2; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Glucose Tolerance Test; Humans; Inflammation; Insulin Resistance; Insulin-Secreting Cells; Interleukin-6; Intra-Abdominal Fat; Leptin; Metabolic Syndrome; Nicotinamide Phosphoribosyltransferase; Obesity; Premenopause; Prospective Studies; Resistin; Risk Factors; Tumor Necrosis Factor-alpha; Weight Loss; Young Adult

We initiated a pilot study to investigate the effects of 8 wks of aerobic exercise training (ET) on insulin sensitivity and inflammatory markers in obese and insulin-resistant minority adolescents. Eleven morbidly obese (BMI 41.4 ± 1.8 kg/m2) minority adolescents were entered into a supervised ET intervention (~180 min/wk at 40-55%VO2PeakR [(VO2Peak-VO2Rest)/VO2Rest]). The effects of training on insulin sensitivity (SI), inflammation and other metabolic syndrome features were examined.. Insulin action improved in response to training, as indicated by a ~37% increase in SI (p = .018). Plasma levels of several proinflammatory cytokines were reduced in response to ET, as indicated by significant decrements in sTNF-R, CCL2, MPO, IL-6, resistin, and leptin, with no significant changes in hsCRP. ET induced reductions in BMI and percent total body fat.. The present study supports the efficacy of ET interventions on metabolic syndrome features in morbidly obese minority youth.

Topics: Adolescent; Black or African American; Body Composition; Body Weight; Chemokine CCL2; Exercise; Exercise Test; Exercise Therapy; Female; Glucose Tolerance Test; Hispanic or Latino; Humans; Insulin Resistance; Leptin; Male; Obesity, Morbid; Oxygen Consumption; Peroxidase; Pilot Projects; Receptors, Tumor Necrosis Factor; Resistin; Statistics, Nonparametric

Obese adolescents are at a greater risk of vitamin D deficiency because vitamin D is thought to be sequestered by excess adipose tissue. Poor vitamin D status has been associated with a higher prevalence of the metabolic syndrome, type 2 diabetes, or both in adults and adolescents.. The objective was to determine in obese adolescents the efficacy and safety of 4000 IU vitamin D3/d and whether subsequent increased circulating concentrations of 25-hydroxyvitamin D [25(OH)D] are associated with improved markers of insulin sensitivity and resistance and reduced inflammation.. Obese adolescent patients [n = 35; mean ± SD age: 14.1 ± 2.8 y; BMI (in kg/m(2)): 39.8 ± 6.1; 25(OH)D: 19.6 ± 7.1 ng/mL] were recruited from the University of Missouri Adolescent Diabetes and Obesity Clinic and were randomly assigned to receive either vitamin D3 (4000 IU/d) or placebo as part of their standard care. Anthropometric measurements, inflammatory markers (IL-6, TNF-α, C-reactive protein), adipokines (leptin, adiponectin), fasting glucose, fasting insulin, and HOMA-IR values were measured at baseline and at 2 follow-up visits (3 and 6 mo).. After 6 mo, there were no significant differences in BMI, serum inflammatory markers, or plasma glucose concentrations between groups. Participants supplemented with vitamin D3 had increases in serum 25(OH)D concentrations (19.5 compared with 2.8 ng/mL for placebo; P < 0.001), fasting insulin (-6.5 compared with +1.2 μU/mL for placebo; P = 0.026), HOMA-IR (-1.363 compared with +0.27 for placebo; P = 0.033), and leptin-to-adiponectin ratio (-1.41 compared with +0.10 for placebo; P = 0.045). Inflammatory markers remained unchanged.. The correction of poor vitamin D status through dietary supplementation may be an effective addition to the standard treatment of obesity and its associated insulin resistance. This trial was registered at clinicaltrials.gov as NCT00994396.

Topics: Adipokines; Adiponectin; Adolescent; Blood Glucose; Body Mass Index; Child; Cholecalciferol; Dietary Supplements; Female; Humans; Inflammation Mediators; Insulin; Insulin Resistance; Leptin; Male; Obesity; Treatment Outcome; Vitamin D; Vitamin D Deficiency; Vitamins

Pediatric acute lymphoblastic leukemia (ALL) survivors are at increased risk for the metabolic syndrome (MS). To establish the trajectory of development during active treatment, we followed patients longitudinally over the first year of maintenance therapy.. In a prospective cohort of 34 pediatric ALL patients, followed over the first 12 months of ALL maintenance, we evaluated changes in body mass index (BMI), blood pressure, fasting insulin and glucose, lipids, Homeostatic Metabolic Assessment (HOMA), leptin, and adiponectin.. Over the study time period, the median BMI z-score increased from 0.29 to 0.66 (P = 0.001), median fasting insulin levels increased from 2.9 to 3.1 µU/ml (P = 0.023), and the proportion of patients with insulin resistance by HOMA (>3.15) increased from 3% to 24% (P = 0.016). Median leptin increased from 2.5 to 3.5 ng/ml (P = 0.001), with levels correlated with BMI z-score. Median adiponectin level decreased from 18.0 to 14.0 µg/ml (P = 0.009), with levels inversely correlated to BMI z-score. No change in median total cholesterol and LDL levels was observed. Median triglycerides decreased (P < 0.001) and there was a trend to increase in HDL (P = 0.058). Blood pressure did not significantly change, although overall prevalence of systolic and diastolic hypertension was high (23.5% and 26.4%, respectively).. Following patients over the first year of ALL maintenance therapy demonstrated that components of the MS significantly worsen over time. Preventive interventions limiting increases in BMI and insulin resistance during maintenance therapy should be targeted during this time period to avoid long-term morbidity associated with the MS in long-term survivors.

Topics: Adolescent; Adult; Blood Glucose; Body Mass Index; Child; Child, Preschool; Fasting; Female; Follow-Up Studies; Humans; Insulin; Insulin Resistance; Leptin; Male; Obesity; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Triglycerides

Obesity is a key factor in the development of the metabolic syndrome (MetS), which is associated with increased cardiometabolic risk. We investigated whether obesity classification by BMI and body fat percentage (BF%) influences cardiometabolic profile and dietary responsiveness in 486 MetS subjects (LIPGENE dietary intervention study).. Anthropometric measures, markers of inflammation and glucose metabolism, lipid profiles, adhesion molecules, and hemostatic factors were determined at baseline and after 12 weeks of four dietary interventions (high saturated fat (SFA), high monounsaturated fat (MUFA), and two low fat high complex carbohydrate (LFHCC) diets, one supplemented with long chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs)).. About 39 and 87% of subjects classified as normal and overweight by BMI were obese according to their BF%. Individuals classified as obese by BMI (≥ 30 kg/m(2)) and BF% (≥ 25% (men) and ≥ 35% (women)) (OO, n = 284) had larger waist and hip measurements, higher BMI and were heavier (P < 0.001) than those classified as nonobese by BMI but obese by BF% (NOO, n = 92). OO individuals displayed a more proinflammatory (higher C reactive protein (CRP) and leptin), prothrombotic (higher plasminogen activator inhibitor-1 (PAI-1)), proatherogenic (higher leptin/adiponectin ratio) and more insulin resistant (higher HOMA-IR) metabolic profile relative to the NOO group (P < 0.001). Interestingly, tumor necrosis factor-α (TNF-α) concentrations were lower post-intervention in NOO individuals compared with OO subjects (P < 0.001).. In conclusion, assessing BF% and BMI as part of a metabotype may help to identify individuals at greater cardiometabolic risk than BMI alone.

Topics: Adiponectin; Adipose Tissue; Body Composition; Body Mass Index; C-Reactive Protein; Cardiovascular Diseases; Diet Therapy; Female; Humans; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Middle Aged; Obesity; Overweight; Plasminogen Activator Inhibitor 1; Reference Values; Risk Factors; Tumor Necrosis Factor-alpha

Vitamin D supplementation has the potential to alleviate the cardiovascular damage in diabetic patients. The present study was designed to evaluate long term impact of high doses of vitamin D on arterial properties, glucose homeostasis, adiponectin and leptin in patients with type 2 diabetes mellitus.. In randomized, placebo-controlled study 47 diabetic patients were assigned into two groups: Group 1 received oral daily supplementation with vitamin D at a dose of 1000 U/day for 12 months. Group 2 received matching placebo capsules. Blood sampling for metabolic parameters, including fasting glucose, lipid profile, HbA1C, insulin, hs-CRP, 25 OH Vit D, adiponectin and leptin was performed at baseline and at the end of the study. Insulin resistance was assessed by homeostasis model assessment (HOMA-IR). Central aortic augmentation index (AI) was evaluated using SphygmoCor.. The two groups were similar at baseline in terms of hemodynamic parameters. After 12 months, AI decreased significantly during the treatment period in patients received vitamin D (p < 0.0001) and did not change in placebo group. Glucose homeostasis parameters, leptin as well as leptin adiponectin ratio did not change in both groups. 25 OH Vit D level significantly increased (p = 0.022) and circulating adiponectin marginally increased (p = 0.065) during 12 month treatment period in active treatment and did not change in placebo group.. High doses of vitamin D supplementation in diabetic patients was associated with significant decrease in AI during one year treatment. This beneficial vascular effect was not associated with improvement in glucose homeostasis parameters.

Topics: Adiponectin; Administration, Oral; Aged; Arteries; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Dietary Supplements; Dose-Response Relationship, Drug; Double-Blind Method; Female; Homeostasis; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Linear Models; Male; Middle Aged; Vitamin D

Recent data suggest excess circulating aldosterone promotes cardiometabolic decline. Weight loss may lower aldosterone levels, but little longitudinal data is available in normotensive adults. We aimed to determine whether, independent of changes in sodium excretion, reductions in serum aldosterone are associated with favorable changes in obesity-related factors in normotensive overweight/obese young adults. We studied 285 overweight/obese young adult participants (body mass index ≥ 25 and<40 kg m⁻², age 20-45 years) in a clinical trial examining the effects of a 1-year diet and physical activity intervention with or without sodium restriction on vascular health. Body weight, serum aldosterone, 24-h sodium and potassium excretion and obesity-related factors were measured at baseline, 6, 12 and 24 months. Weight loss was significant at 6 (7%), 12 (6%) and 24 months (4%; all P<0.0001). Decreases in aldosterone were associated with decreases in C-reactive protein, leptin, insulin, homeostasis assessment of insulin resistance, heart rate, tonic cardiac sympathovagal balance and increases in adiponectin (all P<0.05) in models adjusting for baseline age, sex, race, intervention arm, time since baseline, and sodium and potassium excretion. Weight loss and reductions in thigh intermuscular fat (intermuscular adipose tissue area; IMAT) were associated with decreases in aldosterone in the subgroup (n=98) with metabolic syndrome (MetS) at baseline (MetS × weight loss, P=0.04; MetS × change in IMAT, P=0.04). Favorable changes in obesity-related factors are associated with reductions in aldosterone in young adults with no risk factors besides excess weight, an important finding, given aldosterone's emergence as an important cardiometabolic risk factor.

Topics: Adiponectin; Adiposity; Adult; Aldosterone; Blood Pressure; C-Reactive Protein; Diet, Sodium-Restricted; Female; Follow-Up Studies; Ghrelin; Humans; Insulin Resistance; Leptin; Life Style; Longitudinal Studies; Male; Metabolic Syndrome; Middle Aged; Motor Activity; Obesity; Overweight; Potassium; Sodium

To examine the effects of a 3-month multidisciplinary intervention on anthropometric measures, physical activity patterns and fitness, inflammatory cytokines, adipocytokines, and growth mediators in obese children.. 21 obese subjects completed the 3-month intervention and were compared with 20 age-, gender- and maturity-matched controls. Subjects underwent anthropometric measurements (weight, height, BMI percentile and waist circumference), blood tests (IL-6, CRP, leptin, adiponectin, insulin, IGF-I and glucose), a progressive treadmill exercise test to evaluate fitness, and habitual activity assessment before and after the intervention.. The intervention led to a significant change of differences in body weight (-1.3 ± 4.1 vs. 2.5 ± 3.3 kg), BMI percentile (-0.96 ± 1.29 vs. 0.19 ± 0.8), waist circumference (-2.1 ± 2.7 vs. 2.9 ± 3.0 cm) and running time (149.9 ± 86.3 vs. -8.2 ± 88.0 s) in the intervention compared to control. There was a significant increase in leisure-time physical activity (Godin questionnaire, 29.04 ± 6.8 vs. -1.3 ± 9.2) and a decrease in sedentary activity (-1.4 ± 0.73 vs. 0.02 ± 0.62 h/day) in the intervention compared to control. Significant change differences in adiponectin (2,308 ± 1,640 vs. -801 ± 465 ng/ml), IGF-I (33.8 ± 37.8 vs. -1.0 ± 36.2 ng/ml), CRP (-0.06 ± 0.29 vs. 0.5 ± 0.86 mg/dl) and HOMA-IR (-0.15 ± 0.57 vs. 0.55 ± 0.84) were found in the intervention group compared to control.. Our results highlight the short-term beneficial effects of a childhood obesity multidisciplinary intervention on anthropometrics, habitual activity, fitness, inflammatory and metabolic measures. The longer-term effects of these changes on obesity-associated metabolic risks are yet to be determined.

Topics: Adipokines; Adiponectin; Adolescent; Body Mass Index; Body Weight; C-Reactive Protein; Child; Diet, Reducing; Exercise; Female; Humans; Inflammation Mediators; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Interleukin-6; Leptin; Male; Pediatric Obesity; Physical Fitness

It has been found that the expression of fatty acid binding protein 2 (FABP2) mRNA is under dietary control. This polymorphism was associated with high insulin resistance, and fasting insulin concentrations.. The aim of our study was to investigate the influence of Thr54 polymorphism in the FABP2 gene on metabolic response, weight loss and serum adipokine levels secondary to a high monounsaturated fat hypocaloric diet.. A sample of 122 obese patients was analyzed in a prospective way. The hypocaloric diet had 1342 kcal, 46.6% of carbohydrates, 34.1% of lipids and 19.2% of proteins, with a 67.5% of monounsaturated fats, and lasted 3 months.. Fifty-five patients (45.1%) had the genotype Ala54/Ala54 (wild group) and 67 (64.9%) patients a mutant genotype, Ala54/Thr54 (54 patients, 44.3%) or Thr54/Thr54 (13 patients, 10.7%). In wild group, body mass index (-1.5±1.2 kg/m2), weight (-4.1±3.6 kg), fat mass (-3.6±3.3 kg), waist circumference (-4.9±2.9 cm), insulin (-1.7±3.6 mUI/l), homeostasis model assessment of insulin resistance (HOMA-IR) (-0.6±1.8 units) and leptin levels decreased (-7.6±7.1 ng/ml). In mutant group, anthropometric parameters improved, without changes in biochemical parameters.. Carriers of Thr54 allele have a different response than wild type obese, with a lack of decrease of insulin levels, leptin levels and HOMA-IR.

Topics: Adult; Alanine; Amino Acid Substitution; Diet, High-Fat; Dietary Fats, Unsaturated; Fatty Acid-Binding Proteins; Female; Genotype; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Mutation, Missense; Obesity; Polymorphism, Single Nucleotide; Threonine

Rabson-Mendenhall syndrome (RMS) is caused by mutations of the insulin receptor and results in extreme insulin resistance and dysglycemia. Hyperglycemia in RMS is very difficult to treat, and patients are at risk for early morbidity and mortality from complications of diabetes.. Our objective was to study 1-year effects of recombinant human methionyl leptin (metreleptin) in 5 patients with RMS and 10-year effects in 2 of these patients.. We conducted an open-label nonrandomized study at the National Institutes of Health.. Patients were adolescents with RMS and poorly controlled diabetes.. Two patients were treated with escalating doses (0.02 up to 0.22 mg/kg/d) of metreleptin for 10 years, including 3 cycles of metreleptin withdrawal and reinitiation. In all 5 patients, 1-year effects of metreleptin (0.22 mg/kg/d) were studied.. Hemoglobin A1c (HbA1c) and body mass index (BMI) z-scores were evaluated every 6 months.. HbA1c decreased from 11.4% ± 1.1% at baseline to 9.3% ± 1.9% after 6 months and 9.7% ± 1.6% after 12 months of metreleptin (P = .007). In patients treated for 10 years, HbA1c declined with each cycle of metreleptin and rose with each withdrawal. BMI z-scores declined from -1.4 ± 1.8 at baseline, to -2.6 ± 1.6 after 12 months of metreleptin (P = .0006). Changes in BMI z-score correlated with changes in HbA1c (P < .0001).. Metreleptin treatment for 12 months was associated with a 1.7% reduction in HbA1c; part of this improvement was likely mediated via decreased BMI. Metreleptin is a promising treatment option for RMS, but additional therapies are needed to achieve HbA1c targets.

Topics: Adolescent; Blood Glucose; Child; Donohue Syndrome; Dose-Response Relationship, Drug; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Insulin Resistance; Leptin; Male; Receptor, Insulin; Treatment Outcome

Gut and adipose tissue hormones play an important role in energy balance control, particularly through the regulation at either short- or long-term food intake after bariatric surgery.. A 15-year-old obese female (BMI 42.2) who was unresponsive to medical treatment underwent gastroplication. Hunger hormone levels (leptin, ghrelin and insulin), weight loss and eating behavior were monitored at 3, 6 and 12 months after surgery.. Weight loss was obtained, progressively achieving a loss of 45.6 kg 1 year after surgery. A strong reduction in insulin concentration and insulin resistance was documented. At 3 months after the operation, a surprising leptin level drop was observed. During the following months a progressive increase in leptin levels and leptin/kg of fat mass were documented. Fasting ghrelin levels increased in the first 3 months, then fell over the next 6 months. Up to 6 months after gastroplication, we observed a less marked drop in plasma ghrelin after meal ingestion, while the values after 1 year showed a substantial fall in the postprandial period despite a further fasting ghrelin increased level. Early achievement of satiety was found.. Hunger hormones level changes seem to be involved in weight loss and eating behavior after gastroplication in adolescents.

Topics: Adolescent; Female; Humans; Insulin; Insulin Resistance; Leptin; Obesity; Stomach

To investigate the effects of acitretin treatment on insulin resistance (IR) and adipokines, particularly retinol-binding protein (RBP)-4.. Thirty-four patients with chronic plaque psoriasis and a control group of 34 healthy volunteers were recruited in the study. Screening for the parameters was performed before starting and after 3 months of acitretin treatment in the psoriasis group. The control group was only evaluated at the beginning of the study and did not receive placebo. We could not compare our results with a placebo control group because of ethical reasons.. Basal adiponectin (p = 0.01), insulin (p < 0.0001) levels and homeostasis model assessment (HOMA) IR (p < 0.0001) were significantly higher in psoriasis patients. After the treatment, insulin (p = 0.014), C peptide (p = 0.011), RBP-4 (p < 0.0001) levels and HOMA-IR (p = 0.008) decreased significantly. Posttreatment leptin (p = 0.036) levels were significantly lower than those of the controls. Posttreatment adiponectin (p = 0.005) and insulin (p = 0.048) levels were higher than those of the controls.. This study showed for the first time that RBP-4 levels and IR are decreased significantly with acitretin treatment. This finding is very important in psoriasis patients because psoriasis may cause insulin resistance and diabetes. Further experimental and clinical studies are needed to clarify the effect of acitretin on adipocyte structure and behavior.

Topics: Acitretin; Adiponectin; Adult; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Humans; Insulin; Insulin Resistance; Leptin; Male; Psoriasis; Retinol-Binding Proteins, Plasma

To explore the effect of electroacupuncture and Chinese kidney-nourishing medicine on insulin (INS), adiponectin (APN), leptin (LEP), and glucolipid metabolism of obese patients with polycystic ovary syndrome (PCOS).. Sixty-seven obese PCOS patients were randomly divided into two groups. Thirty-three patients in the acupuncture-medicine group were treated three times a week with electroacupuncture at the Tianshu (ST 25), Zhongwan (CV 12), Qi-hai (CV 6), Sanyinjiao (SP 6), Geshu (BL 17), and Ciliao (BL 32) acupoints. They also took the Chinese drug, Tiankui capsule, for 3 months as a course of treatment. Point-taking and treatment in the electroacupuncture group of 34 patients was the same as those in the acupuncture-medicine group. We observed and compared the changes in the obesity-related indexes of body weight (BW), body mass index (BMI), and waist-hip ratio (WHR), as well as fasting plasma glucose (FPG), fasting insulin (FINS), APN, and LEP.. BW, BMI, WHR, and FINS decreased and insulin sensitivity index (ISI) and APN were higher in the acupuncture-medicine group than in the electroacupuncture group (P < 0.01). There was no obvious difference in LEP between the two groups (P > 0.05).. Acupuncture combined with medicine is better than just electroacupuncture for obese PCOS patients by improving obesity-related indexes, insulin sensitivity, and APN level. This indicates that acupuncture-medicine therapy is worth clinical popularization.

Topics: Adiponectin; Adolescent; Adult; Body Weight; Combined Modality Therapy; Drugs, Chinese Herbal; Electroacupuncture; Female; Glucose; Humans; Insulin Resistance; Leptin; Obesity; Polycystic Ovary Syndrome; Waist-Hip Ratio; Young Adult

Modifications in body fat in obese patients during puberty determine changes in adipokines that affect insulin sensitivity.. We hypothesized that the leptin/adiponectin (L/A) ratio and free leptin index (FLI) are good markers of insulin resistance (IR) and total body fat (TBF) during pubertal development.. A prospective study of 32 obese girls (OG) and age-matched control girls (CG) was performed. OG were divided into those that maintained a weight loss (WL) of >1 SD of initial body mass index (BMI) (WL group, n = 25) and those without WL (NWL group, n = 7). Oral glucose tolerance tests (OGTT) were performed to evaluate IR. Correlations of adipokines, L/A, and FLI with BMI, waist circumference, percentage of TBF (%TBF) and IR were performed over pubertal development.. The L/A ratio and FLI were increased in OG at baseline. Both indexes decreased in the WL group as puberty progressed, with no change in CG or NWL. In the WL group, a correlation between L/A and FLI with OGTT and %TBF, and L/A and homeostasis model assessment (HOMA) was found throughout the study.. The L/A ratio and FLI are good markers to follow changes in IR and %TBF after WL during puberty. Insulin more accurately reflects the changes in IR than HOMA.

Topics: Adiponectin; Biomarkers; Body Mass Index; Child; Female; Follow-Up Studies; Humans; Insulin Resistance; Leptin; Models, Biological; Obesity; Prospective Studies; Puberty; Waist Circumference

Hypovitaminosis D has been associated with an increased prevalence of Type 2 diabetes mellitus (DMT2) and metabolic syndrome manifestations. The purpose of this study was to examine the association between 25-hydroxy-vitamin D (25-OH-VitD) levels and indices of insulin resistance (IR), including adipocytokines, in a Saudi population with or without DMT2.. A total of 266 subjects (153 DMT2 and 113 healthy controls) aged 26-80 yr were randomly selected from the existing Biomarkers Screening in Riyadh Program (RIYADH Cohort). Subjects were assessed clinically, anthropometry was performed, morning blood chemistries, including fasting glucose (FG), triglycerides, total cholesterol, LDL cholesterol (LDL-C), and HDL cholesterol were obtained. Homeostasis model assessment of IR (HOMA-IR) was calculated, and serum 25-OH-VitD, leptin, adiponectin, resistin, insulin, high sensitivity CRP (hsCRP), and tumor necrosis factor α concentrations were measured using specific assays.. In DMT2 subjects, negative correlations between 25-OH-vitD and body mass index (BMI), FG, insulin, HOMA-IR, cholesterol, LDL-C, and hsCRP were observed, while a positive correlation between 25-OH-VitD and adiponectin was detected. The later remained significant after controlling for BMI. Interestingly, only weak and nonsignificant associations between 25-OH-VitD and metabolic parameters were observed in the control group, whereas, when the entire population was examined, negative correlations were evident primarily between 25-OH-VitD and FG, HOMA-IR, total cholesterol, LDL-C. These associations remained significant after controlling for BMI.. These results suggest that hypovitaminosis D associations with metabolic disturbances are accentuated in DMT2. The BMIindependent positive correlation between 25-OH-VitD and adiponectin suggests a potential role for this adipocytokine as a link between 25-OH-VitD and IR in patients with DMT2.

Topics: Adipokines; Adiponectin; Adult; Aged; Aged, 80 and over; Body Mass Index; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Prognosis; Vitamin D; Vitamin D Deficiency; Young Adult

The purpose of the present secondary analysis study was to investigate the ability of the body adiposity index (BAI) to detect changes in % body fat levels before and after a weight loss intervention when compared to % body fat levels measured using dual-energy X-ray absorptiometry (DXA) and to examine the relationship between the BAI with cardiometabolic risk factors.. The study population for this secondary analysis included 132 non-diabetic obese sedentary postmenopausal women (age: 57.2 ± 4.7 years, BMI: 35.0 ± 3.7 kg/m(2)) participating in a weight loss intervention that consisted of a calorie-restricted diet with or without resistance training. We measured: (1) visceral fat using CT-scan, (2) body composition using DXA, (3) hip circumference and height from which the BAI was calculated, and (4) cardiometabolic risk factors such as insulin sensitivity (using the hyperinsulinemic-euglycemic clamp), blood pressure as well as fasting plasma lipids, hsC-reactive protein (CRP), leptin, and glucose.. Percent body fat levels for both methods significantly decreased after the weight loss intervention. In addition, the percent change in % body fat levels after the weight loss intervention was significantly different between % body fat measured using the DXA and the BAI (-4.5 ± 6.6 vs. -5.8 ± 5.9%; p = 0.03, respectively). However, we observed a good overall agreement between the two methods, as shown by the Bland-Altman analysis, for percent change in % body fat. Furthermore, similar correlations were observed between both measures of % body fat with cardiometabolic risk factors. However, results from the multiple linear regression analysis showed that % body fat using the BAI appeared to predict cardiometabolic risk factors differently than % body fat using the DXA in our cohort.. Estimating % body fat using the BAI seems to accurately trace variations of % body fat after weight loss. However, this index showed differences in predicting cardiometabolic risk factors when compared to % body fat measured using DXA.

Topics: Absorptiometry, Photon; Adiposity; Blood Glucose; Blood Pressure; Body Composition; Body Mass Index; C-Reactive Protein; Caloric Restriction; Cardiovascular Diseases; Cohort Studies; Female; Humans; Insulin Resistance; Intra-Abdominal Fat; Leptin; Linear Models; Middle Aged; Obesity; Postmenopause; Risk Factors; Triglycerides; Weight Loss

CCAAT/enhancer-binding protein alpha (CEBPA) is a transcription factor involved in adipogenesis and energy homeostasis. Caloric restriction reduces CEBPA protein expression in patients with metabolic syndrome (MetS). A previous report linked rs12691 SNP in CEBPA to altered concentration of fasting triglycerides. Our objective was to assess the effects of rs12691 in glucose metabolism in Metabolic Syndrome (MetS) patients.. Glucose metabolism was assessed by static (glucose, insulin, adiponectin, leptin and resistin plasma concentrations) and dynamic (disposition index, insulin sensitivity index, HOMA-IR and acute insulin response to glucose) indices, performed at baseline and after 12 weeks of 4 dietary interventions (high saturated fatty acid (SFA), high monounsaturated fatty acid (MUFA), low-fat and low-fat-high-n3 polyunsaturated fatty acid (PUFA)) in 486 subjects with MetS. Carriers of the minor A allele of rs12691 had altered disposition index (p = 0.0003), lower acute insulin response (p = 0.005) and a lower insulin sensitivity index (p = 0.025) indicating a lower insulin sensitivity and a lower insulin secretion, at baseline and at the end of the diets. Furthermore, A allele carriers displayed lower HDL concentration.. The presence of the A allele of rs12691 influences glucose metabolism of MetS patients.

Topics: Adiponectin; Adult; Aged; Alleles; Blood Glucose; Body Mass Index; Body Weight; CCAAT-Enhancer-Binding Proteins; Dietary Fats; Dietary Supplements; DNA; Fasting; Fatty Acids; Fatty Acids, Monounsaturated; Fatty Acids, Omega-3; Female; Genotype; Humans; Insulin; Insulin Resistance; Insulin Secretion; Leptin; Lipid Metabolism; Male; Metabolic Syndrome; Middle Aged; Polymorphism, Single Nucleotide; Resistin; Triglycerides

Given that the repetitive loss and regain of body weight, termed weight cycling, is a prevalent phenomenon that has been associated with negative physiological and psychological outcomes, the purpose of this study was to investigate weight change and physiological outcomes in women with a lifetime history of weight cycling enrolled in a 12-month diet and/or exercise intervention.. 439 overweight, inactive, postmenopausal women were randomized to: i) dietary weight loss with a 10% weight loss goal (N=118); ii) moderate-to-vigorous intensity aerobic exercise for 45 min/day, 5 days/week (n=117); ii) both dietary weight loss and exercise (n=117); or iv) control (n=87). Women were categorized as non-, moderate- (≥3 losses of ≥4.5 kg), or severe-cyclers (≥3 losses of ≥9.1 kg). Trend tests and linear regression were used to compare adherence and changes in weight, body composition, blood pressure, insulin, C-peptide, glucose, insulin resistance (HOMA-IR), C-reactive protein, leptin, adiponectin, and interleukin-6 between cyclers and non-cyclers.. Moderate (n=103) and severe (n=77) cyclers were heavier and had less favorable metabolic profiles than non-cyclers at baseline. There were, however, no significant differences in adherence to the lifestyle interventions. Weight-cyclers (combined) had a greater improvement in HOMA-IR compared to non-cyclers participating in the exercise only intervention (P=.03), but no differences were apparent in the other groups.. A history of weight cycling does not impede successful participation in lifestyle interventions or alter the benefits of diet and/or exercise on body composition and metabolic outcomes.

Topics: Adiponectin; Blood Glucose; Blood Pressure; Body Composition; C-Peptide; C-Reactive Protein; Diet, Reducing; Exercise; Female; Humans; Insulin; Insulin Resistance; Interleukin-6; Leptin; Linear Models; Middle Aged; Overweight; Postmenopause; Weight Gain; Weight Loss

Evidence for a causal relationship between sleep-loss and metabolism is derived primarily from short-term sleep deprivation studies in the laboratory. The objective of this study was to investigate whether small changes in sleep duration over a three week period while participants are living in their normal environment lead to changes in insulin sensitivity and other metabolic parameters.. Nineteen healthy, young, normal-weight men were randomised to either sleep restriction (habitual bedtime minus 1.5h) or a control condition (habitual bedtime) for three weeks. Weekly assessments of insulin sensitivity by hyperinsulinaemic-euglycaemic clamp, anthropometry, vascular function, leptin and adiponectin were made. Sleep was assessed continuously using actigraphy and diaries.. Assessment of sleep by actigraphy confirmed that the intervention reduced daily sleep duration by 01:19 ± 00:15 (SE; p<0.001). Sleep restriction led to changes in insulin sensitivity, body weight and plasma concentrations of leptin which varied during the three week period. There was no effect on plasma adiponectin or vascular function.. Even minor reductions in sleep duration lead to changes in insulin sensitivity, body weight and other metabolic parameters which vary during the exposure period. Larger and longer longitudinal studies of sleep restriction and sleep extension are warranted.

Topics: Adiponectin; Adult; Blood Pressure; Body Composition; Body Weight; Glucose Clamp Technique; Humans; Insulin Resistance; Leptin; Longitudinal Studies; Male; Sleep; Sleep Deprivation; Young Adult

GH substitution in GH deficiency (GHD) must be subcutaneously administered daily. A new sustained-release formulation of GH (LB03002) has been developed, which has to be injected once a week. As a substudy to the phase III study, we performed this prospective study to evaluate the influence of LB03002 on metabolic variables and hormones.. Eleven patients with GHD [four women/seven men, 58 years (29-69 years)] without GH therapy were included in the study. Eight patients were treated with LB03002 for 12 months and three patients received placebo for 6 months followed by LB03002 for 6 months. A 3-h oral glucose tolerance test (OGTT) was performed at study entry and at study end. Additionally, IGF-I, cholesterol, LDL, HDL, triglycerides, leptin, ghrelin, HbA1c and C-peptide were measured. Body composition was evaluated by dual-energy X-ray absorptiometry (DXA), and waist/hip ratio (WHR) and waist/height (WHtR) ratio were measured by tape and scale.. Multiple of upper limit of normal (xULN) of IGF-I (0·23 (0·09-0·4) vs 0·71 (0·4-1·04), P < 0·01), WHR (0·98 (0·86-1·04) vs 1·01 (0·86-1·05), P < 0·05) and ghrelin levels [119·8 ng/l (67·7-266·6) vs 137 ng/l (67-289·5), P < 0·05] were significantly higher, whereas fat mass (FM) [34·7% (20·4-49·2) vs 32·4% (16·7-48·5), P < 0·05] and leptin [11·2 μg/l (3·3-55·7) vs 7·05 μg/l (2·4-54·3), P < 0·05] were significantly lower at study end. Glucose, insulin, HOMA-IR, ISI, HOMA-β, C-peptide and HbA1c during OGTT were not significantly different before and after GH substitution, neither were BMI, WHtR, bone mineral density and lipid variables.. Substitution with LB03002 showed statistically significant reduction in FM, which reduces leptin levels and increases ghrelin levels but does not seem to influence glucose and lipid metabolism.

Topics: Adult; Aged; Blood Glucose; Body Composition; Delayed-Action Preparations; Drug Administration Schedule; Female; Ghrelin; Glucose Tolerance Test; Growth Hormone; Humans; Insulin; Insulin Resistance; Leptin; Lipids; Male; Middle Aged

High-molecular weight (HMW) adiponectin is the biologically active form of adiponectin and is related to enhanced insulin sensitivity and metabolic function. Previously, we found that 7 d of exercise improves insulin sensitivity in obese subjects; however, whether short-term exercise training affects HMW adiponectin in obese persons is unknown.. We examined the effect of seven consecutive days of supervised vigorous exercise (60 min · d(-1), 85% HRmax) on HMW adiponectin and leptin secretion in 17 obese individuals (age = 55 ± 3 yr; body mass index = 33.7 ± 0.9 kg · m(-2)). Insulin sensitivity was calculated from an oral glucose tolerance test (ISIOGTT) using the Matsuda Index. Fasting plasma HMW adiponectin and leptin were quantified from blood samples obtained before the ISIOGTT. Glucose and insulin measures were obtained before and every 30 min during the test. Dual-energy x-ray absorptiometry was used to determine body composition, and indirect calorimetry was used to assess fat oxidation.. After the intervention, there was a significant increase in HMW adiponectin (3202 ± 543 vs 3878 ± 682 ng · mL(-1), P = 0.02) and a decrease in leptin (36.8 ± 5.1 vs 31.1 ± 4.2 μg · mL(-1), P = 0.03). Further, we observed an increase in ISIOGTT (1.7 ± 0.3 vs 2.1 ± 0.3, P = 0.04) and a decrease in glucose area under the curve (30,871 ± 2105 vs 28,469 ± 1657 mg · dL(-1) for 3 h, P = 0.01). The increase in HMW adiponectin was positively associated with the increase in basal fat oxidation (r = 0.57, P = 0.03), consistent with an improvement in adipose tissue metabolic function.. The data suggest that 7 d of exercise is sufficient not only to improve insulin sensitivity and fat oxidation but also to favorably alter adipokine secretion, independent of changes in body weight or composition.

Topics: Adiponectin; Adipose Tissue; Blood Glucose; Body Composition; Exercise; Fats; Female; Glucose Tolerance Test; Heart Rate; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Obesity

Low birth weight (LBW) is associated with an increased risk of insulin resistance and downregulation of oxidative phosphorylation (OXPHOS) genes when exposed to a metabolic challenge of high-fat overfeeding (HFO). To elaborate further on the differential effects of HFO in LBW subjects, we measured in vivo mitochondrial function, insulin secretion, hepatic glucose production, and plasma levels of key regulatory hormones before and after 5 days of HFO in 20 young LBW and 26 normal-birth-weight (NBW) men. The LBW subjects developed peripheral insulin resistance after HFO due to impaired endogenous glucose storage (9.42 ± 4.19 vs. 5.91 ± 4.42 mg·kg FFM(-1)·min(-1), P = 0.01). Resting muscle phosphorcreatine and total ATP in muscle increased significantly after HFO in LBW subjects only, whereas additional measurements of mitochondrial function remained unaffected. Despite similar plasma FFA levels, LBW subjects displayed increased fat oxidation during insulin infusion compared with normal-birth-weight (NBW) subjects after HFO (0.37 ± 0.35 vs. 0.17 ± 0.33 mg·kg FFM(-1)·min(-1), P = 0.02). In contrast to NBW subjects, the plasma leptin levels of LBW subjects did not increase, and the plasma gastric inhibitory polypeptide (GIP) as well as pancreatic polypeptide (PP) levels increased less in LBW compared with NBW subjects during HFO. In conclusion, HFO unmasks dissociation between insulin resistance and mitochondrial dysfunction in LBW subjects, suggesting that insulin resistance may be a cause, rather than an effect, of impaired muscle OXPHOS gene expression and mitochondrial dysfunction. Reduced increments in response to HFO of fasting plasma leptin, PP, and GIP levels may contribute to insulin resistance, lower satiety, and impaired insulin secretion in LBW subjects.

Topics: Adenosine Triphosphate; Adipokines; Adult; Cross-Over Studies; Denmark; Diabetes Mellitus, Type 2; Dietary Fats; Gastric Inhibitory Polypeptide; Glucose; Humans; Infant, Low Birth Weight; Infant, Newborn; Insulin Resistance; Leptin; Lipid Metabolism; Male; Mitochondria, Muscle; Muscle, Skeletal; Pancreatic Polypeptide; Phosphocreatine; Protein Precursors; Registries; Young Adult

The lipodystrophies (LD) are characterized by metabolic abnormalities (insulin resistance, hypertriglyceridemia, and diabetes) and a polycystic ovarian syndrome (PCOS) phenotype. Therapeutic administration of leptin improves insulin sensitivity and the metabolic features.. The objective of the study was to investigate whether the PCOS features are corrected by increasing insulin sensitivity as a function of leptin treatment.. This was a prospective, open-label trial using leptin replacement in various forms of lipodystrophy.. The study was performed at the Clinical Center at the National Institutes of Health.. Twenty-three female patients with LD were enrolled in a leptin replacement trial from 2000 to the present. Different parameters were assessed at baseline and after 1 yr of therapy.. Patients were treated with leptin for at least 1 yr.. We evaluated free testosterone, SHBG, and IGF-I at baseline and after 1 yr of leptin.. Testosterone levels decreased from 3.05 ±0.6 ng/ml at baseline to 1.7 ±0.3 ng/ml (P = 0.02). SHBG increased from 14.5 ±2 to 25 ±3.5 nmol/liter after 1 yr of leptin therapy. There were no significant changes in the levels of gonadotropins and ovarian size as a result of leptin replacement therapy. IGF-I increased significantly after leptin therapy from 150 ±14 to 195 ±17. There was a significant decrease in triglycerides and glycosylated hemoglobin in the context of reduced insulin requirements.. In the present study, we show that LD may be a model for the common forms of PCOS and that the endocrine features are corrected by leptin therapy, which reduces insulin resistance.

Topics: Adolescent; Adult; Child; Female; Follow-Up Studies; Hormone Replacement Therapy; Humans; Hyperandrogenism; Insulin Resistance; Leptin; Lipodystrophy; Polycystic Ovary Syndrome; Time Factors; Young Adult

To investigate the effect of a soy isoflavone extract over insulin sensitivity and plasma leptin levels.. Eighty postmenopausal women were randomly assigned to participate for 24 months either to a physical exercise and Mediterranean diet program (Control group: CG) or this intervention plus a daily oral intake of a soy isoflavone extract (Soy isoflavone group: SIG). Anthropometry, body composition analysis, blood biochemistry, menopausal symptoms and health-related quality of life were assessed at baseline and every 6 months.. Sixty-five women completed the protocol with no differences found among groups at baseline in age and time since the menopause. At month 24, body mass index (BMI) was lower in the SIG as compared to the CG. Fat mass, glucose, insulin, HOMA-IR, tumor necrosis factor-α (TNF-α), Kupperman Index and Cervantes Scale values significantly decreased in the SIG as compared to baseline and to CG values. Kupperman scores and serum TNF-α levels significantly decreased in both studied groups. No changes in plasma leptin levels were observed after 24 months within and between groups. When analysis was stratified according to BMI values, changes in the aforementioned parameters displayed a similar trend; however, the impact over glucose, insulin and HOMA-IR values was more evident among obese women assigned to the SIG.. Diet, physical exercise and a daily oral intake of soy isoflavones exerted a beneficial effect on the homeostatic model in postmenopausal women which was not related to significant changes in plasma leptin levels, despite a decrease in TNF-α, fat mass and Kupperman values.

Topics: Blood Glucose; Body Composition; Body Mass Index; Diet, Mediterranean; Exercise; Female; Glycine max; Humans; Insulin; Insulin Resistance; Isoflavones; Leptin; Longitudinal Studies; Middle Aged; Postmenopause; Quality of Life; Tumor Necrosis Factor-alpha

This study aimed to determine in obese women if endocannabinoid receptor antagonism has effects on fatty acid and triglyceride metabolism and insulin sensitivity which are independent from the metabolic effects of weight loss. Fourteen obese (BMI=33.0±0.5 kg/m(2)) (mean±SEM) Caucasian post-menopausal women, aged 57.8±4.7 years were studied. The women were randomised to 2 groups, one group received the endocannabinoid receptor antagonist rimonabant (20 mg/d) for 12 weeks. A control group achieved the same weight loss by a hypocaloric dietary intervention over 12 weeks. Palmitate production rate (Ra), a measure of lipolysis, and palmitate oxidation rate, and VLDL(1) and VLDL(2) triglyceride (TG) kinetics, were measured using isotopic tracers before and after the intervention. Weight loss was not different in the 2 groups; 2.6±0.5 kg with rimonabant and 3.1±1.0 kg in the control group. Palmitate Ra increased with rimonabant with no change in the control group (p=0.03 between groups). Palmitate oxidation rate increased with rimonabant but decreased in the control group (p=0.005 between groups). VLDL(1) TG secretion rate decreased in the control group and increased in the rimonabant group (p=0.008 between groups). There was no significant effect on insulin sensitivity. This study suggests that endocannabinoid receptor antagonism for 12 weeks in obese women increased lipolysis and fatty acid oxidation. The increase in VLDL(1) TG secretion rate may be due to the increase in lipolysis which exceeded the increase in fatty acid oxidation.

Topics: Adiponectin; Aged; Breath Tests; Cannabinoid Receptor Antagonists; Cholesterol; Diet, Reducing; Energy Intake; Energy Metabolism; Fatty Acids; Female; Humans; Insulin Resistance; Leptin; Lipolysis; Lipoproteins, VLDL; Middle Aged; Obesity; Oxidation-Reduction; Palmitic Acids; Piperidines; Pyrazoles; Rimonabant; Triglycerides; United Kingdom; Weight Loss

We evaluated the long-term effects of rosuvastatin and simvastatin on insulin sensitivity and secretion in patients with well-controlled type 2 diabetes.. After a 3 weeks run-in, 27 eligible patients were randomly assigned to receive either rosuvastatin 20 mg daily (Group 1) or simvastatin 20 mg daily (Group 2) for 6 months; thereafter they were switched to the other treatment for additional 6 months. Patients were recruited among individuals attending the outpatient service of the Diabetology Unit of the "Policlinico Tor Vergata" University Hospital, Rome, Italy. Serum lipids, glucose and insulin, glycated hemoglobin, C-reactive protein, TNF-α, leptin, adiponectin, insulin sensitivity by euglycemic-hyperinsulinemic clamp, β-cells function by HOMA-β were assessed at months 0, 6 and 12. Additionally, endothelial function was assessed by use of the brachial artery reactivity technique.. Besides marked reduction in lipid levels, glycated hemoglobin significantly increased from baseline after 12 months in both Group 1 (+0.8 ± 0.2%, p < 0.001) and Group 2 (+0.9 ± 0.3%; p < 0.001). Similar trends were observed for fasting glucose in both groups. No changes in insulin sensitivity were detected throughout the study, whereas HOMA-β significantly decreased from baseline after 12 months in both Group 1 (-21.9%, p < 0.01) and Group 2 (-38.9%; p < 0.001). In addition, both treatments similarly decreased C-reactive protein and leptin, as well as improved endothelial function. No changes in anthropometric measures were observed.. In well-controlled type 2 diabetic patients both rosuvastatin and simvastatin significantly impaired glycemic control and insulin secretion, without affecting insulin sensitivity.

Topics: Adiponectin; Biomarkers; Blood Glucose; Brachial Artery; C-Reactive Protein; Chi-Square Distribution; Cross-Over Studies; Diabetes Mellitus, Type 2; Endothelium, Vascular; Female; Fluorobenzenes; Glucose Clamp Technique; Glycated Hemoglobin; Homeostasis; Hospitals, University; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Leptin; Lipids; Male; Middle Aged; Pyrimidines; Rome; Rosuvastatin Calcium; Simvastatin; Single-Blind Method; Sulfonamides; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

Reduced energy expenditure following weight loss is thought to contribute to weight gain. However, the effect of dietary composition on energy expenditure during weight-loss maintenance has not been studied.. To examine the effects of 3 diets differing widely in macronutrient composition and glycemic load on energy expenditure following weight loss.. A controlled 3-way crossover design involving 21 overweight and obese young adults conducted at Children's Hospital Boston and Brigham and Women's Hospital, Boston, Massachusetts, between June 16, 2006, and June 21, 2010, with recruitment by newspaper advertisements and postings.. After achieving 10% to 15% weight loss while consuming a run-in diet, participants consumed an isocaloric low-fat diet (60% of energy from carbohydrate, 20% from fat, 20% from protein; high glycemic load), low-glycemic index diet (40% from carbohydrate, 40% from fat, and 20% from protein; moderate glycemic load), and very low-carbohydrate diet (10% from carbohydrate, 60% from fat, and 30% from protein; low glycemic load) in random order, each for 4 weeks.. Primary outcome was resting energy expenditure (REE), with secondary outcomes of total energy expenditure (TEE), hormone levels, and metabolic syndrome components.. Compared with the pre-weight-loss baseline, the decrease in REE was greatest with the low-fat diet (mean [95% CI], -205 [-265 to -144] kcal/d), intermediate with the low-glycemic index diet (-166 [-227 to -106] kcal/d), and least with the very low-carbohydrate diet (-138 [-198 to -77] kcal/d; overall P = .03; P for trend by glycemic load = .009). The decrease in TEE showed a similar pattern (mean [95% CI], -423 [-606 to -239] kcal/d; -297 [-479 to -115] kcal/d; and -97 [-281 to 86] kcal/d, respectively; overall P = .003; P for trend by glycemic load < .001). Hormone levels and metabolic syndrome components also varied during weight maintenance by diet (leptin, P < .001; 24-hour urinary cortisol, P = .005; indexes of peripheral [P = .02] and hepatic [P = .03] insulin sensitivity; high-density lipoprotein [HDL] cholesterol, P < .001; non-HDL cholesterol, P < .001; triglycerides, P < .001; plasminogen activator inhibitor 1, P for trend = .04; and C-reactive protein, P for trend = .05), but no consistent favorable pattern emerged.. Among overweight and obese young adults compared with pre-weight-loss energy expenditure, isocaloric feeding following 10% to 15% weight loss resulted in decreases in REE and TEE that were greatest with the low-fat diet, intermediate with the low-glycemic index diet, and least with the very low-carbohydrate diet.. clinicaltrials.gov Identifier: NCT00315354.

Topics: Adult; Cholesterol, HDL; Cross-Over Studies; Diet, Carbohydrate-Restricted; Diet, Fat-Restricted; Energy Metabolism; Female; Glycemic Index; Humans; Hydrocortisone; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Nutritive Value; Obesity; Overweight; Plasminogen Activator Inhibitor 1; Triglycerides; Weight Loss; Young Adult

Elevated thyroid-stimulating hormone (TSH) concentrations in association with normal/slightly elevated free triiodothyronine (fT(3)) and/or free thyroxine (fT(4)) have been consistently found in obese children. To examine relationships between adiposity, insulin sensitivity, and TSH, fT(3) and fT(4).. 240 overweight/obese prepubertal children were studied. Fasting TSH, fT(3), fT(4), glucose, insulin, C-peptide, lipids, leptin and adiponectin were evaluated. Insulin sensitivity and resistance were estimated [quantitative insulin check index (QUICKI), insulin sensitivity index (ISI), and hepatic insulin resistance index]. Body fat was measured by dual-energy X-ray absorptiometry. The central obesity index was calculated as the ratio of fat tissue in the trunk region to fat tissue in the leg region.. The multiple regression analysis with age, gender and measures of fatness as covariates showed that QUICKI was the only significant negative predictor of TSH and central obesity index the strongest positive predictor of fT(3), in association with either age or hepatic insulin resistance index, and that the only positive determinant of fT(4) was hepatic insulin resistance index.. Reduced insulin sensitivity is associated with augmented TSH and fT(4), while progressive central fat accumulation is strictly related to a parallel increase in fT(3) levels, independently from total body fat. Further studies are needed to understand mechanisms linking thyroid function to insulin sensitivity and body composition in obese children.

Topics: Adiponectin; Adiposity; Blood Glucose; C-Peptide; Child; Female; Humans; Insulin; Insulin Resistance; Leptin; Lipids; Male; Obesity; Thyroid Function Tests; Thyroxine; Triiodothyronine

Concerns regarding worsening insulin sensitivity associated with statin treatment have recently emerged. Therefore the aim of this study was to assess and compare the effects of 90-day monotherapies with fenofibrate and atorvastatin, as well as combined therapy, on fasting plasma glucose, insulin resistance index, adipokines (leptin, resistin, adiponectin) and levels of proinflammatory cytokines (TNF-α, IL-6) in patients with impaired fasting glucose (IFG) and mixed hyperlipidemia.. 67 patients were randomly assigned to four treatment arms: monotherapy with atorvastatin, monotherapy with fenofibrate, combined therapy (fenofibrate and torvastatin) or therapeutic lifestyle change. The study lasted for 90 days. All participants received counseling regarding proper diet and physical activity.. Compared to the control subjects, prediabetic patients exhibited elevated plasma levels of leptin, resistin, TNF-α and IL-6, and a lower plasma level of adiponectin. All therapeutic interventions resulted in significant alterations in the lipid profile. Insulin resistance index (HOMA-IR) was reduced after treatment with fenofibrate. The effect of atorvastatin on insulin resistance was comparable to therapeutic lifestyle change alone. Therapy with hypolipidemic drugs caused increases in adiponectin levels and decreases in leptin and resistin. An additive effect of the combined treatment on plasma IL-6 level was also observed.. Fenofibrate-based treatment was associated with improved insulin sensitivity. Atorvastatin did not cause a deterioration in insulin sensitivity. Hypolipidemic therapies resulted in significant changes in the proinflammatory cytokine network as well as in adipokine levels. At the end of the study the measured parameters nearly resembled those of the healthy subjects.

Topics: Adipokines; Adiponectin; Adult; Aged; Analysis of Variance; Atorvastatin; Biomarkers; Blood Glucose; Cytokines; Drug Therapy, Combination; Female; Fenofibrate; Glucose Metabolism Disorders; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipoproteinemia Type V; Hypolipidemic Agents; Inflammation Mediators; Insulin; Insulin Resistance; Interleukin-6; Leptin; Lipids; Male; Middle Aged; Poland; Pyrroles; Resistin; Risk Reduction Behavior; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

Lipodystrophy encompasses a group of rare disorders characterized by deficiency of adipose tissue resulting in hypoleptinemia, and metabolic abnormalities including insulin resistance, diabetes, dyslipidemia, and nonalcoholic steatohepatitis. Leptin replacement effectively ameliorates these metabolic derangements. We report effects of leptin discontinuation and resumption in a child with acquired generalized lipodystrophy.. Intermittent treatment with leptin with follow-up over 5 years.. Pretreatment metabolic abnormalities included insulin resistance, hypertriglyceridemia and steatohepatitis. Leptin was started at the age of 10 years. After 2 years, the family requested discontinuation of leptin due to lack of visible physical changes. Nine months later, worsened metabolic abnormalities and arrest of pubertal development were observed. Leptin was restarted, followed by improvements in metabolic parameters. Laboratory changes (before vs. 6 months after restarting leptin) were: fasting glucose from 232 to 85 mg/dl, insulin from 232 to 38.9 µU/ml, HbA(1c) from 7.5 to 4.8%, triglycerides from 622 to 96 mg/dl, ALT from 229 to 61 U/l, AST from 91 to 18 U/l, and urine protein:creatinine ratio from 5.4 to 0.3. Progression of puberty was observed 1 year after restarting leptin.. Initial leptin therapy likely prevented progression of metabolic abnormalities. Treatment discontinuation led to rapid metabolic decomposition and pubertal arrest. Reintroduction of leptin reversed metabolic abnormalities and allowed normal pubertal progression.

Topics: Adolescent; Alanine Transaminase; Blood Glucose; Child; Fatty Liver; Female; Glycated Hemoglobin; Humans; Insulin Resistance; Leptin; Lipodystrophy; Non-alcoholic Fatty Liver Disease; Puberty; Triglycerides

The aim of the study was to compare the baseline and the 18-month follow-up for weight and metabolic characteristics of superobese (SO) (body mass index [BMI] ≥50 kg/m(2)) and morbidly obese (MO) (BMI <50 kg/m(2)) adolescents who participated in a prospective longitudinal study of gastric banding delivered in an adolescent multidisciplinary treatment program.. Clinical information was extracted from an institutional review board-approved database of bariatric adolescents. Fasting cytokine and acute phase protein serum levels were analyzed by enzyme-linked immunosorbent assay. Liver histopathologies were assessed using the Kleiner's classification score.. Other than BMI, MO (n = 11) and SO (n = 7) patients have similar degree of insulin resistance, dyslipidemia, and nonalcoholic fatty liver disease. Serum C-reactive protein (10.2 ± 5.6 SO vs 4 ± 3.9 μg/mL MO [P < .02]) and leptin (71 ± 31 SO vs 45 ± 28 MO ng/mL [P = .04]) were more elevated in SO patients. Although weight loss is similar (30 ± 19 kg MO vs 28 ± 12 kg SO, P = .8 at 18 months; mean percent change in BMI, 22.8% ± 11.6% vs 20.5% ± 10.3% SO, P = .2), SO patients has less resolution of insulin resistance and dyslipidemia but experienced significantly improved health-related quality of life.. The SO adolescents demonstrate equivalent short-term weight loss and improved quality of life but delayed metabolic response to a gastric banding-based weight loss treatment program compared with MO patients, illustrating the importance of early referral for timely intervention of MO patients.

Topics: Acute-Phase Proteins; Adolescent; Biomarkers; Body Mass Index; Cross-Sectional Studies; Cytokines; Dyslipidemias; Enzyme-Linked Immunosorbent Assay; Fatty Liver; Follow-Up Studies; Gastroplasty; Humans; Insulin Resistance; Laparoscopy; Leptin; Metabolic Syndrome; Non-alcoholic Fatty Liver Disease; Obesity, Morbid; Prospective Studies; Treatment Outcome; Weight Loss; Weight Reduction Programs

Daughters of diabetes patients have lower insulin sensitivity than women with no diabetes family history, but increase insulin sensitivity to a greater extent with exercise training. This study aimed to determine whether differences in circulating concentrations of adiponectin and leptin, and adipose tissue expression of their genes and receptors played a role. Women offspring of patients with type 2 diabetes mellitus (n = 34; age, 35.6 ± 7.0 years; body mass index, 28.1 ± 5.1 kg/m²) and matched controls with no diabetes family history (n = 36; age, 33.6 ± 6.1 years; body mass index, 27.3 ± 4.7 kg/m²) participated. Blood and abdominal subcutaneous adipose tissue samples were obtained at baseline and after a controlled 7-week endurance-type exercise intervention (sessions were performed at 65%-80% of maximum heart rate). At baseline, no significant differences were observed between groups in circulating leptin or adiponectin concentrations, or expression of their genes or receptors. In response to exercise, plasma leptin decreased more in offspring than controls (-32.2% vs -7.3%, P = .005 for interaction); and the long isoform of the leptin receptor messenger RNA (mRNA) increased significantly only in the offspring (+39.4%, P = .026 vs +7.7%, P = .892). Leptin mRNA decreased similarly in both groups (-24.7% vs -25.0%, P < .05 for both). Furthermore, changes in plasma leptin (r = -0.432, P < .001) and leptin mRNA (r = -0.298, P = .019) correlated significantly with changes in insulin sensitivity. Plasma adiponectin decreased similarly in both groups (-12.1% vs -15.2%, P < .01 for both), but no significant changes were observed in adiponectin-related gene expression. This work shows that exercise training has differing effects on leptin-related variables between women with and without a diabetes family history and suggests that these molecular differences may contribute to the differential effects of exercise training on insulin sensitivity between these 2 groups.

Topics: Abdominal Fat; Adiponectin; Adult; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Exercise; Family; Female; Gene Expression; Humans; Insulin; Insulin Resistance; Leptin; Physical Endurance; Receptors, Adiponectin; Receptors, Leptin

The aim of the study was to evaluate the effects of 12-month treatment with sibutramine plus L-carnitine compared with sibutramine alone on body weight, glycemic control, insulin resistance, and inflammatory state in type 2 diabetes mellitus patients. Two hundred fifty-four patients with uncontrolled type 2 diabetes mellitus (glycated hemoglobin [HbA(1c)] >8.0%) in therapy with different oral hypoglycemic agents or insulin were enrolled in this study and randomized to take sibutramine 10 mg plus L-carnitine 2 g or sibutramine 10 mg in monotherapy. We evaluated at baseline and after 3, 6, 9, and 12 months these parameters: body weight, body mass index, HbA(1c), fasting plasma glucose, postprandial plasma glucose, fasting plasma insulin, homeostasis model assessment of insulin resistance index, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, leptin, tumor necrosis factor-α, adiponectin, vaspin, and high-sensitivity C-reactive protein. Sibutramine plus L-carnitine gave a faster improvement of fasting plasma glucose, postprandial plasma glucose, lipid profile, leptin, tumor necrosis factor-α, and high-sensitivity C-reactive protein compared with sibutramine alone. Furthermore, there was a better improvement of body weight, HbA(1c), fasting plasma insulin, homeostasis model assessment of insulin resistance index, vaspin, and adiponectin with sibutramine plus L-carnitine compared with sibutramine alone. Sibutramine plus L-carnitine gave a better and faster improvement of all the analyzed parameters compared with sibutramine alone without giving any severe adverse effect.

Topics: Aged; Appetite Depressants; Blood Glucose; Body Weight; C-Reactive Protein; Carnitine; Cholesterol; Cyclobutanes; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Insulin Resistance; Leptin; Longitudinal Studies; Male; Middle Aged; Tumor Necrosis Factor-alpha; Vitamin B Complex

The efficacy of sibutramine has been demonstrated in randomized trials in obese/overweight patients including those with type 2 diabetes mellitus (T2DM). Our objective was to evaluate the effects of 1-year treatment with sibutramine compared to placebo on body weight, glycaemic control, lipid profile, and inflammatory parameters in type 2 diabetic patients.. Two hundred and forty-six patients with uncontrolled T2DM [glycated haemoglobin (HbA(1c) ) > 8·0%] in therapy with different oral hypoglycaemic agents or insulin were randomized to take 10 mg of sibutramine or placebo for 12 months. We evaluated at baseline, and after 3, 6, 9, and 12 months these parameters: body weight, body mass index (BMI), HbA(1c) , fasting plasma glucose (FPG), post-prandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index (HOMA-IR), total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), triglycerides (Tg), leptin, tumour necrosis factor-α (TNF-α), adiponectin (ADN), vaspin, high sensitivity C-reactive protein (Hs-CRP).. We observed a decrease of body weight after 9 and 12 months in the group treated with sibutramine, but not in the control group. Regarding glycaemic and lipid profile, although there are differences seen over time within each of the groups, we did not obtain any significant differences between the two groups. Both placebo and sibutramine gave a similar improvement of HOMA-IR, leptin, TNF-α, ADN, and Hs-CRP. No vaspin variations were observed in either group.. Sibutramine resulted in a decrease in body weight at 9 months and at 12 months that was not observed with placebo. Although there were differences seen over time within each of the groups, there were no significant differences between groups for any other parameter that we measured.

Topics: Adiponectin; Appetite Depressants; Blood Glucose; Body Mass Index; Body Weight; C-Reactive Protein; Comorbidity; Cyclobutanes; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Inflammation; Insulin; Insulin Resistance; Leptin; Lipids; Male; Middle Aged; Obesity; Placebos; Randomized Controlled Trials as Topic; Thiazolidinediones; Time Factors

To evaluate the effects of 1-year treatment with orlistat plus L-carnitine compared to orlistat alone on body weight, glycemic and lipid control, and inflammatory parameters in obese type 2 diabetic patients. Two hundred and fifty-eight patients with uncontrolled type 2 diabetes mellitus (T2DM) [glycated hemoglobin (HbA(1c)) > 8.0%] in therapy with different oral hypoglycemic agents or insulin were enrolled in this study and randomized to take orlistat 120 mg three times a day plus L-carnitine 2 g one time a day or orlistat 120 mg three times a day. We evaluated the following parameters at baseline and after 3, 6, 9, and 12 months: body weight, body mass index (BMI), glycated hemoglobin (HbA(1c) ), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index (HOMA-IR), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (Tg), adiponectin (ADN), leptin, tumor necrosis factor-α (TNF-α), vaspin, and high-sensitivity C-reactive protein (Hs-CRP). We observed a better decrease in body weight, glycemic profile, HOMA-IR, LDL-C, and ADN and a faster improvement in FPI, TC, Tg, leptin, TNF-α, Hs-CRP with orlistat plus L-carnitine compared to orlistat alone. We also recorded an improvement in vaspin with orlistat plus l-carnitine not reached with orlistat alone. Orlistat plus L-carnitine gave a better improvement in body weight, glycemic and lipid profile compared to orlistat alone; furthermore, a faster and better improvement in inflammatory parameters was observed with orlistat plus L-carnitine compared to orlistat alone.

Topics: Adiponectin; Anti-Inflammatory Agents; Anti-Obesity Agents; Blood Glucose; Body Mass Index; Body Weight; C-Reactive Protein; Carnitine; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Inflammation; Insulin; Insulin Resistance; Lactones; Leptin; Lipoproteins, HDL; Lipoproteins, LDL; Male; Middle Aged; Obesity; Orlistat; Thiazolidinediones; Time Factors

Highly active antiretroviral therapy (HAART)-induced lipoatrophy is characterized by hypoleptinemia and insulin resistance. Evidence suggests that pioglitazone and recombinant methionyl human leptin (metreleptin) administration has beneficial effects in human immunodeficiency virus (HIV)-infected lipoatrophic patients. This proof-of-concept study aimed at evaluating whether the combination of metreleptin and pioglitazone has favorable effects, above and beyond pioglitazone alone, on both metabolic outcomes and peripheral lipoatrophy in HIV-infected patients on HAART. Nine HIV-positive men with at least 6 months of HAART exposure, clinical evidence of lipoatrophy, and low leptin concentrations (≤4 ng/mL) were placed on pioglitazone treatment (30 mg/d per os) and were randomized to receive either metreleptin (0.04 mg/kg subcutaneously once daily; n = 5) or placebo (n = 4) for 3 months in a double-blinded fashion. Compared with placebo, metreleptin reduced fasting serum insulin concentration, increased adiponectin concentration, reduced the homeostasis model assessment index of insulin resistance, and attenuated postprandial glycemia in response to a mixed meal (all P ≤ .02), but did not affect trunk and peripheral fat mass. HIV control was not affected, and no major adverse effects were observed. Metreleptin administration in HIV-positive, leptin-deficient patients with lipoatrophy treated with pioglitazone improves postprandial glycemia and insulin sensitivity. Results from this pilot study should be confirmed in larger clinical trials.

Topics: Adiponectin; Adult; Antiretroviral Therapy, Highly Active; Blood Glucose; Body Mass Index; Drug Therapy, Combination; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Pilot Projects; Pioglitazone; Postprandial Period; Thiazolidinediones

Fasting leptin and ghrelin levels were measured in 36 insulin-sensitive (IS) and 28 insulin-resistant (IR) men who consumed a legume-enriched low-glycemic index (LG) diet or healthy American (HA) diet in a randomly ordered cross-over feeding study consisting of two 4-week periods. Weight remained stable over the entire study. Fasting plasma leptin was significantly reduced from pre-study levels by both the LG (18.8%, P < 0.001) and HA (16.1%, P < 0.001) diets, whereas fasting ghrelin did not change. By subgroup analysis according to prestudy insulin status, leptin was reduced in IR subjects after both the LG (17.1%, P < 0.01) and the HA (33.3%, P < 0.001) diets, whereas IS subjects responded only after the LG diet (23.1%, P < 0.01). Thus, a legume-rich LG index diet may be a beneficial strategy for reducing circulating leptin concentrations, even under conditions of weight maintenance.

Topics: Body Weight; Cross-Over Studies; Fabaceae; Ghrelin; Glycemic Index; Humans; Insulin; Insulin Resistance; Leptin; Male

This study was designed to investigate the effect of a low-calorie diet with carbohydrates eaten mostly at dinner on anthropometric, hunger/satiety, biochemical, and inflammatory parameters. Hormonal secretions were also evaluated. Seventy-eight police officers (BMI >30) were randomly assigned to experimental (carbohydrates eaten mostly at dinner) or control weight loss diets for 6 months. On day 0, 7, 90, and 180 blood samples and hunger scores were collected every 4 h from 0800 to 2000 hours. Anthropometric measurements were collected throughout the study. Greater weight loss, abdominal circumference, and body fat mass reductions were observed in the experimental diet in comparison to controls. Hunger scores were lower and greater improvements in fasting glucose, average daily insulin concentrations, and homeostasis model assessment for insulin resistance (HOMA(IR)), T-cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) levels were observed in comparison to controls. The experimental diet modified daily leptin and adiponectin concentrations compared to those observed at baseline and to a control diet. A simple dietary manipulation of carbohydrate distribution appears to have additional benefits when compared to a conventional weight loss diet in individuals suffering from obesity. It might also be beneficial for individuals suffering from insulin resistance and the metabolic syndrome. Further research is required to confirm and clarify the mechanisms by which this relatively simple diet approach enhances satiety, leads to better anthropometric outcomes, and achieves improved metabolic response, compared to a more conventional dietary approach.

Topics: Adipokines; Adiponectin; Adipose Tissue; Adult; Blood Glucose; C-Reactive Protein; Cholesterol; Diet, Carbohydrate-Restricted; Diet, Reducing; Dietary Carbohydrates; Fasting; Feeding Behavior; Female; Humans; Hunger; Insulin; Insulin Resistance; Interleukin-6; Leptin; Male; Middle Aged; Obesity; Obesity, Abdominal; Tumor Necrosis Factor-alpha; Weight Loss

Estrogen sulfotransferase (EST) catalyzes the inactivation of estrone and estradiol in numerous tissues. Animal studies suggest that EST modulates glucose and lipid metabolism in adipose tissue, but it is unknown whether EST is expressed in human adipose tissue and, if so, how its expression relates to features of the metabolic syndrome.. Cross-sectional data from 16 obese men and women with metabolic dysregulation were collected as part of a larger randomized trial at an academic medical center.. Participants underwent assessment of body composition, oral glucose tolerance testing, measurement of serum hormones and inflammatory markers, and sc fat biopsy to assess adipose expression of TNF-α, suppressor of cytokine signaling 3 (SOCS3), leptin, adiponectin, and EST.. EST expression was detectable in sc adipose tissue from both men and women. Log(10) EST mRNA was not significantly associated with age, race, sex or menopausal status, or circulating levels of estrogen or testosterone. In univariate analysis, log(10) EST mRNA was significantly associated with visceral adipose tissue area (r = 0.57, P = 0.02) as well as adipose tissue expression of TNF-α (r = 0.94, P < 0.0001) and SOCS3 mRNA (r = 0.93, P < 0.0001). The associations between EST expression and TNF-α and SOCS3 held in multivariate modeling controlling for age, race, sex and menopausal status, and visceral adiposity. EST expression was not significantly associated with the adipose tissue levels of leptin or adiponectin expression.. EST is expressed in abdominal sc adipose tissue of both obese males and females in association with expression of TNF-α and SOCS3, suggesting potential roles in inflammation. Further studies are needed to determine the specific metabolic roles of EST expression in human adipose tissue.

Topics: Adiponectin; Adult; Body Composition; Cross-Sectional Studies; Female; Glucose Tolerance Test; Humans; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Middle Aged; Obesity; Subcutaneous Fat; Sulfotransferases; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Tumor Necrosis Factor-alpha

Patients with moderate-to-severe plaque-type psoriasis exhibit increased cardiovascular mortality. Recent publications point towards psoriasis-induced insulin resistance as an important pathomechanism driving cardiovascular comorbidity in these patients. As the hormonal status in general and sex hormone-binding globulin (SHBG) in particular serve as sensitive indicators for insulin resistance, we analysed these parameters in the context of a set of multiple additional clinical and laboratory measurements in a cohort of male patients. Of 33 consecutively enrolled male patients receiving continuous systemic therapy for their moderate-to-severe plaque-type psoriasis, 23 male patients for whom all parameters could be collected over a 24-week treatment period were included in this analysis. At baseline, testosterone levels varied between 212 and 660 ng/ml (median: 377.0), and SHBG between 11.9 and 46.0 nmol/l (median: 29.2), thus documenting lack of hypogonadism among these patients. Clinically, 19/23 patients experienced at least a 50% reduction in their PASI under therapy. Using a multivariate regression model to further analyse the sub-group of patients responding to treatment, hs-CRP, PASI, leptin and resistin all improved under effective systemic anti-inflammatory therapy, thus losing their significant influence on SHBG. SHBG performed well as a sensitive biomarker for insulin resistance and systemic inflammation in these patients. Its improvement, as well as the reduction of resistin serum levels, most likely reflects a state of reduced cardiovascular risk in patients undergoing effective continuous systemic therapy. Long-term safety data, generated e.g. from psoriasis registries, are needed to assess whether this effect translates into reduced cardiovascular mortality.

Topics: Adult; Aged; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Disease Progression; Follow-Up Studies; Humans; Inflammation; Insulin Resistance; Leptin; Male; Middle Aged; Pilot Projects; Prospective Studies; Psoriasis; Resistin; Risk; Sex Hormone-Binding Globulin; Testosterone

To study the relationship between serum leptin and insulin resistance, and to analyze the effect of acupuncture on serum leptin level in patients with type-II diabetes mellitus (DM).. A total of 80 type-II DM patients were randomized into acupuncture and medication groups. Acupuncture was applied to Yishu (EX), Feishu (BL13), Pishu (BL 20), etc. according to syndrome identification. The treatment was given once every other day for 12 weeks. For patients in the medication group, Glibenclamide (2.5-7.5 mg/time, 1-2 times/d according to blood sugar level) was given for 12 weeks. Fasting blood glucose (FBG), fasting insulin (FINS) and fasting leptin (FLP) were detected by using glucose oxidase method, radioimmunoassay and ELISA, respectively. Insulin sensitivity index (ISI) and homeostasis model assessment-insulin resistance (HOMA-IR) were calculated.. In comparison with pre-treatment, FBG levels and HOMA-IR in both acupuncture and medication groups, and FINS and FLP levels in the acupuncture group were decreased significantly (P < 0.01), while ISI in both acupuncture and medication groups, and FINS level in the medication group were increased remarkably after the treatment (P < 0.01). Comparison between two groups showed that after the treatment, FINS and FLP levels, and HOMA-IR of the acupuncture group were considerably lower than those of the medication group (P < 0.01), while ISI of the acupuncture group was significantly higher than that of the medication group (P < 0.01).. Acupuncture therapy is effective in lowering FLP level, which may contribute to its clinical effect in improving type-II DM.

Topics: Acupuncture Therapy; Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Fasting; Female; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged

The aim of the study was to evaluate the effect of quinapril on HOMA-IR, high sensitive C-reactive protein and leptin. Total 54 hypertensive and 24 control subjects were included in this study. Blood pressure, leptin, high sensitive C-reactive protein, and HOMA-IR were determined at baseline and after 3 months quinapril treatment. After treatment with quinapril HOMA-IR (p = 0.04), high sensitive C-reactive protein (p = 0.027), and leptin (p = 0.046) were decreased in hypertensive patients. Quinapril may be used as a therapy for improving blood pressure as well as the insulin resistant, hyperleptinemic, and low-grade inflammatory state in hypertension.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; C-Reactive Protein; Female; Homeostasis; Humans; Hypertension; Inflammation; Insulin Resistance; Leptin; Male; Middle Aged; Quinapril; Tetrahydroisoquinolines; Treatment Outcome

The intake of wholemeal foods is consistently associated with reduced risk of type 2 diabetes and cardiovascular diseases in epidemiological studies, although the mechanisms of this association are unclear. Here we aim to compare in healthy subjects the metabolic effects of a diet rich in wholemeal wheat foods versus one based on the same products in refined form.. Fifteen healthy individuals (12 M/3 F), mean age 54.5+/-7.6 years, BMI 27.4+/-3.0 kg/m(2) (mean+/-SD), participated in a randomized sequential crossover study. After 2 weeks run-in, participants were randomly assigned to two isoenergetic diets with similar macronutrient composition, one rich in wholemeal wheat foods and the other with the same foods but in refined form (cereal fibre 23.1 vs. 9.8 g/day). After the two treatment periods (each lasting 3 weeks) plasma glucose and lipid metabolism, antioxidant activity, acetic acid, magnesium, adipokines, incretins and high-sensitivity C-reactive protein (hs-CRP) were measured at fasting and for 4h after a standard test meal (kcal 1103, protein 12%, CHO 53%, fat 35%) based on wholemeal or refined wheat foods, respectively. After the two diets there were no differences in fasting nor in postprandial plasma parameter responses; only glucose was slightly but significantly lower at 240 min after the refined wheat food meal compared to the wholemeal wheat food meal. Conversely, after the wholemeal diet both total (-4.3%; p<0.03) and LDL (-4.9%; p<0.04) cholesterol levels were lower than after the refined wheat diet at fasting.. Consumption of wholemeal wheat foods for 3 weeks reduces significantly fasting plasma cholesterol as well as LDL cholesterol levels in healthy individuals without major effects on glucose and insulin metabolism, antioxidant status and sub-clinical inflammation markers.

Topics: Blood Glucose; Blood Pressure; Body Weight; C-Peptide; Cardiovascular Diseases; Cholesterol; Cholesterol, LDL; Cross-Over Studies; Diet; Fasting; Female; Food Handling; Gastric Inhibitory Polypeptide; Ghrelin; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Risk Factors; Triticum

To detect the levels of visfatin and leptin in the serum as well as in the follicular fluid (FF) of polycystic ovary syndrome (PCOS) patients undergoing controlled ovarian stimulation and to compare them with the levels found in age- and weight-matched normally ovulating women under IVF treatment.. Prospective study.. Assisted Reproduction Unit, Second Department of Obstetrics and Gynecology, University of Athens, Aretaieion Hospital, Athens, Greece.. Forty patients with diagnosed PCOS and 40 age- and weight-matched non-PCOS control women enrolled in the IVF program.. Blood and FF samples were collected from all subjects at oocyte retrieval.. Visfatin and leptin levels were measured in serum and FF using ELISA.. Serum visfatin levels were significantly increased in women with PCOS, whereas FF visfatin levels, which were lower than serum levels, did not differ between groups. Serum leptin levels did not differ between groups and were lower than FF levels.. Women with polycystic ovaries exhibit significantly increased serum visfatin and decreased FF leptin levels compared with control subjects of similar age and body mass index, indicating a probable role for visfatin in the general state of insulin resistance and a local contribution in the follicle for leptin in patients undergoing IVF treatment.

Topics: Adult; Age Factors; Body Mass Index; Cytokines; Female; Fertilization in Vitro; Follicular Fluid; Humans; Infertility, Female; Insulin; Insulin Resistance; Leptin; Nicotinamide Phosphoribosyltransferase; Ovulation Induction; Polycystic Ovary Syndrome; Pregnancy

Hypopituitarism, often characterized by hypogonadism, is associated with central obesity, increased cardiovascular and endocrine morbidity and mortality. In Turner syndrome, which is also characterized by hypogonadism liver enzymes are often elevated, but readily suppressed by a short course of hormone replacement therapy (HRT). We investigated the effect of HRT on liver enzymes, lipid levels and measures of insulin sensitivity 26 in hypopituitary women.. We studied 26 hypopituitary women (age 38.8+/-11.0 (mean+/-SD years), BMI 27.4+/-5.1kg/m(2)) during HRT and 28days off therapy.. We measured liver enzymes, fasting levels of lipids, insulin and glucose as well as adiponectin and leptin levels. Body composition was assessed by means of anthropometry and bioimpedance.. Alanine transaminase (ALT) and aspartate transaminase (AST) increased after discontinuation of HRT (ALT; treated: 22.3+/-11.5 vs. untreated: 27.1+/-11.1 (U/L) (P<0.02); AST; treated: 20.4+/-6.1 vs. untreated: 24.6+/-8.9 (U/L) (P<0.002)), whereas other liver function tests remained unchanged. Measures of insulin sensitivity and fasting lipids were also unaffected by HRT, whereas leptin levels decreased with cessation of HRT (leptin; treated: 23 (8-71) vs. untreated: 20 (8-64) (mug/L) (P<0.0005)).. Short time discontinuation of HRT in young hypopituitary women increased liver enzymes, whereas measures of insulin sensitivity and lipid levels remained unchanged. We speculate that the estrogen component of HRT has beneficial effects on hepatic metabolism through various pathways. Further studies including liver imaging and with a time-dependent design are needed to clarify the role of HRT on liver enzyme levels, metabolic variables and liver fat content.

Topics: Adiponectin; Adult; Alanine Transaminase; Aspartate Aminotransferases; Blood Glucose; Body Mass Index; Female; Hormone Replacement Therapy; Human Growth Hormone; Humans; Hypogonadism; Hypopituitarism; Insulin; Insulin Resistance; Leptin; Lipids; Liver; Obesity; Withholding Treatment

To examine the effects of acute altitude-induced hypoxia on the hormonal and metabolic response to ingested glucose, 8 young, healthy subjects (5 men and 3 women; age, 26 +/- 2 years; body mass index, 23.1 +/- 1.0 kg/m(2)) performed 2 randomized trials in a hypobaric chamber where a 75-g glucose solution was ingested under simulated altitude (ALT, 4300 m) or ambient (AMB, 362 m) conditions. Plasma glucose, insulin, C-peptide, epinephrine, leptin, and lactate concentrations were measured at baseline and 30, 60, 90, and 120 minutes after glucose ingestion during both trials. Compared with AMB, the plasma glucose response to glucose ingestion was reduced during the ALT trial (P = .04). There were no differences in the insulin and C-peptide responses between trials or in insulin sensitivity based on the homeostasis model assessment of insulin resistance. Epinephrine and lactate were both elevated during the ALT trial (P < .05), whereas the plasma leptin response was reduced compared with AMB (P < .05). The data suggest that the plasma glucose response is suppressed at ALT, but this is not due to insulin per se because insulin and C-peptide levels were similar for both trials. Elevated plasma epinephrine and lactate during ALT are indicative of increased glycogenolysis, which may have masked the magnitude of the reduced glucose response. We conclude that, during acute altitude exposure, there is a rapid metabolic response that is accompanied by a shift in the hormonal milieu that appears to favor increased glucose utilization.

Topics: Adult; Altitude; Blood Glucose; C-Peptide; Epinephrine; Female; Glucose; Humans; Hypoxia; Insulin; Insulin Resistance; Lactic Acid; Leptin; Male; Solutions

Sibutramine and metformin are drugs commonly used to obtain weight loss. We aimed to compare the effects of sibutramine alone with that of sibutramine plus metformin combination on weight loss, insulin sensitivity, leptin and C reactive protein in obese women. Seventy obese women were included. After a diet period of month (baseline), each individual was randomly assigned to receive 15 mg sibutramine (sibutramine group; n = 36) or 15 mg sibutramine plus 1,700 mg metformin per day (sibutramine plus metformin group; n = 34) during the next 12 months. Body weight, insulin resistance by the homeostasis model assessment model (HOMA-IR), leptin and C reactive protein were measured at baseline, after 3 months and after 12 months. Mean weight losses in sibutramine and sibutramine plus metformin groups were 5.3 +/- 4.0% (P < 0.001) and 6.8 +/- 3.9% (P < 0.001) after 3 months, and 10.5 +/- 4.4% (P < 0.001) and 15.7 +/- 4.6% (P = 0.007) after 12 months, respectively. HOMA-IR value also decreased in both sibutramine (P = 0.045 and P = 0.002) and sibutramine plus metformin groups (P = 0.04 and P = 0.015) after 3 and 12 months, respectively. Similarly, serum leptin levels decreased in both sibutramine (P = 0.04, P = 0.01) and sibutramine plus metformin groups (P = 0.023, P = 0.025) after 3 and 12 months, respectively. There was also significant reductions in serum C reactive protein levels in both sibutramine (P = 0.045, P = 0.02) and sibutramine plus metformin groups (P = 0.007, P = 0.001) after 3 and 12 months, respectively. These decrements of body weight, HOMA-IR, serum leptin and C reactive protein levels were not statistical significance between these two groups both after 3 and 12 months (P > 0.05). Combination of sibutramine with metformin did not result in any further effects on weight loss, insulin resistance, leptin and C reactive protein levels when compared to sibutramine alone.

Topics: Adult; Appetite Depressants; C-Reactive Protein; Cyclobutanes; Drug Therapy, Combination; Female; Humans; Insulin Resistance; Leptin; Metformin; Middle Aged; Obesity; Treatment Outcome; Weight Loss

Pathologic changes in the liver are common in morbidly obese patients, and insulin resistance may potentiate the progression of nonalcoholic steatohepatitis to fibrosis and cirrhosis. This study investigates the impact of leptin and adiponectin in morbidly obese diabetic and nondiabetic patients with regard to histopathologic changes in the liver.. Thirty-seven morbidly obese patients who underwent bariatric surgery with liver biopsies were enrolled in the study. Fourteen were diabetic and 23 were nondiabetic. Intraoperative liver tissue was sent for histopathologic analysis and extraneous intraoperative tissue was snap-frozen in liquid nitrogen. Total RNA was extracted and RNA was reverse transcribed to cDNA. Real-time quantitative PCR was performed to determine relative gene expression levels. The data were analyzed using a logarithmic transformation and normalized by 18S ribosome expression. Student's t test was used for statistical analysis with p < or = 0.05 as significant.. Adiponectin expression was downregulated 4.4-fold (p < or = 0.05) in liver samples with evidence of inflammation on pathology. When hepatic inflammation was evaluated separately, there were no statistically significant differences in adiponectin levels between the diabetic and nondiabetic patients. However, overall adiponectin levels in hepatic samples of diabetic patients were 3.8-fold higher than those of nondiabetic patients (p < or = 0.05). There were no significant differences in leptin levels regardless of hepatic pathology or diabetic status.. This study illustrates that there is a downregulation of adiponectin in morbidly obese patients with inflammatory infiltrates in the liver. Variations in adiponectin levels could be an indicator of disease progression since inflammatory infiltrates are commonly associated with nonalcoholic steatohepatitis (NASH) in morbidly obese patients. Currently, we are using human myofibroblasts derived from livers of morbidly obese people to further investigate the molecular mechanisms involved in the progression of fatty liver to fibrosis and cirrhosis.

Topics: Adiponectin; Adult; Biopsy; Diabetes Complications; Disease Progression; Down-Regulation; Fatty Liver; Female; Gene Expression; Humans; Insulin Resistance; Leptin; Liver; Liver Cirrhosis; Male; Middle Aged; Obesity, Morbid

The aims of this study are to examine in children: (i) obesity-related alterations in satiety factors such as leptin, ghrelin, and obestatin; (ii) the link between satiety factors and cardiometabolic risk factors; and (iii) the impact of a physical activity-based lifestyle intervention on the levels of these satiety factors in the obese. We studied a total of 21 adolescents (BMI percentile, 99.0 +/- 0.6 for 15 obese and 56.2 +/- 1.1 for 6 lean). The obese subjects underwent a 3-month randomized controlled physical activity-based lifestyle intervention. Leptin, soluble leptin receptor (sOB-R), ghrelin, and obestatin levels were determined as the primary outcome measures. Other markers of cardiometabolic disease such as inflammation and insulin resistance were also determined. Body composition was measured by dual-energy X-ray absorptiometry. The concentrations of ghrelin, obestatin, and sOB-R were significantly lower in the obese children compared to the lean controls, whereas that of leptin was higher (all P < 0.05). Although intervention led to a net increase in obestatin (P < 0.01) and no change in ghrelin levels, the balance between ghrelin and obestatin (ratio of ghrelin to obestatin, G/O) decreased (P < 0.02). Intervention reduced leptin and increased sOB-R (P < 0.01 for both). Significant associations between satiety factors and other cardiometabolic risk factors were also observed. Taken together, alterations in the levels of satiety factors are evident early in the clinical course of obesity, but physical activity-based lifestyle intervention either prevented their continued increase or normalized their levels. These beneficial effects appear to aid in the maintenance of body weight and reduction in cardiovascular risk.

Topics: Adolescent; Biomarkers; Body Weight; Cardiovascular Diseases; Exercise; Female; Ghrelin; Humans; Inflammation; Insulin Resistance; Leptin; Life Style; Male; Motor Activity; Obesity; Receptors, Leptin; Satiation

Atypical antipsychotic medications like olanzapine (OLZ) induce weight gain and increase the risk of diabetes in patients with schizophrenia. The goal of this study was to assess potential mechanisms of OLZ-induced weight gain and accompanying metabolic effects. Healthy, lean, male volunteers received OLZ and placebo (PBO) in a randomized, double-blind, crossover study. In periods 1 and 2, subjects received OLZ (5 mg for 3 days then OLZ 10 mg for 12 days) or matching PBO separated by a minimum 12-day washout. Twenty-four hour food intake (FI), resting energy expenditure (REE), activity level, metabolic markers, and insulin sensitivity (IS) were assessed. In total, 30 subjects were enrolled and 21 completed both periods. Mean age and BMI were 27 years (range: 18-49 years) and 22.6 +/- 2.2 kg/m(2), respectively. Relative to PBO, OLZ resulted in a 2.62 vs. 0.08 kg increase in body weight (P < 0.001) and 18% (P = 0.052 or 345 kcal) increase in FI. Excluding one subject with nausea and dizziness on the day of OLZ FI measurement, the increase in FI was 547 kcal, (P < 0.05). OLZ increased REE relative to PBO (113 kcal/day, P = 0.003). Significant increases in triglycerides, plasminogen activator inhibitor-I (PAI-I), leptin, and tumor necrosis factor-alpha (TNF-alpha) were observed. No significant differences in activity level or IS were observed. This study provides evidence that OLZ pharmacology drives the early increase in weight through increased FI, without evidence of decreased energy expenditure (EE), activity level, or short-term perturbations in IS.

Topics: Adolescent; Adult; Antipsychotic Agents; Basal Metabolism; Benzodiazepines; Biomarkers; Double-Blind Method; Energy Intake; Exercise; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Olanzapine; Plasminogen Activator Inhibitor 1; Reference Values; Triglycerides; Tumor Necrosis Factor-alpha; Weight Gain; Young Adult

Adiponectin and leptin are adipocytokines associated with insulin resistance. The objective of this study was to evaluate the performance of the adiponectin-leptin ratio as a measure of insulin resistance in comparison with other surrogate measures of insulin resistance based on fasting insulin and glucose levels [homeostasis model assessment (HOMA), quantitative insulin sensitivity check index (QUICKI), fasting glucose/insulin ratio] and with measures based on fasting insulin and triglyceride levels (McAuley index) in Caucasian patients with Type 2 diabetes (T2D).. In 70 patients included in DEMAND (delapril and manidipine for nephroprotection in diabetes) study, fasting samples of plasma insulin and adiponectin were determined by a radioimmunoassay, whereas plasma leptin was determined by an enzyme-linked immunosorbent assay. Insulin resistance estimates were derived by the established equations and compared with the direct measurement of insulin resistance obtained with the euglycemic hyperinsulinemic clamp. Insulin resistance estimates and the clamp derived sensitivity index were compared by correlation analysis.. The adiponectin-leptin ratio correlated best with the clamp derived sensitivity index (r=0.553, p<0.001) compared to other surrogate measures of insulin resistance. In multiple linear regression models including different surrogate measures of insulin resistance as independent predictors of the sensitivity index, the model with the adiponectin-leptin ratio accounted for the highest variability of the sensitivity index (r2=0.336, p<0.001).. The adiponectin-leptin ratio is associated with insulin resistance, measured with the euglycemic hyperinsulinemic clamp, in Caucasians with T2D. The association with clamp derived sensitivity index is even stronger than that of HOMA, QUICKI, fasting glucose/insulin ratio or McAuley index and is independent of body mass index or glycemic control. The adiponectin-leptin ratio promises to become a new laboratory marker of insulin resistance in T2D.

Topics: Adiponectin; Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Enzyme-Linked Immunosorbent Assay; Fasting; Female; Glucose Clamp Technique; Humans; Insulin; Insulin Resistance; Leptin; Male; Sensitivity and Specificity

Hyperinsulinemia and obesity-related metabolic disturbances are common and have been associated with increased cancer risk and poor prognosis. To investigate this issue in relation to prostate cancer, we conducted a nested case-control study within the Prostate Cancer Prevention Trial (PCPT), a randomized, placebo-controlled trial testing finasteride versus placebo for primary prevention of prostate cancer. Cases (n = 1,803) and controls (n = 1,797) were matched on age, PCPT treatment arm, and family history of prostate cancer; controls included all eligible non-whites. Baseline bloods were assayed for serum C-peptide (marker of insulin secretion) and leptin (an adipokine) using ELISA. All outcomes were biopsy determined. Logistic regression calculated odds ratios (OR) for total prostate cancer and polytomous logistic regression calculated ORs for low-grade (Gleason <7) and high-grade (Gleason >7) disease. Results were stratified by PCPT treatment arm for C-peptide. For men on placebo, higher versus lower serum C-peptide was associated with a nearly 2-fold increased risk of high-grade prostate cancer (Gleason >7; multivariate-adjusted OR, 1.88; 95% confidence interval, 1.19-2.97; P(trend) = 0.004). When C-peptide was modeled as a continuous variable, every unit increase in log(C-peptide) resulted in a 39% increased risk of high-grade disease (P = 0.01). In contrast, there was no significant relationship between C-peptide and high-grade prostate cancer among men receiving finasteride. Leptin was not independently associated with high-grade prostate cancer. In conclusion, these results support findings from other observational studies that high serum C-peptide and insulin resistance, but not leptin, are associated with increased risk of high-grade prostate cancer. Our novel finding is that the C-peptide-associated risk was attenuated by use of finasteride.

Topics: C-Peptide; Case-Control Studies; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Finasteride; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Prostatic Neoplasms; Risk Factors

To document prospective weight and anthropometric changes in children and adolescents during the first 12 weeks of treatment with risperidone and evaluate metabolic outcomes including plasma leptin levels.. Eight patients with psychotic disorders (ages 11-17) who had started risperidone (mean: 1.80 mg/day; sd = 1.04) in the prior 4 weeks participated in this observational study. Fasting morning blood samples were obtained at baseline and week 8 to assess glucose, leptin, cortisol, insulin, and triglycerides. Measures of body mass index (BMI), weight, waist and hip circumference, blood pressure, and heart rate were obtained weekly.. Participants increased in mean weight (4.16 kg; sd = 4.36; p = 0.03) and BMI (1.47 kg/m(2); sd = 1.53; p = 0.03) with five out of eight gaining at least 7% of baseline body weight. They had a 4.03 cm (sd = 3.82; p = 0.02) increase in waist circumference and a 5.17 cm (sd = 3.68; p = 0.01) increase in hip circumference. Leptin trended higher, but did not reach statistical significance. There were no significant changes in glucose, insulin, cortisol, blood pressure, or heart rate.. Subjects experienced significant increases in weight, BMI, hip and waist circumference during the first 3 months of treatment. Better powered research with more advanced anthropometric assessment is warranted to further elucidate mechanisms of antipsychotic associated weight gain in youth.

Topics: Adolescent; Anthropometry; Antidepressive Agents, Second-Generation; Body Mass Index; Body Size; Body Weight; Child; Day Care, Medical; Diagnostic and Statistical Manual of Mental Disorders; Female; Hip; Humans; Insulin Resistance; Leptin; Male; Pilot Projects; Psychotic Disorders; Risperidone; Waist Circumference; Weight Gain

Our aim was to determine the influence of weight reduction on total (T-) and high-molecular weight (HMW-) adiponectin in obese (OB) prepubertal children. Seventy OB prepubertal white patients were followed for 18 months and studied after reducing their BMI by 1 (n = 51) and 2 standard deviation scores (SDS) (n = 21) under conservative treatment, and 6 months after achieving weight loss (n = 44). Body composition dual-energy X-ray absorptiometry (DXA) and serum levels of T- and HMW-adiponectin, resistin, leptin, leptin soluble receptor (sOB-R), tumoral necrosis factor-α and interleukin-6 were determined. The control group consisted of 61 healthy prepubertal children. At diagnosis T-adiponectin was higher (P < 0.01; confidence interval (+0.04) - (+0.15)) and HMW-adiponectin lower (P < 0.001; confidence interval (-0.45) - (-0.21)) in OB children than in controls. A reduction in body fat increased T- and HMW-adiponectin and sOB-R (all P < 0.001) and decreased leptin (P < 0.001) and interleukin-6 levels (P < 0.05). After 6 months of sustained weight reduction a decrease in tumoral necrosis factor-α (P < 0.01) occurred, whereas weight recovery increased leptin (P < 0.001) and decreased T-adiponectin (P < 0.05). HMW-adiponectin levels negatively correlated with homeostasis model assessment (HOMA) index and BMI in the whole cohort (both P < 0.001), as did T-adiponectin levels and HOMA index in OB patients (P < 0.01), but neither T- nor HMW-adiponectin correlated with body fat content (BFC) in OB children. We conclude that the impairment of T- and HMW-adiponectin levels in childhood obesity is different to that in elder OB patients, showing closer relationship with carbohydrate metabolism parameters than with BFC, but increasing their levels after weight loss and in association with metabolic improvement.

Topics: Absorptiometry, Photon; Adiponectin; Adipose Tissue; Body Mass Index; Case-Control Studies; Child; Female; Humans; Insulin Resistance; Interleukin-6; Leptin; Male; Obesity; Reference Values; Tumor Necrosis Factor-alpha; Weight Gain; Weight Loss

We investigated the effects of daily palatinose intake on the risk factors of metabolic syndrome in sedentary non-obese Japanese adults.. Japanese adults (40 females and 10 males, age: 53 +/- 9 years, range: 31-72 years old) were randomized into two groups for a double-blind, placebo-controlled intervention study and given either 40 g/day palatinose-blended sugar (PS group) or 40 g/day sucrose (S group) in their diet for 12 weeks.. After the intervention, the insulin resistance index (HOMA-IR) had significantly decreased only in the PS group; the inter-group difference was significant at P = 0.006. Although the S group showed a significant increase in the leptin concentration and the systolic blood pressure, the PS group showed no significant changes; the inter-group differences were significant at P = 0.018 and P = 0.037, respectively.. Palatinose intake possibly improves insulin sensitivity when compared with sucrose intake.

Topics: Adult; Aged; Blood Pressure; Dietary Sucrose; Dietary Supplements; Double-Blind Method; Female; Humans; Insulin Resistance; Isomaltose; Leptin; Male; Metabolic Syndrome; Middle Aged; Risk Factors; Sedentary Behavior; Sucrose

Treatment with olanzapine is associated with obesity, diabetes mellitus, and dyslipidemia. Reports have indicated that orally disintegrating tablets (ODT) cause less weight gain than oral standard tablets (OST). The aim of this study was to compare the effect of short-term treatment with these 2 distinct olanzapine formulations on glucose and lipid metabolism in healthy men.. Twelve healthy men (mean ± SEM age: 25.1 ± 5.5 years) received olanzapine ODT (10 mg od, 8 days), olanzapine OST (10 mg od, 8 days), or no intervention in a randomized crossover design. At breakfast and dinner, glucose, insulin, free fatty acids (FFA), and triglyceride concentrations were measured at 10-minute intervals from 30 minutes prior to 2 hours after ingestion of standard meals. Leptin and adiponectin concentrations were measured at 20- and 30-minute intervals, respectively, between 0000h-1200h. Physical activity was assessed with an accelerometer. Fuel oxidation was measured in fasting condition by indirect calorimetry. The study was conducted from April 2006 through September 2006.. Treatment with olanzapine ODT and OST equally elevated the homeostasis model assessment of insulin resistance (HOMA-IR) (P = .005). At breakfast, both formulations equally increased fasting and postprandial triglyceride concentrations (P = .013 and P = .005, respectively) while decreasing fasting and postprandial FFA concentrations (P = .004 and P = .009, respectively). Body weight, body composition, physical activity, or fuel oxidation did not differ between treatment modalities.. Eight days of treatment with both olanzapine formulations similarly increased HOMA-IR and triglyceride concentrations and decreased FFA concentrations in response to standard meals without affecting anthropometrics or physical activity. These data suggest that olanzapine hampers insulin action via mechanistic routes other than body adiposity or physical inactivity.. controlled-trials.com. Identifier: ISRCTN17632637.

Topics: Adiponectin; Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Cross-Over Studies; Dosage Forms; Energy Metabolism; Fatty Acids, Nonesterified; Homeostasis; Humans; Insulin; Insulin Resistance; Leptin; Male; Motor Activity; Olanzapine; Reference Values; Triglycerides; Young Adult

The purpose of the study was to test prospectively whether healthy individuals with a family history of type 2 diabetes are more susceptible to adverse metabolic effects during experimental overfeeding.. We studied the effects of 3 and 28 days of overfeeding by 5,200 kJ/day in 41 sedentary individuals with and without a family history of type 2 diabetes (FH+ and FH- respectively). Measures included body weight, fat distribution (computed tomography) and insulin sensitivity (hyperinsulinaemic-euglycaemic clamp).. Body weight was increased compared with baseline at 3 and 28 days in both groups (p < 0.001), FH+ individuals having gained significantly more weight than FH- individuals at 28 days (3.4 +/- 1.6 vs 2.2 +/- 1.4 kg, p < 0.05). Fasting serum insulin and C-peptide were increased at 3 and 28 days compared with baseline in both groups, with greater increases in FH+ than in FH- for insulin at +3 and +28 days (p < 0.01) and C-peptide at +28 days (p < 0.05). Fasting glucose also increased at both time points, but without a significant group effect (p = 0.1). Peripheral insulin sensitivity decreased in the whole cohort at +28 days (54.8 +/- 17.7 to 50.3 +/- 15.6 micromol min(-1) [kg fat-free mass](-1), p = 0.03), and insulin sensitivity by HOMA-IR decreased at both time points (p < 0.001) and to a greater extent in FH+ than in FH- (p = 0.008). Liver fat, subcutaneous and visceral fat increased similarly in the two groups (p < 0.001).. Overfeeding induced weight and fat gain, insulin resistance and hepatic fat deposition in healthy individuals. However, individuals with a family history of type 2 diabetes gained more weight and greater insulin resistance by HOMA-IR. The results of this study suggest that healthy individuals with a family history of type 2 diabetes are predisposed to adverse effects of overfeeding.. ClinicalTrials.gov NCT00562393. The study was funded by the National Health and Medical Research Council (NHMRC), Australia (no. #427639).

Topics: Adult; Analysis of Variance; Australia; Body Composition; C-Peptide; Diabetes Mellitus, Type 2; Feeding Behavior; Female; Genetic Predisposition to Disease; Glucose; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Overnutrition; Risk Factors; Sedentary Behavior; Weight Gain

Insulin resistance ameliorates after bariatric surgery, yet there is still a need for data on the acute effect of Roux-en-Y gastric bypass (RYGBP) on insulin sensitivity.. The objective of the study was to describe the acute effect of RYGBP on insulin sensitivity, measured by both the euglycemic-hyperinsulinemic clamp and homeostasis model assessment insulin resistance index (HOMA-IR).. Evaluations were conducted before and 1 month after RYGBP at State University of Campinas (São Paulo, Brazil).. Patients included 19 premenopausal women with metabolic syndrome aged 35.3 (6.7) yr, body mass index 45.50 (3.74) kg/m2 [mean (sd)]. Six had mild type 2 diabetes, seven impaired glucose tolerance, and six normal glucose tolerance.. The volunteers underwent RYGBP either alone or combined with omentectomy. Euglycemic-hyperinsulinemic clamp, HOMA-IR, nonesterified fatty acids, leptin, ultrasensitive C-reactive protein, adiponectin, and IL-6 were assessed at baseline and 4.5 (0.9) wk postoperatively.. Fasting glucose decreased [99.2 (13.1) to 83.6 (8.1) mg/dl, P<0.01] along with a reduction in fasting insulin [30.4 (17.0) to 11.4 (6.3) mU/liter, P<0.01]. M value did not improve postoperatively [25.82 (6.30) to 22.02 (6.05) micromol/kgFFM.min] despite of a decrease in body weight [114.8 (14.5) to 102.3 (14.5) kg, P<0.001]. This finding was discordant to the observation of an improvement in HOMA-IR [3.85 (2.10) to 1.42 (0.76), P<0.01]. Nonesterified fatty acids increased. Leptin and C-reactive protein decreased. IL-6 and adiponectin remained unchanged.. A month after RYGBP, fasting glucose metabolism improves independent of a change in peripheral insulin sensitivity.

Topics: Adiponectin; Adult; Blood Glucose; Body Mass Index; C-Reactive Protein; Diabetes Mellitus, Type 2; Enzyme-Linked Immunosorbent Assay; Fatty Acids, Nonesterified; Female; Gastric Bypass; Glucose Clamp Technique; Humans; Insulin Resistance; Interleukin-6; Leptin; Metabolic Syndrome; Obesity, Morbid; Statistics, Nonparametric; Treatment Outcome

To evaluate the effects of 1-year treatment with orlistat compared with placebo on different inflammatory parameters in type 2 obese diabetic patients.. Two hundred and fifty-four type 2 diabetic patients were randomized to take orlistat 120 mg three times a day or placebo for 12 months. We evaluated at baseline and after 3, 6, 9 and 12 months: leptin, tumor necrosis factor (TNF)-alpha, adiponectin (ADN), vaspin and high-sensitivity C-reactive protein (HS-CRP), body weight, waist circumference, body mass index (BMI), lipid profile, glycemic profile, fasting plasma insulin (FPI) and homeostasis model assessment insulin resistance index (HOMA-IR).. Regarding inflammatory parameters, there was a significant improvement of ADN and TNF-alpha, and a faster decrease of leptin and HS-CRP in the orlistat group compared with the control group. We also recorded a significant reduction of body weight and BMI with orlistat, but not with placebo. A faster improvement of glycemic profile and FPI was obtained with orlistat compared with the controls. Also, there was a significant reduction of lipid profile with orlistat, not reached with placebo.. Orlistat was more effective than placebo in ameliorating inflammatory parameters such as ADN and TNF-alpha, and anthropometric parameters.

Topics: Adiponectin; Anti-Obesity Agents; Biomarkers; Blood Glucose; Body Mass Index; Body Weight; C-Reactive Protein; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Inflammation Mediators; Insulin; Insulin Resistance; Italy; Lactones; Leptin; Lipids; Male; Middle Aged; Obesity; Orlistat; Placebo Effect; Serpins; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha; Waist Circumference

The role of leptin in atypical antipsychotic-induced metabolic dysfunction was explored by assessing the anthropometric and metabolic profile and the response to metformin (MET) of clozapine- (CLZ) treated schizophrenia patients according to their single nucleotide polymorphisms (SNPs) in the leptin promoter (LEP2548/GA) and leptin receptor (LEPR Q223R) genes.. Phase 1. Body mass index (BMI), waist circumference, serum glucose, HbA1C, lipids, leptin, cortisol, insulin resistance index (HOMA-IR), metabolic syndrome and the frequencies of SNPs were assessed in 56 CLZ-treated patients (78.6% males). Phase 2. Fifty two phase 1 subjects were randomly assigned to MET XR (n=23) (1000 mg/day) or placebo (n=29) for 14 weeks. Changes in anthropometric and biochemical variables were compared between the SNPs.. Phase 1. The QQ group displayed the lowest triglyceride levels (p<0.05). No other significant difference was observed. Phase 2. Change in anthropometric variables did not differ between the genotypes in any treatment group. After MET, glucose levels significantly increased in the GG group (p<0.05), whereas the HOMA-IR and the low density cholesterol significantly decreased in the QQ- but not in the (QR+RR) group (p<0.05). No differences were observed after placebo.. BW response to CLZ was not related to LEP- and LEPR-SNPs. The GG and (QR+RR) genotypes showed an unexpectedly opposite and blunted response to MET administration respectively.

Topics: Adult; Antipsychotic Agents; Blood Glucose; Body Mass Index; Clozapine; Double-Blind Method; Female; Genotype; Humans; Hydrocortisone; Hypoglycemic Agents; Insulin Resistance; Leptin; Male; Metabolic Diseases; Metformin; Middle Aged; Pharmacogenetics; Polymorphism, Single Nucleotide; Receptors, Leptin; Schizophrenia; Venezuela

Continuous high glycemic load and inactivity challenge glucose homeostasis and fat oxidation. Hyperglycemia and high intramuscular glucose levels mediate insulin resistance, a precursor state of type 2 diabetes. The aim was to investigate whether a carbohydrate (CHO)-reduced diet combined with high-intensity interval training (HIIT) enhances the beneficial effects of the diet alone on insulin sensitivity and fat oxidation in obese individuals. Nineteen obese subjects underwent 14 days of CHO-reduced and energy-restricted diet. Ten of them combined the diet with HIIT (4 min bouts at 90% VO(2peak) up to 10 times, 3 times a week). Oral glucose insulin sensitivity (OGIS) increased significantly in both groups; [diet-exercise (DE) group: pre 377 ± 70, post 396 ± 68 mL min(-1) m(-2); diet (D) group: pre 365 ± 91, post 404 ± 87 mL min(-1) m(-2); P < 0.001]. Fasting respiratory exchange ratio (RER) decreased significantly in both groups (DE group: pre 0.91 ± 0.06, post 0.88 ± 0.06; D group: pre 0.92 ± 0.07, post 0.86 ± 0.07; P = 0.002). VO(2peak) increased significantly in the DE group (pre 27 ± 5, post 32 ± 6 mL kg(-1) min(-1); P < 0.001), but not in the D group (pre 26 ± 9, post 26 ± 8 mL kg(-1) min(-1)). Lean mass and resistin were preserved only in the DE group (P < 0.05). Fourteen days of CHO-reduced diet improved OGIS and fat oxidation (RER) in obese subjects. The energy-balanced HIIT did not further enhance these parameters, but increased aerobic capacity (VO(2peak)) and preserved lean mass and resistin.

Topics: Adult; Blood Glucose; Caloric Restriction; Diet, Carbohydrate-Restricted; Exercise; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Interleukin-10; Interleukin-6; Leptin; Male; Middle Aged; Obesity; Oxygen Consumption; Resistin; Tumor Necrosis Factor-alpha

Insulin resistance is a major feature of type 2 diabetes mellitus, obesity and nonalcoholic fatty liver disease (NAFLD). Several studies pointed out the possible role of increased leptin in NAFLD in humans. The aim of this study is to determine the effect of metformin on plasma leptin levels in obese patients with type 2 diabetes mellitus and NAFLD compared with lifestyle interventions. Thirty-four obese patients with newly diagnosed type 2 diabetes mellitus were prospectively followed for 6 months. All patients had ultrasonographic evidence of NAFLD at baseline. The patients were randomized into two groups: group 1 (n = 15) followed lifestyle changes only and group 2 (n = 19) received metformin (1,700 mg/day). At the end of treatment, BMI, WHR, HbA1c, fasting glucose, leptin, HOMA-IR, alanine aminotransferase values decreased in both groups. No significant difference in the end-points was observed between two groups. Only in group 2, LDL decreased and HDL increased significantly. Liver echogenity decreased significantly at the end of study in both groups. The percentage of patients who no longer had evidence of NAFLD was not significantly different between the groups (20% of patients on lifestyle intervention vs. 16% of patients on metformin). The data demonstrate that, metformin and lifestyle interventions equally affected the plasma leptin levels, BMI and degree of NAFLD in obese patients with type 2 diabetes mellitus. In addition, the effects of metformin on the variables were not found to be mediated by leptin.

Topics: Adult; Body Mass Index; Diabetes Mellitus, Type 2; Exercise; Fatty Liver; Female; Glycated Hemoglobin; Humans; Hypertension; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Life Style; Lipoproteins; Liver Function Tests; Male; Metformin; Middle Aged; Obesity; Triglycerides

Lipophilic and hydrophilic statins have different effects on adiponectin and insulin resistance in experimental studies and different effects on the rate of onset of new diabetes in large scale clinical studies. Therefore, we hypothesized that simvastatin and pravastatin may have differential metabolic effects in hypercholesterolemic patients.. This was a randomized, single-blind, placebo-controlled, parallel study. Age, gender, and body mass index were matched. Forty-three patients were given placebo, simvastatin 20mg, or pravastatin 40 mg, respectively once daily for 2 months.. Simvastatin and pravastatin therapy significantly changed lipoprotein levels and improved flow-mediated dilation after 2 months when compared with baseline (P<0.001) or placebo treatment (P<0.001 by ANOVA). Simvastatin therapy significantly increased insulin levels (mean % changes; 127%, P=0.014) and decreased plasma adiponectin levels (10%, P=0.012) and insulin sensitivity as assessed by QUICKI (6%, P=0.007) when compared with baseline. By contrast, pravastatin therapy did not significantly change insulin levels (-3%, P=0.437) but significantly increased plasma adiponectin levels (9%, P=0.011) and insulin sensitivity (6%, P=0.008) when compared with baseline. In addition, these effects of simvastatin were significant when compared with pravastatin (P<0.001 for insulin levels by ANOVA on Ranks, P<0.001 for adiponectin and P=0.001 for QUICKI by ANOVA). When compared with baseline, simvastatin significantly increased plasma leptin levels (35%, P=0.028), but pravastatin did not (1%, P=0.822).. Despite causing comparable changes in lipoprotein and endothelium-dependent dilation, simvastatin and pravastatin therapy had differential metabolic effects in hypercholesterolemic patients that may be clinically relevant.

Topics: Adiponectin; C-Reactive Protein; Double-Blind Method; Endothelium, Vascular; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Insulin; Insulin Resistance; Leptin; Lipoproteins; Male; Middle Aged; Pravastatin; Simvastatin; Treatment Outcome; Vasodilation

Effects of glucomannan as a supplementary treatment in type 2 diabetes mellitus were investigated by measuring ghrelin, leptin and insulin responses to OGTT. Glucomannan enhanced prandial ghrelin reduction when given before glucose load and impeded the rise of fasting ghrelin after 4-week supplement. Ghrelin-induced feeding may be attenuated by glucomannan.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dietary Supplements; Fasting; Ghrelin; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Leptin; Mannans; Placebos; Postprandial Period; Time Factors

Compared with glucose-sweetened beverages, consumption of fructose-sweetened beverages with meals elevates postprandial plasma triglycerides and lowers 24-h insulin and leptin profiles in normal-weight women. The effects of fructose, compared with glucose, ingestion on metabolic profiles in obese subjects has not been studied.. The objective of the study was to compare the effects of fructose- and glucose-sweetened beverages consumed with meals on hormones and metabolic substrates in obese subjects.. The study had a within-subject design conducted in the clinical and translational research center.. Participants included 17 obese men (n = 9) and women (n = 8), with a body mass index greater than 30 kg/m(2).. Subjects were studied under two conditions involving ingestion of mixed nutrient meals with either glucose-sweetened beverages or fructose-sweetened beverages. The beverages provided 30% of total kilocalories. Blood samples were collected over 24 h.. Area under the curve (24 h AUC) for glucose, lactate, insulin, leptin, ghrelin, uric acid, triglycerides (TGs), and free fatty acids was measured.. Compared with glucose-sweetened beverages, fructose consumption was associated with lower AUCs for insulin (1052.6 +/- 135.1 vs. 549.2 +/- 79.7 muU/ml per 23 h, P < 0.001) and leptin (151.9 +/- 22.7 vs. 107.0 +/- 15.0 ng/ml per 24 h, P < 0.03) and increased AUC for TG (242.3 +/- 96.8 vs. 704.3 +/- 124.4 mg/dl per 24 h, P < 0.0001). Insulin-resistant subjects exhibited larger 24-h TG profiles (P < 0.03).. In obese subjects, consumption of fructose-sweetened beverages with meals was associated with less insulin secretion, blunted diurnal leptin profiles, and increased postprandial TG concentrations compared with glucose consumption. Increases of TGs were augmented in obese subjects with insulin resistance, suggesting that fructose consumption may exacerbate an already adverse metabolic profile present in many obese subjects.

Topics: Adolescent; Adult; Beverages; Blood Glucose; Body Mass Index; Cross-Over Studies; Diet; Eating; Fatty Acids, Nonesterified; Female; Fructose; Ghrelin; Glucose; Hormones; Humans; Insulin; Insulin Resistance; Leptin; Male; Obesity; Postprandial Period; Sex Characteristics; Triglycerides; Uric Acid; Young Adult

The objective of this study was to investigate the effect of long-term exercise training on concentrations of five hormones related to appetite and insulin resistance in overweight adolescents. In addition, we were interested in the relationships of these hormones with each other and with anthropometric and/or cardiovascular disease marker changes. Participants were >or=the 85th percentile for BMI for age and sex and participated in an 8-month supervised aerobic training program. Anthropometrics, cardiovascular fitness assessment, and fasting blood samples were taken pre- and post-training. Glucose, insulin, total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, leptin, active ghrelin, total peptide YY (PYY), adiponectin, and resistin concentrations were measured. The participants increased their time to exhaustion on an incremental treadmill test and decreased both percent body fat and blood triglyceride concentrations. Total PYY concentration increased and resistin concentration decreased after long-term exercise training, which are favorable outcomes. Leptin concentrations were related to weight, percent body fat, waist circumference, and triglyceride concentrations pre- and post-training. The changes in resistin concentrations were related to the changes in triglyceride concentrations. We conclude that long-term exercise training has beneficial effects for overweight adolescents with respect to PYY and resistin, hormones related to appetite and insulin sensitivity.

Topics: Adiponectin; Adiposity; Adolescent; Appetite; Biomarkers; Blood Glucose; Cardiovascular Diseases; Exercise Therapy; Exercise Tolerance; Female; Ghrelin; Humans; Insulin; Insulin Resistance; Leptin; Male; Overweight; Peptide YY; Resistin; Time Factors; Treatment Outcome; Triglycerides

To investigate the influence of the Trp64Arg polymorphism in the beta 3-adrenoreceptor gene on adipocytokines, insulin resistance and weight loss secondary to a low fat versus a low carbohydrate diet.. A population of 193 obese patients was analyzed. A nutritional evaluation was performed at the beginning and at the end of a 2-month period in which subjects received 1 of 2 hypocaloric diets.. 172 (89.1%; 44 males, 128 females) subjects had the genotype Trp64/Trp64 (wild-type group) and 21 subjects (10.9%; 4 males, 17 females) had Trp64/Arg64 (mutant-type group). In the wild-type group BMI, weight, fat mass, waist circumference, systolic blood pressure, glucose, triglycerides, insulin, homeostasis model assessment (HOMA) and leptin decreased significantly regardless of the diet. In the mutant-type group, this was the case for BMI, weight, waist circumference, fat mass and leptin levels. Only leptin levels have a significant decrease in the wild-type group (diet I 13.7%, diet II 26.3%, p < 0.05 for both). In the mutant group, leptin decreased as well (diet I 22.5%, diet II 30.1%, p < 0.05 for both).. The metabolic effect of mild weight reduction by 2 hypocaloric diets is greatest in subjects homozygous for the normal beta 3-adrenoreceptor gene. Improvement in glucose, insulin and HOMA is better than in the mutant-type group.

Topics: Adipokines; Anthropometry; Calorimetry, Indirect; Diet, Carbohydrate-Restricted; Diet, Fat-Restricted; Diet, Reducing; Female; Genotype; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Mutation; Obesity; Polymorphism, Genetic; Prospective Studies; Receptors, Adrenergic, beta-3; Resistin; Weight Loss

Carbohydrate-restricted diets (CRDs) have been shown to reduce body weight, whereas whole egg intake has been associated with increased satiety. The purpose of this study was to evaluate the effects of additional dietary cholesterol and protein provided by whole eggs while following a CRD on insulin resistance and appetite hormones. Using a randomized blind parallel design, subjects were allocated to an egg (640 mg/d additional dietary cholesterol) or placebo (0 mg/d additional dietary cholesterol) group for 12 weeks while following a CRD. There were significant reductions in fasting insulin (P < .025) and fasting leptin concentrations (P < .01) for both groups, which were correlated with the reductions in body weight and body fat (P < .05 and P < .01, respectively). Both groups reduced insulin resistance as measured by the homeostatic model assessment of insulin resistance (P < .025). There was a significant decrease in serum glucose levels observed after the intervention. We did not observe the expected increases in plasma ghrelin levels associated with weight loss, suggesting a mechanism by which subjects do not increase appetite with CRD. To confirm these results, the subjective measures of satiety using visual analog scale showed that both groups felt more "full" (P < .05), "satisfied" (P < .001), and "wanted to eat less" (P < .001) after the intervention. These results indicate that inclusion of eggs in the diet (additional dietary cholesterol) did not modify the multiple beneficial effects of CRD on insulin resistance and appetite hormones.

Topics: Adult; Aged; Analysis of Variance; Appetite; Blood Glucose; Body Composition; Body Weight; Cholesterol, Dietary; Diet, Carbohydrate-Restricted; Diet, Reducing; Dietary Proteins; Eggs; Energy Intake; Ghrelin; Hormones; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Pancreatic Polypeptide; Peptide YY; Satiation

In contrast to the general population, a higher body mass index is associated with better survival among hemodialysis patients. Theoretically, high energy supplementation in these patients ought to lead to weight gain over time, but the benefits of this strategy are unclear.. The objective was to assess whether high energy supplementation in nondiabetic hemodialysis patients might adversely affect insulin resistance -- a known risk factor for cardiovascular disease.. We first investigated the association between body fat mass and insulin resistance (homeostasis model assessment of insulin resistance; HOMA-IR) in nondiabetic hemodialysis patients in a cross-sectional analysis (study 1). Of the 106 individuals studied, 55 were randomly assigned to either high energy supplementation (an extra 475 kcal/d; n = 28) or not (n = 27) for 12 wk to assess prospective changes in body fat mass and insulin resistance (study 2).. In study 1, body fat mass (P < 0.05) and C-reactive protein (CRP) (P < 0.05) each contributed independently to HOMA-IR. In study 2, 41 patients completed the study. The 20 patients who received high energy supplementation had a significantly greater increase in body fat mass (P < 0.05), CRP (P < 0.05), and HOMA-IR (P < 0.001) than did the 21 controls.. Body fat mass and CRP are primary determinants of insulin resistance in nondiabetic hemodialysis patients. High energy supplementation, because it increases adiposity and inflammation, exacerbates insulin resistance. A long-term study is needed to clarify the metabolic effects of high energy supplementation on cardiovascular disease outcomes in hemodialysis patients.

Topics: Adipose Tissue; Adiposity; Adult; Aged; Aged, 80 and over; Blood Glucose; Body Mass Index; C-Reactive Protein; Cross-Sectional Studies; Dietary Supplements; Female; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Patient Selection; Renal Dialysis; Serum Albumin; Weight Gain

Clozapine is the most effective agent in treatment-resistant schizophrenia. However, it is frequently associated with excessive body weight (BW) gain, type 2 diabetes mellitus and hyperlipidemia. The antidiabetic metformin (MET) has proved effective to assist in BW control during olanzapine administration. Therefore, we aimed to test whether MET may improve the metabolic profile in patients under prolonged clozapine administration.. In a double-blind, parallel group protocol, 61 patients (94.4% with schizophrenia) receiving clozapine (196.8+/-132 mg daily, range: 25-500) for more than 3 consecutive months (86.5+/-40.6 months, range: 4-168) were randomly allocated to extended release MET (n=31; 500 to 1000 mg daily) or placebo (n=30) group for 14 weeks. The BW, the body mass index, waist circumference, serum glucose, insulin, lipids, glycated hemoglobin (HBA1c), leptin and cortisol, and the HOMA-IR index were assessed at baseline, and weeks 7 and 14.. MET was well tolerated and the mental state was not impaired during the study. The protocol was completed by all the placebo subjects and by 24 MET-treated patients. In a complete analysis at week 14, without including data of the 7 dropouts, the MET group lost -1.87+/-2.9 kg, whereas the placebo group had a stable BW: 0.16+/-2.9 kg, p=0.01 for the between group comparisons (effect size: 0.70). Leptin levels also tended to decrease after MET (p=0.08). Insulin and the triglyceride-HDL-C ratio significantly decreased (p<0.05, effect size 0.59 and 1.99 respectively) and the HDL-C significantly increased (p=0.001, effect size 0.95) after MET.. MET improves metabolic control during prolonged clozapine administration.

Topics: Adult; Anthropometry; Antipsychotic Agents; Blood Glucose; Blood Pressure; Body Mass Index; Body Weight; Cholesterol, HDL; Clozapine; Double-Blind Method; Drug Delivery Systems; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Humans; Hydrocortisone; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Male; Metformin; Middle Aged; Schizophrenia; Statistics, Nonparametric; Waist Circumference

Vitamin D receptors are present in many tissues. Hypovitaminosis D is considered to be a risk factor for atherosclerosis.. This study explores the effects of vitamin D replacement on insulin sensitivity, endothelial function, inflammation, oxidative stress, and leptin in vitamin D-deficient subjects.. Twenty-three asymptomatic vitamin D-deficient subjects with 25-hydroxyvitamin D [25(OH)D] levels below 25 nmol/liter were compared with a control group that had a mean 25(OH)D level of 75 nmol/liter. The vitamin D-deficient group received 300,000 IU im monthly for 3 months. The following parameters were evaluated before and after treatment: vitamin D metabolites, leptin, endothelial function by brachial artery flow mediated dilatation (FMD), insulin sensitivity index based on oral glucose tolerance test, and lipid peroxidation as measures of thiobarbituric acid reactive substances (TBARS).. FMD measurements were significantly lower in 25(OH)D-deficient subjects than controls (P = 0.001) and improved after replacement therapy (P = 0.002). Posttreatment values of TBARS were significantly lower than pretreatment levels (P < 0.001). A positive correlation between FMD and 25(OH)D (r = 0.45; P = 0.001) and a negative correlation between FMD and TBARS (r = -0.28; P < 0.05) were observed. There was a significant increase in leptin levels after therapy, and the leptin levels were positively correlated with 25(OH)D levels (r = 0.45; P < 0.05).. This study shows that 25(OH)D deficiency is associated with endothelial dysfunction and increased lipid peroxidation. Replacement of vitamin D has favorable effects on endothelial function. Vitamin D deficiency can be seen as an independent risk factor of atherosclerosis. Hypovitaminosis D-associated endothelial dysfunction may predispose to higher rates of cardiovascular disease in the winter.

Topics: Adult; Atherosclerosis; Biomarkers; Blood Flow Velocity; Blood Pressure; Brachial Artery; Endothelium, Vascular; Female; Humans; Insulin Resistance; Leptin; Linear Models; Lipid Peroxidation; Male; Oxidative Stress; Risk Factors; Treatment Outcome; Vitamin D; Vitamin D Deficiency; Waist-Hip Ratio

Insulin resistance, a key component of the metabolic syndrome, is a risk factor for diabetes mellitus and cardiovascular disease. Acetyl-L-carnitine infusion acutely ameliorated insulin sensitivity in type 2 diabetics with insulin resistance. In this sequential off-on-off pilot study, we prospectively evaluated the effects of 24-week oral acetyl-L-carnitine (1 g twice daily) therapy on the glucose disposal rate (GDR), assessed by hyperinsulinemic euglycemic clamps, and components of the metabolic syndrome in nondiabetic subjects at increased cardiovascular risk a priori segregated into 2 groups with GDR < or =7.9 (n=16) or >7.9 (n=16) mg/kg per minute, respectively. Baseline GDR and systolic blood pressure were negatively correlated (n=32; P=0.001; r=-0.545), and patients with GDR < or =7.9 mg/kg per minute had higher systolic/diastolic blood pressure than those with higher GDR. Acetyl-L-carnitine increased GDR from 4.89+/-1.47 to 6.72+/-3.12 mg/kg per minute (P=0.003, Bonferroni-adjusted) and improved glucose tolerance in patients with GDR < or =7.9 mg/kg per minute, whereas it had no effects in those with higher GDRs. Changes in GDR were significantly different between groups (P=0.017, ANCOVA). Systolic blood pressure decreased from 144.0+/-13.6 to 135.1+/-8.4 mm Hg and from 130.8+/-12.4 to 123.8+/-10.8 mm Hg in the lower and higher GDR groups, respectively (P<0.05 for both; P<0.001 overall) and progressively recovered toward baseline over 8 weeks posttreatment. Total and high molecular weight adiponectin levels followed specular trends. Diastolic blood pressure significantly decreased only in those with higher GDRs. Treatment was well tolerated in all of the patients. Acetyl-L-carnitine safely ameliorated arterial hypertension, insulin resistance, impaired glucose tolerance, and hypoadiponectinemia in subjects at increased cardiovascular risk. Whether these effects may translate into long-term cardioprotection is worth investigating.

Topics: Acetylcarnitine; Adiponectin; Administration, Oral; Adult; Blood Glucose; Blood Pressure; Cardiovascular Diseases; Double-Blind Method; Drug Administration Schedule; Female; Glucose Tolerance Test; Humans; Hypertension; Insulin Resistance; Leptin; Male; Middle Aged; Prospective Studies; Treatment Outcome; Vitamin B Complex; Young Adult

Chronic kidney disease (CKD) is associated with an increased incidence of cardiovascular disease (CVD). A few studies have demonstrated elevated plasma adiponectin and leptin levels in CKD. The aims of this study were to assess whether 1) estimated glomerular filtration rate (eGFR) is associated with plasma leptin and adiponectin; and 2) adiponectin and leptin (partly) explain associations of CKD with endothelial dysfunction, insulin resistance, and low-grade inflammation in patients with K/DOQI Stage 3 - 5 CKD.. Baseline data from 91 patients with Stage 3 - 4 CKD in the anti-oxidant therapy in chronic renal insufficiency study, a randomized, double-blind, placebo-controlled trial, in which the effects of oxidative stress-lowering treatment on vascular function and structure were studied, and from 50 dialysis naïve patients, who took part in an open-label, randomized study that compared two peritoneal dialysis regimens, used in the analysis. All subjects for both the studies were recruited in the same centres.. The association between eGFR and adiponectin was non-linear. In multivariate analysis, log-eGFR (unstandardized beta = 8.303 microg/ml, p < 0.0001) was the strongest determinant of adiponectin, and body mass index the strongest determinant of leptin (beta = 2.477 ng/ml, p < 0.0001). Plasma adiponectin and leptin did not modify the associations between eGFR and plasma von Willebrand factor or soluble vascular adhesion molecule-1. Plasma leptin had the strongest association with the homeostatic model assessment (HOMA-IR) index. Plasma C-reactive protein had no association with adiponectin or leptin.. In patients with K/DOQI Stage 3 - 5 CKD, renal function had a significant non-linear inverse association with and was the strongest predictor of adiponectin. BMI was the strongest predictor of plasma leptin. Plasma adiponectin and leptin did not explain, and thus presumably are not involved in, the association between eGFR and some markers of endothelial dysfunction.

Topics: Adiponectin; Antioxidants; Body Mass Index; Cross-Sectional Studies; Double-Blind Method; Female; Glomerular Filtration Rate; Humans; Inflammation; Insulin Resistance; Kidney Failure, Chronic; Kidney Function Tests; Leptin; Male; Middle Aged; Multivariate Analysis; Peritoneal Dialysis; von Willebrand Factor

High sugar and fat intakes are known to increase intrahepatocellular lipids (IHCLs) and to cause insulin resistance. High protein intake may facilitate weight loss and improve glucose homeostasis in insulin-resistant patients, but its effects on IHCLs remain unknown.. The aim was to assess the effect of high protein intake on high-fat diet-induced IHCL accumulation and insulin sensitivity in healthy young men.. Ten volunteers were studied in a crossover design after 4 d of either a hypercaloric high-fat (HF) diet; a hypercaloric high-fat, high-protein (HFHP) diet; or a control, isocaloric (control) diet. IHCLs were measured by (1)H-magnetic resonance spectroscopy, fasting metabolism was measured by indirect calorimetry, insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp, and plasma concentrations were measured by enzyme-linked immunosorbent assay and gas chromatography-mass spectrometry; expression of key lipogenic genes was assessed in subcutaneous adipose tissue biopsy specimens.. The HF diet increased IHCLs by 90 +/- 26% and plasma tissue-type plasminogen activator inhibitor-1 (tPAI-1) by 54 +/- 11% (P < 0.02 for both) and inhibited plasma free fatty acids by 26 +/- 11% and beta-hydroxybutyrate by 61 +/- 27% (P < 0.05 for both). The HFHP diet blunted the increase in IHCLs and normalized plasma beta-hydroxybutyrate and tPAI-1 concentrations. Insulin sensitivity was not altered, whereas the expression of sterol regulatory element-binding protein-1c and key lipogenic genes increased with the HF and HFHP diets (P < 0.02). Bile acid concentrations remained unchanged after the HF diet but increased by 50 +/- 24% after the HFHP diet (P = 0.14).. Protein intake significantly blunts the effects of an HF diet on IHCLs and tPAI-1 through effects presumably exerted at the level of the liver. Protein-induced increases in bile acid concentrations may be involved. This trial was registered at www.clinicaltrials.gov as NCT00523562.

Topics: 3-Hydroxybutyric Acid; Adult; Bile Acids and Salts; Cross-Over Studies; Dietary Fats; Dietary Proteins; Energy Intake; Fatty Acids, Nonesterified; Humans; Insulin Resistance; Leptin; Lipid Metabolism; Liver; Male; Sterol Regulatory Element Binding Protein 1; Tissue Plasminogen Activator; Young Adult

Prognostic biomarkers are needed to identify children at increased cardiometabolic risk. The objective was to study whether markers of metabolism and inflammation, for example, circulating plasma adiponectin, leptin, interleukin-8, and hepatocyte growth factor, are associated with cardiometabolic risk factors in childhood and adolescence. This was a cross-sectional and prospective study, and the setting was the Danish part of the European Youth Heart Studies I and II. Participants were randomly selected girls and boys 8 to 10 years of age with complete baseline data (n = 256) and complete follow-up data 6 years later (n = 169). Cardiometabolic risk profile was calculated using a continuous composite score derived from summing of 6 factors standardized to the sample means (Z scores): body mass index, homeostasis model assessment of insulin resistance, total serum cholesterol to serum high-density lipoprotein cholesterol ratio, serum triglycerides, systolic blood pressure, and the reciprocal value of fitness (maximum watts per kilogram). Overweight was defined using international classification of body mass index cutoff points for children. Plasma adiponectin, leptin, interleukin-8, and hepatocyte growth factor were assessed using immunochemical assays. Linear relationships were found between metabolic risk score and both plasma adiponectin (inverse, P = .02) and plasma leptin (P < .0001) at baseline after adjustment for several confounders. In overweight but not normal-weight children, plasma adiponectin at baseline was inversely associated with metabolic risk score 6 years later (P = .04). In childhood, both hypoadiponectinemia and hyperleptinemia accompany a negative metabolic risk profile. In addition, circulating plasma adiponectin may be a useful biomarker to identify overweight children at greater future risk of the cardiometabolic adverse effects of overweight.

Topics: Adiponectin; Adolescent; Blood Pressure; Body Mass Index; Child; Cytokines; Denmark; Disease Progression; Female; Hepatocyte Growth Factor; Humans; Insulin Resistance; Interleukin-8; Leptin; Lipids; Male; Metabolic Diseases; Overweight; Regression Analysis; Risk Assessment

Polycystic ovary syndrome (PCOS) is an endocrinological and metabolic disorder which may concern about 3-8% of women. Some PCOS women have the increased leptin concentration in blood serum. Leptin concentration is higher in patients with high body mass index (BMI) and impaired tissue sensitivity to insulin. The aim of this study was to determine leptin concentrations in PCOS patients before and after metformin treatment depending on BMI, insulin resistance calculated on the basis of the Homeostasis Model Assessment (HOMA) index, as well as concentrations of androgens: testosterone and androstendion. Such values as BMI, insulin resistance according to the HOMA index, and concentrations of androstendion, testosterone and leptin were determined in 35 patients with PCOS before and after 3-month metformin treatment administered in daily doses of 2 x 850 mg. Increased leptin levels before the therapy were observed in 91.3% (21 out of 23) of obese patients, in 75% (9 out of 12) non-obese patients, in 100% (8 patients) insulin resistance women, in 81.5% (22 out of 27) insulin sensitive patients, in 94.7% (18 out of 19) women with elevated androstendion concentration and in 75% (12 out of 16) with normal androstendion concentration, in 93.7% (15 out of 16) patients with increased testosterone concentration and in 78.9% (15 out of 19) patients with testosterone concentrations within the normal range. After treatment statistically significant decrease in leptin concentration was obtained in the patients with BMI

Topics: Androgens; Body Mass Index; Female; Humans; Hypoglycemic Agents; Insulin Resistance; Leptin; Metformin; Polycystic Ovary Syndrome

Low resting energy expenditure (REE) and respiratory quotient (RQ) have been shown in adults to predispose to obesity and diabetes mellitus.. To correlate REE and RQ in 73 obese children and young adults (body mass index [BMI] 37 +/- 10 kg/m2) with measures of insulin secretion and resistance (IR) indices, percent carbohydrate and fat oxidation, and prolactin and leptin levels.. During a 3-day admission, REE and RQ were determined by indirect calorimetry. Blood chemistries and oral glucose tolerance test (OGTT) were obtained, and intravenous glucose tolerance test (IVGTT) modified by tolbutamide was conducted after an overnight fast, permitting calculation of acute insulin response (AIR), insulin resistance (SiIVGTT), and disposition index (DI).. Patients fell into two groups according to their SiIVGTT: those with normal insulin sensitivity (NIS) and those with insulin resistance (IR). IR patients were subdivided on the basis of DI (cut-off value 0.13 min(-1)) into compensated (CIR) or decompensated (DIR) groups. CIR patients had higher RQ, REE corrected by BMI, AIR, and carbohydrate oxidation and lower fat oxidation than NIS and DIR patients. REE correlated positively with BMI, leptin, and AIR, and negatively with SiIVGTT.. Findings in the CIR and DIR groups support the correlation of REE with metabolic changes consistent with an increased risk of diabetes mellitus.

Topics: Adolescent; Blood Glucose; Body Mass Index; Child; Energy Metabolism; Female; Humans; Insulin; Insulin Resistance; Insulin Secretion; Leptin; Male; Obesity; Prolactin

Athletes frequently adjust their training volume in line with their athletic competition schedule, onset of sport injury, and retirement. Whether maintenance of partial training activity during the detraining period can preserve optimal body composition and insulin sensitivity is currently unknown. Sixteen elite kayak athletes (mean VO2max: 58.5 ml.kg(-1).min(-1), s = 1.77) were randomly assigned to a totally detrained group (age: 20.8 years, s = 0.7; body mass index: 23.74, s = 0.54) or partially detrained group (age: 21.8 years, s = 0.7; body mass index: 23.20, s = 1.02), whereby totally detrained participants terminated their training routine completely and the partially detrained participants preserved approximately 50% of their previous training duration with equivalent intensity for one month. Body mass, waist circumference, oral glucose tolerance test, insulin, leptin, cortisol, and testosterone were measured during the trained state and after detraining. Waist circumferences for both the partially detrained and totally detrained groups were significantly elevated after detraining, with no group difference. However, body mass was reduced in both groups. Significant elevations in the area under the curve for insulin and fasted leptin with detraining were observed. These changes were greater in the totally detrained participants. In conclusion, the present results show that maintaining partial training activity cannot prevent an increase in waist circumference. During the detraining period, the magnitude of increase in plasma insulin and leptin concentrations was regulated in an activity-dependent manner.

Topics: Adult; Analysis of Variance; Area Under Curve; Blood Glucose; Body Mass Index; Glucose Tolerance Test; Humans; Insulin Resistance; Leptin; Obesity; Physical Education and Training; Sports; Time Factors

Nutritional strategies to treat obesity often influence neuroendocrine factors related to body weight control. The present study aimed to investigate whether the inclusion of three fatty fish servings per week within a hypocaloric diet may have specific healthy effects on insulin and leptin functions.. Thirty-two subjects (body mass index = 31.6 +/- 3.5 kg m(-2)) aged 36 +/- 7 years, were assigned to a control or fish-based energy-restricted diet over an 8-week period. Anthropometry, body composition, lipid profile, leptin and insulin values were measured at the start and at the end of the dietary intervention.. Both experimental diets resulted in a similar mean weight loss (control = 5.3 +/- 2.6% versus fish-based = 5.5 +/- 2.5%; P = 0.783). A significant reduction in insulin resistance, as determined by the homeostatic model assessment index (HOMA-IR = insulin x glucose/22.5), was observed after the fish-based intervention. The change in circulating leptin was higher in the fish-based diet compared to the control group. Sixteen percent of the variability in the change of adjusted-leptin could be explained (P = 0.034) by the HOMA index change and the type of diet.. Three servings a week of fatty fish included in an energy-restricted diet appears to be a valid strategy for specifically improving insulin sensitivity and leptin levels in obese subjects, which could involve a better body weight regulation after a nutritional intervention period.

Topics: Adult; Anthropometry; Body Composition; Body Mass Index; Diet, Reducing; Dietary Fats, Unsaturated; Female; Humans; Insulin; Insulin Resistance; Leptin; Male; Obesity; Patient Compliance; Seafood; Weight Loss

Leptin replacement rescues the phenotype of morbid obesity and hypogonadism in leptin-deficient adults. However, leptin's effects on insulin resistance are not well understood. Our objective was to evaluate the effects of leptin on insulin resistance. Three leptin-deficient adults (male, 32 yr old, BMI 23.5 kg/m(2); female, 42 yr old, BMI 25.1 kg/m(2); female, 46 yr old, BMI 31.7 kg/m(2)) with a missense mutation of the leptin gene were evaluated during treatment with recombinant methionyl human leptin (r-metHuLeptin). Insulin resistance was determined by euglycemic hyperinsulinemic clamps and by oral glucose tolerance tests (OGTTs), whereas patients were on r-metHuLeptin and after treatment was interrupted for 2-4 wk in the 4th, 5th, and 6th years of treatment. At baseline, all patients had normal insulin levels, C-peptide, and homeostatic model assessment of insulin resistance index, except for one female diagnosed with type 2 diabetes. The glucose infusion rate was significantly lower with r-metHuLeptin (12.03 +/- 3.27 vs. 8.16 +/- 2.77 mg.kg(-1).min(-1), P = 0.0016) but did not differ in the 4th, 5th, and 6th years of treatment when all results were analyzed by a mixed model [F(1,4) = 0.57 and P = 0.5951]. The female patient with type 2 diabetes became euglycemic after treatment with r-metHuLeptin and subsequent weight loss. The OGTT suggested that two patients showed decreased insulin resistance while off treatment. During an off-leptin OGTT, one of the patients developed a moderate hypoglycemic reaction attributed to increased posthepatic insulin delivery and sensitivity. We conclude that, in leptin-deficient adults, the interruption of r-metHuLeptin decreases insulin resistance in the context of rapid weight gain. Our results suggest that hyperleptinemia may contribute to mediate the increased insulin resistance of obesity.

Topics: Adult; Blood Glucose; Female; Follow-Up Studies; Glucose; Glucose Tolerance Test; Hormone Replacement Therapy; Humans; Hypogonadism; Infusion Pumps; Insulin; Insulin Resistance; Leptin; Life Style; Male; Middle Aged; Obesity, Morbid

The prevalence of metabolic syndrome is increasing along with breast cancer incidence worldwide. Because fenretinide improves insulin action and glucose tolerance in insulin-resistant obese mice and because tamoxifen has shown to regulate several markers involved in metabolic syndrome, we sought to investigate the effect of fenretinide or tamoxifen at low dose on features linked to insulin resistance in premenopausal women at risk for breast cancer. We randomized 235 women to low-dose tamoxifen (5 mg/daily), fenretinide (200 mg/daily), or their combination or placebo for 2 years. We used the homeostasis model assessment (HOMA; fasting insulin x glucose/22.5) to estimate insulin sensitivity. Women were considered to improve insulin sensitivity when they shifted from a HOMA >/=2.8 to <2.8. There was no effect of fenretinide or tamoxifen on HOMA overall, but overweight women (body mass index, >or=25 kg/m(2)) had a 7-fold greater probability to normalize HOMA after 2 years of fenretinide treatment [odds ratio (OR), 7.0; 95% confidence interval (95% CI), 1.2-40.5], with 25% of women improving their insulin sensitivity, whereas tamoxifen decreased insulin sensitivity by almost 7 times compared with subjects not taking tamoxifen (OR, 0.15; 95% CI, 0.03-0.88). In this group only, 5% improved their insulin sensitivity. Interestingly, women with intraepithelial or microinvasive neoplasia had higher HOMA (3.0) than unaffected subjects (2.8; P = 0.07). Fenretinide can positively balance the metabolic profile in overweight premenopausal women and this may favorably affect breast cancer risk. Furthermore, features of the metabolic syndrome should be taken into consideration before proposing tamoxifen for breast cancer prevention. The clinical implications of these results require further investigations.

Topics: Antineoplastic Agents; Body Mass Index; Breast Neoplasms; Cholesterol, HDL; Double-Blind Method; Female; Fenretinide; Humans; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Premenopause; Retinol-Binding Proteins, Plasma; Tamoxifen

To evaluate the effect of Ramadan fasting on parameters of insulin resistance in trained athletes at rest and after aerobic exercise.. Nine male rugby players (age 19 +/- 2 yr, height 1.78 +/- 0.74 m) were tested 3 times: 1 week before observance of Ramadan (C), at the end of the first week (R1), and during the fourth week (R2). They performed a progressive cycle-ergometer test at each visit. Data collected at rest and at the end of aerobic exercise included simple anthropometry (body mass, body-mass index, body fat, fat-free mass), biochemical parameters (serum glucose, cholesterol, HDL cholesterol, triglycerides, creatinine, and serum proteins), and selected hormone concentrations (plasma insulin, leptin, and adiponectin).. Ramadan fasting was associated with a reduction of body mass and body fat (R2 vs. C, p < .01) without significant change in leptin or adiponectin levels.. Lipolysis might have occurred because of increased plasma triglycerides and HDL cholesterol concentrations.

Topics: Adiponectin; Adolescent; Body Composition; Body Mass Index; Cholesterol, HDL; Exercise; Exercise Test; Fasting; Football; Humans; Insulin; Insulin Resistance; Leptin; Male; Proteins; Triglycerides; Young Adult

To analyze the effects of the surgical removal of subcutaneous adipose tissue by ultrasound-assisted megalipoplasty (UAM) on energy expenditure and adipocytokine concentrations in obese women.. Fifteen premenopausal obese women with BMI 37.5+/-6.3 kg/m(2) (range: 30.7-53.6 kg/m(2)) underwent UAM. Body composition (by DEXA), resting metabolic rate (REE) by indirect calorimetry, insulin resistance (by the HOMA method), leptin, C-reactive protein, interleukin-6, resistin and adiponectin were measured before and 1, 3, 28 and 180 days after the procedure.. UAM significantly reduced fat mass at day 3, without further changes in the following days. REE increased at day 3 after UAM, returned to baseline levels at day 28 and significantly declined at day 180. Leptin levels transiently increased after UAM and then declined according to fat mass reduction. C-reactive protein, interleukin-6 and resistin levels acutely increased after UAM and then returned to the baseline levels. Adiponectin levels acutely declined after the procedure and then stabilized to a plasma level slightly lower than at baseline. Insulin resistance deteriorated in the acute post-operative phase and then improved.. The surgical removal of subcutaneous fat was associated to an acute inflammatory reaction with high REE and insulin-resistance. Later on, the metabolic effects of fat mass removal appeared, with a reduction of leptin levels and REE and an improvement of insulin resistance.

Topics: Adipokines; Adiponectin; Adolescent; Adult; Blood Glucose; Body Composition; Body Weight; C-Reactive Protein; Calorimetry, Indirect; Energy Metabolism; Female; Humans; Insulin Resistance; Interleukin-6; Leptin; Lipectomy; Middle Aged; Obesity; Premenopause; Resistin; Severity of Illness Index; Subcutaneous Fat; Time Factors; Treatment Outcome; Ultrasonography, Interventional

Chronic heart failure (CHF) is characterized by increased insulin resistance and hyperleptinaemia. We aimed to study effects of selective and non-selective beta-blockers on body weight, insulin resistance, plasma concentrations of leptin and resistin in patients with CHF.. Twenty-six non-cachectic beta-blocker-naive patients with CHF were randomized and treated with either carvedilol or bisoprolol. Body weight, plasma concentrations of leptin, resistin, fasting glucose and insulin were measured at baseline and after 6 months of therapy. Insulin resistance was estimated by homeostasis model assessment- estimated insulin resistance (HOMA-IR).. Body weight increased significantly in the carvedilol group (mean change + 2.30 kg, p = 0.023) while it did not change in the bisoprolol group (mean change -0.30 kg, p = 0.623) (ns between groups). Plasma leptin concentration increased only in the carvedilol group (mean change + 4.20 ng/ml, p = 0.019) (ns between groups). Fasting glucose and resistin remained unchanged in both groups. After 6 months, mean plasma insulin concentration changed significantly differently (p = 0.015) in the bisoprolol (mean change +3.1 microU/ml) compared to the carvedilol group (mean change -6.3 microU/ml) and HOMA-IR was consequently higher in the bisoprolol compared to the carvedilol group (5.2 +/- 4.2 vs 2.8 +/- 1.6, p = 0.046).. This study found different metabolic effects of carvedilol and bisoprolol in non-cachectic patients with CHF. With unchanged fasting plasma glucose concentration after 6 months of treatment, carvedilol significantly decreased plasma insulin concentration and insulin resistance compared to bisoprolol.

Topics: Adrenergic beta-Antagonists; Aged; Bisoprolol; Blood Glucose; Body Weight; Carbazoles; Carvedilol; Chronic Disease; Female; Heart Failure; Homeostasis; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Propanolamines; Resistin

Biliopancreatic diversion (BPD) restores normal glucose tolerance in a few weeks in morbid obese subjects with type 2 diabetes, improving insulin sensitivity. However, there is less known about the effects of BPD on insulin secretion. We tested the early effects of BPD on insulin secretion in obese subjects with and without type 2 diabetes.. Twenty-one consecutive morbid obese subjects, 9 with type 2 diabetes (T2DM) and 12 with normal fasting glucose (NFG) were evaluated, just before and 1 month after BPD, by measuring body weight (BW), glucose, adipocitokines, homeostasis model assessment of insulin resistance (HOMA-IR), acute insulin response (AIR) to e.v. glucose and the insulinogenic index adjusted for insulin resistance ([DeltaI5/DeltaG5]/HOMA-IR).. Preoperatively, those with T2DM differed from those with NFG in showing higher levels of fasting glucose, reduced AIR (57.9 +/- 29.5 vs. 644.9 +/- 143.1 pmol/l, P < 0.01) and reduced adjusted insulinogenic index (1.0 +/- 0.5 vs. 17.6 +/- 3.9 1/mmol(2), P < 0.001). One month following BPD, in both groups BW was reduced (by approximately 11%), but all subjects were still severely obese; HOMA-IR and leptin decreased significanlty, while high-molecular weight (HMW) adiponectin and adjusted insulinogenic index increased. In the T2DM group, fasting glucose returned to non-diabetic values. AIR did not change in the NFG group, while in the T2DM group it showed a significant increase (from 58.0 +/- 29.5 to 273.8 +/- 47.2 pmol/l, P < 0.01). In the T2DM group, the AIR percentage variation from baseline was significantly related to changes in fasting glucose (r = 0.70, P = 0.02), suggesting an important relationship exists between impaired AIR and hyperglycaemia.. BPD is able to restore AIR in T2DM even just 1 month after surgery. AIR restoration is associated with normalization of fasting glucose concentrations.

Topics: Adiponectin; Adult; Biliopancreatic Diversion; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Fasting; Female; Homeostasis; Humans; Insulin; Insulin Resistance; Insulin Secretion; Leptin; Male; Obesity; Weight Loss

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

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

Pulmonary emphysema is associated with cachexia and disregulation of the hormones regulating the glycolipid metabolism, insulin resistance, and altered substrate utilization. This study aimed at identifying the effects of lung volume reduction surgery (LVRS) on glycolipidic hormones compared to respiratory rehabilitation (RR).. Thirty-three patients with moderate-to-severe emphysema who were undergoing video-assisted thoracoscopic LVRS were compared to 31 similar patients who refused the operation and followed a standardized RR program. All patients were evaluated before and 12 months after treatment for respiratory function, body composition, glycolipidic hormones, metabolic parameters, and insulin resistance, which was calculated using the homeostatic model assessment index for insulin resistance (HOMA-IR). These groups were compared to a matched healthy control population.. Only after LVRS significant improvements were obtained in respiratory function (FEV1, +25.2%; p<0.0001; residual volume, -19.5%; p<0.0001), metabolic parameters (total cholesterol, +13.1%; p<0.01; high-density lipoprotein cholesterol, +11.2%; p<0.01; triglycerides, +18.4; p<0.001; nonesterified fatty acid, -19.7%; p<0.001), and body composition (fat-free mass [FFM], +6.5%; p<0.01; fat mass [FM], +11.9%; p<0.01). The leptin/FM ratio (-6.1%; p<0.01) and resistin/FM ratio (-5.6%; p<0.01) decreased, whereas the adiponectin/FM ratio (+6.9%; p<0.01) and ghrelin (+9.2%; p<0.01) increased, together with reductions in glycemia (-8.8%; p<0.01), insulin level (-20.4%; p<0.001), and HOMA-IR (-27.2%; p<0.0001). The decrement in residual volume was correlated with increment of FFM (rho=-0.49; p<0.02), FM (rho=-0.55; p<0.009), and ghrelin (rho=-0.52; p<0.01), and also with decreases in leptin corrected for FM (rho=0.50; p<0.02) and, marginally, HOMA-IR (rho=0.35; p=0.07).. After LVRS, glycolipidic hormone levels and nutritional status significantly improved, along with insulin resistance reduction and more physiologic utilization of substrates. Correlations between residual volume and body composition as well as glycolipidic hormone levels suggest that postoperative recovery in respiratory dynamics may induce favorable clinical changes when compared to RR.

Topics: Adiponectin; Aged; Body Composition; Ghrelin; Glycolipids; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Nutritional Status; Pneumonectomy; Prospective Studies; Pulmonary Emphysema; Resistin

This study aimed to determine the effect of supplementation with conjugated linoleic acids (CLAs) plus n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFAs) on body composition, adiposity, and hormone levels in young and older, lean and obese men. Young (31.4+/-3.9 years) lean (BMI, 23.6+/-1.5 kg/m2; n=13) and obese (BMI, 32.4+/-1.9 kg/m2; n=12) and older (56.5+/-4.6 years) lean (BMI, 23.6+/-1.5 kg/m2; n=20) and obese (BMI, 32.0+/-1.6 kg/m2; n=14) men participated in a double-blind placebo-controlled, randomized crossover study. Subjects received either 6 g/day control fat or 3 g/day CLA (50:50 cis-9, trans-11:trans-10, cis-12) and 3 g/day n-3 LC-PUFA for 12 weeks with a 12-week wash-out period between crossovers. Body composition was assessed by dual-energy X-ray absorptiometry. Fasting adiponectin, leptin, glucose, and insulin concentrations were measured and insulin resistance estimated by homeostasis model assessment for insulin resistance (HOMA-IR). In the younger obese subjects, CLA plus n-3 LC-PUFA supplementation compared with control fat did not result in increased abdominal fat and raised both fat-free mass (2.4%) and adiponectin levels (12%). CLA plus n-3 LC-PUFA showed no significant effects on HOMA-IR in any group but did increase fasting glucose in older obese subjects. In summary, supplementation with CLA plus n-3 LC-PUFA prevents increased abdominal fat mass and raises fat-free mass and adiponectin levels in younger obese individuals without deleteriously affecting insulin sensitivity, whereas these parameters in young and older lean and older obese individuals were unaffected, apart from increased fasting glucose in older obese men.

Topics: Adiponectin; Adult; Blood Glucose; Body Composition; Cross-Over Studies; Dietary Supplements; Double-Blind Method; Fatty Acids, Omega-3; Humans; Insulin; Insulin Resistance; Leptin; Linoleic Acids, Conjugated; Male; Middle Aged; Obesity

Adiponectin increases insulin sensitivity, protects arterial walls against atherosclerosis, and regulates glucose metabolism, and is decreased in obese, insulin resistant, and type 2 diabetic patients. Adiponectin circulates in plasma as high, medium, and low molecular weight forms (HMW, MMW, and LMW). The HMW form was suggested to be closely associated with insulin sensitivity. This study investigated whether diet-induced changes in insulin sensitivity were associated with changes in adiponectin multimeric complexes.. Twenty obese women with highest and twenty obese women with lowest diet induced changes in insulin sensitivity (responders and non-responders respectively), matched for weight loss (body mass index (BMI)=34.5 (s.d. 2.9) resp. 36.5 kg/m(2) (s.d. 4.0) for responders and non-responders), were selected from 292 women who underwent a 10-week low-caloric diet (LCD; 600 kcal/d less than energy requirements). Plasma HMW, MMW, and LMW forms of adiponectin were quantified using Western blot method.. LCD induced comparable weight reduction in responders and non-responders by 8.2 and 7.6 kg. Homeostasis model assessment insulin resistance index decreased by 48.1% in responders and remained unchanged in non-responders. Total plasma adiponectin and the quantity of HMW and MMW remained unchanged in both groups, while LMW increased by 16.3% in non-responders. No differences between both groups were observed at baseline and after the study. Total plasma adiponectin, MMW, and LMW were negatively associated with fasting insulin levels at baseline.. No differences in total plasma adiponectin, HMW, MMW, and LMW forms were observed between responders and non-responders following 10-week LCD, suggesting that adiponectin is not a major determinant of weight loss-induced improvements in insulin sensitivity.

Topics: Adiponectin; Body Weights and Measures; Caloric Restriction; Diet, Fat-Restricted; Dimerization; Europe; Female; Humans; Insulin Resistance; Leptin; Lipids; Molecular Weight; Obesity; Weight Loss

Low adiponectin levels have been associated with high body mass index, low insulin sensitivity, and diabetes.. To assess the relationships between changes in serum adiponectin concentration and adiposity, glucose, and insulin in response to long-term overfeeding in identical twins and to calculate the twin resemblance in serum adiponectin concentrations.. Twenty-four sedentary young men [mean (+/-SD) age, 21+/-2 yr] who constituted 12 pairs of healthy identical twins were studied for metabolic and adiponectin changes in response to overfeeding.. Subjects were overfed by 84,000 kcal over a 100-day period.. The overfeeding study provides an opportunity to examine the relationships between adiponectin and changes in body weight, adiposity, plasma glucose and insulin.. Serum adiponectin concentration correlated positively with body weight (r= 0.41, p=0.05) at baseline but not with indicators of adiposity or with visceral fat. No relationship existed between baseline adiponectin concentration and body weight or adiposity gains with overfeeding. However, serum adiponectin decreased significantly by -2.35+/-0.48 microg/ml (p=0.001) in response to overfeeding. Baseline adiponectin levels correlated negatively with changes in plasma fasting glucose levels (r=-0.53, p=0.01) and homeostasis model assessment index (r=-0.41, p=0.05), independently of fat mass. The intrapair coefficient for twin resemblance (r=0.75, p=0.001) strongly suggests that baseline serum adiponectin concentration is a familial trait.. These data provide evidence that adiponectin concentration is a familial trait in normal-weight individuals, that it decreases when challenged by positive energy balance, and that its overfeeding-induced variations are correlated with glucose and insulin levels.

Topics: Adiponectin; Adult; Blood Glucose; Humans; Insulin; Insulin Resistance; Leptin; Male; Overnutrition; Twins, Monozygotic

Few studies have directly compared rosiglitazone and metformin effects on adipocytokines. The aim was to observe the possible effects of rosiglitazone and metformin on glycemic control, insulin sensitivity, plasma leptin (pL), adiponectin (ADN), tumor necrosis factor-alpha (TNF-alpha), and resistin (R) in overweight and obese diabetic patients intolerant to metformin.. Six hundred and ninety-four consecutive overweight and obese type 2 diabetic patients were evaluated and 56 patients were intolerant to metformin at maximum dosage. We added rosiglitazone to metformin in these intolerant patients (RM) and we compared them with 61 patients treated with metformin (M) in a single-blind placebo-controlled trial. We evaluated body mass index (BMI), glycated hemoglobin (HbA(1c)), fasting plasma glucose (FPG), fasting plasma insulin (FPI), pL, ADN, TNF-alpha, and R at baseline and after 3 and 6 months. Furthermore, we calculated insulin resistance index (HOMA-index) using FPG and FPI.. Glycated hemoglobin, FPG, FPI, and HOMA-index results were lower than baseline values in RM and M groups. Glycated hemoglobin and HOMA-index values were significantly lower in RM group compared to M group at 6 months. Plasma leptin, ADN, TNF-alpha, and R were significantly improved in RM group compared to M group at 6 months.. No BMI change was observed, probably because rosiglitazone was added to metformin, that could mitigate the body increase of rosiglitazone. Rosiglitazone improved glycemic control and insulin resistance-correlated parameters when added to intolerant metformin patients. These data suggest that rosiglitazone may be the drug of choice for the treatment of overweight and obese type 2 diabetic patients.

Topics: Adiponectin; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Italy; Leptin; Male; Metformin; Middle Aged; Obesity; Overweight; Resistin; Rosiglitazone; Single-Blind Method; Thiazolidinediones; Tumor Necrosis Factor-alpha

Lack of leptin is implicated in insulin resistance and other metabolic abnormalities in generalized lipodystrophy; however, the efficacy, safety, and underlying mechanisms of leptin-replacement therapy in patients with generalized lipodystrophy remain unclear.. Seven Japanese patients with generalized lipodystrophy, two acquired and five congenital type, were treated with the physiological replacement dose of recombinant leptin during an initial 4-month hospitalization followed by outpatient follow-up for up to 36 months.. The leptin-replacement therapy with the twice-daily injection dramatically improved fasting glucose (mean +/- SE, 172 +/- 20 to 120 +/- 12 mg/dl, P < 0.05) and triglyceride levels (mean +/- SE, 700 +/- 272 to 260 +/- 98 mg/dl, P < 0.05) within 1 wk. The leptin-replacement therapy reduced insulin resistance evaluated by euglycemic clamp method and augmented insulin secretion at glucose tolerance test with different responses between acquired and congenital types. Improvement of the fatty liver was also observed. The efficacy and safety of the once-daily injection were comparable to those of the twice-daily injection. The leptin-replacement therapy ameliorated macro- and microalbuminuria and showed no deterioration of neuropathy and retinopathy of these patients. The leptin-replacement therapy is beneficial to diabetic complications and lipodystrophic ones. Two patients developed antileptin antibodies but not neutralizing antibodies. The therapy was well tolerated, and its effects were maintained for up to 36 months without any notable adverse effects such as hypoglycemia, high blood pressure, or reduction of bone mineral density.. The present study demonstrates the efficacy and safety of the long-term leptin-replacement therapy and possible mechanisms of leptin actions in patients with generalized lipodystrophy.

Topics: Adolescent; Adult; Albuminuria; Blood Glucose; Child; Diabetes Complications; Fatty Liver; Female; Follow-Up Studies; Glucose Clamp Technique; Glucose Tolerance Test; Hormone Replacement Therapy; Humans; Hyperinsulinism; Injections, Subcutaneous; Insulin Resistance; Leptin; Lipodystrophy; Male; Time Factors; Treatment Outcome; Triglycerides

Thiazolidinediones (TZD) may improve insulin resistance in patients with diabetes and HIV. The novel adipocytokines visfatin and retinol-binding protein-4 (RBP-4) have been proposed to influence the development of impaired glucose tolerance. The impact of TZD on these cytokines is yet unknown. In this randomized, double-blind, placebo-controlled parallel group study, 37 lean HIV-positive subjects aged 19-50 years were treated with 8 mg/day rosiglitazone (n=20) or placebo (n=17) for 6 months. Insulin sensitivity was estimated from the homeostasis model assessment (HOMA) index. Fasting visfatin, RBP-4, leptin, and adiponectin plasma concentrations were analyzed by immunoassays. Rosiglitazone had no effect on impaired insulin sensitivity, but increased median plasma visfatin from 6.2 ng/ml (95% CI: 5.9; 6.5) to 13.7 ng/ml (12.6; 19.1) (P<0.001) and adiponectin from 3.2 ng/ml (2.2; 4.0) to 4.0 ng/ml (3.3; 8.5; P<0.001). RBP-4 was lowered from 21.0 ng/ml (19.6; 23.1) to 16.3 ng/ml (15.2; 17.0; P<0.001), and leptin concentrations were unchanged. Adipocytokine concentrations were stable in subjects receiving placebo, where a deterioration in insulin sensitivity was detectable (P<0.05). Changes in visfatin and RBP-4 were correlated in subjects receiving rosiglitazone (r=-0.64, P<0.01) but not placebo (r=0.12, P=0.15). TZD treatment affects circulating adipocytokine concentrations in subjects with HIV. Reductions in RBP-4 and increases in visfatin may contribute to the pharmacodynamic action of TZD on glucose homeostasis. Quantification of adipocytokines might be useful to assess TZD treatment effectiveness in insulin-resistant subjects with HIV.

Topics: Adiponectin; Adipose Tissue; Adult; Cytokines; Female; HIV Seropositivity; Humans; Hypoglycemic Agents; Insulin Resistance; Leptin; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Regression Analysis; Retinol-Binding Proteins; Retinol-Binding Proteins, Plasma; Rosiglitazone; Thiazolidinediones

In this study, the Authors assessed some insulin counter-regulatory factors, fibrinogen and C-reactive protein after olanzapine administration, and the effect of metformin on these variables, 37 patients with chronic schizophrenia were given olanzapine (10 mg/day for 14 weeks). Nineteen patients received metformin (850-2550 mg/day) and 18 received placebo in a randomized, double-blind protocol. The following variables were quantified before and after olanzapine: cortisol, leptin, tumor necrosis factor-alpha, glucagon, growth hormone, fibrinogen and C-reactive protein. Results were correlated with the changes in body weight and the insulin resistance index. We have reported elsewhere that metformin did not prevent olanzapine-induced weight gain, and the insulin resistance index significantly decreased after metformin and placebo; Baptista T, et al. Can J Psychiatry 2006; 51: 192-196. Cortisol, tumor necrosis factor-alpha and fibrinogen levels significantly decreased in both groups. Glucagon significantly increased after metformin (P=0.03). Leptin tended to increase after placebo (P=0.1) and displayed a small nonsignificant reduction after metformin. The C-reactive protein did not change significantly in any group. Contrarily to most published studies, olanzapine was associated with decreased insulin resistance. Decrements in cortisol, fibrinogen and tumor necrosis factor-alpha levels point to an improvement in the metabolic profile. The trend for leptin to increase after placebo, but not after metformin in spite of similar weight gain suggests a beneficial effect of this antidiabetic agent.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; C-Reactive Protein; Double-Blind Method; Female; Fibrinogen; Glucagon; Human Growth Hormone; Humans; Hydrocortisone; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Metformin; Middle Aged; Olanzapine; Schizophrenia; Sex Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

This study was undertaken to determine whether insulin resistance associated with combination hormone replacement therapy (HRT) is mediated by changes in serum markers of inflammation or in serum adipocyte hormones.. Forty-five postmenopausal women, aged 55 +/- 7 years, were examined from a randomized, double-blind placebo-controlled trial evaluating the effect of HRT on insulin-stimulated glucose disposal and body composition. Volunteers were randomly assigned to conjugated estrogens 0.625 mg plus medroxyprogesterone acetate 2.5 mg vs placebo for 1 year. At baseline and at 1 year, body composition was assessed by dual photon x-ray absorptiometry scans; body fat distribution was measured by computed tomographic scans at the L4/L5 vertebral disk space; insulin sensitivity was measured by euglycemic hyperinsulinemic clamp; interleukin-6 (IL-6), leptin, and adiponectin were measured by enzyme-linked immunosorbent assay; and c-reactive protein (CRP) was measured by radioimmunoassay.. HRT increased CRP by 121% compared with a 32% increase with placebo (P = .03); HRT decreased glucose disposal by 17% compared with no change with placebo (P = .04) as reported previously. HRT did not affect body composition, body fat distribution, IL-6, leptin, or adiponectin. The increase in CRP did not correlate with the decrease in glucose disposal in the HRT group (R = 0.11, P = .65).. Treatment with HRT for one year increases CRP, but does not alter IL-6, adiponectin, or leptin. The change in CRP was not, however, related to the decrease in glucose disposal with HRT treatment.

Topics: Adiponectin; Adiposity; Biomarkers; Body Composition; C-Reactive Protein; Double-Blind Method; Estrogens, Conjugated (USP); Female; Hormone Replacement Therapy; Humans; Insulin Resistance; Interleukin-6; Leptin; Medroxyprogesterone Acetate; Middle Aged

The aim of this study was to identify the effect of surgically removing subcutaneous fat by abdominoplasty on leptin concentrations and insulin sensitivity. An open clinical trial with a noninterventional parallel group was carried out in 12 obese women. After randomization, 6 volunteers were selected for abdominoplasty, and the other 6 women were considered as the noninterventional group. A metabolic profile, including leptin concentrations, and insulin tolerance test to assess insulin sensitivity were performed on all volunteers before intervention or nonintervention and 40-50 days afterward. A significant reduction in body mass index (30.7 +/- 0.9 versus 29.6 +/- 0.7 kg/m; P = 0.02) and in leptin concentrations (41.3 +/- 10.6 versus 32.0 +/- 10.2 ng/mL; P = 0.02) was observed after abdominoplasty. Insulin sensitivity did not change after intervention. In conclusion, surgically removing subcutaneous fat by abdominoplasty decreased leptin concentrations, with no change in insulin sensitivity.

Topics: Adult; Body Mass Index; Female; Humans; Insulin Resistance; Leptin; Middle Aged; Obesity; Statistics, Nonparametric; Subcutaneous Fat

Excessive body weight gain (BWG) is a clinically relevant side effect of olanzapine administration. The primary objective of this study was to assess whether metformin prevents or reverses BWG in patients with schizophrenia or bipolar disorder under olanzapine administration. Secondarily we evaluated diverse metabolic variables.. Eighty patients taking olanzapine (5-20 mg daily for more than 4 consecutive months) were randomly allocated to metformin (n=40; 850 to 2550 mg daily) or placebo (n=40) group in a 12-week double-blind protocol. Waist circumference (WC) body weight (BW), body mass index (BMI) fasting glucose, glycated hemoglobin (Hb1c), insulin, an insulin resistance index (HOMA-IR) lipids, leptin, c-reactive protein, fibrinogen, cortisol and the growth hormone (GH) were evaluated at baseline and at week 12 of treatment.. The metformin group lost 1.4+/-3.2 kg (p=0.01) and tended to decrease its leptin levels, whereas the placebo group maintained a stable weight: -0.18+/-2.8 kg (p=0.7). The HOMA-IR significantly increased after placebo (p=0.006) and did not change after metformin (p=0.8). No ostensible differences were observed in the other variables, even though metformin did not improve the lipid profile and the Hb1c levels.. Metformin may safely assist olanzapine-treated patients in body weight and carbohydrate metabolism control.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Blood Glucose; Body Mass Index; Body Weight; Brief Psychiatric Rating Scale; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Energy Metabolism; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Resistance; Leptin; Lipids; Male; Metformin; Middle Aged; Olanzapine; Schizophrenia; Statistics as Topic

Melkersson proposed leptin dysregulation as a factor in the olanzapine-induced metabolic dysfunction. Their suggestion was based on the absence of the expected positive correlation between serum leptin levels and the BMI, and the loss of the sex-dependent difference in leptin levels, which are higher in women. Although subsequent studies did not confirm that proposal, few of them assessed basal leptin levels and corrected for body fat percentage. Along with these variables, we added a precise definition of participants out of the expected positive correlation in a large sample of schizophrenia patients. Sixty patients (26 women and 34 men) with severe schizophrenia undergoing chronic hospitalization and conventional antipsychotic treatment were switched to olanzapine (10-20 mg/day). We assessed at baseline, and at weeks 8 and 16 of treatment, the percentage of participants with abnormal correlation (out of the 95% confidence interval in the regression line) between leptin levels and the BMI, and the correlation between leptin and insulin, glucose, the insulin resistance index, c-reactive protein (CRP) and treatment response. Leptin levels were higher in women than in men (P<0.01). The positive correlation between leptin levels, BMI and percentage of fat were preserved. After olanzapine, 3.8% of women and 2.9-5.8% of men were out the 95% confidence interval, and the proportion was similar at baseline. Glucose, insulin, the insulin resistance index and the CRP levels significantly increased after olanzapine. The impact of olanzapine on leptin regulation appears discrete and limited to a small number of participants. Additional studies must clarify the features that render them to metabolic dysregulation.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; C-Reactive Protein; Female; Humans; Insulin; Insulin Resistance; Leptin; Linear Models; Male; Middle Aged; Multivariate Analysis; Olanzapine; Schizophrenia; Sex Factors; Weight Gain

Peptide YY (PYY) is released from the distal small intestine and colon after meals and reduces appetite by increasing satiety. The amount of PYY released is proportional to calories ingested. Fat ingestion has also been reported to stimulate PYY release.. The objective of the study was to determine whether macronutrient composition influences postprandial serum PYY levels by comparing 1 wk of a weight-maintenance low-carbohydrate, high-fat (LCHF) diet with a low-fat, high-carbohydrate (LFHC) diet.. In this randomized crossover study, 18 obese subjects (14 females, 4 males, mean body mass index 35.6 +/- 2.9 kg/m(2)) were randomly assigned initially to 1 wk of a weight-maintenance LCHF or LFHC diet, after which a test meal of identical composition was given and serum PYY levels were assessed for 2.5 h postprandially. After a 1-wk washout period, subjects were crossed over and retested.. After 1 wk, mean postprandial area under the curve PYY after the LCHF test meal was 1.5-fold greater than after the LFHC test meal (P < 0.001). The LCHF diet led to 55% higher levels of postprandial serum PYY levels, compared with the LFHC diet (P = 0.005).. These data show that a LCHF diet stimulates PYY secretion more than a LFHC diet in obese individuals.

Topics: Adiponectin; Adult; Blood Glucose; Body Weight; Cross-Over Studies; Diet, Carbohydrate-Restricted; Diet, Fat-Restricted; Dietary Carbohydrates; Dietary Fats; Energy Intake; Female; Homeostasis; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Peptide YY; Postprandial Period

To observe the efficacy of diet control and aerobic exercises on the patients with metabolic syndrome(MS).. Sixty sedentary patients with MS were randomly divided into a diet control group, an aerobic exercise group, and a diet control combined with aerobic exercise group, each group with 20 persons. Patients in the simple diet control group ate a low-salt, low-cholesterol, low-calorie and high-cellulose diet; patients in the simple aerobic exercises group performed aerobic exercise 30 minutes every time, 3-5 times per week for 12 weeks; while patients in the combination therapy group performed aerobic exercises and diet control. Fasting serum insulin and free fatty acid (FFA) were measured by radio immunity and enzyme-colorimetric method. Serum leptin concentration was measured by enzyme linked immunosorbent assay (ELISA). Homeostasis model assessment (HOMA) insulin resistance index was calculated using the homeostasis model assessment equation. Twenty healthy subjects were selected as the control group.. Serum concentration of FFA, blood pressure, and leptin and insulin resistance index (IRI)of patients with MS significantly increased compared with those of the controls. After 12 weeks, IRI and body mass index (BMI)significantly decreased but blood fat and leptin did not change significantly in the diet control group. IRI and BMI significantly decreased, and triglyceride, FFA and leptin also significantly decreased in the combination therapy group.. Simple diet control and aerobic exercises are beneficial for patients with MS. It could significantly improve the effect of diet control combined with aerobic exercises on patients with metabolic syndrome.

Topics: Adult; Aged; Body Mass Index; Diet; Exercise; Exercise Therapy; Fatty Acids, Nonesterified; Female; Humans; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Middle Aged; Triglycerides

Ghrelin is a major hormone, regulating the energy balance of the body. Weight gain is a significant side effect of valproic acid, which has not been clearly identified pathogenetically. The aim of this study was to investigate the effect of valproic acid on ghrelin and its potential effects on weight gain and growth. Each patient and control group consisted of 35 children aged 3 to 15 years. Fasting serum glucose, insulin, C-peptide, leptin, ghrelin, insulin-like growth factor-1, and insulin-like growth factor binding protein-3 levels were measured in patients treated with valproic acid before and at month 6 of treatment. A significant increase in body weight, body mass index, height, and height standard deviation scores was observed in all patients after 6 months of treatment. Significant increases in growth velocity and weight gain were observed in the patient group compared with controls at 6 months of therapy. A significant increase in serum ghrelin levels (P < .01) was detected at the same time in the study group. A negative correlation of ghrelin with insulin-like growth factor-1 and insulin-like growth factor binding protein-3 was detected. Serum ghrelin levels were significantly increased (P < .05), and insulin-like growth factor-1 and insulin-like growth factor binding protein-3 levels were significantly decreased (P < .01 and P < .05, respectively) in the prepubertal group at 6 months of treatment, but no significant change was observed in the pubertal group. Consequently, ghrelin levels significantly increase in the prepubertal children treated with valproic acid. The weight gain in using valproic acid may be associated with the increase in ghrelin level in the early treatment period.

Topics: Adolescent; Anticonvulsants; Blood Glucose; Body Height; Body Mass Index; Body Weight; C-Peptide; Child; Child, Preschool; Epilepsy; Female; Ghrelin; Humans; Insulin; Insulin Resistance; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Male; Puberty; Valproic Acid; Weight Gain

Obese individuals are frequently hyperleptinemic and insulin resistant. Chronic exercise is associated with improvements in plasma leptin level and insulin sensitivity; however, little is known about the acute effect of exercise on these parameters. The aim of this study was to evaluate the acute effect of aerobic exercise on plasma leptin and insulin sensitivity in obese women with stable caloric intake.. Twenty-three obese women (age 41.2 +/- 10.3 years, body mass index 40.7 +/- 6.7 kg/m2) were included to the study. All subjects were admitted to an exercise program (45-minute walking sessions at 60-80% of maximum heart rate) every day except weekends for four weeks (total 20 exercise sessions). Insulin resistance was evaluated by HOMA model. Plasma glucose, insulin and leptin levels were determined at baseline and at the end of the first, seventh, and twentieth exercise session.. Baseline and at the end of the first, seventh, and twentieth exercise session plasma leptin levels were 59.1 +/- 20.1, 58.5 +/- 21.0, 53.4 +/- 21.9, and 51.2 +/- 20.5 ng/ml and HOMA-r were 2.75 +/- 1.47, 1.77 +/- 0.71, 1.73 +/- 0.89, 1.62 +/- 0. 70, respectively. Compared to baseline, at the end of the seventh (p = 0.021) and twentieth exercise session (p = 0.003), plasma leptin levels were significantly low. Plasma leptin level did not change significantly at the end of the first exercise session (p > 0.05). At the end of the first exercise session (p = 0.005), end of the seventh (p = 0.003) and twentieth exercise session (p = 0.007) HOMA-r was lower than baseline. There was no correlation between weight loss during exercise period and the change of leptin, and HOMA-r. Fasting plasma glucose, insulin and leptin levels were determined at baseline and at the end of the first, seventh, and twentieth exercise session.. Our study suggests that acute exercise decreases insulin resistance at the first exercise session with no effect on leptin levels. Significant leptin decrement was evident at the first week and lasted during the entire four weeks exercise session.

Topics: Adult; Blood Glucose; Energy Intake; Exercise Therapy; Female; Humans; Insulin; Insulin Resistance; Leptin; Middle Aged; Obesity; Time Factors; Weight Loss

The aim of our study was to determine whether adipocyte-derived hormones leptin, adiponectin and resistin contribute to the improvement of insulin sensitivity after very-low calorie diet (VLCD). Therefore, serum levels of these hormones were measured in fourteen obese females before and after three weeks VLCD and in seventeen age- and sex-matched healthy controls. Body mass index, HOMA index, serum insulin and leptin levels in obese women before VLCD were significantly higher than in control group (BMI 48.01+/-2.02 vs. 21.38+/-0.42 kg/m(2), HOMA 10.72+/-2.03 vs. 4.69+/-0.42, insulin 38.63+/-5.10 vs. 18.76+/-1.90 microIU/ml, leptin 77.87+/-8.98 vs. 8.82+/-1.52 ng/ml). In contrast, serum adiponectin and soluble leptin receptors levels were significantly lower in obese women before VLCD than in the control group. No differences were found in serum glucose and resistin levels between the obese group before VLCD and the control group. VLCD significantly decreased BMI, HOMA index, serum glucose, insulin and leptin levels and increased soluble leptin receptor levels. The changes in serum adiponectin and resistin levels in obese women after VLCD did not reach statistical significance. We conclude that leptin and soluble leptin receptor levels were affected by VLCD while adiponectin and resistin concentrations were not. Therefore, other mechanisms rather than changes in the endocrine function of the adipose tissue are probably involved in the VLCD-induced improvement of insulin sensitivity.

Topics: Adiponectin; Blood Glucose; Body Mass Index; Caloric Restriction; Female; Humans; Insulin; Insulin Resistance; Leptin; Obesity; Receptors, Cell Surface; Receptors, Leptin; Resistin; Treatment Outcome

Although treatment with antipsychotics, particularly olanzapine and clozapine, has been implicated in weight gain and higher incidence of diabetes, the mechanism of these adverse reactions remains unclear. The purposes of this study were to explore the early effects of olanzapine on serum levels of ghrelin, adiponectin and leptin, three recently identified hormones that play crucial roles in the regulation of energy balance and glucose metabolism. Thirteen patients with schizophrenia who had not received any medication in the 4 weeks prior to this study were included. The patients received olanzapine at an average dose of 14.5mg/day. Serum levels of ghrelin, adiponectin, leptin and insulin, as well as weight and fasting glucose, were investigated at the baseline and at 4 weeks. Serum ghrelin levels had decreased (p 0.03) and leptin had increased (p 0.02), while adiponectin and insulin levels had not significantly changed at Week 4 (p 0.29 and p 0.25, respectively). Weight had increased (p 0.01), while fasting glucose had not significantly changed (p 0.46). These findings suggest that ghrelin levels decrease and leptin levels increase after initiation of olanzapine therapy. Weight gain is also considered to be an early change, while change in insulin sensitivity is not an early change of treatment with olanzapine. Further large-scale and longitudinal studies are warranted to elucidate metabolic changes involving ghrelin, adiponectin, leptin and insulin and their impact on weight and glucose metabolism during treatment with olanzapine and other antipsychotics.

Topics: Adiponectin; Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Female; Ghrelin; Humans; Insulin; Insulin Resistance; Leptin; Male; Olanzapine; Peptide Hormones; Prospective Studies; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

To evaluate levels of soluble receptor (sOB-R) and free leptin in women with polycystic ovarian syndrome (PCOS) and note any relationships with insulin resistance, adiposity, and androgens. Leptin is an adipokine that circulates in a free form and bound to an sOB-R. Only free leptin is biologically active.. Prospective, case-control study.. University-based reproductive endocrinology practice.. Forty women with PCOS and severe insulin resistance and 15 body mass index (BMI)-matched ovulatory controls.. Measurements of serum insulin, leptin, sOB-R at fasting and during a standard oral glucose tolerance test (OGTT), and measurements before and after treatment with rosiglitazone.. Fasting glucose, insulin, leptin, sOB-R, T, and DHEAS levels in women with PCOS and controls were measured to investigate the relationship of sOB-R and the free leptin index (FLI) to insulin, adipocity, and androgens and to investigate the effect of acute hyperinsulinemia during OGTT and the effect of improvement of insulin resistance with rosiglitazone on the leptin system. FLI was calculated by dividing leptin levels by sOB-R.. Total leptin and FLI correlated significantly with BMI in both patients with PCOS and in controls. There was a significant negative correlation between DHEAS and sOB-R in PCOS. Leptin, sOB-R, and FLI were not significantly different in the two groups, and neither sOB-R nor FLI correlated with insulin or glucose levels. The sOB-R levels increased significantly 3 hours after oral glucose ingestion, resulting in a significant decline in FLI.. [1] Adiposity rather than insulin resistance appears to be the main determinant of leptin levels and FLI. [2] Acute increase in insulin levels during OGTT is associated with an increase in levels of sOB-R. [3] DHEAS may play a role in leptin bioavailability by modulating sOB-R levels.

Topics: Acanthosis Nigricans; Adiposity; Adult; Androgens; Body Mass Index; Case-Control Studies; Comorbidity; Female; Humans; Incidence; Insulin Resistance; Leptin; Obesity; Polycystic Ovary Syndrome; Receptors, Cell Surface; Receptors, Leptin; Risk Assessment; Risk Factors; Texas

Many formulas have been proposed to calculate insulin sensitivity and studies have shown their effectiveness. However, few studies have been done to compare formulas.. Seventy-two obese participants completed a randomized weight loss study. Weight loss, change in body fat and change in waist circumference were used as surrogates for change in insulin sensitivity. Correlation coefficients were calculated for each of these surrogates with proposed formulas for insulin sensitivity found in the literature.. The change in insulin sensitivity using the formula proposed by McAuley (exp(2.63-0.28 x ln(fasting insulin)-0.31 x ln(fasting triglyceride in mmol/l)) showed the greatest correlation with weight loss (r=-0.59, p<0.0001) and was statistically superior to change in fasting glucose, fasting insulin and homeostasis model assessment (HOMA).. The insulin sensitivity formula proposed by McAuley provides an accurate means of detecting insulin resistance. As it does not require a glucose tolerance test, it is also easier and less expensive than most other formulas. Use of this formula rather than fasting glucose would detect many more patients with insulin resistance who are at risk for subsequent diabetes and other complications.

Topics: Adipose Tissue; Blood Glucose; Body Mass Index; Body Size; Body Weight; C-Reactive Protein; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Obesity; Weight Loss

Zinc is important for insulin synthesis, storage and secretion. When zinc concentration decrease, there is a concomitant reduction in insulin secretion and peripheral insulin sensitivity.. To assess the effects of zinc sulfate on insulin sensitivity, leptin and androgens in obese individuals.. A randomized, double-blind, placebo-controlled clinical trial was performed in 14 obese volunteers between 21 and 30 years old, with body mass index (BMI) (3) 27 kg/m2. During one month, seven subjects received 100 mg/day of zinc sulfate orally (ZnG) and the other seven received placebo, as control group (CG). At baseline and after the intervention, insulin sensitivity was measured using a euglycemic-hyperinsulinemic clamp technique. Blood glucose, serum lipids, zinc, androgens and leptin were also measured in a fasting blood sample.. After the intervention, a rise in zinc concentrations from 11.8 to 16.9 umol/L; p=0.001 and in leptin levels from 15.2 to 27.7 ng/mL; p=0.029, was observed in the ZnG. No changes were observed in the CG. There were no significant changes in insulin sensitivity and androgens after the intervention with zinc sulfate.. Zinc increased the leptin concentrations in obese individuals, but did not modify insulin sensitivity and androgens.

Topics: Adult; Androgens; Dietary Supplements; Double-Blind Method; Humans; Insulin Resistance; Leptin; Male; Obesity; Reference Values; Spectrophotometry, Atomic; Zinc

Topics: Blood Glucose; Case-Control Studies; Dietary Fats; Dietary Fiber; Female; Humans; Insulin; Insulin Resistance; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor I; Leptin; Middle Aged

Psychosocial factors, such as stress and vital exhaustion, are associated with an increased risk of cardiovascular events, and women report more psychosocial ill-being after an acute myocardial infarction than men. We have earlier shown that a cognitive-behavioural intervention in women with ischaemic heart disease (IHD) improved psychosocial well-being. In the present study, we tested the hypothesis that the improvement in psychosocial well-being is associated with an improvement in biochemical indicators of cardiovascular risk.. Randomized-controlled trial in northern Sweden.. Outpatient care.. Women with IHD were randomized to either a 1-year cognitive-behavioural stress management programme or usual care. Of the 159 women who completed the study, 77 were in the intervention group, and 82 in the control group.. A 1-year cognitive-behavioural stress management programme versus conventional care.. Group assignment was not found to be a determinant of waist circumference, high sensitive C-reactive protein (hs-CRP), fibrinogen, von Willebrand factor (vWF), plasminogen activator inhibitor type 1 (PAI-1) activity, tissue plasminogen activator (tPA) activity, tPA antigen, tPA-PAI-1 complex, leptin, or HOMA2 insulin resistance index (HOMA2-IR) at follow up. Changes in psychosocial variables were not associated with changes in any of the biological risk indicators.. Even if our cognitive-behavioural stress management programme had effects on proximal targets, such as stress behaviour and vital exhaustion, we found no improvement in intermediate biochemical targets related to the metabolic syndrome and IHD. Our results challenge the proposition that the relationship between psychological well-being and biological cardiovascular risk indicators is a direct cause-effect phenomenon.

Topics: Biomarkers; C-Reactive Protein; Cognitive Behavioral Therapy; Female; Fibrinogen; Humans; Insulin Resistance; Leptin; Middle Aged; Myocardial Ischemia; Plasminogen Activator Inhibitor 1; Prospective Studies; Risk Factors; Stress, Psychological; Tissue Plasminogen Activator; von Willebrand Factor

The mechanisms by which glucocorticoid therapy promotes obesity and insulin resistance are incompletely characterized. Modulations of the metabolically active hormones, tumour necrosis factor alpha (TNF alpha), ghrelin, leptin and adiponectin are all implicated in the development of these cardiovascular risk factors. Little is known about the effects of short-term glucocorticoid treatment on levels of these hormones.. Using a blinded, placebo-controlled approach, we randomised 25 healthy men (mean (SD) age: 24.2 (5.4) years) to 5 days of treatment with either placebo or oral dexamethasone 3 mg twice daily. Fasting plasma TNFalpha, ghrelin, leptin and adiponectin were measured before and after treatment.. Mean changes in all hormones were no different between treatment arms, despite dexamethasone-related increases in body weight, blood pressure, HDL cholesterol and insulin. Changes in calculated indices of insulin sensitivity (HOMA-S, insulin sensitivity index) were strongly related to dexamethasone treatment (p < 0.001).. Our data do not support a role for TNF alpha, ghrelin, leptin or adiponectin in the insulin resistance associated with short-term glucocorticoid treatment.

Topics: Adiponectin; Adult; Ghrelin; Glucocorticoids; Health; Hormones; Humans; Insulin Resistance; Leptin; Male; Peptide Hormones; Time Factors; Tumor Necrosis Factor-alpha

Obesity is characterized by a low-grade inflammatory state, which could play a role in insulin resistance. Dynamic strength training improves insulin sensitivity.. The objective of this study was to investigate, in obese subjects, whether the insulin sensitizing effect of dynamic strength training is associated with changes in plasma levels and gene expression of adipokines potentially involved in the development of insulin resistance.. Twelve obese male subjects were investigated before and at the end of 3 months of dynamic strength training. Insulin sensitivity was evaluated using euglycemic-hyperinsulinemic clamp. Blood samples and needle biopsy samples of sc abdominal adipose tissue were obtained. The plasma levels and adipose tissue mRNA levels of adiponectin, leptin, IL-1beta, IL-6, and TNF-alpha were determined.. The training induced an increase in the whole-body glucose disposal rate by 24% (P = 0.04). The body weight was not altered during the training. Plasma levels of leptin decreased during the training (16.6 +/- 6.3 vs. 13.1 +/- 5.7 ng/ml) by 21% (P < 0.02), whereas no change in plasma levels of other adipokines and C-reactive protein was observed. Gene expression of the investigated adipokines was not changed in sc adipose tissue during the training.. In obese subjects, the dynamic strength training resulted in an improvement of whole-body insulin sensitivity. The increase in insulin sensitivity was not associated with training-induced modifications of plasma levels or adipose tissue gene expression of adipokines supposedly involved in the development of insulin resistance.

Topics: Adiponectin; Cytokines; Exercise; Gene Expression; Humans; Insulin Resistance; Interleukin-1beta; Interleukin-6; Leptin; Male; Middle Aged; Muscle Strength; Obesity; Subcutaneous Fat; Tumor Necrosis Factor-alpha

Decreased levels of GH and total IGF-I have been reported in obesity. It has been hypothesized that increased free (biologically active) IGF-I levels generated from IGF-binding protein (IGFBP) protease activity could be the mechanism for the low GH release in dieting obese subjects. However, no published data exist on free IGF-I levels, acid labile subunit (ALS), or IGFBP protease activity in relation to GH release during a hypocaloric diet. The main purpose of this study was to determine free IGF-I, ALS, IGFBPs-1-4, and IGFBPs-1-3 protease activity in relation to 24-h GH release before and after a short-term very low-calorie diet (VLCD).. Six obese subjects before weight loss, five after an average weight loss of 36.1 kg, and five age-and sex-matched lean controls underwent a 4-day VLCD. All subjects were studied on two occasions, once during normal basic diet and again during the last day of the VLCD (1.6 MJ).. Free IGF-I was determined by a non-competitive immunoradiometric assay.. Free IGF-I levels decreased in concert with increased ALS and unchanged blunted GH release after a VLCD in the obese subjects. IGFBPs-1-3 proteolytic activity was found to be unchanged by hypocaloric diet in all groups.. We conclude that free IGF-I decreases after a short-term hypocaloric diet in obese subjects with no concomitant change in 24-h GH release. Circulating free IGF-I per se cannot be the main mechanism of the attenuated GH release in dieting obese subjects.

Topics: Adult; Body Mass Index; Body Weight; Caloric Restriction; Carrier Proteins; Diet, Reducing; Endopeptidases; Female; Glycoproteins; Human Growth Hormone; Humans; Insulin Resistance; Insulin-Like Growth Factor Binding Protein 2; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor Binding Protein 4; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Growth Factor I; Leptin; Male; Obesity; Protein Denaturation; Thinness; Time Factors; Weight Loss

Leptin is thought to be a lipostatic signal that contributes to body weight regulation. Zinc might play an important role in appetite regulation and its administration stimulates leptin production. However, there are few reports in the literature on its role on leptin levels in the obese population. The present work assesses the effect of zinc supplementation on serum leptin levels in insulin resistance (IR). A prospective double-blind, randomized, clinical, placebo-controlled study was conducted. Fifty-six normal glucose-tolerant obese women (age: 25-45 yr, body mass index [BMI] = 36.2 +/- 2.3 kg/m2) were randomized for treatment with 30 mg zinc daily for 4 wk. Baseline values of both groups were similar for age, BMI, caloric intake, insulin concentration, insulin resistance, and zinc concentration in diet, plasma, urine, and erythrocytes. Insulin and leptin were measured by radioimmunoassay and IR was estimated by the homeostasis model assessment (HOMA). The determinations of zinc in plasma, erythrocytes, and 24- h urine were performed by using atomic absorption spectrophotometry. After 4 wk, BMI, fasting glucose, and zinc concentration in plasma and erythrocyte did not change in either group, although zinc concentration in the urine increased from 385.9 +/- 259.3 to 470.2 +/- 241.2 +/- microg/24 h in the group with zinc supplementation (p < 0.05). Insulin did not change in the placebo group, whereas there was a significant decrease of this hormone in the supplemented group. HOMA also decreased from 5.8 +/- 2.6 to 4.3 +/- 1.7 (p < 0.05) in the zinc-supplemented group but did not change in the placebo group. Leptin did not change in the placebo group. In the zinc group, leptin was 23.6 +/- 12.3 microg/L and did not change. More human data from a unique population of obese individuals with documented insulin resistance would be useful in guiding future studies on zinc supplementation (with higher doses or longer intervals) or different measures.

Topics: Adult; Blood Glucose; Dietary Supplements; Double-Blind Method; Humans; Insulin Resistance; Leptin; Middle Aged; Obesity; Placebos; Prospective Studies; Spectrophotometry, Atomic; Zinc

Ghrelin is postulated to be an orexigenic signal that promotes weight regain after weight loss (WL). However, it is not known whether this putative effect of ghrelin is sustained after weight stabilization. The objective of this study was to investigate the relationship of plasma ghrelin concentrations to active WL and weight maintenance in obese subjects.. This study was a randomized clinical trial, with a 12-month follow-up period. Obese Mexican-American women matched for age and BMI were randomized to a 12-month WL program (n = 25) or no intervention (controls, n = 23). Interventions included diet, exercise, and orlistat. Body weight and fasting ghrelin, leptin, insulin, and glucose concentrations were measured at baseline and 6 and 12 months.. The WL group lost 8.5% of body weight after 6 months and maintained the new weight for the next 6 months. Ghrelin concentrations increased significantly at 6 months but returned to baseline at 12 months. Baseline ghrelin concentrations were directly related to the degree of WL achieved after 12 months. Controls experienced no change in BMI or ghrelin levels. There were no associations between plasma ghrelin and leptin or insulin concentrations.. Consistent with previous results, ghrelin rises in response to WL, perhaps as a counterregulatory mechanism. However, the present results indicate that ghrelin concentrations return to baseline with sustained weight maintenance, suggesting that its effects are unlikely to regulate long-term energy balance. Baseline ghrelin concentrations are related to the degree of WL that can be achieved by active weight reduction.

Topics: Adult; Analysis of Variance; Body Mass Index; Body Weight; Female; Follow-Up Studies; Ghrelin; Health Promotion; Humans; Insulin; Insulin Resistance; Leptin; Mexican Americans; Middle Aged; Obesity; Peptide Hormones; Radioimmunoassay; Time Factors; Waist-Hip Ratio; Weight Loss

Adiponutrin is a newly described white adipose tissue (WAT)-derived protein whose function and regulation remain widely unclear in humans though it is suggested to be related to insulin sensitivity. Recently, we found that adiponutrin expression is reduced in type 2 diabetic subjects in basal and insulin-stimulated states. To examine adiponutrin regulation by the insulin pathway in relation to other WAT-related proteins with well-known relation to insulin signaling and action, we examined in healthy young men (1) the association of adiponutrin with p85alpha PI3K and HKII, leptin, adiponectin, and acylation-stimulating protein (ASP) and (2) the regulation of adiponutrin and WAT-derived proteins by 3-h hyperinsulinemic euglycemic clamp (HIEG). At baseline (N = 20), adiponutrin expressions were positively correlated with those of p85alpha PI3K (R = 0.54, P = 0.017), HKII (R = 0.58, P = 0.010), and serum leptin (R = 0.51, P = 0.036), but not with any other parameter measured including insulin sensitivity. Hyperinsulinemia (N = 10, +2365% above baseline) significantly increased the expression of adiponutrin (+770%, P = 0.002), p85alpha PI3K (+150%, P = 0.033), HKII (+147%, P = 0.007), and serum leptin (+11%, P = 0.031), while it decreased serum adiponectin (-15%, P = 0.001). In the insulin-stimulated state, adiponutrin mRNA expression levels correlated with basal p85alpha PI3K (R = 0.76, P = 0.018) and HKII (R = 0.86, P = 0.003) expression levels, with percentage increase in insulin (R = 0.73, P = 0.040), and with insulin-stimulated state HKII (R = 0.82, P = 0.007), leptin (R = 0.84, P = 0.005), and adiponectin (R = 0.85, P = 0.004) mRNA levels. In healthy young men, adiponutrin expression is upregulated [corrected] by hyperinsulinemia and is related to basal and/or insulin-stimulated p85alpha PI3K, HKII, adiponectin, and leptin expression levels. We hypothesize that insulin-mediated regulation of adiponutrin expression is under the PI3K pathway. The relevance of the present findings to reduced adiponutrin expression in type 2 diabetes is discussed.

Topics: Adiponectin; Adipose Tissue, White; Adult; Blood Glucose; Complement C3; Diabetes Mellitus, Type 2; Gene Expression Regulation; Glucose; Hexokinase; Humans; Insulin; Insulin Resistance; Leptin; Male; Membrane Proteins; Phosphatidylinositol 3-Kinases

Patients with chronic kidney disease (CKD) present a high prevalence of insulin resistance (IR). Some studies suggest that angiotensin II may influence some cellular pathways that contribute to the pathogenesis of IR and stimulate the release of proinflammatory cytokines. Fifty-two patients who had stages 3 and 4 CKD and no diabetes were administered an angiotensin receptor blocker (ARB), olmesartan (40 mg), for 16 wk. Before and after ARB treatment, metabolic and inflammatory parameters and adipokines were measured. IR was calculated by Homeostasis Model Assessment (HOMA) index. Baseline data were compared with data that were obtained from 25 healthy control individuals of similar age and normal renal function. Compared with control subjects, patients with CKD presented significantly higher BP and waist circumference, higher triglycerides and lower HDL levels, higher insulin levels, and higher mean HOMA index (6.0 +/- 2.7 versus 2.9 +/- 2.2 muU/ml x mmol/L; P < 0.001). In addition, patients with CKD had increased levels of high-sensitivity C-reactive protein, TNF-alpha, and IL-6. In patients with CKD, leptin was positively correlated to abdominal obesity, insulin levels, and IL-6, and adiponectin was inversely correlated to abdominal obesity and insulin levels. Olmesartan treatment resulted in a significant decrease of BP, urinary protein excretion, plasma glucose (99 +/- 16 versus 92 +/- 14 mg/dl; P < 0.05), insulin (23.1 +/- 8.8 versus 19.9 +/- 9; P < 0.05), HOMA index (6.0 +/- 2.7 versus 4.7 +/- 2.8; P < 0.05), and glycated hemoglobin (5.33 +/- 0.58 versus 4.85 +/- 0.81%; P < 0.01). At the same time, there was a significant reduction of high-sensitivity C-reactive protein levels, from 4.45 mg/L (2.45 to 9.00) to 3.55 mg/L (1.80 to 5.40; P < 0.05) and fibrinogen (412 +/- 100 versus 370 +/- 105 mg/dl; P < 0.05). There were no significant differences in adipokine levels after olmesartan treatment. These data demonstrate that patients with CKD have a high prevalence of IR, metabolic syndrome, and chronic inflammation and that the administration of the ARB olmesartan improves IR and inflammation markers in these patients. Plasma adipokine levels that are related to several metabolic risk factors in patients with CKD were not modified by ARB therapy.

Topics: Adipokines; Adiponectin; Adult; Aged; Aged, 80 and over; Angiotensin II Type 1 Receptor Blockers; C-Reactive Protein; Chronic Disease; Female; Humans; Imidazoles; Inflammation; Insulin; Insulin Resistance; Interleukin-6; Kidney Diseases; Leptin; Male; Metabolic Syndrome; Middle Aged; Olmesartan Medoxomil; Tetrazoles; Waist-Hip Ratio

To specify changes in clinicolaboratory parameters in reduction of obesity in patients with diabetes mellitus type 2 (DM-2).. Antropometry, densitometry of fat tissue (FT) were made and parameters of fat and carbohydrate metabolism (lipidogram, glycated hemoglobin, immunoreactive insulin), FT secretory activity (leptin, adiponectin, TNF-alpha) were studied in 75 obese DM-2 patients. After the above primary examination all the patients were randomized into 2 groups: group 1 (n = 55) received xenical (120 mg 3 times a day) and kept moderate hypocaloric diet; group 2 (n = 20) received only the above diet therapy. Active treatment lasted 24 weeks.. In addition to symptoms of metabolic syndrome (MS) the patients were found to have secretory disturbances of FT activity: elevation of leptin and TNF-alpha levels, subnormal adiponectin. These alterations directly correlated with body mass, FT mass gain, increase in waist circumference. Hyperleptinemia, hyperinsulinemia and hypoadiponectinemia were considered as markers of insulin resistance (IR) and related conditions. Xenical promoted a significant weight loss resulting in a positive trend in the parameters of adipokines, fat and carbohydrate metabolism, in reduction of IR.. Xenical is beneficial for patients with DM-2 and obesity because it improves metabolic processes.

Topics: Adiponectin; Adipose Tissue; Anthropometry; Anti-Obesity Agents; Biomarkers; Body Weight; Caloric Restriction; Carbohydrate Metabolism; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Insulin; Insulin Resistance; Lactones; Leptin; Lipids; Male; Metabolic Syndrome; Middle Aged; Obesity; Orlistat; Tumor Necrosis Factor-alpha

Obesity is often complicated by hypertension, and both conditions are risk factors for atherosclerosis. Leptin has attracted attention as a possible cause of hypertension in obese persons. We investigated the effect of a slow-release alpha1-receptor blocker, bunazosin hydrochloride, on leptin levels and insulin resistance in obese hypertensive patients with hyperleptinemia. The subjects were 17 patients (12 men and 5 women aged 56.1 +/- 12.2 years) with essential hypertension who were not receiving alpha1-receptor blockers. They had a body mass index (BMI) > or = 25 kg/m2 and a plasma leptin concentration > or = 5 ng/ml. They received oral therapy with bunazosin hydrochloride at doses of up to 9 mg/day. The plasma leptin concentration, body weight, blood pressure, heart rate, fasting blood glucose, plasma insulin concentration, and free fatty acid level were compared between before and after treatment. Although there was no significant change of BMI, there was a significant decrease of plasma leptin after treatment (10.6 +/- 5.4 ng/ml vs. 8.7 +/- 3.4 ng/ml, p = 0.0128), as well as a significant decrease of plasma insulin (9.8 +/- 4.8 microU/ml vs. 8.1 +/- 4.6 microU/ml, p = 0.0494) and HOMA-R (2.9 +/- 2.1 vs. 2.2 +/- 1.5, p = 0.0237). In conclusion, bunazosin hydrochloride reduced the plasma leptin level and improved insulin resistance in hypertensive patients with obesity and hyperleptinemia.

Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Adult; Aged; Blood Pressure; Body Mass Index; Delayed-Action Preparations; Fatty Acids, Nonesterified; Female; Heart Rate; Humans; Hypertension; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Quinazolines; Receptors, Leptin; Treatment Outcome

The aim of our study was to investigate the metabolic effect of telmisartan and irbesartan in subjects treated with rosiglitazone, a well-known insulin-sensitizing drug, in order to clarify the direct metabolic effects of the two former drugs. Patients were enrolled, evaluated, and followed at 3 Italian centers. We evaluated 188 type 2 diabetic patients with metabolic syndrome (94 males and 94 females in total; 49 males and 46 females, aged 56+/-5, treated with telmisartan; and 45 males and 48 females, aged 55+/-4, treated with irbesartan). All had been diabetic for at least 6 months, and glycemic control by the maximum tolerated dietary changes and maximum tolerated dose of oral hypoglycemic agents had been attempted and failed in all cases. All patients took a fixed dose of rosiglitazone, 4 mg/day. We administered telmisartan (40 mg/day) or irbesartan (150 mg/day) in a randomized, controlled, double-blind clinical manner. We evaluated body mass index (BMI), glycemic control (HbA1c fasting plasma glucose and insulin levels [FPG, and FPI, respectively], and homeostasis model assessment [HOMA] index), lipid profile (total cholesterol [TC], low density lipoprotein-cholesterol [LDL-C], high density lipoprotein-cholesterol [HDL-C], and triglycerides [TG]), systolic and diastolic blood pressure (SBP and DBP), tumor necrosis factor-alpha (TNF-alpha), and leptin during the 12 months of this treatment. No BMI change was observed after 6 or 12 months in either group. Significant decreases in HbAlc and FPG were observed after 6 months in the telmisartan group, and after 12 months in both groups. The decrease in HbA1c and FPG at 12 months was statistically significant only in the telmisartan group. A significant decrease in FPI was observed at 12 months in both groups, and this decrease was significantly greater in the telmisartan group. Significant decreases in the HOMA index were observed at 6 and 12 months in both groups, and the decrease in the HOMA index after 12 months was significantly greater in the telmisartan group than in the irbesartan group. Significant changes in SBP, DBP, TC, and LDL-C were observed after 6 and 12 months in both groups. Significant decreases in TNF-alpha and leptin levels were observed after 6 months in the telmisartan group, and after 12 months in both groups. In conclusion, in this study of patients with type 2 diabetes mellitus and metabolic syndrome, telmisartan seemed to result in a greater improvement in glycemic and lipid contr

Topics: Angiotensin II Type 1 Receptor Blockers; Benzimidazoles; Benzoates; Biphenyl Compounds; Blood Glucose; Blood Pressure; Body Mass Index; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Insulin Resistance; Irbesartan; Leptin; Lipids; Male; Middle Aged; Rosiglitazone; Telmisartan; Tetrazoles; Thiazolidinediones; Tumor Necrosis Factor-alpha

A role for high leptin levels in the proinflammatory state associated with obesity has been proposed on the basis of observational studies, but a recent interventional study employing administration of long-acting pegylated leptin resulting in very high pharmacologic levels in obese subjects did not support this idea. These interventional studies have not yet been independently confirmed, however, and varying levels and duration of hyperleptinemia as well as the presence of comorbidities such as diabetes have not yet been investigated as potential effect modifiers. We performed three interventional studies involving administration of recombinant methionyl human leptin (r-metHuLeptin) to lean, otherwise healthy obese, and obese diabetic subjects to investigate whether increasing circulating leptin levels over a wide spectrum of values (from low physiologic to high pharmacologic) would alter serum levels of inflammatory markers and other cytokines important in the T helper cell response. Increasing leptin levels from low physiologic to high physiologic in lean men and from higher physiologic to low pharmacologic in obese men over 3 d did not alter serum interferon-gamma, IL-10, TNF-alpha, monocyte chemoattractant protein-1, or soluble intercellular adhesion molecule-1. In obese subjects with type 2 diabetes mellitus, the administration of r-metHuLeptin for 4 or 16 wk, resulting in high pharmacologic leptin levels, did not activate the TNF-alpha system or increase cytokines or inflammatory markers, including IL-10, IL-6, C-reactive protein, monocyte chemoattractant protein-1, and soluble intercellular adhesion molecule-1. These findings do not support an etiopathogenic role for leptin in proinflammatory states associated with leptin excess such as obesity and have direct relevance for the potential future therapeutic use of r-metHuLeptin in humans.

Topics: Adult; Biomarkers; C-Reactive Protein; Chemokine CCL2; Humans; Insulin Resistance; Intercellular Adhesion Molecule-1; Interleukin-10; Interleukin-6; Leptin; Male; Obesity; Tumor Necrosis Factor-alpha

The objective of this study is to assess the effects of sibutramine on body weight, body fat distribution, insulin resistance, plasma leptin, lipid profile and blood pressure profiles in hypertensive obese patients.. Eighty-six central obese hypertensive patients (BMI = 39 +/- 5 kg/m(2), 84% of women, 48 +/- 8.5 years old) were placed on a hypocaloric diet and placebo therapy for 4 weeks. They were then randomized to receive sibutramine (10 mg) or placebo for 24 weeks. Both, before therapy and at the end of the study, the waist and hip circumferences were measured and the waist/hip ratio (WHR) was calculated; abdominal ultrasonography was performed in order to estimate the amount of subcutaneous fat (SF) and visceral fat (VF), and the visceral/subcutaneous ratio. Beyond HOMA-r, another insulin resistance index (IRIp) was calculated by means of the formula: peak of blood glucose after oral glucose load x plasma insulin level/10(4). Fasting plasma leptin and lipid levels were also determined.. Sibutramine induced greater weight reduction than placebo (6.7 vs. 2.5%, p < 0.001). Reductions in WHR (0.97 +/- 0.08 vs. 0.94 +/- 0.07, p < 0.01), IRIp (0.11 +/- 0.07 vs. 0.09 +/- 0.06 mmol mu/l(2)) and VF (6.4 +/- 2.4-6.0 +/- 2.4 cm, p < 0.01) were observed only with sibutramine. Plasma leptin decreased with placebo (24 +/- 15 vs. 18 +/- 10 UI/l, p < 0.01), but not with sibutramine (18.8 +/- 8.4 vs. 18.2 +/- 13.2 UI/l). No clinically significant change in lipid profile was observed in both groups. Moreover, office and 24-h blood pressure values did not change during placebo or sibutramine therapy, whereas a significant increase in office heart rate, from 78.3 +/- 7.3-82 +/- 7.9 b.p.m., p = 0.02, was observed with sibutramine.. Sibutramine therapy induced greater body weight loss than placebo in hypertensive obese patients. This was associated with WHR reduction, decreases in VF and insulin resistance. The maintenance of leptin levels during sibutramine therapy may be important to avoid weight recovery, although this finding must be confirmed by other prospective studies.

Topics: Adult; Antihypertensive Agents; Appetite Depressants; Chi-Square Distribution; Cyclobutanes; Drug Therapy, Combination; Female; Glucose Tolerance Test; Humans; Hypertension; Insulin Resistance; Leptin; Lipids; Male; Middle Aged; Obesity; Waist-Hip Ratio; Weight Loss

This study examined the effects of exercise on metabolic risk variables insulin, leptin, glucose, and triglycerides in overweight/obese postmenopausal women.. Sedentary women (n = 173) who were overweight or obese (BMI > or = 25 kg/m(2) or > or =24 kg/m(2) with > or =33% body fat), 50 to 75 years of age, were randomized to 12 months of exercise (> or =45 minutes of moderate-intensity aerobic activity 5 d/wk) or to a stretching control group. Body composition (DXA) and visceral adiposity (computed tomography) were measured at baseline and 12 months. Insulin, glucose, triglycerides, and leptin were measured at baseline and 3 and 12 months. Insulin resistance was evaluated by the homeostasis model assessment formula. Differences from baseline to follow-up were calculated and compared across groups.. Exercisers had a 4% decrease and controls had a 12% increase in insulin concentrations from baseline to 12 months (p = 0.0002). Over the same 12-month period, leptin concentrations decreased by 7% among exercisers compared with remaining constant among controls (p = 0.03). Homeostasis model assessment scores decreased by 2% among exercisers and increased 14% among controls from baseline to 12 months (p = 0.0005). The exercise effect on insulin was modified by changes in total fat mass (trend, p = 0.03), such that the exercise intervention abolished increases in insulin concentrations associated with gains in total fat mass.. Regular moderate-intensity exercise can be used to improve metabolic risk variables such as insulin and leptin in overweight/obese postmenopausal women. These results are promising for health care providers providing advice to postmenopausal women for lifestyle changes to reduce risk of insulin resistance, coronary heart disease, and diabetes.

Topics: Adipose Tissue; Aged; Blood Glucose; Body Composition; Exercise; Female; Homeostasis; Humans; Insulin; Insulin Resistance; Leptin; Life Style; Metabolic Syndrome; Middle Aged; Obesity; Patient Compliance; Postmenopause; Risk Factors; Triglycerides

The role of resistin in human biology remains uncertain. We measured serum resistin levels in Japanese patients with (n=111) and without (n=98) type 2 diabetes mellitus and investigated the significance of this hormone in the pathophysiology of diabetes. The levels of serum adiponectin and leptin were also measured. Resistin levels were increased significantly in patients with type 2 diabetes compared with non-diabetic subjects (24.7+/-2.6 vs. 15.0+/-1.2 ng/ml, p=0.0013). However, there was no correlation in either patient group between serum resistin levels and markers of insulin resistance, obesity or hyperlipidaemia. These results were in direct contrast to the data of leptin or adiponectin, both of which were closely related to these clinical markers of diabetes. Multivariate regression analysis on the combined data of the two groups demonstrated that the presence of diabetes and HDL cholesterol levels were significant predictors of serum resistin levels (diabetes: beta=0.159, p=0.035; HDL: beta=-0.172, p=0.039). No correlation was observed between C-reactive protein and resistin adjusted for BMI. Taken together, these findings demonstrate that serum resistin levels are increased in patients with type 2 diabetes, but this increase is not linked to markers of insulin resistance or adiposity. Further studies are necessary to elucidate the significance of serum resistin concentration in human pathophysiology.

Topics: Adiponectin; Aged; Biomarkers; Body Mass Index; Body Weight; C-Reactive Protein; Diabetes Mellitus, Type 2; Female; Hormones, Ectopic; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Male; Middle Aged; Obesity; Patient Selection; Reference Values; Resistin

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

Aim of this study was to compare the effect of valsartan and felodipine on blood pressure (BP), plasma leptin (L), insulin sensitivity and plasma norepinephrine (NE) in obese hypertensive patients. Ninty-six obese patients (body mass index [BMI] > or = 30 kg/m2) with mild to moderate essential hypertension (diastolic blood pressure [DBP] > 90 and < 110 mmHg, as evaluated with an appropriately sized cuff) aged 31-60 years, were randomized to a valsartan (80 mg/day for 16 weeks; n = 48) or felodipine (5 mg/day for 16 weeks; n = 48) treatment group after a 2-week wash-out period. After the first 4 weeks of treatment there was a titration with dose-doubling in non responder patients (DBP > 90 mmHg). At the end of the placebo period and of active treatment period, BP and BMI were evaluated and a venous sample was drawn at the same hour in the morning to evaluate plasma L and NE. Insulin resistance index (HOMA-IR) was calculated. No dietary advice was prescribed. Both valsartan and felodipine significantly decreased BP values (-19.3/15 mmHg and -18.9/13.6 mmHg, respectively p < 0.001 vs. placebo), with no difference between treatments. However, felodipine increased plasma NE (+124 pg/ml, +38.2%, p < 0.05 vs. placebo and < 0.01 vs. valsartan) and had no effect on L, body weight and HOMA-IR index, while valsartan did not modify NE and produced a significant reduction in L (-3.7 ng/ml, -10.1%, p < 0.05 vs. placebo), BMI (-1.7 kg/m2, -4.7%, p < 0.01 vs. placebo) and HOMA-IR index (-1.6, -20%, p < 0.05 vs. placebo). These results suggest that in hypertensive obese subjects, treatment with valsartan might offer an advantage over treatment with felodipine, since valsartan may help to improve obesity-related disorders in addition to lowering BP.

Topics: Aged; Antihypertensive Agents; Felodipine; Female; Humans; Hypertension; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Tetrazoles; Treatment Outcome; Valine; Valsartan

The regulation and function of systemic ghrelin levels appear to be associated with food intake and energy balance rather than GH. Since GH, in turn, acutely induces lipolysis and insulin resistance in skeletal muscle, we aimed to study the isolated and combined effects of GH, free fatty acids (FFAs) and insulin sensitivity on circulating ghrelin levels in human subjects.. Seven GH-deficient patients (aged 37 +/- 4 years (mean +/- s.e.)) were studied on four occasions in a 2 x 2 factorial design with and without GH substitution and with and without administration of acipimox, which lowers FFA levels by inhibition of the hormone-sensitive lipase, in the basal state and during a hyperinsulinemic euglycemic clamp.. Serum FFA levels decreased with acipimox administration irrespective of GH status. The GH-induced reduction in insulin sensitivity was countered by acipimox. Fasting ghrelin levels decreased insignificantly during GH administration alone, but were reduced by 33% during co-administration of GH and acipimox (Aci) (in ng/l): 860 +/- 120 (-GH - Aci), 711 +/- 130 (-GH + Aci), 806 +/- 130 (+GH - Aci), 574 +/- 129 (+GH + Aci), P < 0.01. The clamp was associated with a further, moderate lowering of ghrelin. GH and acipimox induced a reciprocal 25% increase in serum leptin levels (microg/l): 11.2 +/- 4.4 (-GH - Aci), 11.7 +/- 4.4 (-GH + Aci), 11.5 +/- 4.4 (+GH - Aci), 13.9 +/- 4.2 (+GH + Aci), P = 0.005.. Our data suggest that antilipolysis via suppression of the hormone-sensitive lipase in combination with GH administration is associated with significant and reciprocal changes in ghrelin and leptin.

Topics: Adult; Drug Combinations; Fasting; Fatty Acids, Nonesterified; Female; Ghrelin; Growth Hormone; Hormone Replacement Therapy; Human Growth Hormone; Humans; Hypolipidemic Agents; Insulin Resistance; Leptin; Lipolysis; Male; Middle Aged; Peptide Hormones; Pyrazines; Steroid Metabolism, Inborn Errors; Sterol Esterase

Major depression in women of reproductive age may be accompanied by multiple endocrine and metabolic disturbances, which, in turn, may affect reproductive functioning. Enhanced cortisol synthesis, impaired leptin production and diminished insulin sensitivity have been reported in some depressed populations. We sought to determine whether an 8-week administration of citalopram would have an effect on these endocrine factors in a group of euglycemic depressed and non-depressed women of reproductive age.. Fourteen depressed and 18 non-depressed women (diagnosed by structured clinical interview) aged between 18 and 45 years completed an 8-week study. All depressed women were treated with citalopram and non-depressed subjects randomized to citalopram or no treatment in an open label cohort study. An oral glucose tolerance test with insulin levels was performed at baseline and at the end of the 8-week trial. Weight, blood pressure, fasting serum cortisol, fasting serum leptin and Beck Depression Inventory were assessed at baseline, 2, 4 and 8 weeks.. Citalopram significantly improved depressive symptoms and Beck Depression Inventory scores in the depressed cohort. Cortisol production was higher in depressed women but did not diminish with citalopram therapy over 8 weeks. Indices of insulin sensitivity and leptin production were similar between depressed and non-depressed women and did not change despite citalopram therapy.. . Insulin sensitivity in moderately depressed women of reproductive age does not differ from that in a similar group of non-depressed women. Insulin sensitivity, cortisol secretion and leptin production do not change significantly in depressed women following an 8-week course of citalopram despite substantial improvement in depression scores.

Topics: Administration, Oral; Adolescent; Adult; Citalopram; Cohort Studies; Depressive Disorder; Drug Administration Schedule; Female; Glucose Tolerance Test; Humans; Hydrocortisone; Insulin; Insulin Resistance; Leptin; Middle Aged; Psychiatric Status Rating Scales; Selective Serotonin Reuptake Inhibitors; Treatment Outcome

To determine the effects of a weight loss program, including dietary modifications, increased physical activity and dietary supplement (L-carnitine or placebo) on anthropometrics, leptin, insulin, the metabolic syndrome (MS) and insulin resistance in overweight /obese premenopausal women.. Participants consumed a hypocaloric diet; 30% protein, 30% fat and 40% carbohydrate in addition to increasing number of steps/day. Carnitine supplementation followed a randomized double blind protocol. Protocol lasted for 10 weeks. Seventy subjects (35 in the control and 35 in the carnitine group) completed the intervention. Anthropometrics, plasma insulin and leptin concentrations and body composition were measured. The number of subjects with the MetSyn and insulin resistance, were assessed at baseline and post-intervention.. Because there were no significant differences between the carnitine and the placebo groups for all measured parameters, participants were grouped together for all analysis. Subjects decreased total energy (-26.6%, p < 0.01) and energy from carbohydrate (-17.3%, p < 0.01) and increased energy from protein by 67% (p < 0.01) and number of steps/day (42.6%, p < 0.01). Body weight (-4.6%, p < 0.001), body mass index (-4.5%, p < 0.01), waist circumference (-6.5%, p < 0.01), total fat mass (-1.7%, p < 0.01), trunk fat mass (-2.0%, p < 0.01), insulin (- 17.9%, p < 0.01) and leptin (-5.9%, p < 0.05) decreased after the intervention. Ten of 19 participants with insulin resistance became insulin sensitive and 7 of 8 participants with the MetSyn no longer had the syndrome after the intervention.. Moderate increases in physical activity and a hypocaloric/high protein diet resulted in multiple beneficial effects on body anthropometrics and insulin sensitivity. Realistic dietary and physical activity goals must be the focus of intervention strategies for overweight and obese individuals.

Topics: Adult; Anthropometry; Body Composition; Carnitine; Diet, Reducing; Dietary Proteins; Dietary Supplements; Double-Blind Method; Exercise; Female; Humans; Insulin; Insulin Resistance; Leptin; Lipids; Metabolic Syndrome; Obesity; Premenopause; Vitamin B Complex; Weight Loss

This pilot study compared the efficacy of orlistat as an adjunctive treatment for obesity between African American and Caucasian adolescents. Twenty obese adolescents with obesity-related co-morbid conditions underwent measurements of body composition, glucose homeostasis by frequently sampled intravenous glucose tolerance test (FSIGT), and fasting lipids before and after 6 months treatment with orlistat 120 mg tid in conjunction with a comprehensive behavioral program. Weight (p < 0.05), BMI (p < 0.001), total cholesterol (p < 0.001), LDL cholesterol (p < 0.001), fasting insulin (p < 0.02) and fasting glucose (p < 0.003) were lower after treatment. Insulin sensitivity, measured during the FSIGT, improved significantly (p < 0.02), as did fasting indices such as the homeostasis model assessment for insulin resistance (p < 0.01). African American subjects exhibited significantly less improvement in weight (p < 0.05), BMI (p < 0.01), waist circumference (p = 0.03), and insulin sensitivity (p = 0.05). Improvements in cholesterol were not significantly different between African Americans and Caucasians. We conclude that Caucasians lost more weight and had greater improvements in insulin sensitivity than African Americans, but both exhibited improvements in plasma lipids. The true benefit of orlistat treatment over a comprehensive behavioral program remains to be determined in placebo-controlled trials.

Topics: Administration, Oral; Adolescent; Behavior Therapy; Black or African American; Blood Glucose; Body Weight; Capsules; Cholesterol, LDL; Clinical Trials as Topic; Comorbidity; Drug Administration Schedule; Energy Metabolism; Female; Humans; Insulin Resistance; Lactones; Leptin; Male; Obesity; Orlistat; Pilot Projects; Treatment Outcome; White People

Adiponectin influences insulin sensitivity and lipid metabolism, but it is not clear whether these effects are correlated with fat mass or distribution. We studied the relationship between plasma adiponectin and leptin levels, insulin sensitivity, and serum lipids by a cross-sectional study (n = 242 subjects) and by an intervention study (95 of 242) to evaluate the effect of weight loss (WL). Considering all subjects both together and subdivided into nonobese (n = 107) and obese (n = 135) groups, plasma adiponectin, but not plasma leptin, was significantly (P < 0.01) correlated with insulin sensitivity [homeostasis model assessment of insulin-resistance index (HOMAIR), insulin sensitivity index (ISI) at oral glucose tolerance test, and clamp in 115 of 242 individuals], high-density lipoprotein cholesterol, and triglycerides. These relationships were still significant (P < 0.01) after adjusting for age, gender, body mass index (BMI), and ISI. After WL (-16.8 +/- 0.8%), plasma adiponectin increased, and plasma leptin decreased (P < 0.0001 for both). Their changes (Delta) were significantly correlated with Delta-BMI (P < 0.05 for both). Delta-Adiponectin, but not Delta-leptin, significantly (P < 0.001) correlated with Delta-high-density lipoprotein cholesterol and Delta-triglycerides; these correlations were independent of age, gender, Delta-BMI, and Delta-ISI (P < 0.005). In conclusion, both cross-sectional and intervention studies indicate that plasma adiponectin level correlates with serum lipids independently of fat mass. The intervention study also suggests that adiponectin increase after WL is correlated with serum lipid improvement independently of insulin sensitivity changes.

Topics: Adiponectin; Adipose Tissue; Adolescent; Adult; Age Factors; Aged; Body Composition; Body Weight; Cholesterol, HDL; Cross-Sectional Studies; Female; Glucose Clamp Technique; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Male; Middle Aged; Obesity; Proteins; Triglycerides; Weight Loss

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

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

Leptin plays an important role in the regulation of body weight and is known to circulate in both free and bound forms. One of the leptin receptor isoforms exists in a circulating soluble form that can bind leptin. Clinical studies have shown that soluble leptin receptor (sOB-R) levels are lower in obese individuals. In the present study, we measured the serum sOB-R level in 419 healthy Japanese subjects (198 men and 221 women, aged 30 to 65 years, body mass index [BMI] 21.7 +/- 2.6 [SD] kg/m2) and in 150 type 2 diabetic patients (96 men and 54 women, BMI 24.3 +/- 3.8 kg/m2). We investigated the relationships between serum sOB-R level and BMI, blood pressure, homeostasis model assessment-insulin resistance index (HOMA-IR), serum leptin and adiponectin levels, lipid profile, and leptin receptor (LEPR) gene Lys109Arg and Gln223Arg polymorphisms. Serum leptin and sOB-R levels were measured by radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA), respectively. The serum sOB-R level in men was significantly higher than that in women. The serum sOB-R level was negatively correlated with BMI, fasting insulin, HOMA-IR, and serum leptin level and positively correlated with high-density lipoprotein (HDL)-cholesterol and serum adiponectin levels. The correlations between serum sOB-R level and fasting insulin, HOMA-IR, serum leptin, adiponectin, and HDL-cholesterol levels were significant even after adjustment for age, sex, and BMI in healthy subjects. There was no association between serum sOB-R level and the LEPR polymorphisms examined. These findings suggest that the serum sOB-R level is negatively correlated with HOMA-IR and serum leptin level and positively correlated with HDL-cholesterol level and serum adiponectin level, independent of age, sex, and BMI, in the Japanese population.

Topics: Adiponectin; Adult; Aged; Blood Pressure; Body Mass Index; Diabetes Mellitus, Type 2; DNA Probes; Enzyme-Linked Immunosorbent Assay; Female; Homeostasis; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Japan; Leptin; Lipids; Male; Middle Aged; Polymorphism, Genetic; Population; Proteins; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction

The metabolic and hormonal impact of rapid dietary changes in type 2 diabetes has not been clarified. The objective of this study was to test whether a short-term, low-fat diet affected metabolic control, insulin sensitivity, lipids and adipocyte hormones in patients with type 2 diabetes with hypertriacylglycerolaemia. Nineteen outpatient subjects (10 M, 9 F) with type 2 diabetes and triacylglycerols >2.2 mmol/L at screening were included in the study. Dietary intake was assessed by weighing during two periods of 3-day baseline diet followed by a 3-day low-fat dietary intervention. The two periods of baseline diet did not differ with respect to relevant variables during intervention. Subjects were advised to increase fibre-rich and low-fat foods and to decrease intake of visible fat in an isoenergetic manner. The percentage of energy from fat was reduced from 39 to 22 (p < 0.0001), median values. Daytime blood glucose did not change and fasting insulin and fasting glucose to insulin ratios were unaffected. Total cholesterol decreased from 6.3 to 6.2 mmol/L (p < 0.005), high-density lipoprotein cholesterol from 1.13 to 1.10 mmol/L (p < 0.048) and the ratio of n-6 to n-3 fatty acids in phospholipids from 2.5 to 1.9 (p < 0.003). Concentrations of leptin decreased from 12.1 to 9.9 ng/mL (p < 0.005) and adiponectin increased from 8.6 to 10.5 microg/mL (p < 0.024). The effect on leptin was confined to women. A low-fat diet intervention for 3 days in insulin-resistant type 2 diabetes affects lipid, adiponectin and leptin levels but fails to improve insulin sensitivity and metabolic control.

Topics: Adiponectin; Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Diet, Fat-Restricted; Female; Humans; Hypertriglyceridemia; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Lipids; Male; Middle Aged; Norway

Leptin can be regarded as a marker of the nutritional status of the body. This study was performed to determine the correlation of leptin levels with insulin (I) and androgens in girls with premature pubarche (PP) and prepubertal controls (C) with (OB) or without (nOB) obesity. We studied 25 girls with PP and 14 C; girls were dived into two subgroups according to body mass index (BMI): OB (18 PP and 8 C) and nOB (7 PP and 6 C). Obesity was defined as BMI >95th percentile for chronological age. Serum levels of leptin, I, glucose (G), DHEAS, testosterone, androstenedione (A), cortisol, SHBG, IGFBP-1 and lipid profile were measured. The fasting G to I ratio (FGIR) was calculated and FGIR <7 was considered as suggestive of I resistance (IR). Data were analyzed comparing PP vs C and OB vs nOB. Serum DHEAS (0.60 +/- 0.45 vs 0.18 +/- 0.22 microg/ml) and A (895.5 +/- 420.4 vs 457.0 +/- 352.1 pg/ml) levels were significantly higher in PP than C. Other hormonal and metabolic parameters were similar. Serum leptin (30.8 +/- 18.3 vs 8.1 +/- 5.9 ng/ml), A (841.8 +/- 471.1 vs 522.5 +/- 317.2 pg/ml), DHEAS (0.53 +/- 0.44 vs 0.31 +/- 0.39 microg/ml), G (88.4 +/- 8.8 vs 80.2 +/- 8.1 mg/dl), I (13.5 +/- 7.7 vs 5.1 +/- 3.7 microU/ml) and total cholesterol (TC) (180.5 +/- 30.9 vs 161.8 +/- 29.5 mg/dl) levels were greater in the OB than in the nOB group. IR was observed in 10 girls with OB and in one with nOB. Leptin was correlated with BMI (r = 0.83), SHBG (r = -0.44), IGFBP-1 (r = -0.47), I (r = 0.37), A (r = 0.48) and TC (r = 0.36), but in multiple regression analysis only with BMI (r2 = 0.72, p < 0.001). Girls with PP and prepubertal OB girls showed elevated leptin levels independent of I and androgen levels. Girls with OB had a greater degree of hyperandrogenism and IR. As obesity, IR and hyperandrogenism are common findings in polycystic ovary syndrome (PCOS), which is more prevalent in young women with a history of PP, a role of leptin in PCOS can be suggested. In addition, girls with PP could be considered a population at risk for plurimetabolic syndrome.

Topics: Androgens; Blood Glucose; Body Mass Index; Child; Dehydroepiandrosterone Sulfate; Female; Humans; Insulin; Insulin Resistance; Leptin; Lipids; Obesity; Puberty, Precocious; Reference Values

To learn more about the factors that regulate adipokines in diabetes, we examined fasting plasma concentrations of adiponectin and C-reactive protein (CRP) in well-characterized groups of age-matched individuals classified as: (1) type 2 diabetes; (2) impaired fasting glucose or mild diabetes (IFG/mild DM); (3) obese, matched for body mass index (BMI); and (4) non-obese. Diabetic subjects were also studied on no phamacologic treatment, after 3 months randomization to metformin or glyburide, and after 3 months crossover to the opposite drug. CRP decreased and adiponectin increased progressively between subjects in groups 1 through 4. CRP was significantly associated with percent (r = 0.45) and total (r = 0.50) fat, insulin sensitivity as S(I) (r = -0.39) or homeostasis model assessment of insulin resistance [HOMA (IR)] (r = -0.36), and hemoglobin A(1c) (HbA(1c)) (r = 0.41). The relationship of CRP to percent fat appeared to be logarithmic and log CRP varied with percent fat independent of gender. Adiponectin concentration was significantly associated with insulin sensitivity as S(I) (r = 0.55) or HOMA (IR) (r = -0.46). Adiponectin concentrations were higher among women overall (all groups included) but not in women classified as type 2 diabetes. Although mean adiponectin was higher in subjects classified as non-obese compared to obese, adiponectin, in sharp contrast to leptin (previously reported data) and to CRP, varied markedly when expressed as a function of adiposity. Multiple regression models confirmed the strong relationship of adiponectin to insulin sensitivity, as well as the relationships of CRP to adiposity and insulin sensitivity. Glyburide treatment of diabetes decreased CRP and did so even though body weight increased. We conclude that both CRP and adiponectin correlate strongly to S(I). CRP, in contrast to adiponectin, is far more dependent on adiposity. The relationship between CRP (like leptin) and gender depends on how CRP is expressed relative to adiposity. Our data raise the possibility that gender differences in adiponectin may be lost in diabetes. Finally, pharmacologic treatment of diabetes may modulate CRP independent of adiposity.

Topics: Adiponectin; Blood Glucose; Body Composition; C-Reactive Protein; Cross-Over Studies; Diabetes Mellitus, Type 2; Female; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Linear Models; Lipids; Male; Metformin; Middle Aged; Obesity; Sex Factors

To investigate whether leptin-induced improvements in glycemic control, hyperlipidemia, and insulin sensitivity in hypoleptinemic patients with generalized lipodystrophies are accompanied by reduction in intrahepatic and intramyocellular lipid (IMCL) accumulation.. We examined the effects 8-10 months of subcutaneous leptin replacement therapy on insulin sensitivity, IMCL, and intrahepatic lipid content in two patients with acquired generalized lipodystrophy and one patient with congenital generalized lipodystrophy. All patients had extreme lack of body fat, low plasma leptin levels, and elevated serum triglycerides, but only two had diabetes. Insulin sensitivity was measured by a high-dose (0.2 IU/kg) insulin tolerance test, as well as by hyperinsulinemic-euglycemic glucose clamp studies in two patients. IMCL and intrahepatic lipid content were measured by (1)H magnetic resonance spectroscopy. All measurements were obtained before and during 2-10 months of leptin therapy.. Glycemic control and lipoprotein levels markedly improved with leptin therapy in the two diabetic patients, and a slight improvement in lipoprotein levels was seen in the nondiabetic patients. Insulin stimulated glucose uptake during 60-120 min of the euglycemic clamp studies, and the rate of glucose disappearance during the insulin tolerance test nearly doubled with leptin therapy. As compared with the baseline period, after 8-10 months of leptin therapy, the mean intrahepatic lipid content was reduced by approximately 80% and the IMCL content was reduced by approximately 42%.. Reduction in IMCL and intrahepatic lipid content may partly explain leptin-induced improvement in insulin sensitivity in patients with generalized lipodystrophy.

Topics: Adolescent; Adult; Blood Glucose; Female; Humans; Insulin Resistance; Leptin; Lipid Metabolism; Lipodystrophy; Liver; Magnetic Resonance Imaging; Male; Muscle, Skeletal; Treatment Outcome

Pioglitazone is considered to reduce insulin resistance. This study was conducted to evaluate the efficacy, safety and clinical profile of pioglitazone in patients whose type 2 diabetes were poorly controlled with alpha-glucosidase inhibitor alone or alpha-glucosidase in combination with sulfonylurea.. Twenty patients with type 2 diabetes were treated with pioglitazone (30 mg q.d.) orally for 16 weeks.. There were significant reductions in HbA1C, FPG and postprandial plasma glucose at week 16. As adverse events, oedema, hypoglycaemia-like reaction, increases in LDH, CPK, etc. were noted. There was no significant change in TNF-alpha. Leptin levels increased significantly at week 16 and were still increasing 4 weeks after the treatment. Per cent body fat was almost constant throughout the study period. When efficacy was classified by demographic variables, pioglitazone was found to be more effective in the subjects who had a higher postprandial 2-h plasma glucose level, leptin level or per cent body fat value.. Pioglitazone was considered to be effective when used in patients whose type 2 diabetes were poorly controlled with alpha-glucosidase inhibitor alone or alpha-glucosidase in combination with sulfonylurea.

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Follow-Up Studies; Glycated Hemoglobin; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Insulin Resistance; Leptin; Lipids; Male; Middle Aged; Pioglitazone; Sulfonylurea Compounds; Thiazoles; Thiazolidinediones; Treatment Failure; Treatment Outcome

Previously undiagnosed diabetes, impaired glucose tolerance, and insulin resistance are common in patients with acute myocardial infarction and coronary heart disease (CHD) and might be involved in early restenosis after stent implantation. To evaluate whether markers of insulin resistance syndrome, including leptin, and endothelial dysfunction are related to increased rate of early restenosis, we studied nondiabetic patients with CHD after successful coronary stenting.. Both patients with CHD undergoing coronary stenting (120 patients) and control subjects (58 patients) were submitted to an oral glucose tolerance test (OGTT). Fasting leptin levels and fasting and postglucose load insulin sensitivity were assessed. Endothelial function was measured by nitrite and nitrate release (NOx) during OGTT. More than 50% of patients treated with stent implantation presented impaired glucose tolerance or type 2 diabetes, which was previously undiagnosed. These patients also had higher glucose, insulin, and leptin levels than control subjects. Among the stented patients, insulin and leptin levels were higher in patients with restenosis than in patients without restenosis. A significant increase in NOx levels was found during OGTT both in patients without restenosis and in control subjects. On the contrary, NOx profiles were blunted in patients with restenosis. At multiple regression analysis, only DeltaAUC-NOx areas and insulin sensitivity index showed an independent correlation with the minimal lumen diameter at follow-up.. We demonstrated that insulin resistance and endothelial dysfunction are independent predictors of early restenosis after coronary stenting.

Topics: Area Under Curve; Blood Glucose; Blood Vessel Prosthesis Implantation; Coronary Angiography; Coronary Disease; Coronary Restenosis; Diabetes Mellitus, Type 2; Endothelium, Vascular; Follow-Up Studies; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Leptin; Middle Aged; Nitric Oxide; Predictive Value of Tests; Regression Analysis; Stents; Vascular Patency

Adiponectin is an adipocyte-secreted protein that circulates in high concentrations in the serum and acts to increase insulin sensitivity. Previous studies have shown that serum adiponectin is inversely associated with fat mass and insulin resistance in humans and that acute fasting decreases adipose tissue adiponectin mRNA expression in rodents. Whether acute energy deprivation, body fat distribution, or serum hormone levels are associated with circulating adiponectin in humans remains largely unknown. To identify predictors of serum adiponectin levels, we evaluated the association of adiponectin with several anthropometric, metabolic, and hormonal variables in a cross-sectional study of 121 women without a known history of diabetes. We also performed interventional studies to assess whether fasting for 48 h and/or leptin administration regulates serum adiponectin in healthy men and women. Our cross-sectional study shows that, in addition to overall obesity, central fat distribution is an independent negative predictor of serum adiponectin and suggests that adiponectin may represent a link between central obesity and insulin resistance. In addition, estradiol is negatively and independently associated with adiponectin, whereas there is no association between serum adiponectin and leptin, cortisol, or free testosterone levels. Our interventional studies demonstrate that neither fasting for 48 h, resulting in a low leptin state, nor leptin administration at physiological or pharmacological doses alters serum adiponectin levels. Further studies are needed to fully elucidate the physiology of adiponectin in humans and its role in the pathogenesis of insulin-resistant states.

Topics: Adiponectin; Adipose Tissue; Adult; Body Mass Index; Cross-Sectional Studies; Eating; Fasting; Female; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Male; Middle Aged; Obesity; Postmenopause; Predictive Value of Tests; Proteins

Resistin is a novel adipocyte-secreted hormone proposed to link obesity with diabetes. Studies in mice have revealed conflicting data however, and the physiological role of circulating resistin in humans remains unknown. We conducted cross-sectional studies in 123 middle-aged women and 120 healthy young subjects and found that serum resistin levels did not correlate with markers of adiposity, including body mass index, waist-to-hip ratio, or fat mass, or insulin resistance assessed by homeostasis model, lipid profile, or serum leptin levels; but females had higher resistin levels than males (P < 0.02). We also found no difference in serum resistin levels between lean healthy and obese insulin-resistant nondiabetic and type 2 diabetic adolescents. Finally, to evaluate the effect of food deprivation and/or leptin administration on resistin levels, we performed interventional studies that revealed no significant difference in resistin levels after 48 h of fasting and/or leptin administration at either physiological or pharmacological doses. We conclude that circulating resistin is unlikely to play a major role in insulin resistance or energy homeostasis in humans.

Topics: Adolescent; Adult; Body Mass Index; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Energy Intake; Fasting; Female; Homeostasis; Hormones, Ectopic; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Male; Middle Aged; Obesity; Resistin

We investigated the effect of an intensive training program on fasting leptin and adiponectin levels.. Sixteen middle-aged men with type 2 diabetes were randomly assigned to either a training or control group. The training program consisted of 8 weeks of supervised endurance exercise (75% VO(2peak), 45 min) twice a week, with intermittent exercise (five 2 min exercises at 85% VO(2peak) separated by 3 min exercises at 50% VO(2peak)) once a week, on an ergocycle.. Training decreased abdominal fat by 44%, increased mid-thigh muscle cross-sectional area by 24%, and improved insulin sensitivity by 58% without significant change in body weight. Compared with controls, no significant variation in leptin or adiponectin levels was observed. However, in the trained group, change in adiponectin correlated with change in body weight (Spearman rank correlation, r(s):-0.76, P=0.03) but not with insulin sensitivity or abdominal adiposity variations.. An 8 week intensive training program inducing a marked reduction in abdominal fat and increase in insulin sensitivity does not affect adiponectin and leptin levels in men with type 2 diabetes.

Topics: Abdomen; Adiponectin; Adipose Tissue; Adult; Diabetes Mellitus, Type 2; Exercise; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Male; Middle Aged; Physical Endurance; Proteins; Weight Loss

Ghrelin is a recently discovered gastric peptide that increases appetite, glucose oxidation, and lipogenesis and stimulates the secretion of GH. In contrast to ghrelin, GH promotes lipolysis, glucose production, and insulin secretion. Both ghrelin and GH are suppressed by intake of nutrients, especially glucose. The role of GH in the regulation of ghrelin has not yet been established. We investigated the effect of GH on circulating levels of ghrelin in relation to its effects on glucose, insulin, body composition, and the adipocyte-derived peptides leptin and adiponectin. Thirty-six patients with adult-onset GH deficiency received recombinant human GH for 9 months in a placebo-controlled study. Body composition and fasting serum analytes were assessed at baseline and at the end of the study. The GH treatment was accompanied by increased serum levels of IGF-I, reduced body weight (-2%) and body fat (-27%), and increased serum concentrations of glucose (+10%) and insulin (+48%). Ghrelin levels decreased in 30 of 36 subjects by a mean of -29%, and leptin decreased by a mean of -24%. Adiponectin increased in the women only. The decreases in ghrelin and leptin correlated with changes in fat mass, fat-free mass, and IGF-I. The reductions in ghrelin were predicted independently of the changes in IGF-I and fat mass. It is likely that the reductions in ghrelin and leptin reflect the metabolic effects of GH on lipid mobilization and glucose production. Possibly, a suppression of ghrelin promotes loss of body fat in GH-deficient patients receiving treatment. The observed correlation between the changes in ghrelin and IGF-I may suggest that the GH/IGF-I axis has a negative feedback on ghrelin secretion.

Topics: Adiponectin; Adult; Blood Glucose; Body Composition; Body Weight; Female; Ghrelin; Growth Disorders; Human Growth Hormone; Humans; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Intercellular Signaling Peptides and Proteins; Leptin; Male; Middle Aged; Peptide Hormones; Proteins; Regression Analysis

To assess the relationship between serum leptin and insulin resistance (IR) in obesity, and to investigate the effects of sibutramine on obesity, serum leptin and IR.. Seventy obese subjects [body mass index (BMI) > or =25 kg/m2] were randomly divided into 2 groups: group B (sibutramine 10 mg/day) and group C (a placebo tablet/day). Both had been treated for 12 weeks. Another 30 healthy adults served as the normal control (group A: BMI < 23 kg/m2). Their height, body weight, waist and hip circumference, fasting plasms glucose (FPG), fasting plasma insulin (FINS), and serum leptin were examined at the baseline and 12 weeks after the therapy. Insulin senstivity index (ISI) was calculated [ISI = 1/(FPG x FINS)]. Multiple linear regression analysis and partial correlation were performed on serum leptin.. The body weight, BMI, waist and hip circumference decreased significantly after the 12 week-treatment with sibutramine in group B (P < 0.01), but those indexes did not change after the treatment with placebo in group C (P > 0.05). The levels of leptin and FINS were higher (P < 0.01), but ISI was lower (P < 0.01) both in group B and C compared with those in group A at the baseline. The levels of serum leptin and FINS decreased (P < 0.01), and ISI increased significantly (P < 0.05) after the treatment with sibutramine in group B, while those indexes did not change after the treatment with placebo in group C. The most important factors to influence serum leptin level were listed as follows: sex > BMI > FINS > ISI (R2 = 0.661, F = 12.662, P < 0.01). The lep- tin was positively correlated with FINS (r = 0.597, P < 0.01) , but negatively correlated with ISI (r = -0.468, P < 0.01 ) after eliminating the effects of sex and BMI. Conclusion Leptin resistance and insulin resistance exist in obesity, and serum leptin is associated with IR. Treatment with sibutramine significantly reduces the body weight and leptin, increases insulin senstivity, and improves IR.

Topics: Adolescent; Adult; Appetite Depressants; Body Mass Index; Cyclobutanes; Double-Blind Method; Female; Humans; Insulin Resistance; Leptin; Linear Models; Male; Middle Aged; Obesity

To evaluate the effect of rosiglitazone on insulin resistance and hyperandrogenism in polycystic ovary syndrome (PCOS).. Rosiglitazone was given 4 mg daily to 30 patients with PCOS for 12 weeks. Before and after treatment, body mass index (BMI), plasma glucose, insulin, levels insulin resistance index (HOMA IR), blood lipid spectrum, leptin, neuropeptide Y, and sex hormone concentrations and ovulation rate were determined and compared.. After 12 weeks of treatment, basal insulin level decreased from (18 +/- 8) to (12 +/- 7) mIU/L (P < 0.01), HOMA IR decreased from 4.3 +/- 1.2 to 2.6 +/- 0.7 (P < 0.01). Luteinizing hormone, free testosterone and androstenedione levels decreased [(15.4 +/- 4.4) versus (7.9 +/- 2.1) U/L, (12.5 +/- 1.9) versus (8.9 +/- 1.4) pmol/L, (9.8 +/- 1.7) versus (7.4 +/- 1.2) nmol/L respectively, P < 0.01]; Dehydroepiandrosterone sulfate level also decreased [(8.7 +/- 3.5) versus (6.9 +/- 2.1) micromol/L, P < 0.05]; Sex hormone binding globulin level increased [(39 +/- 3) versus (58 +/- 5) nmol/L, P < 0.01]. Plasma leptin level was decreased [(18 +/- 4) versus (13 +/- 3) microg/L, P < 0.01]. Ovulation rate increased to 50%.. Rosiglitazone might decrease plasma leptin level and improve insulin sensitivity, which led to alleviation of hyperandrogenism and resumption of ovulation and menses in patients with PCOS.

Topics: Administration, Oral; Adult; Androstenedione; Blood Glucose; Body Weight; Female; Follicle Stimulating Hormone; Humans; Hyperandrogenism; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Lipids; Luteinizing Hormone; Menstruation; Neuropeptide Y; Ovulation; Polycystic Ovary Syndrome; Rosiglitazone; Testosterone; Thiazoles; Thiazolidinediones; Treatment Outcome

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

Glucocorticoids induce insulin resistance in humans, whereas thiazolidinediones enhance insulin sensitivity. Although the effects of glucocorticoids and thiazolidinediones have been assessed in isolation, interaction between these drugs, which both act as ligands for nuclear receptors, has been less well studied. Therefore, we examined the metabolic effects of dexamethasone and troglitazone, alone and in combination, for the first time in humans. A total of 10 healthy individuals with normal glucose tolerance (age 40 +/- 11 years, BMI 31 +/- 6.1 kg/m(2)) were sequentially studied at baseline, after 4 days of dexamethasone (4 mg/day), after 4-6 weeks on troglitazone alone (400 mg/day), and again after 4 days of dexamethasone added to troglitazone. Key metabolic variables included glucose tolerance assessed by blood glucose and insulin responses to an oral glucose tolerance test (OGTT), insulin sensitivity evaluated via hyperinsulinemic-euglycemic clamp, free fatty acids (FFAs) and FFA suppressibility by insulin during the clamp study, and fasting serum leptin. Dexamethasone drastically impaired glucose tolerance, with fasting and 2-h OGTT insulin values increasing by 2.3-fold (P < 0.001) and 4.4-fold (P < 0.001) over baseline values, respectively. The glucocorticoid also induced a profound state of insulin resistance, with a 34% reduction in maximal glucose disposal rates (GDRs; P < 0.001). Troglitazone alone increased GDRs by 20% over baseline (P = 0.007) and completely prevented the deleterious effects of dexamethasone on glucose tolerance and insulin sensitivity, as illustrated by a return of OGTT glucose and insulin values and maximal GDR to near-baseline levels. Insulin-mediated FFA suppressibility (FFA decline at 30 min during clamp/FFA at time 0) was also markedly reduced by dexamethasone (P = 0.002). Troglitazone had no effect per se, but it was able to normalize FFA suppressibility in subjects coadministered dexamethasone. Futhermore, the magnitudes of response of FFA suppressibility and GDR to dexamethasone were proportionate. The same was true for the reversal of dexamethasone-induced insulin resistance by troglitazone, but not in response to troglitazone alone. Leptin levels were increased 2.2-fold above baseline by dexamethasone. Again, troglitazone had no effect per se but blocked the dexamethasone-induced increase in leptin. Subjects experienced a 1.7-kg weight gain while taking troglitazone but no other untoward effects. We conclude that in

Topics: Adult; Chromans; Dexamethasone; Drug Interactions; Energy Metabolism; Fatty Acids, Nonesterified; Female; Glucocorticoids; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin Resistance; Leptin; Male; Middle Aged; Thiazoles; Thiazolidinediones; Troglitazone

Since hyperandrogenism in simple obesity is assumed to arise from hyperinsulinism and/or increased insulin-like growth factor I (IGF-I) or leptin levels, we examined how in patients with Prader-Willi syndrome (PWS), the most frequent form of syndromal obesity, the accelerated adrenarche can be explained despite hypothalamic-pituitary insufficiency with low levels of insulin and IGF-I.. In 23 children with PWS and a mean age of 5.6 years, height, weight, fat mass, fasting insulin concentration, insulin resistance (by HOMA-R; see text), and leptin and IGF-I levels were determined to test whether they explain the variance of the levels of dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), of androstenedione, and of cortisol before and during 42 months of therapy with growth hormone.. The baseline DHEAS, DHEA, and androstenedione concentrations were increased as compared with age-related reference values, whereas the cortisol level was always normal. During growth hormone treatment, the DHEA concentration further rose, and the cortisol level decreased significantly. The insulin and IGF-I concentrations were low before therapy, while fat mass and leptin level were elevated. The hormonal covariates provided alone or together between 24 and 60% of the explanation for the variance of adrenal androgen levels, but the anthropometric variables did not correlate with them.. In children with PWS, elevated androgen levels correlate with hormones that are usually associated with adiposity. However, the lack of direct correlations between disturbed body composition and androgen levels as well as the increased sensitivity to insulin and IGF-I are abnormalities specific to PWS, potentially caused by the underlying hypothalamic defect.

Topics: Adolescent; Adrenal Glands; Analysis of Variance; Androgens; Androstenedione; Anthropometry; Body Composition; Child; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Female; Growth Hormone; Hormone Replacement Therapy; Humans; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Male; Obesity; Prader-Willi Syndrome; Prospective Studies; Puberty, Precocious

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 obese gene product--leptin (LEP)--is a hormone released from adipose tissue implicated in the regulation of nutritional state and energy balance. The aim of this study was to assess the relationship between plasma LEP levels and nutritional state, secretion of hormones of the hypothalamic-pituitary axis, and personality traits in patients with anorexia nervosa (AN). The study was performed in 22 women with AN aged 19.45 +/- 0.92 yrs, mean BMI of 15.48 +/- 0.29 kg/m2, 14 healthy women with normal body weight (NW), aged 29.71 +/- 2.4 yrs, mean BMI of 21.22 +/- 0.43 kg/m2, and 19 obese women without metabolic disorders (OTY), aged 34.5 +/- 2.65 yrs, mean BMI of 37.47 +/- 2.06 kg/m2. Hormone levels were measured with RIA test kits. Psychological examination was carried out by means of Gough-Helibrun's and Catell's personality tests. Body mass index (BMI) and body composition, i.e. body fat mass (BF) and body fat percentage (%BF) were determined with a DEXA instrument (Lunar Co., WI, USA). Absolute plasma LEP levels and the LEP/%BF index were lowest in patients with AN whereas LEP/BF index did not differ among AN, NW, and OTY groups (Table 1). In all groups, LEP levels were positively correlated with BMI, BF, and %BF (Table 2). Plasma neuropeptide Y (NPY), beta-endorphin (B-EP), and galanin (GAL) levels in AN were significantly higher than in NW and OTY groups (Table 3). Plasma GAL levels were positively correlated with LEP/BF and LEP/%BF in AN patients only. Moreover in the AN group, serum/plasma levels of insulin (I), insulin-like growth hormone-1 (IGF-1), luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol (E2), and free triiodothyronine (fT3) were significantly lower, and levels of cortisol (F) significantly higher than in NW and OTY groups (Table 4). Plasma LEP levels in AN patients were positively correlated with IRI, IGF-1, free thyroxine (fT4), and FSH levels, and negatively correlated with thyrotrophin (TSH) levels. Personality traits in patients with AN were significantly correlated with hormone levels (Tables 5 and 6), BMI and body fat content (Table 6).. 1) Leptin secretion from adipose tissue is not related to the nutritional state. 2) High levels of NPY, beta-EP, and GAL in AN confirm that starvation is deliberate in these patients. Low LEP levels in AN may lead to secondary amenorrhea and thyroid function disorders, as well as enhanced cortisol and growth hormone secretion of hypothalamic origin. A positive correlation between levels of LEP and IGF-1 and IRI may reflect mechanisms preserving adipose tissue and protecting from hypoglycemia and insulin resistance. A positive correlation between LEP and fT4 levels suggests a tendency to energy-sparing under conditions of low energy intake. Lack of correlation between LEP and F levels apparently reflects peripheral cortisol resistance in AN. 3) Both undernutrition and abnormal hormone secretion (LEP, F, fT3, IGF-1, LH, E2) are related to social self-withdrawal, defensive attitudes, low self-esteem and high level of self-supervision in AN.

Topics: Adipose Tissue; Adult; Amenorrhea; Anorexia Nervosa; Female; Human Growth Hormone; Humans; Hydrocortisone; Hypothalamus; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Metabolic Diseases; Nutritional Status; Starvation; Thyroid Diseases

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 aim of this study was to evaluate the effects of sibutramine on plasma leptin levels, body weight and glucose metabolism in non-dieting women. Fourteen healthy, non-diabetic, obese women were studied before treatment, after 1 week of placebo administration, and after a 2-week course of sibutramine (10 mg/day). At each of these stages, we assessed body composition, measured the levels of plasma leptin, C-peptide and various biochemical parameters, and also recorded plasma insulin and glucose levels during oral glucose tolerance tests. After 1 week of placebo treatment, there were no significant changes in any of the parameters. However, two weeks of 10 mg/day sibutramine dropped plasma leptin levels from a mean (+/-SE) of 48.84+/-4.54 to 42.84+/-4.74 ng/ml (p<0.04), reduced BMI from 39.36+/-2.01 to 38.57+/-1.93 kg/m2 (p<0.002), and decreased insulin resistance (IR, as measured using the homeostasis model assessment of insulin resistance) from 5.59+/-0.85 to 3.66+/-0.43 (p<0.02). There was no correlation between the reduction in leptin concentration and the decrease in BMI, fat mass, percent body fat, IR, C-peptide, or the area under curve for glucose or insulin. There was also no correlation between the decrease in leptin levels and the increases that occurred in the insulin sensitivity index or the hepatic sensitivity index. The results showed that treatment with 10 mg/day sibutramine significantly reduces BMI, IR and leptin levels in non-dieting obese women.

Topics: Adult; Appetite Depressants; Blood Glucose; Body Mass Index; C-Peptide; Cyclobutanes; Female; Glucose Tolerance Test; Homeostasis; Humans; Insulin; Insulin Resistance; Leptin; Liver; Obesity; Placebos

To investigate whether weekly subcutaneous administration of 60 mg of long-acting pegylated human leptin (PEG-OB) for 8 weeks was able to influence weight loss, metabolic profile and inflammatory status of obese subjects on a mildly hypoenergetic diet (deficit: 3.2 MJ/day).. A prospective, randomized, double-blind and placebo-controlled single-center trial.. Twenty-eight healthy, obese subjects (16 women, 12 men; age 22-65 y; body mass index 27.7-38.7 kg/m2).. Bodyweight, metabolic profile (including lipids), C-reactive protein (CRP) and soluble TNF alpha-receptor (sTNF-R) 55 and 75 levels.. At the end of the study no significant differences in the delta or percentage weight loss between the placebo (n = 14) and PEG-OB (n = 14) groups was observed. Also the changes in metabolic profile, CRP, sTNF-R55 and R75 concentrations between the two groups after 8 weeks of treatment did not differ.. Weekly injection of 60 mg PEG-OB did not lead to additional weight loss after 8 weeks of treatment. Furthermore, PEG-OB administration did not affect the changes in metabolic profile and the inflammatory status of obese subjects.

Topics: Adolescent; Adult; Aged; Blood Glucose; Body Mass Index; Body Weight; C-Reactive Protein; Double-Blind Method; Female; Humans; Inflammation; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Placebos; Prospective Studies; Receptors, Leptin; Receptors, Tumor Necrosis Factor; Weight Loss

Although it is known that plasma leptin concentrations correlate with the amount of adipose tissue in the body, little information is available on the long-term effects on leptin concentrations of changes in diet and exercise.. We wanted to examine whether changes in dietary energy sources and exercise-mediated energy expenditure, alone or in combination, affect plasma leptin concentrations.. In a randomized, 2 x 2 factorial trial, 186 men with metabolic syndrome were divided into 4 groups: diet, exercise, a combination of diet and exercise, and control. Data on dietary intake, physical fitness, and demographics were collected and plasma leptin concentrations were measured before and after a 1-y intervention period.. Plasma leptin concentrations, body mass index, and fat mass decreased in association with long-term reductions in food intake as well as increased physical activity. By adjusting for either body mass index or fat mass, we observed a highly significant reduction in plasma leptin concentration after both the diet and the exercise interventions. There was no interaction between the interventions, suggesting a direct and additive effect of changes in diet and physical activity on plasma leptin concentrations.. Long-term changes in lifestyle consisting of decreased intake of dietary fat and increased physical activity reduced plasma leptin concentrations in humans beyond the reduction expected as a result of changes in fat mass.

Topics: Adipose Tissue; Adult; Body Mass Index; Cardiovascular Diseases; Diet; Dietary Fats; Exercise; Health Behavior; Humans; Insulin Resistance; Leptin; Longitudinal Studies; Male; Middle Aged; Risk Factors; Smoking; Weight Loss

To determine the clinical, hormonal and biochemical effect of 4-5 months of insulin-sensitizing therapy (hypocaloric diet+metformin) in obese patients with polycystic ovary syndrome (PCOS).. Prospective study.. Twenty-three obese patients with PCOS, 19 obese patients without menstrual disturbances and 11 healthy control women were recruited from the Department of Endocrinology and Endocrine Gynecology, Medical Academy, Bialystok, Poland. Obese patients received 500 mg metformin together with hypocaloric diet three times daily for 4-5 months, after baseline study. The clinical parameters, menstrual pattern and serum concentrations of insulin, leptin, IGF-I, insulin-dependent proteins (sex hormone-binding protein (SHBG), insulin-like growth factor-binding protein-1 (IGFBP-1)), gonadotropins and sex steroids were determined before and after treatment.. In the baseline study, obese patients with PCOS had significantly higher insulin, testosterone and LH concentrations in comparison with the other groups. The serum leptin, IGF-I, IGFBP-1 and SHBG were not different between the two groups of obese patients, but there was a significant difference in comparison with the control group. After metformin therapy a significant reduction in BMI, % of body fat and leptin concentration were observed in both groups of obese patients. Fasting insulin, testosterone and LH concentrations decreased significantly only in the PCOS group. Six out of 11 patients in the PCOS group had more regular menstrual cycles; two patients conceived.. Insulin-sensitizing therapy could be considered as an additional therapeutic option in obese women with PCOS.

Topics: Adult; Blood Glucose; Diet, Reducing; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor I; Leptin; Metformin; Obesity; Polycystic Ovary Syndrome

Troglitazone is effective in approximately 50% in patients with type 2 diabetes (NIDDM). In this study, we investigated the relations between serum leptin levels and clinical efficacy of troglitazone. Forty-five type 2 diabetic patients (23 men and 22 women) from our outpatient clinic were treated with troglitazone 400 mg daily for 12 weeks. Fasting plasma glucose (FPG), HbA1c, body weight, serum insulin and leptin concentrations were measured before and after troglitazone treatment. After 12 weeks of troglitazone treatment, FPG (before versus after, 179+/-33 vs. 138+/-26 mg/dl, mean+/-SD), HbA1c (7.8+/-1.3 vs. 6.9+/-1.0%), IRI (8.3+/-4.3 vs. 6.3+/-3.4 microU/ml) and HOMA-R index (homeostasis model assessment of insulin resistance) (3.8+/-2.4 vs. 2.2+/-1.3) decreased significantly, while body mass index (BMI) slightly increased (26.3+/-3.5 vs. 26.6+/- 3.6 kg/m(2)), and serum leptin remained unchanged (8.5+/-7.2 vs. 9.1+/-8.7 ng/ml). Reduction in FPG (DeltaFPG) after troglitazone treatment were correlated with reduction in HOMA-R (DeltaHOMA-R) (r=0.721, P<0.0001). DeltaFPG was correlated with serum leptin (r=0.441, P<0.01), HOMA-R (r=0.460, P<0.01) and FPG (r=-0.781, P<0.0001) at baseline, but not with BMI and serum IRI at baseline. Furthermore, serum leptin at baseline was significantly correlated with DeltaHOMA-R (r=0.634, P<0.01). Leptin concentration before treatment therefore, can be used as an predictor for clinical efficacy of troglitazone in patients with type 2 diabetes.

Topics: Biomarkers; Blood Glucose; Chromans; Diabetes Mellitus, Type 2; Fasting; Female; Glycated Hemoglobin; Homeostasis; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Models, Biological; Predictive Value of Tests; Regression Analysis; Thiazoles; Thiazolidinediones; Time Factors; Troglitazone

Weight reduction is recommended for the treatment of subjects with insulin resistance (IR) syndrome; however, the relative importance of the decrease in body fat or the negative energy balance achieved during a hypo-energetic diet in the improvement of this metabolic syndrome is still debated. Therefore, we undertook to study their relative impact on amelioration of the metabolic abnormalities associated with IR in obese subjects. Twelve obese subjects (six males and six females, mean+/-s.d. body mass index 36.1+/-4.7 kg/m(2)) aged 38-57 years were investigated. During the first phase they were fed a hypo-energetic diet for 6 weeks (week 0-6). During the second phase, lasting 4 weeks (week 6-10) they consumed an iso-energetic diet. During the third phase (week 10-16) the subjects were put again on a hypo-energetic diet. Insulin sensitivity (SI) was assessed by an insulin-enhanced, frequently sampled i.v. glucose tolerance test with minimal model analysis. All subjects reduced weight during both hypo-energetic periods: 5.49+/-0.75 and 2.32+/-0.37%, means+/-s.e.m., P<0.005, week 0-6 and 10-16 respectively. One-third of this loss was achieved within the first week of each period. SI increased by 353+/-121 and 147+/-38% (P<0.005), means+/-s.e.m., at the end of both hypo-energetic periods (week 6 vs 0 and 16 vs 10 respectively). Two-thirds of this improvement were observed within the first week of each period (week 1 vs 0 and 11 vs 10 respectively). During the iso-energetic weight-maintaining period (week 10 vs 6), SI decreased by 43.5+/-7.9% (P<0.002). Serum levels of leptin and triglyceride followed a similar pattern, but to a lesser extent. It may be concluded that negative energy balance is more effective when compared with maintaining a stable lower weight in achieving an improvement in the metabolic parameters of the IR syndrome.

Topics: Adult; Analysis of Variance; Blood Glucose; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Cholesterol, VLDL; Dietary Carbohydrates; Energy Metabolism; Female; Glucose Tolerance Test; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Triglycerides

The present study was performed to investigate the effects of the intestinal fatty acid-binding protein (FABP2) gene Ala54Thr polymorphism and the beta(3)-adrenergic receptor (beta3AR) gene Trp64Arg polymorphism on body mass index (BMI), blood pressure, heart rate, glucose and lipid profiles, and serum leptin level in 196 young men aged 21 to 39 years, 186 older normoglycemic men (fasting plasma glucose [FPG] < 110 mg/dL) aged 40 to 65 years, and 122 older hyperglycemic men, including 77 type 2 diabetic patients. Genomic DNA was extracted from the peripheral blood, and these polymorphisms were assessed by the polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) method. In the older groups, the beta3AR Arg64-allele frequency tended to be lower and the FABP2 Thr/Thr54 genotype frequency tended to be higher in hyperglycemic patients, although these differences did not reach statistical significance. Also, there were no significant differences in the genotype or allele frequency of either variant between the 27 hyperlipidemic and 204 normolipidemic subjects. In the younger group, there were no significant differences in any of the parameters measured between the genotypes of beta3AR or FABP2. In the older normoglycemic subjects, heart rate was significantly lower (P =.037) in beta3AR Arg64-positive subjects, and FPG was significantly higher in subjects with the FABP2 Thr/Thr genotype than the other genotypes (99.8 +/- 5.6 v 96.5 +/- 5.6 mg/dL, P =.010). In the older hyperglycemic group, the beta3AR Arg64-positive group had significantly lower high-density lipoprotein (HDL) cholesterol and free fatty acid (FFA) levels (P =.024 and P =.043, respectively). There were no synergistic effects of these 2 variants on any measured parameter, but only the FABP2 Thr/Thr genotype was related to a higher FPG in the older normoglycemic men. In conclusion, no major difference was associated with the beta3AR Trp64Arg or FABP2 Ala54Thr polymorphism in terms of type 2 diabetes or hyperlipidemia in young to older Japanese men. However, a slight but significant increase in FPG was observed in older Japanese men with the FABP2 Thr/Thr genotype.

Topics: Adult; Aged; Aging; Amino Acid Substitution; Blood Glucose; Blood Pressure; Body Mass Index; Carrier Proteins; Fasting; Fatty Acid-Binding Protein 7; Fatty Acid-Binding Proteins; Gene Frequency; Genotype; Humans; Hyperglycemia; Insulin Resistance; Leptin; Lipids; Male; Middle Aged; Neoplasm Proteins; Polymorphism, Genetic; Receptors, Adrenergic, beta-3; Tumor Suppressor Proteins

Topics: Androgens; Blood Glucose; Blood Pressure; Body Constitution; Body Mass Index; Dihydrotestosterone; Double-Blind Method; Fasting; Homeostasis; Humans; Insulin; Insulin Resistance; Leptin; Lipids; Male; Middle Aged; Placebos; Testosterone

The role of leptin in human pathophysiology elicits considerable interest in view of its potential role as a treatment tool for obesity and other insulin resistant states, like type 2 diabetes mellitus (T2DM). Leptin has been extensively studied in obese humans, and much less so in other pathologic conditions. Leptin level has been reported to correlate with percent body fat mass (%FM), fasting serum insulin (FPI), insulin sensitivity and blood pressure. The aim of this study was to compare the leptin concentration, and its relationship with some anthropometric and biochemical parameters related to insulin resistance in 140 moderately obese type 2 diabetics (T2DM) and 160 age and weight matched non-diabetic controls in order to get a better insight into the possible role of leptin in the metabolic abnormalities of diabetes. The leptin levels were lower in the diabetic population only when both sexes were combined (p < 0.05) and were higher in the females of both groups. Among the nondiabetics, the leptin levels appeared to be related to BMI, %FM, HDL and FPI, while this was not the case in the diabetics. After correction for BMI, leptin appeared to be correlated with the FPI levels only in the non-diabetic females. When plasma leptin was included in a multiple linear regression model with plasma leptin as a dependent variable, BMI, W:Hr and FPI levels were significantly related to leptin in the non diabetic population, while no relationship reached the level of statistical significance among the diabetics, with the exception of the borderline value for the FPI (p = .052). In conclusion, leptin levels were independent of any of the parameters examined in our diabetic population, possibly due to the progressive loss of the normal mechanisms of leptin regulation with advancing disease. Conclusive data can only be obtained from the longitudinal study of a cohort of newly diagnosed diabetic subjects.

Topics: Aged; Body Composition; Body Mass Index; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Humans; Insulin; Insulin Resistance; Leptin; Lipids; Male; Middle Aged; Sex Characteristics

Hyperleptinemia may be part of the insulin resistance syndrome. We studied serum leptin in preeclampsia, which is an insulin-resistant state, and sought associations between leptin and insulin or insulin sensitivity during and after pregnancy. Twenty-two proteinuric preeclamptic women and 16 normotensive controls were studied during the third trimester. Leptin was higher in preeclampsia (mean +/- SE, 34.6 +/- 3.9 v 20.0 +/- 3.3 microg/L, P = .002) and correlated directly with the level of proteinuria (r = .47, P = .03) and normal pregnancy (r = .52, P = .04), whereas insulin sensitivity as assessed by an intravenous glucose tolerance test showed no relationship to leptin. Leptin was 19.0 +/- 3.6 microg/L in 14 preeclamptic women and 10.1 +/- 2.0 microg/L (P = .11) in 11 controls 3 months after delivery. Leptin correlated directly with insulin both in preeclamptic puerperal women (r = .63, P = .02) and in controls (r = .81, P = .003). Leptin and insulin sensitivity correlated only in preeclamptic puerperal women (r = -.59, P = .02). In conclusion, (1) serum leptin is elevated in preeclampsia, (2) insulin is an important determinant of serum leptin in preeclamptic and normotensive women both during pregnancy and in the puerperium, and (3) hyperleptinemia may be part of the insulin resistance syndrome also in women with prior preeclampsia.

Topics: Adult; Body Mass Index; Female; Humans; Insulin; Insulin Resistance; Leptin; Pre-Eclampsia; Pregnancy; Radioimmunoassay; Reference Values

Sleep apnea and associated daytime sleepiness and fatigue are common manifestations of mainly obese middle-aged men. The onset of sleep apnea peaks in middle age, and its morbid and mortal sequelae include complications from accidents and cardiovascular events. The pathophysiology of sleep apnea remains obscure. The purpose of this study was to test three separate, albeit closely related, hypotheses. 1) Does sleep apnea contribute to the previously reported changes of plasma cytokine (tumor necrosis factor-alpha and interleukin-6) and leptin levels independently of obesity? 2) Among obese patients, is it generalized or visceral obesity that predisposes to sleep apnea? 3) Is apnea a factor independent from obesity in the development of insulin resistance? Obese middle-aged men with sleep apnea were first compared with nonapneic age- and body mass index (BMI)-matched obese and age-matched lean men. All subjects were monitored in the sleep laboratory for 4 consecutive nights. We obtained simultaneous indexes of sleep, sleep stages, and sleep apnea, including apnea/hypopnea index and percent minimum oxygen saturation. The sleep apneic men had higher plasma concentrations of the adipose tissue-derived hormone, leptin, and of the inflammatory, fatigue-causing, and insulin resistance-producing cytokines tumor necrosis factor-alpha and interleukin-6 than nonapneic obese men, who had intermediate values, or lean men, who had the lowest values. Because these findings suggested that sleep apneics might have a higher degree of insulin resistance than the BMI-matched controls, we studied groups of sleep-apneic obese and age- and BMI-matched nonapneic controls in whom we obtained computed tomographic scan measures of total, sc, and visceral abdominal fat, and additional biochemical indexes of insulin resistance, including fasting plasma glucose and insulin. The sleep apnea patients had a significantly greater amount of visceral fat compared to obese controls (<0.05) and indexes of sleep disordered breathing were positively correlated with visceral fat, but not with BMI or total or sc fat. Furthermore, the biochemical data confirmed a higher degree of insulin resistance in the group of apneics than in BMI-matched nonapneic controls. We conclude that there is a strong independent association among sleep apnea, visceral obesity, insulin resistance and hypercytokinemia, which may contribute to the pathological manifestations and somatic sequelae of this condition.

Topics: Analysis of Variance; Blood Pressure; Body Composition; Cytokines; Fatigue; Humans; Insulin Resistance; Interleukin-6; Leptin; Male; Middle Aged; Obesity; Respiratory Mechanics; Sleep Apnea Syndromes; Sleep Stages; Tomography, X-Ray Computed; Tumor Necrosis Factor-alpha

Controversial effects of weight reduction on gonadotropin secretion in obesity have been reported. As a result of pulsatility, single serum samples or frequent sampling studies are somewhat limited with regard to monitoring LH and FSH concentrations. We studied follicular phase nocturnal urinary (nu) LH and FSH secretion and glucose metabolism (150-min euglycemic hyperinsulinemic clamp) during 1 menstrual cycle/30-day period before and after weight reduction in 10 severely overweight infertility patients (age, 29 +/- 3.1 yr; body mass index, 37.1 +/- 3.3 kg/m2; +/-SEM). A 6-week very low calorie diet was followed by a 4-week normocaloric period. The urinary LH and FSH results reported represent samples taken 12 to 2 days before the LH surge, or 10 consecutive samples in the case of amenorrhea. We observed a decrease of 8% (P < 0.001) in percent body fat mass and a 5% (P < 0.005) reduction in waist to hip ratio. Mean nu-LH decreased by 45% [6.06 +/- 1.05 (+/-SEM) to 3.22 +/- 0.71 IU/L], whereas mean nu-FSH remained unchanged. Insulin-stimulated glucose uptake increased by 41% (P < 0.01), which was accounted for by a significant increase in nonoxidative glucose disposal (P = 0.003). Serum sex hormone-binding globulin concentrations increased by 39% (P < 0.01), and insulin-like growth factor (IGF)-binding protein-1 (IGFBP-1) levels increased by 46% (P < 0.05). Fasting serum insulin concentrations decreased by 38%, those of leptin by 37%, those of androstenedione by 32%, those of testosterone by 20% (all P < 0.01), and those of dehydroepiandrosterone sulfate by 13% (P < 0.05). The percent change in nu-LH correlated negatively with glucose uptake (r = -0.76; P < 0.01) and the increase in serum sex hormone-binding globulin (r = -0.85; P < 0.005) and positively with the percent change in waist to hip ratio (r = 0.79; P < 0.01). The absolute nu-LH levels after weight reduction correlated significantly with fasting insulin concentrations (r = 0.88; P < 0.001) and negatively with glucose uptake (r = -0.67; P < 0.05). No significant relationships were found between absolute levels or changes in nu-LH concentrations and leptin, IGF-I, IGFBP-3, or IGFBP-1 concentrations. Our findings suggest that weight reduction with a very low calorie diet results in a decrease in nu-LH concentrations, a reduction in the LH/FSH ratio, and FSH predominance favoring folliculogenesis. The decrease in LH concentrations is inversely related to the severity of insulin resistance. It is po

Topics: Adult; Blood Glucose; Body Composition; Female; Follicle Stimulating Hormone; Humans; Insulin; Insulin Resistance; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Growth Factor I; Leptin; Luteinizing Hormone; Obesity; Steroids; Weight Loss

Topics: Autonomic Nervous System Diseases; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Female; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Syndrome

Troglitazone, which improves peripheral insulin resistance of experimental diabetic animals and diabetic patients, affects ob gene expression in the adipose tissue of rodents. The present study was undertaken to examine a hypothesis that clinical administration of troglitazone may reduce circulating leptin levels and affect eating behavior in NIDDM patients.. Troglitazone was administered at a dosage of 200 mg twice daily for 12 weeks in 20 poorly controlled NIDDM patients. Chronological changes in glycemic control, serum lipids, immunoreactive leptin (IRL) levels, and BMI were measured. Body fat weight was also assessed by bioelectric impedance.. Troglitazone significantly decreased fasting plasma glucose, serum immunoreactive insulin, and HbA1c levels. Serum levels of IRL and triglyceride were significantly reduced by troglitazone administered for 4, 8, and 12 weeks. Troglitazone administration significantly increased the BMI in NIDDM patients, and two-thirds of the patients complained of increased hunger after the start of troglitazone administration.. Troglitazone significantly reduces circulating leptin levels at clinical doses. It may affect the eating behavior of poorly controlled NIDDM patients through the improvement of glycemic control and/or the reduction of circulating leptin.

Topics: Blood Glucose; Body Mass Index; Chromans; Diabetes Mellitus, Type 2; Energy Intake; Feeding Behavior; Glycated Hemoglobin; Humans; Hunger; Hypoglycemic Agents; Insulin Resistance; Islets of Langerhans; Leptin; Lipids; Middle Aged; Proteins; Thiazoles; Thiazolidinediones; Troglitazone

The polycystic ovary syndrome (PCOS) is characterized by menstrual disturbances, chronic anovulation and hyperandrogenism and is associated with insulin resistance and hyperinsulinemia. Leptin, the product of the ob gene, is an adipocyte-secreted molecule that signals the magnitude of energy stores to the brain and has been recently shown to have important effects on the reproductive axis of rodents. To assess the potential contribution of leptin to the pathogenesis of PCOS, we measured leptin levels in 24 obese women with PCOS and 12 weight- and age-matched controls and determined whether alterations in hyperinsulinemia produced by administration of the insulin-sensitizing agent troglitazone had an effect on serum leptin levels. Leptin concentrations at baseline were not different in women with PCOS (38.1 +/- 2.15 ng/mL) and controls (33.12 +/- 2.39 ng/mL). Moreover, leptin concentrations remained unchanged after treatment with troglitazone (38.1 +/- 2.15 vs. 39.21 +/- 2.65 ng/mL). Baseline leptin correlated strongly with body mass index in both controls (r = 0.59; P < 0.05) and women with PCOS (r = 0.70; P = 0.0004). Leptin levels were not associated with baseline insulin, testosterone, non-sex hormone-binding globulin (SHBG)-bound testosterone, dehydroepiandrosterone sulfate, estradiol, or SHBG. Finally, despite significantly reduced insulin, non-SHBG-bound testosterone, and estradiol levels after troglitazone treatment of women with PCOS, their leptin levels remained unchanged. We conclude that circulating leptin levels in patients with PCOS do not differ from those in age- and weight-matched controls. Furthermore, increased circulating insulin due to insulin resistance does not appear to alter circulating leptin levels in women with PCOS.

Topics: Adult; Body Mass Index; Chromans; Double-Blind Method; Female; Humans; Hyperinsulinism; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Obesity; Osmolar Concentration; Polycystic Ovary Syndrome; Proteins; Thiazoles; Thiazolidinediones; Troglitazone

Topics: Adult; Humans; Insulin Resistance; Leptin; Middle Aged; Positive-Pressure Respiration; Proteins; Sleep Apnea Syndromes

The prevalence of obesity and overweight in children has been increasing rapidly worldwide and threatens society with various chronic diseases that these children are born with. High-protein ketogenic diets and intermittent nutrition are thought to be protective against obesity and metabolic syndrome MetS. However, the exact effects and results, insulin resistance, and the role of leptin in the functioning mechanism of these diets have not been fully elucidated. The aim of this study was to investigate the roles of insulin resistance and leptin hormone on the effects of body composition with a high-protein ketogenic diet and intermittent nutrition combination.. Thirty-two young non-obese rats were randomly divided into four equal groups. Both the standard diet and the high-protein ketogenic diet were given ad libitum and intermittently to the rats for 6 wk. The body weight and fat mass of the rats were measured at the end of the experiment. The fasting glucose, leptin, insulin, high- and low-density lipoprotein, and triacylglycerols were measured with the blood samples.. The lowest body weight was observed in the intermittent and high-protein ketogenic diet group, followed by the free high-protein ketogenic diet and standard intermittent diet group, respectively. Also, the lowest body fat mass was observed in the intermittent and high-protein ketogenic diet group, followed by the standard intermittent diet group. Although there was no change in leptin, insulin, high- and low-density lipoprotein, and triacylglycerol levels in any group, the lowest blood glucose rate was observed in the intermittent and high-protein ketogenic diet group.. The results of the present study revealed that an intermittent high-protein ketogenic diet is more effective than others in weight loss without disrupting biochemical health parameters, and the applied diets do not prevent growth and development.

Topics: Animals; Blood Glucose; Body Composition; Body Weight; Child; Diet, Ketogenic; Humans; Insulin; Insulin Resistance; Leptin; Lipoproteins, LDL; Obesity; Rats

Obstructive sleep apnea (OSA) has a close relation with obesity and perturbation in adipokines and hepatokines, which are linked to OSA consequences such as insulin resistance, dyslipidemia, and endothelial dysfunction. This study aimed to assess the relation of C1q/TNF-related protein 9 (CTRP9) and angiopoietin-like protein 3 (ANGPTL3) with OSA and biochemical measurements.. Serum levels of ANGPTL3, CTRP9, adiponectin, leptin, intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion protein 1 (VCAM-1) were determined in 74 OSA patients and 27 controls using enzyme-linked immunosorbent assay kits.. Levels of ANGPTL3, CTRP9, leptin, ICAM-1, and VCAM-1 were increased in the patients compared to the controls, whereas adiponectin levels decreased. ANGPTL3 had a positive correlation with total cholesterol, triglyceride, low-density lipoprotein cholesterol, ICAM-1, and VCAM-1 and was inversely correlated with leptin. CTRP9 showed a positive correlation with body mass index, insulin resistance, ICAM-1, and VCAM-1.. The results indicated the relation of ANGLTP3 and CTRP9 with OSA and its complications, which suggested a possible role for these factors in the consequences of OSA.

Topics: Adiponectin; Angiopoietin-Like Protein 3; Cholesterol; Humans; Insulin Resistance; Intercellular Adhesion Molecule-1; Leptin; Lipid Metabolism; Sleep Apnea, Obstructive; Vascular Cell Adhesion Molecule-1

Puberty has been described as a life stage of considerable metabolic risk specially for those with obesity. The low-grade systemic inflammatory status associated with obesity could be one of the connections with metabolic syndrome (MetS). Thus, we aimed to assess the relationship between inflammatory and cardiovascular biomarkers and the development of MetS during puberty. Seventy-five children from the PUBMEP study (33 females), aged 4-18 years, were included. Cardiovascular and inflammatory biomarkers were measured in the prepubertal and pubertal stage, including high-sensitivity C-reactive protein (CRP), leptin, tumor necrosis factor-alpha (TNFα), interleukin 8 (IL8), monocyte chemoattractant protein 1 (MCP-1), total plasminogen activator inhibitor-1 (tPAI), resistin, adiponectin, myeloperoxidase (MPO), and soluble intercellular adhesion molecule-1 (sICAM-1). MetS was diagnosed at each measurement point. Mixed-effects and logistic regressions were performed. Those children with MetS in puberty presented higher prepubertal values of several cardiometabolic biomarkers in comparison to those without MetS (z-score body mass index (zBMI), waist circumference, insulin, HOMA-IR, leptin, and tPAI (p < 0.05)). For prepubertal children with obesity, the odds of developing MetS in puberty were significantly higher in those having high zBMI (OR = 4.27; CI: 1.39-22.59) or high concentrations of tPAI (OR = 1.19; CI: 1.06-1.43).. Those with obesity with higher prepubertal tPAI plasma levels had 19% higher odds of having MetS at puberty highlighting the existence of association between MetS, obesity, and inflammation already in puberty. Thus, assessing cardiometabolic and inflammatory status in children with obesity already at prepuberty is key to avoiding future comorbidities.. • Inflammation, metabolic syndrome, and obesity may have their onset in childhood. • Puberty is a life stage characterized for an increased cardiovascular risk.. • Prepuberty state could be an early indicator of future cardiometabolic risk. • Children with obesity and high total plasminogen have higher odds of future metabolic syndrome.

Topics: Adiponectin; Adolescent; Biomarkers; Body Mass Index; Cardiovascular Diseases; Child; Child, Preschool; Female; Humans; Inflammation; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Obesity; Puberty

Serum soluble leptin receptor (sOb-R) may protect against future type 2 diabetes or serve as a marker for protective features, but how sOb-R is regulated is largely unknown.. This work aimed to test how serum sOb-R is influenced by glucose, insulin, body fat, body mass index (BMI), food intake, and physical activity.. We performed an epidemiological triangulation combining cross-sectional, interventional, and Mendelian randomization study designs. In 5 independent clinical studies (n = 24-823), sOb-R was quantified in serum or plasma by commercial enzyme-linked immunosorbent assay kits using monoclonal antibodies. We performed mixed-model regression and 2-sample Mendelian randomization.. In pooled, cross-sectional data, leveling by study, sOb-R was associated inversely with BMI (β [95% CI] -0.19 [-0.21 to -0.17]), body fat (-0.12 [-0.14 to -0.10), and fasting C-peptide (-2.04 [-2.46 to -1.62]). sOb-R decreased in response to acute hyperinsulinemia during euglycemic glucose clamp in 2 independent clinical studies (-0.5 [-0.7 to -0.4] and -0.5 [-0.6 to -0.3]), and immediately increased in response to intensive exercise (0.18 [0.04 to 0.31]) and food intake (0.20 [0.06 to 0.34]). In 2-sample Mendelian randomization, higher fasting insulin and higher BMI were causally linked to lower sOb-R levels (inverse variance weighted, -1.72 [-2.86 to -0.58], and -0.20 [-0.36 to -0.04], respectively). The relationship between hyperglycemia and sOb-R was inconsistent in cross-sectional studies and nonsignificant in intervention studies, and 2-sample Mendelian randomization suggested no causal effect of fasting glucose on sOb-R.. BMI and insulin both causally decreased serum sOb-R levels. Conversely, intensive exercise and food intake acutely increased sOb-R. Our results suggest that sOb-R is involved in short-term regulation of leptin signaling, either directly or indirectly, and that hyperinsulinemia may reduce leptin signaling.

Topics: Body Mass Index; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Glucose; Humans; Insulin; Insulin Resistance; Leptin; Receptors, Leptin

Sedentary life style separated during COVID-19 pandemic. Patients with cardiovascular diseases (CVD) are vulnerable with sedentary life style. Therefore, the aim of this study was to investigate the effect of 8 weeks of combined and high intensity interval training (HIIT) on C Reactive protein, galectin-3, leptin, fibrinogen and insulin resistance index in coronary heart disease after COVID-19.. Thirty-six cardiovascular patients (55.14 ± 1.4 years, 78.6 ± 5.1 kg) were divided into three groups of combined exercise (n=13), HIIT (n=12) and control group (n=11). Combined exercise consisted of aerobic (4 weeks) and aerobic + HIIT exercise (4 weeks), three sessions per weeks. The protocol of the HIIT group included performing high intensity interval training, three sessions per weeks for 8 weeks. Blood samples were taken 24 h before the first training session and 48 h after the last training. C Reactive protein (CRP), galectin-3, leptin, fibrinogen measured with ELISA kit.. CRP, galectin-3 and fibrinogen decreased significantly after 8 weeks of combined training and HIIT (compare to pre-test). Also, insulin resistance index after 8 weeks of combined exercise showed a significant decrease compare to pre-test (p<0.05). After 8 weeks, CRP, galectin-3 and insulin resistance significantly decreased compare to control group (p<0.05).. In the patient with CVD, combined exercise training may be more effective than HIIT in reducing metabolic and heart risk factors after an epidemic such as COVID-19. However, change of leptin need to more studies.

Topics: C-Reactive Protein; Cardiovascular Diseases; Coronary Disease; COVID-19; Exercise; Fibrinogen; Galectin 3; Humans; Inflammation; Insulin; Insulin Resistance; Leptin; Pandemics; Risk Factors

Background: some studies have evaluated the association of the rs1805134 genetic variant of the LEPR gene with obesity. Aims: the objective was to explore the association of the rs1805134 genetic variant of the LEPR gene with obesity measures and metabolic syndrome in obese Caucasian adults. Methods: we conducted a cross-sectional study in 212 obese subjects with body mass index (BMI) greater than 30 kg/m2. Measurements of adiposity parameters, blood pressure, fasting blood glucose, insulin concentration, insulin resistance (HOMA-IR), lipid profile, C-reactive protein, and prevalence of metabolic syndrome were determined. Results: the distribution of rs1805134 was 128 TT (60.4 %), 77 TC (36.3 %), and 7 CC (3.3 %). C-allele carriers showed higher levels of BMI, body weight, body fat mass, waist circumference, insulin, HOMA-IR, triglycerides, total energy intake, and carbohydrate intake than non-C-allele carriers. A logistic regression analysis reported a high percentage of elevated waist circumference (OR = 2.22, 95 % CI = 1.201-4.97; p = 0.02), hyperglycemia (OR = 1.54, 95 % CI = 1.01-5.44; p = 0.01), and metabolic syndrome percentage (OR = 1.41, 95 % CI = 1.04-5.39; p = 0.03) in C-allele carriers. Conclusions: subjects with the C-allele of the rs1805134 variant of the LEPR gene showed a worse metabolic pattern with a higher percentage of metabolic syndrome, central obesity and hyperglycaemia, probably related to higher energy intake.. Antecedentes: algunos estudios han evaluado la asociación de la variante genética rs1805134 del gen LEPR con la obesidad. Objetivos: el objetivo fue explorar la asociación de la variante genética rs1805134 del gen LEPR con los parámetros de obesidad y síndrome metabólico en adultos caucásicos obesos. Métodos: realizamos un estudio transversal en 212 sujetos obesos con índice de masa corporal (IMC) superior a 30 kg/m2. Se determinaron los parámetros de adiposidad, presión arterial, glucemia en ayunas, concentración de insulina, resistencia a la insulina (HOMA-IR), perfil lipídico, proteína C-reactiva y prevalencia de síndrome metabólico. Resultados: la distribución del rs1805134 fue de 128 TT (60,4 %), 77 TC (36,3 %) y 7 CC (3,3 %). Los portadores del alelo C mostraron niveles más altos de IMC, peso corporal, masa grasa corporal, circunferencia de la cintura, insulina, HOMA-IR, triglicéridos, ingesta total de energía y consumo de carbohidratos que los portadores sin alelo C. El análisis de regresión logística mostró un alto porcentaje de pacientes con elevada circunferencia de la cintura (OR = 2,22, IC 95 % = 1,201-4,97; p = 0,02), hiperglucemia (OR = 1,54, IC 95 % = 1,01-5,44; p = 0,01) y síndrome metabólico (OR = 1,41, IC 95 % = 1,04-5,39; p = 0,03) en los portadores del alelo C. Conclusiones: los sujetos con alelo C de la variante rs1805134 del gen LEPR mostraron un peor patrón metabólico con mayor porcentaje de síndrome metabólico, obesidad central e hiperglucemia, probablemente relacionado con una mayor ingesta energética.

Topics: Adult; Body Mass Index; Cross-Sectional Studies; Eating; Humans; Hyperglycemia; Insulin; Insulin Resistance; Leptin; Metabolic Syndrome; Obesity; Polymorphism, Single Nucleotide; Receptors, Leptin

This study tested the hypothesis that obesity and metabolic abnormalities correlate with background parenchymal enhancement (BPE), the volume and intensity of enhancing fibroglandular breast tissue on dynamic contrast-enhanced magnetic resonance imaging.. Participants included 59 premenopausal women at high risk of breast cancer. Obesity was defined as BMI ≥ 30 kg/m. BMI was positively correlated with BPE (r = 0.69; p < 0.001); participants with obesity had higher BPE than those without obesity (404.9 ± 189.6 vs. 261.8 ± 143.8 cm. In premenopausal women at high risk of breast cancer, increased BPE is associated with obesity, insulin resistance, leptin, and adiponectin.

Topics: Adiponectin; Breast Neoplasms; Female; Humans; Inflammation; Insulin Resistance; Leptin; Lipids; Obesity

Mitochondrial dysfunction has been reported in obesity and insulin resistance, but primary genetic mitochondrial dysfunction is generally not associated with these, arguing against a straightforward causal relationship. A rare exception, recently identified in humans, is a syndrome of lower body adipose loss, leptin-deficient severe upper body adipose overgrowth, and insulin resistance caused by the p.Arg707Trp mutation in

Topics: Adiponectin; Adipose Tissue; Animals; Humans; Hydrolases; Insulin Resistance; Leptin; Lipodystrophy; Mice; Mitochondria; Obesity

Lean Non-alcoholic Fatty Liver Disease (NAFLD) shares a similar disease burden to those of their overweight counterparts and should be detected early. We hypothesized that the adiponectin-leptin ratio (AL ratio) could be a good marker for early detection of lean NAFLD independent of insulin resistance.. A total of 575 adults without diabetes were enrolled in a community-based study. The subjects were stratified into the lean controls, lean NAFLD, simple overweight/obesity and overweight/obesity NAFLD groups according to body mass index (BMI) and ultrasonographic fatty liver indicators. Serum adiponectin and leptin levels were measured by enzyme-linked immunosorbent assay. Multivariate logistic regression analyses were performed to estimate the odds ratio of having NAFLD in relation to the tertiles of serum AL concentration after adjustment. Receiver operating characteristic (ROC) analyses were applied to evaluate the diagnostic performance of the AL ratio for NAFLD.. The mean age of the participants was 42.8 ± 11.5 years. Comparing with the lean controls, the odds of having lean NAFLD for the highest versus the lowest tertile of AL ratio was 0.28(95%CI: 0.12-0.69) after adjustment. Putting AL ratio, BMI, triglyceride, AST/ALT ratio to the diagnosis performance of NAFLD, the ROC was 0.85 (95% CI: 0.82-0.88), 0.83 (95% CI 0.78-0.87) and 0.86 (95% CI 081-0.91) for all NAFLD, NAFLD in women and NAFLD in men, respectively. (. The study revealed that the AL ratio could be a good biomarker to early distinguish lean NAFLD patients from lean controls independent of insulin resistance. [AQ3]Key messagesThe prevalence of non-alcoholic fatty liver disease (NAFLD) increases globally and is related to liver diseases and metabolic dysfunctions. Lean subset of NAFLD shares a similar disease burden to those of their overweight counterparts and should be detected early.Adiponectin-leptin ratio were associated with the severity of steatosis and was a predictor of obese NAFLD better than each single adipokine. To date, there is no investigation that explores specifically for the relationship between lean NAFLD and AL ratio.Our study found that adiponectin-leptin ratio is a sole independent marker regardless of insulin resistance in lean NAFLD. Having lean NAFLD for the highest versus the lowest tertile of adiponectin-leptin ratio was 0.28(95%CI: 0.12-0.69) after adjustment of age, sex, current smoking, exercise habits, HOMA-IR and AST/ALT. ROC for the NAFLD performance is good for the early detection (0.85; 95% CI: 0.82-0.88). Further rigorous investigation is necessary and should be promptly performed.

Topics: Adiponectin; Adult; Body Mass Index; Female; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Obesity; Overweight

Adipose tissue is not only a storage place for fat, but also an endocrine organ, secreting bioactive molecules which influence body metabolism. Such molecules are known as adipocytokines. In the past years the coincidence between adipocytokines and fetal growth restriction disorders was found. The aim of the study was to estimate serum levels of adiponectin, leptin and resistin in children born small for gestational age, compared to children born at an appropriate size for gestational age.. The study consisted of 35 children aged seven to nine years, born SGA (small for gestational age) on term and 25 healthy children (14 girls, 11 boys), born with proper birthweight (AGA-appropriate for gestational age)-control group.. Adiponectin and leptin levels were significantly higher in the SGA group compared to the AGA group (. Children born SGA have abnormal adipose tissue biomarkers profiles.

Topics: Adipokines; Adiponectin; Body Weight; Child; Female; Fetal Growth Retardation; Gestational Age; Humans; Infant, Newborn; Infant, Small for Gestational Age; Insulin Resistance; Leptin; Male; Resistin

The mechanisms link obesity and hypertension are not well understood. One possibility is the alterations in adipose-derived adipokines that modulate insulin resistance (IR) and cardiovascular homeostasis. We aimed to assess the associations between hypertension and four adipokine levels in Chinese youth, and to examine to what extent the associations are mediated by IR. We utilized cross-sectional data from the Beijing Children and Adolescents Metabolic Syndrome (BCAMS) Study Cohort (n = 559, mean age = 20.2 years). Plasma leptin, adiponectin, retinol binding protein 4 (RBP4) and fibroblast growth factor 21 (FGF21) levels were assayed. The relationships between adipokines and hypertension and the possible mediation effect of IR were evaluated. Youth with hypertension have lower adiponectin and higher leptin, FGF21 (all P < 0.001) and RBP4 levels (p = 0.06) compared to their counterparts. Moreover, the co-existence of these two or more adipokine abnormalities in youth leads to a 9-fold increased risk for hypertension (OR: 9.19; 95% CI, 4.01-21.08) compared with these without abnormalities. However, in the fully adjusted and BMI-adjusted analyses, only FGF21 was a significant predictor of hypertension (OR: 2.12; 95% CI, 1.34-3.36). Mediation analysis revealed that the associations between leptin, adiponectin, RBP4 and hypertension are totally mediated by IR (proportion: 63.9%, 65.4%, and 31.6%, respectively), while BMI and IR partly mediated the association between FGF21 and hypertension (proportion: 30.6%, 21.2%). Our findings suggest that dysregulation of adipokines might result in hypertension in youth. Leptin, adiponectin and RBP4 may exert their functions in hypertension through adiposity-related IR, whereas FGF21 might be used as an independent marker of hypertension in youth.

Topics: Adipokines; Adiponectin; Adolescent; Beijing; Child; Cross-Sectional Studies; Humans; Hypertension; Insulin Resistance; Leptin; Obesity; Retinol-Binding Proteins, Plasma; Young Adult

Non-alcoholic fatty liver disease is associated with obesity. A subclinical inflammation state, endothelial dysfunction, and parameters related to metabolic syndrome (MetS), have been documented in children with obesity. We aimed to determine the changes that occur in liver enzymes levels in response to the standard treatment of childhood obesity, also assessing any associations with liver enzyme levels, leptin, and markers of insulin resistance (IR), inflammation, and parameters related to MetS in prepubertal children.. We carried out a longitudinal study in prepubertal children (aged 6-9 years) of both sexes with obesity; a total of 63 participants were recruited. Liver enzymes, C-reactive protein (CRP), interleukin-6, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), soluble intercellular adhesion molecule-1 (sICAM-1), leptin, homeostasis model assessment for IR (HOMA-IR), and parameters related to MetS were measured.. After standard treatment for 9 months, children who lowered their standardised body mass index (SDS-BMI) had significantly lower systolic blood pressure (p = 0.0242), diastolic blood pressure (p = 0.0002), HOMA-IR (p = 0.0061), and levels of alanine aminotransferase (ALT) (p = 0.0048), CRP (p = 0.0001), sICAM-1 (p = 0.0460), and IL-6 (p = 0.0438). There was a significant association between the changes that occur with treatment, in the ALT levels, and changes in leptin (p = 0.0096), inflammation biomarkers [CRP (p = 0.0061), IL-6 (p = 0.0337), NLR (p = 0.0458), PLR (p = 0.0134)], and HOMA-IR (p = 0.0322).. Our results showed that a decrease in ALT levels after the standard treatment for 9 months was associated with favourable changes in IR markers (HOMA-IR) and inflammation (IL-6, CRP, NLR, and PLR).

Topics: Biomarkers; Body Mass Index; C-Reactive Protein; Child; Female; Humans; Inflammation; Insulin; Insulin Resistance; Interleukin-6; Leptin; Liver; Longitudinal Studies; Male; Metabolic Syndrome; Pediatric Obesity

Identifying plasma molecules associated with skeletal muscle properties can elucidate the pathophysiology of sarcopenia. Because adipocytokines are a promising candidate marker, the current study aimed to clarify the possible associations between adiponectin and leptin levels and mid-thigh muscle cross-sectional area and mean attenuation value, which are indices of muscle mass and fat deposition in muscle, respectively.. The current study included 1440 older Japanese adults (mean age 69.3 years). Mid-thigh skeletal muscle cross-sectional area and mean attenuation value were evaluated through computed tomography scan. A low attenuation value showed a greater fat deposition in muscle. Circulating adiponectin and leptin levels were assessed using blood specimens collected during the baseline investigation.. Plasma leptin level was inversely correlated with muscle cross-sectional area, but not with attenuation value. The association with cross-sectional area was independent of possible confounding factors including body size (Q1: reference; Q2: β = -0.032, P = 0.033; Q3: β = -0.064, P < 0.001; Q4: β = -0.111, P < 0.001). In contrast, adiponectin level was independently and inversely associated with attenuation value (Q1: reference; Q2: β = -0.044, P = 0.122; Q3: β = -0.080, P = 0.006; Q4: β = -0.159, P < 0.001), but not with cross-sectional area. These associations between adipocytokine levels and muscle properties were independent of abdominal fat area and insulin resistance.. There were adiposity- and insulin resistance-independent associations between adipocytokines levels and skeletal muscle mass and fat deposition in muscle, suggesting an involvement of adipocytokines in muscle properties. Geriatr Gerontol Int 2023; 23: 444-449.

Topics: Adiponectin; Aged; Humans; Insulin Resistance; Leptin; Muscle, Skeletal; Obesity

Leptin inhibits food intake and reduces the size of body fat depots, changing adipocyte sensitivity to insulin to restrain lipid accrual. This adipokine may modulate the production of cytokines that could diminish insulin sensitivity, particularly in visceral adipose tissue. To explore this possibility, we examined the effects of chronic central administration of leptin on the expression of key markers of lipid metabolism and its possible relationship with changes in inflammatory- and insulin-signaling pathways in epididymal adipose tissue. Circulating non-esterified fatty acids and pro- and anti-inflammatory cytokines were also measured. Fifteen male rats were divided into control (C), leptin (L, icv, 12 μg/day for 14 days), and pair-fed (PF) groups. We found a decrease in the activity of glucose-6-phosphate dehydrogenase and malic enzyme in the L group, with no changes in the expression of lipogenic enzymes. A reduction in the expression of lipoprotein lipase and carnitine palmitoyl-transferase-1A, together with a decrease in the phosphorylation of insulin-signaling targets and a low-grade inflammatory pattern, were detected in the epididymal fat of L rats. In conclusion, the decrease in insulin sensitivity and increased pro-inflammatory environment could regulate lipid metabolism, reducing epididymal fat stores in response to central leptin infusion.

Topics: Adipose Tissue; Animals; Cytokines; Inflammation; Insulin; Insulin Resistance; Leptin; Lipid Metabolism; Male; Rats

To assess whether small-for-gestational-age (SGA) - an indicator of poor fetal growth, may affect metabolic health biomarkers in infancy and explore the predictors.. This was a nested matched (1:2) prospective observational study of 65 SGA (birth weight < 10th percentile) and 130 optimal-for-gestational-age (OGA, birth weight 25th-75th percentiles, control) infants in the 3D birth cohort with subjects recruited in Canada from 1 May 2010 to 31 August 2012. The outcomes included homeostasis model assessment of insulin resistance (HOMA-IR) and beta-cell function (HOMA-β), circulating leptin and adiponectin concentrations at age 2 years.. HOMA-IR, HOMA-β, leptin and adiponectin concentrations were similar in SGA versus OGA infants. Female sex and accelerated growth in length during mid-infancy (3-12 months) were associated with higher HOMA-IR. Caucasian ethnicity and decelerated growth in weight during late infancy (12-24 months) were associated with lower HOMA-IR. Current BMI was positively associated with circulating adiponectin in SGA infants only (+13.4% [4.0%-23.7%] per BMI z score increment).. Insulin resistance and secretion, circulating leptin and adiponectin levels were normal in SGA subjects in infancy at age 2 years. The novel observation in SGA-specific positive association between current BMI and circulating adiponectin suggests dysfunctional adiposity-adiponectin negative feedback loop development during infancy in SGA subjects.

Topics: Adiponectin; Birth Weight; Child, Preschool; Female; Fetal Growth Retardation; Humans; Infant; Insulin; Insulin Resistance; Leptin

Topics: Adiponectin; Birth Weight; Body Mass Index; East Asian People; Fatty Acids, Nonesterified; Female; Fetal Macrosomia; Homeostasis; Humans; Insulin; Insulin Resistance; Leptin; Triglycerides

Insulin resistance and disrupted secretion of adipokines are the major contributors to the pathogenesis of polycystic ovary syndrome (PCOS). Previous research has indicated that adiponectin/leptin (A/L) and HOMA/adiponectin (H/A) ratios have a strong association with insulin resistance and metabolic syndrome. The current study aimed to assess the predictability of the A/L and H/A ratios for PCOS women infertility and recurrent pregnancy loss (RPL). In this study, we investigated the association of A/L and H/A ratios with PCOS, as well as infertility and RPL in Iranian women with PCOS.. This case-control study included 150 PCOS (60 infertile and 90 PCOS-RPL) and 50 non-PCOS women. Clinical, biochemical, and hormonal features were evaluated, and the A/L and H/A ratios were calculated.. The A/L and H/A ratios were significantly decreased and increased in women with PCOS, respectively. A significant association was observed between the A/L and H/A ratios with PCOS, as well as PCOS-infertile and PCOS-RPL, even after adjusting for potential confounders. Although there was no significant difference between PCOS-infertile and PCOS-RPL subgroups, ROC curve analysis showed that A/L and H/A ratios could strongly predict PCOS with the area under the curve (AUC) of 0.867 and 0.861, respectively.. The ratios of A/L and H/A may serve as biomarkers to distinguish women with PCOS from non-PCOS in the Iranian population. However, it seems that they are not discriminatory markers for PCOS-associated RPL and infertility.

Topics: Adiponectin; Body Mass Index; Case-Control Studies; Female; Humans; Infertility; Insulin; Insulin Resistance; Iran; Leptin; Polycystic Ovary Syndrome; Pregnancy

Topics: Adipose Tissue; Cross-Sectional Studies; Exercise Test; Female; Humans; Insulin Resistance; Leptin; Male; Young Adult

To evaluate the relationship of genetic variability of adiponectin (ADIPOQ), leptin (LEP) and leptin receptor (LEPR) genes with glucose-insulin system and markers of subclinical atherosclerosis (ATS) in patients with newly diagnosed type 2 diabetes.. In 794 subjects we performed: 1) euglycemic hyperinsulinemic clamp to assess insulin sensitivity; 2) mathematical modelling of a 5h-OGTT to estimate β-cell function; 3) resting ECG; 4) carotid artery and lower limb artery eco-doppler sonography to identify ATS; 5) genotyping of tag-SNPs within ADIPOQ, LEP and LEPR gene.. Regression analyses showed: 1) adiponectin levels were negatively associated with BMI, waist-to-hip ratio and triglycerides and positively with HDL and insulin sensitivity (p-all<0.03); 2) leptin levels were positively associated with BMI, HDL-cholesterol and plasma triglycerides and negatively with insulin sensitivity (p-all<0.001). Two SNPs (rs1501299 and rs2241767) within ADIPOQ gene were associated with circulating levels of adiponectin. The ADIPOQ-GAACA haplotype was associated with plasma adiponectin (p=0.034; β=-0.24), ECG abnormalities (p=0.012; OR=2.76), carotid ATS (p=0.025; OR=2.00) and peripheral limb artery ATS (p=0.032; OR=1.90). The LEP-CTA haplotype showed an association with ischemic ECG abnormalities (p=0.017; OR=2.24). Finally, LEPR-GAACGG was associated with circulating leptin (p=0.005; β=-0.31) and worst β-cell function (p=0.023; β=-15.10). Omnibus haplotype analysis showed that ADIPOQ haplotypes were associated with levels of adiponectin and common carotid artery ATS, LEP with peripheral limb artery ATS, whereas LEPR haplotypes influenced circulating levels of leptin.. Results of this study reinforce knowledge on adipokines' role in regulating glucose metabolism; in particular highlighted the potential atherogenic role of leptin and the anti atherogenic role of adiponectin.

Topics: Adiponectin; Atherosclerosis; Diabetes Mellitus, Type 2; Glucose; Humans; Insulin Resistance; Insulins; Leptin; Triglycerides

The molecular mechanisms underlying diet-induced obesity are complex and remain unclear. The activation of the aryl hydrocarbon receptor (AhR), a xenobiotic sensor, by obesogens may contribute to diet-induced obesity through influences on lipid metabolism and insulin resistance acting at various sites, including adipose tissue. Thus, our hypothesis was that conditional AhR depletion, specifically from mature adipose tissue (CadKO), would improve high-fat diet (HFD)-induced metabolic dysfunction. CadKO protects mice from HFD-induced weight gain. CadKO females eat fewer calories, leading to increased energy expenditure (EE) and improved glucose tolerance on HFD. Our exploration of adipose tissue biology suggests that the depletion of AhR from adipocytes provides female mice with an increased capacity for adipogenesis and lipolysis, allowing for the maintenance of a healthy adipocyte phenotype. The HFD-induced leptin rise was reduced in CadKO females, but the hypothalamic leptin receptor (LepR) was increased in the energy regulatory regions of the hypothalamus, suggesting an increased sensitivity to leptin. The estrogen receptor α (ERα) was higher in CadKO female adipose tissue and the hypothalamus. CadKO males displayed a delayed progression of obesity and insulin resistance. In males, CadKO ameliorated proinflammatory adipocytokine secretion (such as TNFα, IL1β, IL6) and displayed reduced inflammatory macrophage infiltration into adipose depots. Overall, CadKO improves weight control and systemic glucose homeostasis under HFD challenge but to a more profound extent in females. CadKO facilitates a lean phenotype in females and mediates healthy adipose-hypothalamic crosstalk. In males, adipose-specific AhR depletion delays the development of obesity and insulin resistance through the maintenance of healthy crosstalk between adipocytes and immune cells.

Topics: Animals; Diet, High-Fat; Female; Glucose; Insulin Resistance; Leptin; Male; Mice; Obesity; Receptors, Aryl Hydrocarbon

Topics: Adolescent; Body Mass Index; Diabetes Mellitus, Type 1; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Metformin

Leptin plays a key role in the regulation of body weight and other endocrine systems. Recently, impairment of leptin gene transcription due to genetic variations in a long noncoding RNA (lncOb) has been described. This retrospective study aims to characterize the clinical and metabolic phenotype of children and adolescents with obesity who were homozygous for the lncOb rs10487505 leptin lowering allele.. Enrolled children underwent an anthropometrical evaluation, biochemical assessment, and genotyping for lncOb rs10487505. Plasma leptin levels were assessed in 150 participants. A total of 434 patients were included and divided into two groups according to rs10487505 recessive inheritance (CC vs. GG/GC).. Children who were homozygous for the C allele showed higher fasting insulin (p = 0.01), homeostasis model assessment of insulin resistance (p = 0.01), lower whole-body insulin sensitivity index (p = 0.02), and lower disposition index (p = 0.03). Moreover, CC patients presented with a higher prevalence of prediabetes (9.3% vs. 3.4%, p = 0.04) and a 2.9-fold (95% CI: 1.1-7.9, p = 0.04) higher risk of prediabetes compared with G-carriers independently from confounders. Leptin plasma levels were significantly lower in the CC group (p = 0.002). Hormone levels correlated with BMI z score (r = 0.19, p = 0.04), fasting insulin (r = -0.34, p < 0.0001), homeostasis model assessment of insulin resistance (r = -0.33, p < 0.0001), and disposition index (r = 0.20, p = 0.04).. The lncOb rs10487505 polymorphism affects leptin circulating levels, worsens insulin resistance, and heightens the risk of prediabetes in children and adolescents with obesity.

Topics: Adolescent; Body Mass Index; Child; Glucose; Humans; Insulin; Insulin Resistance; Leptin; Pediatric Obesity; Prediabetic State; Retrospective Studies

Previous evidence suggest that a sexual dimorphism in exercise fat oxidation and adipokines levels may explain a lower risk of cardio-metabolic disorders in women. Therefore, we investigated the role of sex in the relationship between adipokines levels, maximal fat oxidation (MFO) during exercise and insulin resistance.. Fifty young adults with excess adiposity (31 women; body fat: 38.7 ± 5.3%) were included in this study. The fasting levels of leptin, adiponectin, glucose and insulin were determined from blood samples and the homeostatic model assessment of insulin resistance index (HOMA-IR) subsequently calculated. Body fat percentage and visceral adipose tissue (VAT) were assessed through dual-energy X-ray absorptiometry whereas MFO was estimated during an incremental-load exercise test after an overnight fasting through indirect calorimetry.. Men had lower levels of body fat (d = 1.80), adiponectin (d = 1.35), leptin (d = 0.43) and MFO (d = 1.25) than women. Conversely, men showed higher VAT (d = 0.85) and fasting glucose levels (d = 0.89). No sex differences were observed in HOMA-IR (d = 0.34). Adipokines levels were not associated with MFO in both sexes (r < 0.30), whereas adiponectin levels were inversely related with HOMA-IR in both men (r = -0.58) and women (r = -0.50). Leptin concentration was associated to HOMA-IR only in men (r = 0.41), while no statistically significant relationships were observed between MFO and HOMA-IR in both sexes (r < 0.44).. Insulin resistance was similar between sexes regardless of superior levels of adipokines and MFO during exercise in women. Therefore, adiponectin and leptin may regulate glucose homeostasis without altering whole body fat oxidation rate during exercise.

Topics: Adipokines; Adiponectin; Adipose Tissue; Adiposity; Exercise; Fasting; Female; Glucose; Humans; Insulin Resistance; Leptin; Male; Obesity; Young Adult

In insulin resistance (IR), it is thought that pancreatic fat accumulation may decrease pancreatic volume, cause an impaired endocrine function, and simultaneously lead to an exocrine dysfunction before diabetes develops.. The association between pancreatic exocrine function and insulin resistance (IR) was assessed in a population with insulin resistance.. This was a descriptive cross-sectional study that included 43 IR cases with no other comorbid diseases or pregnancy and 41 healthy controls. Fasting blood adiponectin, leptin, pancreatic amylase, lipase, and stool fecal elastase-1 (FE-1) were studied and compared in both groups.. The IR group consisted of 38 females (88.3%) and five males (11.6%), while the control group consisted of 31 females (75.6%) and ten males (24.3%). FE-1 levels were significantly lower in the IR group (P-value <0.01). Blood glucose, insulin, and HbA1c levels were significantly higher in the IR group than in the control (P-value of <0.01, <0.01, <0.01, respectively). Leptin levels were significantly higher in the IR group compared to the controls (P-value = 0.013). After dividing the whole group (n: 84) into two groups as FE-1 <200 μg/g (n: 61) and FE-1 ≥200 μg/g (n: 23), logistic regression analysis was performed; the significant predictor of low FE-1 was HOMA-IR (ODD ratio: 4.27, P-value <0.01, 95% confidence interval for ODD ratio: 1.95-9.30).. This study showed that IR is associated with pancreatic exocrine dysfunction.

Topics: Cross-Sectional Studies; Female; Humans; Insulin; Insulin Resistance; Leptin; Male; Pancreatic Diseases; Turkey

The physiological effects of fibroblast growth factor 21 (FGF21), leading to beneficial metabolic outcomes, have been extensively revealed in recent decades. Significantly elevated serum levels of FGF21 in obesity and type 2 diabetes mellitus (T2DM) are referred to as FGF21 resistance. However, Asian population tend to develop metabolic disorders at a lesser degree of obesity than those of Western. This study aimed to explore factors potentially related to serum FGF21 according to the severity of metabolic disorders in patients with T2DM. This cross-sectional study included 176 T2DM patients. The patients were categorized according to whether they had hepatic steatosis (fatty liver index [FLI] ≥ 60), insulin resistance (homeostasis model assessment of insulin resistance [HOMA-R] ≥ median), and/or overweight/obesity (body mass index [BMI] ≥ 25.0 kg/m2). Independent predictors of serum FGF21 were determined using multiple linear regression analysis in these 3 groups of T2DM patients. Circulating FGF21 levels were correlated positively with BMI, abdominal fat areas, leptin, and plasminogen activator inhibitor-1 (PAI-1). After adjustment for potential confounders, multiple linear regression analysis identified leptin as a factor strongly associated with serum FGF21 levels in all patients. Moreover, PAI-1 was a significant predictor of FGF21 in those with FLI < 60, BMI < 25.0 kg/m2, and HOMA-R < median, while leptin was the only independent factor in each of their counterparts. The factors related to serum FGF21 differ according to the severity of metabolic disorders. FGF21 appears to be independently associated with PAI-1 in T2DM patients: without overweight/obesity, those free of insulin resistance, and those without hepatic steatosis.

Topics: Cross-Sectional Studies; Diabetes Mellitus, Type 2; Fatty Liver; Humans; Insulin Resistance; Leptin; Obesity; Overweight; Plasminogen Activator Inhibitor 1

Perilipin 5 (Plin5) is well known to maintain the stability of intracellular lipid droplets (LDs) and regulate fatty acid metabolism in oxidative tissues. It is highly expressed in the heart, but its roles have yet to be fully elucidated.. Plin5-deficient mice and Plin5/leptin-double-knockout mice were produced, and their histological structures and myocardial functions were observed. Critical proteins related to fatty acid and glucose metabolism were measured in heart tissues, neonatal mouse cardiomyocytes and Plin5-overexpressing H9C2 cells. 2-NBDG was employed to detect glucose uptake. The mitochondria and lipid contents were observed by MitoTracker and BODIPY 493/503 staining in neonatal mouse cardiomyocytes.. Plin5 deficiency impaired glucose utilization and caused insulin resistance in mouse cardiomyocytes, particularly in the presence of fatty acids (FAs). Additionally, Plin5 deficiency increased the NADH content and elevated the expression of lactate dehydrogenase (LDHA) in cardiomyocytes, which resulted in increased lactate production. Moreover, when fatty acid oxidation was blocked by etomoxir or LDHA was inhibited by GSK2837808A in Plin5-deficient cardiomyocytes, glucose utilization was improved. Leptin-deficient mice exhibited myocardial hypertrophy, insulin resistance and altered substrate utilization, and Plin5 deficiency exacerbated myocardial hypertrophy in leptin-deficient mice.. Our results demonstrated that Plin5 plays a critical role in coordinating fatty acid and glucose oxidation in cardiomyocytes, providing a potential target for the treatment of metabolic disorders in the heart.

Topics: Animals; Cardiomegaly; Fatty Acids; Glucose; Insulin Resistance; Lactic Acid; Leptin; Mice; Perilipin-5

Olanzapine (OLZ) is an atypical antipsychotic agent for psychotic disorders. Evidence has shown that OLZ is related to metabolic side effects, including obesity, hypertension, and insulin resistance. Thymoquinone (TQ) is the principal bioactive component of Nigella sativa. Several studies have been conducted to investigate the effectiveness of TQ in alleviating metabolic abnormalities. In the current research work, the protective effects of TQ on metabolic disorders induced by OLZ and possible underlying mechanisms were investigated.. Wistar rats were exposed to TQ alone (10 mg/kg), OLZ (5 mg/kg), or OLZ plus TQ (2.5, 5, or 10 mg/kg) given daily by intraperitoneal injection. After the treatment, variations in body weight, food intake, systolic blood pressure, serum leptin, biochemical factors, liver malondialdehyde (MDA), and glutathione (GSH) content were evaluated. Protein expression of AMPK in the liver was also measured by a western blotting test. OLZ increased body weight, food intake, MDA levels, and blood pressure. OLZ also elevated glucose, triglyceride, low-density lipoprotein cholesterol, and leptin serum levels. It decreased GSH. In the western blot, decreased AMPK protein level was obtained. These changes were attenuated by TQ co-administration.. The present study demonstrates the effectiveness of TQ on OLZ-induced metabolic abnormalities related to its antioxidant activity and regulation of glucose homeostasis and lipid metabolism.

Topics: AMP-Activated Protein Kinases; Animals; Benzoquinones; Glucose; Insulin Resistance; Leptin; Obesity; Olanzapine; Rats; Rats, Wistar

Adipokines dysregulation, the main reason for cognitive impairments (CI) induced by diabetes, shows a sex-dependent pattern inherently and in response to exercise. This study aimed to compare the attenuating effect of 8-week high intensity-interval training (HIIT) on type 2 diabetes (T2D)-induced CI between male and female rats with a special focus on adiponectin and leptin. 28 male & 28 female Wistar rats with an average age of 8 weeks were randomly assigned into four groups: control (Con), exercise (EX), Diabetes (T2D), and Type 2 diabetes + exercise (T2D + Ex). Rats in EX and T2D + EX groups performed HIIT for eight weeks (80-100% Vmax, 4-10 intervals). T2D was induced by 2 months of a high-fat diet and a single dose of STZ (35 mg/kg) administration. Leptin and adiponectin levels in serum were measured along with hippocampal expression of leptin and adiponectin receptors, AMP-activated protein kinase (AMPK), dephosphorylated glycogen synthase kinase-3 beta (Dep-GSK3β), Tau, and beta-amyloid (Aβ). Homeostasis model assessments (HOMAs) and quantitative insulin-sensitivity check index (QUICKI) indices were calculated. Our results showed that following T2D, serum levels of APN, and hippocampal levels of adiponectin receptor 1 (APNR1) were higher and HOMA-IR was lower in female than male rats (P < 0.05). However, after 8 weeks of HIIT, hippocampal levels of APNR1 and AMPK as well as QUICKI were lower and hippocampal levels of GSK, Tau, and Aβ were higher in females compared to male rats (P < 0.05). While the risk of CI following T2D was more in male than female rats HIIT showed a more ameliorating effect in male animals with APN1 as the main player.

Topics: Adiponectin; AMP-Activated Protein Kinases; Animals; Cognition; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Female; Insulin Resistance; Leptin; Male; Rats; Rats, Wistar; Receptors, Adiponectin; Sex Characteristics

Obesity can be categorized as metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO). However, individuals with MHO are characterized by the absence of metabolic syndrome (MS) and appear to have lower inflammation levels compared to MUO. This study aimed to investigate the association of obesity phenotypes with leptin (LEP) and adiponectin (ADP). According to the inclusion and exclusion criteria, we selected 178 subjects from the previous cross-sectional survey. Based on the body mass index (BMI) and diagnostic criteria of MS, we divided the individuals into three groups, including healthy control group (HC group), metabolically healthy obesity group (MHO group) and metabolically unhealthy obesity group (MUO group). The concentrations of LEP and ADP in serum were measured, and the association of these two cytokines with different obesity phenotypes were subsequently analyzed. Compared to both the HC and MHO groups, the MUO group showed significantly higher BMI, waist circumference (WC), waist-hip ratio (WHR), triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), fasting plasma glucose (FPG), homeostasis model assessment of insulin resistance (Homa-IR) and blood pressure (P < 0.05). In contrast, serum high-density lipoprotein cholesterol (HDL-C) was notably lower in the MUO group (P < 0.05). ADP was found to have a positive correlation with systolic blood pressure (SBP) and a negative correlation with FPG in the MHO group. In the MUO group, LEP demonstrated a positive correlation with fasting insulin (FINS) and Homa-IR, while ADP showed a positive correlation with TC and SBP. Linear regression analysis further indicated that SBP (β = 0.234, P = 0.043), TG (β = - 0.292, P = 0.001) and LDL-C (β = 0.626, P = 0.000) were independently correlated with ADP, and BMI (β = 0.398, P = 0.002) was independently correlated with LEP in obese individuals. In conclusion, ADP and LEP were closely related with glucose and lipid metabolism in obese individuals, these two cytokines might play critical roles in obesity-associated metabolic disorders.

Topics: Adiponectin; Body Mass Index; Cholesterol, LDL; Cross-Sectional Studies; Cytokines; Humans; Insulin Resistance; Leptin; Metabolic Syndrome; Obesity; Obesity, Metabolically Benign; Phenotype; Triglycerides

Obesity consists in the accumulation of adipose tissue accompanied by low grade chronic inflammation and is considered a pandemic disease. Recent studies have observed that obesity affects females and males in a sex-dependent manner. In addition, several works have demonstrated that parental obesity increases the risk to develop obesity, insulin resistance, diabetes, and reproductive disorders. Considering that intergenerational effects of obesity may occur in a sex-dependent manner, we studied male. Five-week-old female and male. HFD altered plasma fasting glucose, insulin and leptin levels, glucose tolerance, adiposity, and beta-cell expression of p16 in F0 rats. Particularly, HFD showed sexual dimorphic effects on body weight gain and insulin sensitivity. Moreover, we observed that parental HFD feeding exerts parental-sex-specific metabolic impairment in the male progeny. Finally, parental metabolic dysfunction could be in part attributed to the increased beta-cell expression of p16; other mechanisms could be involved in the offspring glucose homeostasis.

Topics: Animals; Diet, High-Fat; Female; Glucose; Homeostasis; Insulin; Insulin Resistance; Leptin; Male; Obesity; Rats; Rats, Wistar; Weight Gain

To investigate the effect of Bo's abdominal acupuncture (BOAA) on fibroblast growth factor 21 (FGF21) and its related adipokines in type 2 diabetes mellitus (T2DM) rats.. This study established obese T2DM rat model by high-fat diet (HFD) with a dose of streptozotocin (STZ, 30 mg/kg). Obese T2DM rats were randomly subdivided into four groups (. Treatment with BOAA attenuated the histopathological changes in visceral fat and restored the alterations in the levels of body weight, fasting blood glucose (FBG), homeostasis model assessment for insulin resistance (HOMA-IR). BOAA treatment significantly decreased the levels of triglyceride, total cholesterol, low density lipoprotein cholesterol, leptin, and increased the serum levels of high-density lipoprotein cholesterol, fibroblast growth factor 21 (FGF21), adiponectin (ADP), peroxisome proliferator-activated receptor γ (PPAR-γ), C-peptide (C-P) in obese T2DM rats. Furthermore, BOAA treatment significantly increased the mRNA expressions of FGF21, ADP, leptin, PPAR-γ, PPAR-α and adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK). Besides, BOAA treatment upregulated the protein expressions of fibroblast growth factor receptors3 (FGFR3), PPAR-. BOAA treatment reduced FBG and body weight, and improved insulin sensitivity through regulating FGF21 signaling pathway and its related adipokine in obese T2DM rats.

Topics: Acupuncture Therapy; Adipokines; AMP-Activated Protein Kinases; Animals; Body Weight; Cholesterol; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Fibroblast Growth Factors; Insulin Resistance; Leptin; Obesity; Peroxisome Proliferator-Activated Receptors; Rats

Topics: Adiponectin; Body Composition; Body Mass Index; Child; Fibronectins; Humans; Insulin Resistance; Leptin; Metabolome; Pediatric Obesity

Children born small for gestational age (SGA) are predisposed to obesity, insulin resistance (IR), and lipid disorders. The HOMA-IR index is commonly used to assess IR (IRIHOMA), calculated from fasting glucose and insulin. However, sometimes, during the oral glucose tolerance test (OGTT), elevated and prolonged postprandial insulin secretion is observed despite normal fasting insulin levels. IRIBelfiore is an IR index that analyses glucose and insulin levels during OGTT according to the method proposed by Belfiore.. was to assess the frequency of IR based on IRIHOMA and IRIBelfiore results in SGA children aged 6-8 years, after catch-up phenomenon, to determine the usefulness of IRIBelfiore in diagnosis of IR and in predicting future metabolic complications.. In 129 SGA normal-height children, aged 6-8 years, height, weight, waist circumference, blood pressure, as well as lipids, IGF-1, cortisol, C-peptide, leptin, adiponectin, and resistin concentrations were measured. The glucose and insulin concentrations were evaluated at 0, 60, and 120 minutes of OGTT.. IRIHOMA was normal in all children, while elevated IRIBelfiore was found in 22.5% of them. Children with IR diagnosed by IRIBelfiore were taller, had higher blood pressure, higher leptin, and lower HDL-cholesterol concentrations.. It seems worth recommending IRIBelfiore derived from OGTT as a valuable diagnostic tool for identifying IR in SGA prepubertal children. Abnormal IRIBelfiore is related to higher blood pressure and lower HDL-cholesterol concentration in this group.. Dzieci urodzone jako za małe w stosunku do wieku ciążowego (SGA) mają predyspozycje do występowania otyłości, insulinooporności (IR) oraz zaburzeń lipidowych. Do oceny IR powszechnie używany jest wskaźnik HOMA (IRIHOMA), wyliczany ze stężenia glukozy i insuliny na czczo. Jednak podczas doustnego testu obciążenia glukozą (OGTT) obserwuje się podwyższone poposiłkowe wydzielanie insuliny, pomimo prawidłowego stężenia insuliny na czczo. IRIBelfiore to indeks analizujący poziom glukozy i insuliny podczas OGTT wg metody zaproponowanej przez Belfiore.. była ocena częstości występowania IR na podstawie wyników IRIHOMA i IRIBelfiore u 6–8-letnich dzieci z SGA, które wykazały zjawisko „doganiania wzrostu”, w celu określenia przydatności wykorzystania IRIBelfiore w rozpoznawania IR i przewidywaniu przyszłych powikłań metabolicznych.. U 129 dzieci z SGA, z prawidłowym wzrostem, będących w wieku 6–8 lat zmierzono wzrost, masę ciała, obwód talii, ciśnienie krwi oraz stężenie lipidów, IGF-1, kortyzolu, peptydu C, leptyny, adiponektyny i rezystyny. Stężenia glukozy i insuliny oceniano w 0, 60. i 120. minucie OGTT.. IRIHOMA był prawidłowy u wszystkich dzieci, natomiast IRIBelfiore był podwyższony u 22,5% z nich. Dzieci z IR rozpoznaną dzięki IRIBelfiore były wyższe, miały wyższe ciśnienie krwi, większe stężenie leptyny i niższe HDL-cholesterolu.. Wydaje się, że warto zarekomendować ocenę IRIBelfiore obliczoną na podstawie OGTT jako użyteczne narzędzie diagnostyczne do rozpoznawania IR u dzieci z SGA będących w okresie przedpokwitaniowym. Nieprawidłowa wartość IRIBelfiore jest związana z wyższym ciśnieniem tętniczym krwi i gorszymi poziomami HDL-cholesterolu w tej grupie.

Topics: Blood Glucose; Child; Cholesterol; Fetal Growth Retardation; Gestational Age; Humans; Incidence; Insulin; Insulin Resistance; Leptin

Maca root extract on insulin, insulin receptor substrate-1 (IRS1), leptin, and NAD-dependent deacetylase sirtuin-1 (SIRT1), as well as body weight changes evaluated in this study for a 60 days model of normal and high-fat diet (HFD) fed rats. 28 male rats allocated to four groups: (i) Control, (ii) Maca (40 mg/kg/day), (iii) HFD, and (iv) HFD + Maca. After the 60 days of study, fat tissue and liver insulin levels decreased in the HFD and HFD + Maca groups in comparison to Control and Maca groups (

Topics: Animals; Diet, High-Fat; Energy Metabolism; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Leptin; Liver; Male; Rats; Sirtuin 1

Fetal overgrowth "programs" an elevated risk of obesity and type 2 diabetes in adulthood. Plausibly, adipokines may be involved in programming metabolic health.. This work aimed to evaluate whether large-for-gestational-age (LGA), an indicator of fetal overgrowth, is associated with altered circulating leptin and adiponectin levels in infancy, and assess the determinants.. In the Canadian 3D birth cohort, we studied 70 LGA (birth weight > 90th percentile) and 140 optimal-for-gestational-age (OGA, 25th-75th percentiles) infants matched by maternal ethnicity, smoking, and gestational age at delivery. The primary outcomes were fasting leptin, and total and high-molecular-weight (HMW) adiponectin concentrations at age 2 years.. LGA infants had higher body mass index (BMI) than OGA infants. However, there were no significant differences in leptin, and total and HMW adiponectin concentrations. Leptin concentrations were positively associated with female sex, weight (z score) gain 0 to 24 months, current BMI, and the sum of triceps and subscapular skinfold thickness, and negatively associated with maternal age and White ethnicity. Female sex was associated with lower total and HMW adiponectin concentrations. Weight (z score) gain 0 to 24 months and current BMI were positively correlated with total and HMW adiponectin concentrations in LGA infants only.. This study is the first to demonstrate that LGA does not matter for circulating leptin and adiponectin concentrations in infancy, and there may be LGA-specific positive associations between weight gain or current BMI and adiponectin concentrations in infancy, suggesting dysfunction in establishing the adiposity-adiponectin negative feedback loop in LGA individuals.

Topics: Adiponectin; Adiposity; Birth Weight; Canada; Case-Control Studies; Child, Preschool; Female; Fetal Macrosomia; Follow-Up Studies; Gestational Age; Humans; Infant; Infant, Newborn; Insulin Resistance; Leptin; Male; Sex Factors; Weight Gain

Hepatic insulin resistance (HIR) is considered to be an independent predictor of metabolic disorders and plays an important role in systemic inflammation, which contributes to abnormalities in cardiovascular disease (CVD) risk factors. The aim of this study was to investigate the relationship between HIR and new markers of cardiovascular risks, including leptin/adiponectin ratio (L/A), lipoprotein(a) [Lp(a)], and tumor necrosis factor alpha (TNF-α), at comparable whole body insulin sensitivity in non-diabetic individuals with or without CVD and at high risk of developing type 2 diabetes.. The HIR index, L/A, Lp(a), and TNF-α were measured in 50 participants with CVD and in 200 without CVD (1:4 ratio). These were also matched for the homeostatic model assessment for insulin resistance (HOMA-IR) and Matsuda-insulin sensitivity index (ISI) in an observational study design.. The HIR index (1.52 ± 0.14 vs. 1.45 ± 0.17, p < 0.02), L/A (3.22 ± 3.10 vs. 2.09 ± 2.27, p < 0.004), and levels of Lp(a) (66.6 ± 49.5 vs. 37.9 ± 3 6.8 mg/dL, p < 0.0001) and TNF-α (18.9 ± 21.8 vs. 5.4 ± 7.1 pg/mL, p < 0.0001) were higher in those with CVD than those without CVD. HOMA-IR and ISI were not significantly different (p = 0.88 and p = 0.35, respectively). The HIR index was directly correlated with L/A (r = 0.41, p < 0.0001), Lp(a) (r = 0.20, p < 0.002), TNF- α (r = 0.14, p < 0.03), and diastolic blood pressure (DBP) (r = 0.13, p < 0.03). The stepwise model analysis showed that L/A, Lp(a), and TNF-α explained about 20% of the variation in the HIR indices of all the participants (p < 0.02).. Our results suggest a positive association between HIR and new markers of cardiovascular risk [L/A, Lp(a), and TNF- α] at comparable whole body insulin sensitivity in those with or without CVD and at high risk of developing type 2 diabetes.

Topics: Adiponectin; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Heart Disease Risk Factors; Humans; Insulin Resistance; Leptin; Lipoprotein(a); Tumor Necrosis Factor-alpha

Metabolic regulation plays a significant role in energy homeostasis, and adolescence is a crucial life stage for the development of cardiometabolic disease (CMD). This study aims to investigate the genetic determinants of metabolic biomarkers-adiponectin, leptin, ghrelin, and orexin-and their associations with CMD risk factors.. We characterized the genetic determinants of the biomarkers among Hispanic/Latino adolescents of the Santiago Longitudinal Study (SLS) and identified the cumulative effects of genetic variants on adiponectin and leptin using biomarker polygenic risk scores (PRS). We further investigated the direct and indirect effect of the biomarker PRS on downstream body fat percent (BF%) and glycemic traits using structural equation modeling.. We identified putatively novel genetic variants associated with the metabolic biomarkers. A substantial amount of biomarker variance was explained by SLS-specific PRS, and the prediction was improved by including the putatively novel loci. Fasting blood insulin and insulin resistance were associated with PRS for adiponectin, leptin, and ghrelin, and BF% was associated with PRS for adiponectin and leptin. We found evidence of substantial mediation of these associations by the biomarker levels.. The genetic underpinnings of metabolic biomarkers can affect the early development of CMD, partly mediated by the biomarkers.. This study characterized the genetic underpinnings of four metabolic hormones and investigated their potential influence on adiposity and insulin biology among Hispanic/Latino adolescents. Fasting blood insulin and insulin resistance were associated with polygenic risk score (PRS) for adiponectin, leptin, and ghrelin, with evidence of some degree of mediation by the biomarker levels. Body fat percent (BF%) was also associated with PRS for adiponectin and leptin. This provides important insight on biological mechanisms underlying early metabolic dysfunction and reveals candidates for prevention efforts. Our findings also highlight the importance of ancestrally diverse populations to facilitate valid studies of the genetic architecture of metabolic biomarker levels.

Topics: Adiponectin; Adolescent; Biomarkers; Cardiovascular Diseases; Ghrelin; Hispanic or Latino; Humans; Insulin; Insulin Resistance; Leptin; Longitudinal Studies; Orexins

Interactions between polymorphisms of the melatonin receptor 1B (MTNR1B) gene and lifestyle intervention for gestational diabetes have been described. Whether these are specific for physical activity or the healthy eating intervention is unknown.. The aim was to assess the interaction between MTNR1B rs10830962 and rs10830963 polymorphisms and lifestyle interventions during pregnancy.. Women with a BMI (in kg/m2) of ≥29 (n = 436) received counseling on healthy eating (HE), physical activity (PA), or both. The control group received usual care. This secondary analysis had a factorial design with comparison of HE compared with no HE and PA compared with no PA. Maternal outcomes at 24-28 wk were gestational weight gain (GWG), maternal fasting glucose, insulin, insulin resistance (HOMA-IR), disposition index, and development of GDM. Neonatal outcomes were cord blood leptin and C-peptide and estimated neonatal fat percentage. The interaction between receiving either the HE or PA intervention and genotypes of both rs10830962 and rs10830963 was assessed using multilevel regression analysis.. GDM risk was increased in women homozygous for the G allele of rs10830962 (OR: 2.60; 95% CI: 1.34, 5.06) or rs10830963 (OR: 2.83; 95% CI: 1.24, 6.47). Significant interactions between rs10830962 and interventions were found: in women homozygous for the G allele but not in the other genotypes, the PA intervention reduced maternal fasting insulin (β: -0.16; 95% CI: -0.33, 0.02; P = 0.08) and HOMA-IR (β: -0.17; 95% CI: -0.35, 0.01; P = 0.06), and reduced cord blood leptin (β: -0.84; 95% CI: -1.42, -0.25; P = 0.01) and C-peptide (β: -0.62; 95% CI: -1.07, -0.17; P = 0.01). In heterozygous women, the HE intervention had no effect, whereas in women homozygous for the C allele, HE intervention reduced GWG (β: -1.6 kg; 95% CI: -2.4, -0.8 kg). No interactions were found.. In women homozygous for the risk allele of MTNR1B rs10830962, GDM risk was increased and PA intervention might be more beneficial than HE intervention for reducing maternal insulin resistance, cord blood C-peptide, and cord blood leptin.

Topics: Adult; Alleles; Blood Glucose; C-Peptide; Diabetes, Gestational; Diet, Healthy; Exercise; Female; Fetal Blood; Genotype; Gestational Weight Gain; Humans; Infant, Newborn; Insulin; Insulin Resistance; Leptin; Life Style; Polymorphism, Genetic; Pregnancy; Pregnancy Outcome; Prenatal Care; Receptor, Melatonin, MT2

Genetic obesity is rare and quite challenging for pediatricians in terms of early identification. Src-homology-2 (SH2) B adapter protein 1 (SH2B1) is an important component in the leptin-melanocortin pathway and is found to play an important role in leptin and insulin signaling and therefore in the pathogenesis of obesity and diabetes. Microdeletions in chromosome 16p11.2, encompassing the SH2B1 gene, are known to be associated with obesity, insulin resistance, hyperphagia, and developmental delay. The aim of our study is to report on a case series of young individuals with 16p11.2 microdeletions, including the SH2B1 gene, and provide detailed information on body mass index (BMI) development and obesity-associated comorbidities. In this way, we want to raise awareness of this syndromic form of obesity as a differential diagnosis of genetic obesity.. We describe the phenotype of 7 children (3 male; age range: 2.8-18.0 years) with 16p11.2 microdeletions, encompassing the SH2B1 gene, and present their BMI trajectories from birth onward. Screening for obesity-associated comorbidities was performed at the time of genetic diagnosis.. All children presented with severe, early-onset obesity already at the age of 5 years combined with variable developmental delay. Five patients presented with elevated fasting insulin levels, 1 patient developed diabetes mellitus type 2, 4 patients had dyslipidemia, and 4 developed nonalcoholic fatty-liver disease.. Chromosomal microdeletions in 16p11.2, including the SH2B1 gene, in children are associated with severe, early-onset obesity and comorbidities associated with insulin resistance. Early genetic testing in suspicious patients and early screening for comorbidities are recommended.

Topics: Adaptor Proteins, Signal Transducing; Adolescent; Body Mass Index; Child; Child, Preschool; Female; Gene Deletion; Humans; Insulin; Insulin Resistance; Leptin; Male; Pediatric Obesity

Arsenic is a risk factor for type 2 diabetes and cardiovascular disease. However, little is known about arsenic effects over adipocyte endocrine functionality, particularly for leptin and adiponectin, and about its interaction with dietary components, which are the main environmental regulators of adipose tissue functionality. The aim of this work was to evaluate leptin and adiponectin in mature 3T3-L1 adipocytes exposed to palmitate (simulating excess fat intake), arsenite, or both throughout two different stages of adipogenesis.. 3T3-L1 adipocytes were exposed starting from the beginning of its differentiation process during 11 d or once adipocytes were mature for 72 h. Adipokines secretion was evaluated by ELISA, intracellular protein levels and secreted adiponectin multimers by Western blot and mRNA abundance by qPCR.. Leptin and adiponectin secretion decreased by arsenite alone or in combination with palmitate due to reduced gene and protein expression of both adipokines. However, leptin was impaired more at the transcriptional level, whereas affections to adiponectin were more relevant at the intracellular protein amount level with changes in the multimers proportion. The gene expression of several of their transcription factors was altered. Additionally, the magnitude of the effects depends on the adipocyte cell stage at which exposure began; adiponectin was more affected when exposure started from differentiation and leptin once adipocytes were mature.. These results in an in vivo model could be translated into less satiety and reduced insulin sensitivity.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Adipokines; Adiponectin; Animals; Arsenic; Arsenites; Cell Differentiation; Gene Expression; Gene Expression Regulation; Insulin; Insulin Resistance; Leptin; Lipid Metabolism; Mice; Palmitic Acid

A novel classification has been introduced to promote precision medicine in diabetes. The current study aimed to investigate the relationship between leptin and resistin levels with novel refined subgroups in patients with type 2 diabetes mellitus (T2DM).. The k-means analysis was conducted to cluster 541 T2DM patients into the following four subgroups: mild obesity-related diabetes (MOD), severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD) and mild age-related diabetes (MARD). Individuals meeting the exclusion criteria were eliminated, the data for 285 patients were analyzed. Characteristics were determined using various clinical parameters. Both the leptin and resistin levels were determined using enzyme-linked immunosorbent assay.. The highest levels of plasma leptin were in the MOD group with relatively lower levels in the SIDD and SIRD groups (P < 0.001). The SIRD group had a higher resistin concentration than the MARD group (P = 0.024) while no statistical significance in resistin levels was found between the SIDD and MOD groups. Logistic regression demonstrated that plasma resistin was associated with a higher risk of diabetic nephropathy (odds ratios (OR) = 2.255, P = 0.001). According to receiver operating characteristic (ROC) curves, the area under the curve (AUC) of resistin (0.748, 95% CI 0.610-0.887) was significantly greater than that of HOMA2-IR (0.447, 95% CI 0.280-0.614) (P < 0.05) for diabetic nephropathy in the SIRD group.. Leptin levels were different in four subgroups of T2DM and were highest in the MOD group. Resistin was elevated in the SIRD group and was closely related to diabetic nephropathy.

Topics: Adult; Age Factors; Cluster Analysis; Diabetes Mellitus, Type 2; Enzyme-Linked Immunosorbent Assay; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Resistin

Although severe obesity is associated with insulin resistance (IR) and inflammation, secretory function of intra-abdominal adipose tissues and their relationships with IR and inflammation markers remain poorly understood. Aims were to measure gene expression of adipogenic (C/EBPα/β, PPARγ-1/2, SREBP-1c, LXRα), lipogenic (SCD1, DGAT-1/2), angiogenic (VEGFα, leptin), and fibrotic (LOX, COL6A3) factors in the round ligament (RL), omental (OM), and mesenteric (ME) fat depots and to evaluate their relationships with IR and inflammation markers in 48 women with severe obesity undergoing bariatric surgery. Gene expression was assessed by RT-qPCR, and plasma glucose and insulin (HOMA-IR calculated), PAI-1, IL-6, TNFα, adiponectin, and leptin levels were determined. C/EBPβ and PPARγ-1/2 mRNA levels were more expressed in the OM (0.001

Topics: Adipogenesis; Female; Fibrosis; Gene Expression; Humans; Inflammation; Insulin; Insulin Resistance; Leptin; Lipogenesis; Obesity, Morbid; Plasminogen Activator Inhibitor 1; PPAR gamma; Sterol Regulatory Element Binding Protein 1; Tumor Necrosis Factor-alpha

Studies have demonstrated the presence of low-affinity immunoglobulins (Igs) directed to leptin, a key hormone of the neuroendocrine axis that regulates appetite and metabolism, in adult healthy subjects, patients with obesity, and type 2 diabetes mellitus. In the present exploratory study, IgG leptin-reactive antibodies were analyzed for the first time in children and adolescents according to body mass index (BMI) and were correlated with biochemical profile (lipid profile, insulin, glucose, and leptin) and metabolic risk indexes [homeostasis model assessment for insulin resistance (HOMA-IR), homeostasis model assessment for β-cell function (HOMA-β), atherogenic index of plasma (AIP)]. One hundred and thirty-six participants were included (children n = 63, adolescents n = 73). An in-house enzyme-linked immunosorbent assay (ELISA) test was performed to measure IgG anti-leptin antibodies (free, total, and immune complexes). In adolescents, free and total IgG anti-leptin antibodies levels were higher in groups with overweight or obesity than in normal-weight group (P < 0.01), while in children, the total fractions were lower in groups with overweight and obesity than in normal weight (P < 0.02). Immune complexes percentage showed opposite correlations with BMI in children (r = 0.4004, P = 0.0473) and adolescents (r = -0.3983, P = 0.0133). IgG anti-leptin antibodies were also correlated with HOMA-IR in children (r = -0.4569, P = 0.0217) and adolescents (r = -0.3589, P = 0.0316), and with AIP (r = -0.3608, P = 0.0261) in adolescents. Our data suggest that the production and affinity of IgG anti-leptin antibodies can be affected by age, body composition, and metabolic conditions; additionally, in normal conditions, IgG anti-leptin antibodies may have a protective role in insulin resistance and cardiovascular events.

Topics: Adolescent; Adult; Antigen-Antibody Complex; Body Composition; Body Mass Index; Child; Diabetes Mellitus, Type 2; Humans; Immunoglobulin G; Insulin; Insulin Resistance; Leptin; Obesity; Overweight

Obesity, a low-grade systemic inflammatory disease, causes inflammation in metabolic tissues. Galectin-3(Gal-3) is one of the lectin molecules involved in inflammatory processes. We evaluated the possible relationship between Gal-3 level and the metabolic inflammatory process before and after obesity surgery.. One hundred participants were included in the study and classified as normal weight, overweight, Class I, II, and III obese. Class III obese group underwent bariatric surgery and evaluated in the 3rd and 6th months after surgery. Glucose, insulin, glycated hemoglobin A1c (HbA1c), homeostatic model assessment of insulin resistance (HOMA-IR), high sensitivity C-reactive protein (hsCRP), Gal-3, interleukin (IL)-6, IL-10, adiponectin, and leptin levels were determined.. Gal-3 levels were higher in Class III obese compared to the normal weight group. Postoperative leptin and hsCRP levels were decreased significantly, but the decrease in IL-6 and Gal-3 levels were not significant. Postoperative increased adiponectin and IL-10 levels were significant. Gal-3 was found significantly higher in insulin resistant group. The correlation between Gal-3 with BMI, adiponectin, leptin, hsCRP levels, and HOMA-IR was found weak.. These findings might support the fact that Gal-3 is one of the molecules involved in the linkage between insulin resistance and meta-inflammation in morbid obese.

Topics: Adiponectin; Bariatric Surgery; Blood Proteins; Galectin 3; Galectins; Humans; Insulin; Insulin Resistance; Leptin

  Single nucleotide variants (SNVs) of ADIPOQ gene on different comorbidities are related to obesity and weight loss. Despite, there are no studies evaluating the effect of rs3774261 on metabolic variables after bariatric surgery. We evaluated the effect of SNV rs3774261 of ADIPOQ gene on biochemical changes after biliopancreatic diversion surgery in morbidly obese subjects for 3 years follow-up.. One hundred and forty-nine patients (111 females/38 males) with morbid obesity (body mass index >40 kg/m2) without diabetes mellitus type 2 were enrolled. Biochemical and anthropometric evaluation were registered before and after 1, 2, and 3 years. Genotype of rs3774261 has been studied.. Total cholesterol, LDL-cholesterol and triglyceride levels decreased in all genotype groups during the study. Although the improvement in glucose, insulin and HOMA-IR was significant in two genotypes (AA and AG); these changes were earlier in the AA genotype than in Ag and GG genotypes. Adiponectin levels increased in a significant way in subjects with AA genotype in the 3 follow-up periods (first year delta: 16.4±0.5 ng/ml; p=0.03, second year delta: 21.3±0.5 ng/ mL; p=0.02 and third year delta: 23.6±0.7 ng/mL; p=0.01) and at 3 years in subjects with AG genotype (delta: 18.3±0.4 ng/ mL; p=0.03). The ratio adiponectin/leptin increased in a significant way in subjects with AA genotype in the 3 follow-up times (first year delta: 0.40±0.1 units; p=0.02, second year delta: 0.58±0.1 units; p=0.01 and third year delta: 0.65±0.1 ng/mL; p=0.01) and at 3 years in subjects with AG genotype (delta: 0.61±0.1 ng/ mL; p=0.02). Subjects with GG genotype did not show a significant improvement in these parameters during the follow-up.. G allele carriers of rs3774261 showed a delay in the improvement of glucose metabolism parameters, adiponectin and adiponectin/leptin ratio.

Topics: Adipokines; Adiponectin; Biliopancreatic Diversion; Female; Genotype; Humans; Insulin Resistance; Leptin; Male; Obesity, Morbid; Polymorphism, Single Nucleotide

Disturbances in eating behaviors have been widely related to obesity. However, little is known about the role of obesity-related biomarkers in shaping habitual patterns of eating behaviors (i.e., eating styles) in childhood. The objective of the present study was to explore the relationships between several biomarkers crucially involved in obesity (ghrelin, insulin resistance, and leptin/adiponectin ratio) and eating styles in children and adolescents with obesity. Seventy participants aged between 8 and 16 (56.2% men) fulfilled the Spanish version of the Dutch Eating Behavior Questionnaire for Children to measure external, emotional, and restrained eating styles. In addition, concentrations of ghrelin, leptin, adiponectin, insulin, and glucose were obtained through a blood test. Hierarchical multiple regression analyses controlling for age and sex were computed for each eating style. Results indicated that individuals with higher ghrelin concentration levels showed lower scores in restrained eating (β = -0.61,

Topics: Adiponectin; Adolescent; Adolescent Behavior; Biomarkers; Child; Child Behavior; Cross-Sectional Studies; Feeding Behavior; Female; Ghrelin; Humans; Insulin Resistance; Leptin; Male; Pediatric Obesity; Regression Analysis; Risk Factors; Spain; Surveys and Questionnaires

Prolonged high-fat diet (HFD) accelerates the cardiovascular, renal, and metabolic dysfunction in hypertensive rats with altered renal development (ARDev). Soluble guanylate cyclase (sGC) stimulation or sodium-glucose cotransporter 2 (SGLT2) inhibition may improve cardiovascular, renal, and metabolic function in settings of hypertension and obesity. This study examined whether 6 wk treatment with an SGLT2 inhibitor (empagliflozin, 7 mg/kg/day) enhances the cardiovascular, renal, and metabolic effects of a sGC stimulator (praliciguat, 10 mg/kg/day) in hypertensive rats with ARDev and prolonged exposure to HFD. Arterial pressure (AP), renal vascular resistance (RVR), fat abdominal volume (FAV), insulin resistance, leptin and triglycerides levels, and intrarenal infiltration of inflammatory cells were higher, but cardiac output and creatinine clearance were lower in hypertensive rats (

Topics: Animals; Benzhydryl Compounds; Creatinine; Diet, High-Fat; Glucose; Hypertension; Insulin Resistance; Leptin; Rats; Sodium-Glucose Transporter 2; Soluble Guanylyl Cyclase; Triglycerides

Lipodystrophy constitutes a spectrum of diseases characterized by a generalized or partial absence of adipose tissue. Underscoring the role of healthy fat in maintenance of metabolic homeostasis, fat deficiency in lipodystrophy typically leads to profound metabolic disturbances including insulin resistance, hypertriglyceridemia, and ectopic fat accumulation. While rare, recent genetic studies indicate that lipodystrophy is more prevalent than has been previously thought, suggesting considerable underdiagnosis in clinical practice. In this article, we provide an overview of the etiology and management of generalized and partial lipodystrophy disorders. We bring together the latest scientific evidence and clinical guidelines and expose key gaps in knowledge. Through improved recognition of the lipodystrophy disorders, patients (and their affected family members) can be appropriately screened for cardiometabolic, noncardiometabolic, and syndromic abnormalities and undergo treatment with targeted interventions. Notably, insights gained through the study of this rare and extreme phenotype can inform our knowledge of more common disorders of adipose tissue overload, including generalized obesity.

Topics: Adipose Tissue; Humans; Hypertriglyceridemia; Insulin Resistance; Leptin; Lipodystrophy; Obesity

SignificanceWhile increasing evidence associates the disruption of circadian rhythms with pathologic conditions, including obesity, type 2 diabetes, and nonalcoholic fatty liver diseases (NAFLD), the involved mechanisms are still poorly described. Here, we show that, in both humans and mice, the pathogenesis of NAFLD is associated with the disruption of the circadian clock combined with perturbations of the growth hormone and sex hormone pathways. However, while this condition protects mice from the development of fibrosis and insulin resistance, it correlates with increased fibrosis in humans. This suggests that the perturbation of the circadian clock and its associated disruption of the growth hormone and sex hormone pathways are critical for the pathogenesis of metabolic and liver diseases.

Topics: Animals; ARNTL Transcription Factors; Circadian Clocks; Diet, High-Fat; Gene Deletion; Gene Expression Regulation; Humans; Insulin Resistance; Leptin; Lipid Metabolism; Male; Mice; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Obesity

Low and high leptin levels are associated with non-alcoholic fatty liver disease (NAFLD). The LncOb rs10487505 variant has been associated with body mass index (BMI), and the C allele was reported as leptin-lowering. We evaluated the association of rs10487505 with leptin levels, liver histology, and surgery-induced weight loss in youths with NAFLD.. One-hundred five obese youths with NAFLD, of whom 19 undergoing laparoscopic sleeve gastrectomy (LSG), were analyzed for rs10487505 and leptin circulating levels.. The G allele frequency was lower in youths with NAFLD than in controls (p = 0.049). No difference was found in anthropometrics, biochemistry and histology between G allele carriers and CC homozygotes, except for leptin levels (p = 0.016). Leptin correlated with body weight, BMI, BMI-z score, waist circumference, insulin resistance/sensitivity, and triglycerides (p ≤ 0.01). A multivariable regression model including body weight and homeostasis model assessment of insulin resistance was a good predictor of plasma leptin (R. LncOb rs10487505 variant was associated with pediatric NAFLD and high leptin levels, and with weight and leptin reduction after LSG in youths.. The interplay of environment, genetics and epigenetics is crucial inflating the risk of non-alcoholic fatty liver disease (NAFLD). Several long non-coding RNA (LncRNAs) are found associated with NAFLD pathogenesis. Here, we evaluated the impact of the genetic variant rs10487505 in LncOb which is involved in the regulation of leptin gene expression. The LncOb rs10487505 is associated with increased levels of leptin, but not with liver histology, in youths with NAFLD. The LncOb rs10487505 was also associated with the significant decrease of leptin and body weight after bariatric surgery.

Topics: Adolescent; Body Mass Index; Child; Humans; Insulin Resistance; Leptin; Liver; Non-alcoholic Fatty Liver Disease; Obesity

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

Obesity is a major concern for global health care systems. Systemic low-grade inflammation in obesity is a major risk factor for insulin resistance. Leptin is an adipokine secreted by the adipose tissue that functions by controlling food intake, leading to satiety. Leptin levels are increased in obesity. Here, we show that leptin enhances the effects of LPS in macrophages, intensifying the production of cytokines, glycolytic rates, and morphological and functional changes in the mitochondria through an mTORC2-dependent, mTORC1-independent mechanism. Leptin also boosts the effects of IL-4 in macrophages, leading to increased oxygen consumption, expression of macrophage markers associated with a tissue repair phenotype, and wound healing. In vivo, hyperleptinemia caused by diet-induced obesity increases the inflammatory response by macrophages. Deletion of leptin receptor and subsequently of leptin signaling in myeloid cells (ObR-/-) is sufficient to improve insulin resistance in obese mice and decrease systemic inflammation. Our results indicate that leptin acts as a systemic nutritional checkpoint to regulate macrophage fitness and contributes to obesity-induced inflammation and insulin resistance. Thus, specific interventions aimed at downstream modulators of leptin signaling may represent new therapeutic targets to treat obesity-induced systemic inflammation.

Topics: Adipose Tissue; Animals; Inflammation; Insulin Resistance; Leptin; Macrophages; Mice; Mice, Inbred C57BL; Obesity

Metabolic dysregulation is currently considered a major risk factor for hippocampal pathology. The aim of the present study was to characterize the influence of key metabolic drivers on functional connectivity of the hippocampus in healthy adults.. Insulin resistance was directly quantified by measuring steady-state plasma glucose (SSPG) concentration during the insulin suppression test and fasting levels of insulin, glucose, leptin, and cortisol, and measurements of body mass index and waist circumference were obtained in a sample of healthy cognitively intact adults (n = 104). Resting-state neuroimaging data were also acquired for the quantification of hippocampal functional cohesiveness and integration with the major resting-state networks (RSNs). Data-driven analysis using unsupervised machine learning (k-means clustering) was then employed to identify clusters of individuals based on their metabolic and functional connectivity profiles.. K-means clustering identified two clusters of increasing metabolic deviance evidenced by cluster differences in the plasma levels of leptin (40.36 (29.97) vs. 27.59 (25.58) μg/L) and the degree of insulin resistance (SSPG concentration: 161.63 (65.27) vs. 125.72 (66.81) mg/dL). Individuals in the cluster with higher metabolic deviance showed lower functional cohesiveness within each hippocampus and lower integration of posterior and anterior components of the left and right hippocampus with the major RSNs. The two clusters did not differ in general intellectual ability or episodic memory.. We identified two clusters of individuals differentiated by abnormalities in insulin resistance, leptin levels, and hippocampal connectivity, with one of the clusters showing greater deviance. These findings support the link between metabolic dysregulation and hippocampal function even in nonclinical samples.

Topics: Adult; Hippocampus; Humans; Insulin; Insulin Resistance; Leptin; Magnetic Resonance Imaging

Obesity usually complicates hypothyroidism. Adipokines like leptin and adiponectin secreted by adipose tissue modulate insulin resistance (IR), appetite, and obesity. The association between adipokines, IR, and thyroid hormone has not been sufficiently studied in children. We investigated leptin and adiponectin as well as IR and their association with thyroid hormone in both lean and hypothyroid children and adolescents with obesity.. The study included 30 lean hypothyroid, 30 hypothyroid children and adolescents with obesity, and 30 healthy lean children as the control group. Serum thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), fasting blood glucose, fasting insulin, homeostatic model assessment method of insulin resistance (HOMA-IR), leptin, and adiponectin levels were estimated in all participants.. Fasting insulin, HOMA-IR, and leptin levels were significantly elevated in hypothyroid children compared to the control group; more in hypothyroid children with obesity. In contrast, adiponectin levels were significantly lower in the hypothyroid children with obesity compared to the lean hypothyroid children and controls. HOMA-IR was positively correlated to TSH and BMI but inversely correlated with fT3 and fT4 in hypothyroid children. There was no correlation between IR and either leptin or adiponectin levels. Leptin and adiponectin levels correlated well with BMI in hypothyroid children and adolescents with obesity.. Insulin resistance and leptin levels are increased in hypothyroid children and adolescents; more in those with obesity. IR is not related to leptin and adiponectin levels, however, leptin and adiponectin levels correlate well with BMI in hypothyroid children and adolescents with obesity.. Insulin resistance (IR) and leptin levels increase in hypothyroid children and adolescent; more with obesity. IR is not related to leptin and adiponectin levels, however leptin and adiponectin levels correlated well with BMI in hypothyroid children and adolescents with obesity.

Topics: Adipokines; Adiponectin; Adolescent; Child; Humans; Hypothyroidism; Insulin; Insulin Resistance; Leptin; Pediatric Obesity; Thyrotropin

The plant Berberis aristata is traditionally used and scientifically validated for treating obesity and hyperlipidemia. It is also traditionally used to treat gynecological abnormalities. Therefore, the present study was designed to evaluate the therapeutic potential of Berberis aristata for obesity-related reproductive changes and chemically characterize it.. High-fat diet was given to 36 female rats for six weeks to induce obesity and infertility. These obese rats were treated with 10 mg/kg orlistat or the plant extract at 125-500 mg/kg for 45 days.. The GC-MS analysis of the plant extract included fructose, thymic acid and other hydrocarbons. The plant extract revealed a remarkable free radical scavenging activity. The treated animals exhibited a decrease in total cholesterol and triglycerides (p<0.001), insulin and leptin levels (p<0.05), visceral fat, and body weight while increasing the estradiol level at 500 mg/kg dose of the plant extract as compared with untreated animals as demonstrated from the histology of the ovary. Oxidative stress biomarkers such as superoxide dismutase, nitric oxide, malondialdehyde and reduced glutathione were significantly (p<0.01-0.001) ameliorated in treated rats.. B. aristata exhibited substantial potential against obesity-inducedreproductive damage in female rats by reducing oxidative stress and resistance to leptin and insulin.

Topics: Animals; Berberis; Diet, High-Fat; Female; Insulin; Insulin Resistance; Leptin; Obesity; Oxidative Stress; Plant Extracts; Rats; Rats, Wistar

Premature pubarche (PP) is a risk factor for metabolic syndrome (MS). The aim was to evaluate if glucose-insulin metabolism, cardiovascular risk factors, familial cardiovascular risk factors (FCVRF) created a risk for insulin resistance (IR) and if PP was a risk factor alone for MS in normal weight prepubertal girls with PP.. Thirty-five prepubertal, non-obese girls with PP with normal birth weight and 35 age-matched control girls were evaluated for FCVRF, anthropometric measurements, blood pressure, lipid profile, fasting blood glucose-insulin, hemoglobin A1c (HbA1c), sex hormone binding globulin (SHBG), leptin, adiponectin, tumor necrosis factor-alpha (TNF-α), androgen levels, and bone age. Oral glucose tolerance test was performed in PP participants. Homeostasis model of assessment of IR (HOMA-IR), fasting glucose/insulin ratio, atherogenic index (AI), and free androgen index (FAI) were calculated. PP participants were further stratified by FCVRF.. HbA1c, lipid profile, testosterone, leptin, adiponectin, TNF-α, HOMA-IR, glucose/insulin ratio, AI, and fasting glucose-insulin levels were similar. In the PP group FAI was significantly higher (p=0.001), whereas SHBG was significantly lower (p=0.010) than the control group. Leptin levels of FCVRF+ and FCVRF- subgroups were 15.2±9.1 and 9.7±7.2 ng/mL, respectively and the difference was significant (p=0.016).. As PP does not appear to be a risk factor alone for impaired glucose metabolism and IR in prepubertal non-obese girls with normal birth weight, it is our opinion that it is unnecessary to examine in detail such cases before puberty. Low SHBG levels in the PP group and high leptin levels in FCVRF+ subgroup might suggest that these may be predictive for MS in the future.

Topics: Adiponectin; Androgens; Birth Weight; Blood Glucose; Cardiovascular Diseases; Female; Glucose; Glycated Hemoglobin; Heart Disease Risk Factors; Humans; Insulin; Insulin Resistance; Leptin; Lipids; Metabolic Syndrome; Puberty, Precocious; Risk Factors; Tumor Necrosis Factor-alpha

The aim of the study was to evaluate adrenal axis hyperactivation measuring hair cortisol levels, and its influence on the relationship among metabolic parameters, inflammation markers and androgens in adult women with PCOS. 44 women (18-34 years) with PCOS diagnosis and a control group of 49 healthy women (19-35 years) were included. In both gropus body mass index (BMI) was calculated and waist circumference (WC) was measured. Hair cortisol, total serum testosterone (TT), serum cortisol, 25 OH vitamin D (25OHD), insulin, high sensitivity C-reactive protein (hsCRP), triglycerides (TG), HDL cholesterol (HDL), glucose and leptin were measured. Bioavailable testosterone (bioT) was calculated. Hair cortisol concentration was higher and significantly different in PCOS patients compared to the control group (130 vs 63 pg/mg of hair, p < 0.001). Subsequently, patients with PCOS were divided into two groups according to hair cortisol levels: group 1 with normal hair cortisol concentration and group 2 with levels above the upper limit of the reference values (128 pg/mg of hair). In group 2, TT significantly correlated with 25OHD, hsCRP, TG/HDL index, BMI, WC, insulin and HOMA (p < 0.05); bioT correlated with hsCRP and leptin (p < 0.05). Finally, 25OHD was inversely correlated with leptin and with TG/HDL index (p < 0.05). High hair cortisol concentration in patients with PCOS confirmed hyperactivation of the HPA axis. The associations observed were only found in patients with PCOS with high hair cortisol levels (> 128 pg/mg of hair), showing a possible effect of HPA axis in these associations.

Topics: Adolescent; Adult; Body Mass Index; C-Reactive Protein; Female; Hair; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Insulin; Insulin Resistance; Leptin; Obesity; Pituitary-Adrenal System; Polycystic Ovary Syndrome; Testosterone; Young Adult

The link between obesity and brain function is a fascinating but still an enigmatic topic. We evaluated the effect of Roux-en-Y gastric bypass (RYGB) on peripheral glucose metabolism, insulin sensitivity, brain glucose utilization and cognitive abilities in people with obesity.. Bariatric surgery improves CMRg directly related to a better cognitive testing result. This study highlights the potential pleiotropic effects of bariatric surgery.. NCT03414333.

Topics: Adult; Bariatric Surgery; Brain; Female; Gastric Bypass; Glucose; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Positron Emission Tomography Computed Tomography

The aim: To investigate the relationship between leptin resistance, lipid and carbohydrate metabolism, blood pressure in obese pregnant women.. Materials and methods: Under observation were 65 women (main group) with obesity (I degree -27 women, II degree - 24 women, III degree - 14 women) in the II trimester of pregnancy, who were hospitalized in the Department of Pathology of Pregnancy KNP «Maternity Clinical house №1 "in Lviv during 2017-2020 on preeclampsia of varying severity, which were sent for inpatient treatment by women's clinics. The control group consisted of 30 healthy pregnant women without obesity.. Results: Serum leptin in obese women was directly correlated with BMI (r = 0.66, p<0.001), body weight (r = 0.29, p<0.05), total cholesterol (cholesterol) (r = 0, 37, p<0,009), low density lipoproteins (LDL cholesterol) (r = 0.33, p<0.05) and inversely with high density particles (HDL cholesterol) (r = -0.37, p<0.02 ). Studies of carbohydrate metabolism indicate the following correlation coefficients of BMI with glucose level r = 0.351; p<0,001, BMI with the level of C-peptide r = 0,450; p<0,001, BMI with HOMA index r = 0,1504; p = 0.036. Inverse correlations of C-peptide were detected with the level of P (r = -0.169; p = 0.025).. Conclusions: The discovery of the relationship between leptin resistance, lipid and carbohydrate metabolism, blood pressure indicates the possibility of using signs of leptin resistance to prevent complications during pregnancy in the second trimester.

Topics: Body Mass Index; C-Peptide; Cholesterol; Female; Humans; Insulin Resistance; Leptin; Obesity; Pregnancy; Pregnant Women

People living with HIV have greater diabetes (T2DM) than the general population despite lower prevalence of overweight/obesity. Both insulin resistance (IR), a T2DM precursor, and HIV are independently associated with chronic inflammation. Inflammation may be a pathophysiological link explaining IR in people living with HIV who are not overweight but is not well understood.. To study the association between inflammation and IR in non-overweight and overweight people living with HIV.. In a cohort of adult people living with HIV with undetectable viral load in Pune, India, we measured fasting insulin, glucose, and 9 inflammatory markers. IR was defined as HOMA-IR ≥2, and non-overweight as BMI ≤23 kg/m. Of 288 participants, 66% (n = 189) were non-overweight. Among non-overweight, prevalence of IR was 34% (n = 65). Each doubling of MCP-1 and leptin was associated with IR on univariate analysis (prevalence ratio (PR) 1.29, 95%CI 1.07-1.53, p < 0.01; PR 1.13 95%CI 1.01-1.26, p = 0.03). Leptin remained associated with IR after adjustment for age, MCP-1, gender, cholesterol, and waist circumference (adjusted PR 1.20 95%CI 1.06-1.36, p < 0.01). Among overweight, prevalence of IR was 69% and no markers were associated with IR.. One in 3 non-overweight people living with HIV in India with controlled viremia have IR. Leptin was associated with IR among non-overweight people living with HIV and may provide insight into the pathophysiology of metabolic disease in this population.

Topics: Adult; Biomarkers; Body Mass Index; Diabetes Mellitus, Type 2; HIV Infections; Humans; India; Inflammation; Insulin; Insulin Resistance; Leptin; Overweight

Obesity is an abnormal or excessive accumulation of fat in the body that exacerbates metabolic and inflammatory processes, and impairs the health of afflicted individuals. β-caryophyllene is a natural sesquiterpene that is a dietary cannabinoid with anti-inflammatory properties and potential activity against metabolic diseases. In the present study, we evaluated the effect of β-caryophyllene on C57BL/6 mice using a diet-induced obesity model. Male mice were randomly assigned to the following groups over a 16-week period: (1) standard diet as lean control, (2) high-fat diet (HFD) as obese control, and (3) HFD + β-caryophyllene with β-caryophyllene at 50 mg/kg. Treatment with β-caryophyllene improved various metabolic parameters including increased total body weight, fasting glucose levels, oral-glucose tolerance, insulin tolerance, fasting triglycerides, adipocyte hypertrophy, and liver macrovesicular steatosis. β-caryophyllene also modulated the levels and expression of immune response factors including adiponectin, leptin, insulin, interleukin-6, tumor necrosis factor-a, and Toll-like receptor-4. Our data indicate that chronic supplementation with β-caryophyllene can improve relevant metabolic and immunological processes in obese mice. This protocol was approved by the Institutional Committee for Care and Use of Laboratory Animals from the University of Guadalajara with protocol code CUCEI/CINV/CICUAL-01/2022.

Topics: Adiponectin; Animals; Anti-Inflammatory Agents; Blood Glucose; Cannabinoids; Diet, High-Fat; Insulin; Insulin Resistance; Interleukin-6; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Polycyclic Sesquiterpenes; Triglycerides; Tumor Necrosis Factors; Weight Gain

Adipose tissue secretes numerous cytokines (termed 'adipokines') that have known or hypothesized actions on skeletal muscle. The majority of adipokines have been implicated in the pathological link between excess adipose and muscle insulin resistance, but approximately half also have documented in vitro effects on myogenesis and/or hypertrophy. This complexity suggests a potential dual role for adipokines in the regulation of muscle mass in homeostasis and the development of pathology. In this study, we used lipodystrophic 'fat-free' mice to demonstrate that adipose tissue is indeed necessary for the development of normal muscle mass and strength. Fat-free mice had significantly reduced mass (∼15%) and peak contractile tension (∼20%) of fast-twitch muscles, a slowing of contractile dynamics and decreased cross-sectional area of fast twitch fibres compared to wild-type littermates. These deficits in mass and contractile tension were fully rescued by reconstitution of ∼10% of normal adipose mass, indicating that this phenotype is the direct consequence of absent adipose. We then showed that the rescue is solely mediated by the adipokine leptin, as similar reconstitution of adipose from leptin-knockout mice fails to rescue mass or strength. Together, these data indicate that the development of muscle mass and strength in wild-type mice is dependent on adipose-secreted leptin. This finding extends our current understanding of the multiple roles of adipokines in physiology as well as disease pathophysiology to include a critical role for the adipokine leptin in muscle homeostasis. KEY POINTS: Adipose-derived cytokines (adipokines) have long been implicated in the pathogenesis of insulin resistance in obesity but likely have other under-appreciated roles in muscle physiology. Here we use a fat-free mouse to show that adipose tissue is necessary for the normal development of muscle mass and strength. Through add-back of genetically modified adipose tissue we show that leptin is the key adipokine mediating this regulation. This expands our understanding of leptin's role in adipose-muscle signalling to include development and homeostasis and adds the surprising finding that leptin is the sole mediator of the maintenance of muscle mass and strength by adipose tissue.

Topics: Adipokines; Adipose Tissue; Animals; Cytokines; Insulin Resistance; Leptin; Mice; Muscle, Skeletal

Polycystic ovary syndrome (PCOS) is a common heterogeneous endocrine disorder, affecting 5-10% of females with hyperandrogenism and prolonged anovulation.. This study was done to understand the serum leptin role in women with PCOS and its link with the body mass index (BMI) and insulin resistance (IR).. This 1-year study was conducted in the Departments of Obstetrics and Gynecology as well as Infertility Unite in AL-Diwaniyah Maternity and Pediatrics Teaching Hospital, Iraq, in which 40 patients with PCOS (study group) and 40 healthy (non-PCOS) patients (control group) participated. After BMI assessment, both the study and control groups were further stratified into subgroups as normal weight and overweight patients. Blood samples were obtained for all patients for the serum leptin level (SLL), fasting blood glucose (FBG), and serum insulin level. The HOMA-IR equation was used to estimate insulin resistance for all patients.. SLL of the PCOS women (mean ± SD, 22.29 ± 10.96 ng/ml) was significantly (P < 0.05) higher (17.89 ± 8.29 ng/ml) when compared to that of the control group. Insulin level was significantly elevated in the obese control and PCOS women (16.87 ± 3.52) µ UI/L and (15.09 ± 5.27) µUI, respectively, compared to normal BMI control and PCOS patients (P ≤ 0.01). Insulin resistance was significantly higher in obese (control and PCOS) patients (2.47 ± 0.40 and 2.30 ± 0.43, respectively), compared to normal BMI (control and PCOS) patients (P ≤ 0.01).. In obese patients, serum leptin significantly correlated with BMI in the presence of hyperinsulinemia and elevated insulin resistance.

Topics: Body Mass Index; Child; Female; Humans; Insulin Resistance; Insulins; Leptin; Obesity; Polycystic Ovary Syndrome; Pregnancy

Ob/ob mice have recently emerged as a model for obesity-related hyperoxaluria as they are obese and excrete more urine oxalate compared to wild type mice. Ob/ob mice are deficient of leptin and develop obesity with hyperphagia and hyperinsulinemia. We hypothesized that insulin resistance and the gut microbiome contribute to hyperoxaluria in ob/ob mice. We developed a new liquid chromatography-mass spectrometry assay for urine oxalate and first compared urine oxalate excretion in ob/ob mice before and after ablation of intestinal bacteria with a standard antibiotic cocktail. We then compared urine oxalate excretion in ob/ob mice before and after leptin replacement or pioglitazone treatment, two maneuvers that reduce insulin resistance in ob/ob mice. Ob/ob mice excreted more oxalate into the urine in a 24-h period compared to wild type mice, but antibiotic, leptin, or pioglitazone treatment did not change urine oxalate excretion in ob/ob mice. Unexpectedly, we found that when food intake was carefully matched between ob/ob and wild type mice, the amount of 24-h urine oxalate excretion did not differ between the two mouse strains, suggesting that ob/ob mice excrete more urine oxalate because of hyperphagia. Since the level of urine oxalate excretion in wild type mice in our study was higher than those reported in prior studies, future work will be needed to standardize the measurement of urine oxalate and to define the range of urine oxalate excretion in wild type mice so that accurate and valid comparisons can be made between wild type mice and ob/ob mice or other mouse models.

Topics: Animals; Anti-Bacterial Agents; Gastrointestinal Microbiome; Hyperoxaluria; Hyperphagia; Insulin Resistance; Leptin; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Obese; Obesity; Oxalates; Pioglitazone

Angiopoietin-like protein 6 (ANGPTL6) is a hepatokine, which, in animal studies, improves insulin sensitivity and increases energy expenditure to counteract insulin resistance.. Evaluate in a human population, the role of serum ANGPTL6 in gestational diabetes mellitus (GDM) or its presence in fetal circulation.. A total of 190 women (115 controls and 75 GDM) and their offspring were studied. Insulin, glucose, ANGPTL6, retinol binding protein 4 (RBP4), and retinol, as well as leptin and adiponectin, were determined in maternal serum obtained at term and from umbilical artery blood at delivery.. At term, pregnant women with GDM showed higher serum concentrations of ANGPTL6, insulin, homeostatic model assessment, and apo-RBP4 (free RBP4) than controls but not of glucose, which remained similar in both groups. Also, in arterial cord serum, ANGPTL6 concentration was increased in GDM neonates with respect to the control group (201 ± 12 ng/mL vs 119 ± 8 ng/mL, respectively). No effect of maternal insulin treatment of some GDM mothers in neonates of either sex on ANGPTL6 levels was observed. In GDM, circulating ANGPTL6 showed no correlation with glucose or insulin concentration or with neonatal adiposity. However, in control pregnancies, the variation in glucose concentration was positively correlated with ANGPTL6 concentration, both in maternal and in cord samples, and cord ANGPTL6 was negatively correlated with neonatal fat mass. Furthermore, in control pregnant women, serum concentrations of ANGPTL6 and apo-RBP4 were negatively correlated.. Serum ANGPTL6 levels are associated with maternal glucose homeostasis and fetal adiposity in normal pregnancy. ANGPTL6 levels in maternal and cord serum GDM pregnancy at term are increased, although its mechanism and physiological role are unknown yet.

Topics: Adiponectin; Angiopoietin-Like Protein 6; Angiopoietin-like Proteins; Animals; Blood Glucose; Diabetes, Gestational; Female; Glucose; Homeostasis; Humans; Infant, Newborn; Insulin; Insulin Resistance; Leptin; Pregnancy; Retinol-Binding Proteins, Plasma; Vitamin A

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

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

Obesity is an expanding global public health problem and a leading cause of metabolic disorders. The hepatokine Fetuin B participates in regulating insulin resistance, glucose metabolism and liver steatosis. However, the mechanism underlying Fetuin B activation remains unclear. Our previous population-based study demonstrated a significant association between serum Fetuin B and body fat mass in an obese population, which indicates its potential in mediating obesity-related metabolic disorders. In the present study, we further revealed a significant correlation between Fetuin B and leptin, the classic adipokine released by expanding adipose tissue, in this obese population. Consistently, elevated Fetuin B and leptin levels were confirmed in diet-induced obese mice. Furthermore, an in vitro study demonstrated that the leptin signalling pathway directly activated the transcription and expression of Fetuin B in primary hepatocytes and AML12 cells in a STAT3-dependent manner. STAT3 binds to the response elements on FetuB promoter to directly activate FetuB transcription. Finally, the mediating effect of Fetuin B in insulin resistance induced by leptin was confirmed according to mediation analysis in this obese population. Therefore, our study identifies leptin-STAT3 as an upstream signalling pathway that activates Fetuin B and provides new insights into the pathogenic mechanisms of obesity-related metabolic disorders.

Topics: Animals; Fatty Liver; Fetuin-B; Humans; Insulin Resistance; Leptin; Mice; Obesity; STAT3 Transcription Factor

BDE-47 (2,2,4,4-tetrabromodiphenyl ether) is a polybrominated diphenyl ether (PBDE) congener, which has the characteristics of high biological detection rate, the highest content and strong biological toxicity, and is widely distributed in organisms. Many studies have found that BDE-47 may also be an environmental risk factor for metabolic diseases such as obesity, insulin resistance, type 2 diabetes, and hypertension. However, the way that PBDEs influence adipocyte differentiation remains unclear. The methylisobutylxanthine, dexamethasone, and insulin method was used to study the effect of BDE-47 on the differentiation of 3T3-L1 cells. The 3T3-L1 cells were exposed by different concentrations of BDE-47, and the effect of cell viability was detected at different stages. In addition, the lipid droplet aggregation of adipocytes was observed and the triglyceride (TG) levels in the cytoplasm were detected after differentiation. The relative mRNA expression levels of leptin, adiponectin, and PPARγ in cells were determined by RT-PCR, and differentially expressed genes were preliminarily screened by digital gene expression profile. Our study found that BDE-47 promoted the differentiation of 3T3-L1 cells. Restriction cubic spline analysis showed that BDE-47 bidirectionally. regulated the mRNA synthesis of TG, PPARγ, and leptin genes and the aggregation of lipid droplets. BDE-47 may induce adipocyte differentiation by activating PPARγ, resulting in the differential expression of genes related to the AMPK signaling pathway, insulin resistance, and other metabolic pathways. The highest and lowest-dose BDE-47 exposure groups had the greatest impact on adipocyte differentiation.

Topics: 3T3-L1 Cells; Animals; Cell Differentiation; Diabetes Mellitus, Type 2; Halogenated Diphenyl Ethers; Insulin Resistance; Leptin; Mice; PPAR gamma; RNA, Messenger

We investigated the effects of aerobic training on adipokine concentrations in women with polycystic ovary syndrome (PCOS).. 120 women, including 60 with PCOS and 60 without PCOS, were divided into six groups (n = 20) based on body fat percentages of 22%-27%, 28%-32%, and 33%-37%. All groups were submitted the same evaluations before and after 16 weeks of aerobic training. These included anthropometric and hemodynamic analyses, cardiopulmonary tests, and laboratory tests. Two-way analysis of variance was performed to evaluate the differences between women with and without PCOS, effect of the body fat percentage, and effect of aerobic training.. Body fat and PCOS were associated with high values of blood glucose, insulin, and testosterone. Body fat also reduced adiponectin levels and increased leptin, tumor necrosis factoralpha (TNF-α), and interleukin-6 (IL-6). In contrast, the PCOS increased only TNF-α and IL-6 levels. In the PCOS group, aerobic training reduced insulin, triglycerides, leptin, and IL-6 levels. It also promoted an increase in adiponectin and high-density lipoprotein levels. However, aerobic training did not alter TNF-α concentrations.. The body fat potentiates metabolic impairments that may be harmful to women with PCOS. Aerobic training appears to promote an important beneficial effect on the metabolic regulation of adipokines, except TNF-α.

Topics: Adipokines; Adiponectin; Adipose Tissue; Body Mass Index; Female; Humans; Insulin; Insulin Resistance; Interleukin-6; Leptin; Polycystic Ovary Syndrome; Tumor Necrosis Factor-alpha

Metabolic regulation in skeletal muscle is essential for blood glucose homeostasis. Obesity causes insulin resistance in skeletal muscle, leading to hyperglycemia and type 2 diabetes. In this study, we performed multiomic analysis of the skeletal muscle of wild-type (WT) and leptin-deficient obese (ob/ob) mice, and constructed regulatory transomic networks for metabolism after oral glucose administration. Our network revealed that metabolic regulation by glucose-responsive metabolites had a major effect on WT mice, especially carbohydrate metabolic pathways. By contrast, in ob/ob mice, much of the metabolic regulation by glucose-responsive metabolites was lost and metabolic regulation by glucose-responsive genes was largely increased, especially in carbohydrate and lipid metabolic pathways. We present some characteristic metabolic regulatory pathways found in central carbon, branched amino acids, and ketone body metabolism. Our transomic analysis will provide insights into how skeletal muscle responds to changes in blood glucose and how it fails to respond in obesity.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Glucose; Insulin Resistance; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Muscle, Skeletal; Obesity

The aim of this is study was to analyse the expression of miR-193b, miR-378, miR-Let7-d, and miR-222 in human visceral adipose tissue (VAT), as well as their association with obesity, insulin resistance (IR), and their role in the regulation of genes controlling adipose tissue homeostasis, including adipocytokines, the phosphatase and tension homologue (PTEN), and tumour protein 53 (p53).. VAT was obtained from normal-weight (NW), overweight, and obese (OW/OB) subjects with and without IR. Stem-loop RT-qPCR was used to evaluate miRNA expression levels. miRTarBase 4.0, miRWalk, and DIANA-TarBase v8 were used for prediction of validated target gene of the miRNA analysed. A qPCR was used to evaluate PTEN, p53, leptin (LEP), and adiponectin (ADIPOQ) mRNA.. miR-222 was lower in IR subjects, and miR-222 and miR-378 negatively correlated with HOMA-IR. PTEN and p53 are miR-222 direct targets according to databases. mRNA expression of PTEN and p53 was lower in OW/OB subjects with and without IR, compared to NW group and its levels positively associated with miR-222. Additionally, p53 and PTEN are positively associated with serum leptin levels. On the other hand, miR-193b and miR-378 negatively correlated with serum leptin but not with mRNA levels. Moreover, miR-Let-7d negatively correlated with serum adiponectin but not with adiponectin mRNA levels.. Lower miR-222 levels are associated with IR, and PTEN and p53 expression; the implication of these genes in adipose tissue homeostasis needs more research.

Topics: Adiponectin; Adipose Tissue; Humans; Insulin Resistance; Intra-Abdominal Fat; Leptin; MicroRNAs; Obesity; PTEN Phosphohydrolase; RNA, Messenger; Tumor Suppressor Protein p53

South-Asian immigrants to Western countries have a high prevalence of type 2 diabetes mellitus (T2DM) and increased adipose tissue insulin resistance (AT-IR), as compared to their Western counterparts. Fetuin-A is a hepatokine known to influence AT-IR.. Can plasma fetuin-A concentrations explain an ethnic difference in adipose tissue insulin resistance?. We performed a two-step euglycemic-hyperinsulinaemic clamp and measured plasma concentrations of fetuin-A and non-esterified fatty acids (NEFA), in 18 Pakistani and 21 Norwegians with T2DM (age 29-45y) in Norway. AT-IR was calculated as NEFA-suppression during the clamp. The adipokines/cytokines leptin, adiponectin, visfatin, PTX3, IL-1β, INF-γ, and IL-4 were measured in fasting plasma. Liver fat was estimated by CT-scans.. Despite a lower BMI, Pakistani patients displayed higher AT-IR than Norwegians. NEFA-suppression during clamp was lower in Pakistani than Norwegians (mean=-20.6%, 95%CI=[-40.8, -0.01] and p = 0.046). Plasma fetuin-A concentration was higher in Pakistani than Norwegians (43.4 ng/mL[12.7,74.0], p = 0.007) and correlated negatively to %NEFA-suppression during clamp (rho=-0.39, p = 0.039). Plasma fetuin-A concentration explained 22% of the ethnic difference in NEFA-suppression during the clamp. Pakistani patients exhibited higher plasma leptin and lower PTX3 levels than Norwegian, and plasma visfatin correlated positively to plasma fetuin-A levels in the Pakistani patients. We observed no correlation between plasma fetuin-A and liver fat, but fetuin-A correlated negatively with plasma IL-1β, INF-γ, and IL-4 concentrations. Plasma IL-4 concentration was lower in Pakistani than in Norwegian patients.. Fetuin-A may contribute to explain the discrepancy in T2DM prevalence between Pakistani and Norwegians patients by influencing AT-IR.

Topics: Adipose Tissue; Adult; alpha-2-HS-Glycoprotein; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Humans; Insulin Resistance; Interleukin-4; Leptin; Middle Aged; Nicotinamide Phosphoribosyltransferase; Norway; Pakistan

Antipsychotic-induced metabolic syndrome (APs-induced Mets) is the most common adverse drug reaction, which affects more than 60% of the psychiatric patients. Although the etiology of APs-induced Mets has been extensively investigated, there is a lack of integrated analysis of the genetic and epigenetic factors. In this study, we performed genome-wide, whole-exome sequencing (WES) and epigenome-wide association studies in schizophrenia (SCZ) patients with or without APs-induced Mets to find the underlying mechanisms, followed by in vitro and in vivo functional validations. By population-based omics analysis, we revealed that rare functional variants across in the leptin and peroxisome proliferator-activated receptors (PPARs) gene sets were imbalanced with rare functional variants across the APs-induced Mets and Non-Mets cohort. Besides, we discovered that APs-induced Mets are hypermethylated in ABCG1 (chr21:43642166-43642366, adjusted P < 0.05) than Non-Mets, and hypermethylation of this area was associated with higher TC (total cholesterol) and TG (triglycerides) levels in HepG2 cells. Candidate genes from omics studies were furtherly screened in C. elegans and 17 gene have been verified to associated with olanzapine (OLA) induced fat deposit. Among them, several genes were expressed differentially in Mets cohort and APs-induced in vitro/in vivo models compared to controls, demonstrating the validity of omics study. Overexpression one of the most significant gene, PTPN11, exhibited compromised glucose responses and insulin resistance. Pharmacologic inhibition of PTPN11 protected HepG2 cell from APs-induced insulin resistance. These findings provide important insights into our understanding of the mechanism of the APs-induced Mets.

Topics: Animals; Antipsychotic Agents; ATP Binding Cassette Transporter, Subfamily G, Member 1; Caenorhabditis elegans; Humans; Insulin Resistance; Leptin; Metabolic Syndrome; Multiomics; Peroxisome Proliferator-Activated Receptors

Material and methods: a retrospective study of childhood acute leukemia survivors. Survivors with a diagnosis of leukemia before 16 years of age in a tertiary hospital, during the period of 1998-2018, were selected, who had completed their treatment at least two years earlier. We examined: blood adipokine levels and carbohydrate metabolism, body composition by bioimpedance, and carotid status by ultrasound. Somatometric measures were also taken. Results: the registry showed 82 children diagnosed with acute leukemia, aged between 6 and 16 years. Only 22 met the criteria to be included in the study. Results reveled that 32 % of the sample met the criteria for overweight-obesity, and 36 % had high insulin resistance indexes (IR). Leptin levels were higher in women (15.45 vs. 3.25; p = 0.044) and in obese and overweight subjects, as was the leptin/adiponectin ratio, which rises in the presence of IR (2.52 vs. 0.45; p = 0.037). We observed an increase in carotid intima-media thickness in relation to BMI (0.008; CI, -0.002 to 0.013; p = 0.007) without any association with an increase in fat mass in these patients (0.204; CI, -0.043 to 0.451; p = 0.101). Conclusions: childhood leukemia survivors have a high cardiovascular risk, characterized by an increase in IR, not associated with an increase in fat mass. This risk could justify the implementation of preventive actions in these long-lived patients.. Material y métodos: estudio retrospectivo de supervivientes de leucemia aguda en edad infantil. Se seleccionaron aquellos supervivientes con diagnóstico de leucemia antes de los 16 años de edad, en un hospital de tercer nivel y durante el período 1998-2018, que hubieran finalizado su tratamiento como mínimo dos años antes. Se analizaron: niveles de adipokinas y metabolismo hidrocarbonado en sangre, composición corporal mediante bioimpedancia y evaluación ecográfica carotídea. Se tomaron además datos somatométricos. Resultados: de 82 niños con diagnóstico de leucemia aguda, con edades comprendidas entre 6 y 16 años, incluidos en el registro, solamente 22 cumplieron los criterios para ser incluídos en el estudio. Entre los resultados destaca que el 32 % de la muestra cumplían los criterios de sobrepeso-obesidad y el 36 % presentaban índices de resistencia insulínica (RI) elevados. Los niveles de leptina fueron más elevados en las mujeres (15,45 vs. 3,25; p = 0,044) y en los individuos con obesidad o sobrepeso, así como la ratio leptina/adiponectina, que se eleva en presencia de RI (2,52 vs. 0,45; p = 0,037). Se observó un incremento del grosor mediointimal carotídeo en relación con el IMC (0,008; IC: -0,002 a 0,013; p = 0,007) sin asociarse a un aumento de masa grasa en estos pacientes (0,204; IC: -0,043 a 0,451; p = 0,101). Conclusiones: los pacientes supervivientes de leucemia en la edad infantil tienen un riesgo cardiovascular elevado, caracterizado por un aumento de la RI no asociado a aumento de la masa grasa. Este riesgo podría justificar la implementación de medidas preventivas en estos pacientes, cada vez más longevos.

Topics: Adipokines; Adiponectin; Adolescent; Cardiovascular Diseases; Carotid Intima-Media Thickness; Child; Cross-Sectional Studies; Female; Heart Disease Risk Factors; Humans; Insulin Resistance; Leptin; Leukemia; Male; Obesity; Overweight; Retrospective Studies; Risk Factors; Survivors

Short-term post-weaning nutrition can result in long-lasting effects in later life. Partial replacement of glucose by galactose in the post-weaning diet showed direct effects on liver inflammation. Here, we examined this program on body weight, body composition, and insulin sensitivity at the adult age. Three-week-old female C57BL/6JRccHsd mice were fed a diet with glucose plus galactose (GAL; 16 energy% (en%) each) or a control diet with glucose (GLU; 32 en%) for three weeks, and afterward, both groups were given the same high-fat diet (HFD). After five weeks on a HFD, an oral glucose tolerance test was performed. After nine weeks on a HFD, energy metabolism was assessed by indirect calorimetry, and fasted mice were sacrificed fifteen minutes after a glucose bolus, followed by serum and tissue analyses. Body weight and body composition were not different between the post-weaning dietary groups, during the post-weaning period, or the HFD period. Glucose tolerance and energy metabolism in adulthood were not affected by the post-weaning diet. Serum adiponectin concentrations were significantly higher (

Topics: Adiponectin; Animals; Body Weight; Diet, High-Fat; Female; Galactose; Glucose; Inflammation; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Mice; Mice, Inbred C57BL; Muscle, Skeletal; RNA, Messenger; Weaning

C1q/tumor necrosis factor-related protein 1 (CTRP1) is an adipokine secreted by adipose tissue, related to chondrocyte proliferation, inflammation, and glucose homeostasis. However, the therapeutic effects on metabolic disorders and the underlying mechanism were unclear. Here, we investigated the functions and mechanisms of CTRP1 in treating obesity and diabetes.. The plasmid containing human CTRP1 was delivered to mice by hydrodynamic injection, which sustained expression of CTRP1 in the liver and high protein level in the blood. High-fat diet (HFD) fed mice and STZ-induced diabetes model were used to study the effects of CTRP1 on obesity, glucose homeostasis, insulin resistance, and hepatic lipid accumulation. The lipid accumulation in liver and adipose tissue, glucose tolerance, insulin sensitivity, food intake, and energy expenditure were detected by H&E staining, Oil-Red O staining, glucose tolerance test, insulin tolerance test, and metabolic cage, respectively. The metabolic-related genes and signal pathways were determined using qPCR and western blotting.. With high blood circulation, CTRP1 prevented obesity, hyperglycemia, insulin resistance, and fatty liver in HFD-fed mice. CTRP1 also improved glucose metabolism and insulin resistance in obese and STZ-induced diabetic mice. The metabolic cage study revealed that CTRP1 reduced food intake and enhanced energy expenditure. The mechanistic study demonstrated that CTRP1 upregulated the protein level of leptin in blood, thermogenic gene expression in brown adipose tissue, and the gene expression responsible for lipolysis and glycolysis in white adipose tissue (WAT). CTRP1 also downregulated the expression of inflammatory genes in WAT. Overexpression of CTRP1 activated AMPK and PI3K/Akt signaling pathways and inhibited ERK signaling pathway.. These results demonstrate that CTRP1 could improve glucose homeostasis and prevent HFD-induced obesity and fatty liver through upregulating the energy expenditure and reducing food intake, suggesting CTRP1 may serve as a promising target for treating metabolic diseases.

Topics: Adipokines; Adipose Tissue, Brown; AMP-Activated Protein Kinases; Animals; Complement C1q; Diabetes Mellitus, Experimental; Diet, High-Fat; Fatty Liver; Glucose; Homeostasis; Humans; Insulin Resistance; Insulins; Leptin; Lipids; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Phosphatidylinositol 3-Kinases; Proteins; Proto-Oncogene Proteins c-akt; Tumor Necrosis Factors

Obesity is associated with metabolic syndrome (MBS), a cluster of components including central obesity, insulin resistance (IR), dyslipidemia, and hypertension. IR is the major risk factor in the development and progression of type 2 diabetes mellitus in obesity and MBS. Predicting preoperatively whether a patient with obesity would have improved or non-improved IR after bariatric surgery would improve treatment decisions.. A prospective cohort study was conducted between August 2019 and September 2021. We identified pre- and postoperative metabolic biomarkers in patients who underwent laparoscopic sleeve gastrectomy. Patients were divided into two groups: group A (IR < 2.5), with improved IR, and group B (IR ≥ 2.5), with non-improved IR. A prediction model and receiver operating characteristics (ROC) were used to determine the effect of metabolic biomarkers on IR.. Seventy patients with obesity and MBS were enrolled. At 12-month postoperative a significant improvement in lipid profile, fasting blood glucose, and hormonal biomarkers and a significant reduction in the BMI in all patients (p = 0.008) were visible. HOMA-IR significantly decreased in 57.14% of the patients postoperatively. Significant effects on the change in HOMA-IR ≥ 2.5 were the variables; preoperative BMI, leptin, ghrelin, leptin/ghrelin ratio (LGr), insulin, and triglyceride with an OR of 1.6,1.82, 1.33, 1.69, 1.77, and 1.82, respectively (p = 0.009 towards p = 0.041). Leptin had the best predictive cutoff value on ROC (86% sensitivity and 92% specificity), whereas ghrelin had the lowest (70% sensitivity and 73% specificity).. Preoperative BMI, leptin, ghrelin, LGr, and increased triglycerides have a predictive value on higher postoperative, non-improved patients with HOMA-IR (≥ 2.5). Therefore, assessing metabolic biomarkers can help decide on treatment/extra therapy and outcome before surgery.

Topics: Biomarkers; Diabetes Mellitus, Type 2; Gastrectomy; Ghrelin; Humans; Insulin; Insulin Resistance; Leptin; Obesity; Obesity, Morbid; Prospective Studies

This study aimed to (1) characterize the variations in serum fructosamine across trimesters and according to pre-pregnancy BMI (ppBMI), and (2) examine associations between fructosamine and adiposity/metabolic markers (ppBMI, first-trimester adiposity, leptin, glucose homeostasis, and inflammation measurements) during pregnancy. Serum fructosamine, albumin, fasting glucose and insulin, leptin, adiponectin, interleukin-6 (IL-6), and C-reactive protein (CRP) concentrations were measured at each trimester. In the first trimester, subcutaneous (SAT) and visceral (VAT) adipose tissue thicknesses were estimated by ultrasound. In the 101 healthy pregnant individuals included (age: 32.2 ± 3.5 y.o.; ppBMI: 25.5 ± 5.5 kg/m2), fructosamine concentrations decreased during pregnancy whereas albumin-corrected fructosamine concentrations increased (p < 0.0001 for both). Notably, fructosamine concentrations were inversely associated with ppBMI, first-trimester SAT, VAT, and leptin (r = −0.55, r = −0.61, r = −0.48, r = −0.47, respectively; p < 0.0001 for all), first-trimester fasting insulin and HOMA-IR (r = −0.46, r = −0.46; p < 0.0001 for both), and first-trimester IL-6 (r = −0.38, p < 0.01). However, once corrected for albumin, most of the correlations lost strength. Once adjusted for ppBMI, fructosamine concentrations were positively associated with third-trimester fasting glucose and CRP (r = 0.24, r = 0.27; p < 0.05 for both). In conclusion, serum fructosamine is inversely associated with adiposity before and during pregnancy, with markers of glucose homeostasis and inflammation, but the latter associations are partially influenced by albumin concentrations and ppBMI.

Topics: Adiponectin; Adiposity; Adult; Blood Glucose; C-Reactive Protein; Female; Fructosamine; Humans; Inflammation; Insulin; Insulin Resistance; Interleukin-6; Leptin; Obesity; Obesity, Abdominal; Pregnancy

Secretion of insulin is compromised in type 2 diabetes (T2DM) individuals and inadequate to accommodate for insulin resistance (IR) in peripheral tissue. Hyperleptinemia reflects leptin resistance, which is a key factor in the production of IR in T2DM patients, making leptin a potential biomarker for evaluating IR levels. The objective of the study was to assess the association of serum leptin and insulin levels among T2DM patients. This case-control research was carried out on T2DM patients. A total of 73 patients diagnosed with T2DM (the case group) and 40 healthy participants (control; group 3) were enrolled according to the American Diabetes Association (ADA) criteria. In the case group, T2DM patients were enrolled with metabolic syndrome (group 1, n = 38) or without metabolic syndrome (group 2, n = 35) according to the WHO criteria. Metabolic profiles of T2DM patients with or without metabolic syndrome were evaluated, and compare these two groups with healthy controls. The subjects of all groups were age- and gender-matched. Body mass index (BMI, P < .01), fasting (P = .0133) and postprandial (P < .01) blood sugar levels, % glycated hemoglobin (HbA1c, P < .01), and lipid profile (P < .01) were found significantly different and higher in group 1 as compared to groups 2 and 3. Serum leptin and insulin levels were found higher and significant in patients with metabolic syndrome (P < .01 for both). The values of serum leptin levels were 10.01 ± 2.7 ng/mL, 6.9 ± 2.4 ng/mL, and 4.11 ± 1.8 ng/mL, and those of serum insulin 120 ± 40.7 µIU/mL, 20.43 ± 5.2 µIU/mL, and 11.4 ± 2.5 µIU/mL in groups 1, 2, and 3, respectively. There was a positive linear correlation between BMI, blood sugar, HbA1c, serum cholesterol (TC), and triglycerides (TG) with serum insulin and leptin levels in the case group. An extremely significant correlation (R = 0.74, P < .001) was found in BMI and serum leptin level in the case group. Serum leptin and insulin levels have a positive association, with serum leptin being a significant predictor of IR syndrome (Evidence Level: 5; Technical Efficacy: Stage 3).

Topics: Blood Glucose; Body Mass Index; Case-Control Studies; Cholesterol; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Insulin; Insulin Resistance; Leptin; Metabolic Syndrome; Triglycerides

Metabolic Associated Fatty Liver Disease (MAFLD) encompasses a spectrum of diseases from simple steatosis to nonalcoholic steatohepatitis (NASH). Here, we investigated the hepatoprotective role of. Male C57BL/6J mice were fed with a high fat diet (HFD, 60% lipids, 42 gr/L sugar in water) for 16 weeks. Moringa extract was administered via gavage during the final 8 weeks. Insulin Tolerance Test (ITT) and HOMA-IR were calculated. Serum levels of insulin, resistin, leptin and PAI-1 and hepatic expression of. Animals treated with Moringa extract improved ITT and decreased SREBP1c hepatic protein, while SIRT1 increased. Hepatic expression of. Moringa prevented progression of liver damage in a model of NASH and improved biochemical, histological and hepatic expression of genes and miRNAs implicated in MAFLD/NASH development.

Topics: Animals; Diet, High-Fat; Epigenesis, Genetic; Insulin; Insulin Resistance; Leptin; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; MicroRNAs; Moringa oleifera; Non-alcoholic Fatty Liver Disease; Plant Extracts; Plasminogen Activator Inhibitor 1; Resistin; Sirtuin 1; Sterol Regulatory Element Binding Protein 1

The aim of this study was to assess the nutritional status and serum concentrations of adipokines in children with irritable bowel syndrome (IBS) and healthy controls. We also sought to evaluate their relation to metabolic parameters.. We studied 33 IBS patients (11 girls, 22 boys) aged 5-17 years and 30 healthy age-matched controls (11 girls, 19 boys). The analysis included anthropometric measurements, body composition parameter measurements using bioimpedance, and biochemical tests and measurements of serum concentrations of leptin, adiponectin, chemerin, and omentin-1.. The results of the anthropometric measurements were comparable between the patients and the controls. The patients had higher triglycerides, HOMA-IRs, and chemerin concentrations than the healthy subjects. The HDL cholesterol and omentin-1 levels were lower than in the controls. Leptin and adiponectin did not differ significantly between the groups. An analysis of the receiver operator curves (ROCs) showed that serum concentrations of chemerin ≥ 232.8 ng/mL had 30% sensitivity and 87% specificity when they were used to differentiate between children with IBS and healthy subjects. In the case of serum omentin-1 concentrations ≤ 279.4 ng/mL, the sensitivity and specificity were 60% and 80%, respectively.. The nutritional status of children with IBS did not differ from that of the healthy controls. We found significant differences in serum chemerin and omentin-1 concentrations between IBS patients and healthy children. These adipokines could be used as IBS biomarkers as they demonstrate good specificity and moderate sensitivity. The serum concentrations of chemerin and omentin-1 in IBS patients were related to nutritional status and insulin resistance.

Topics: Adipokines; Adiponectin; Adolescent; Chemokines; Child; Child, Preschool; Cytokines; Female; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Irritable Bowel Syndrome; Leptin; Male; Nutritional Status

Functional disorders in obesity are largely due to a decrease in tissue sensitivity to insulin and leptin. One of the ways to restore it is inhibition of protein phosphotyrosine phosphatase 1B (PTP1B) and T-cell protein phosphotyrosine phosphatase (TCPTP), negative regulators of the insulin and leptin signaling. Despite progress in the development of inhibitors of these phosphatases, commercial preparations based on them have not been developed yet, and the mechanisms of action are poorly understood. The aim of the work was to study the effect of new derivatives of 4-oxo-1,4-dihydrocinnoline (PI04, PI06, PI07) on the activity of PTP1B and TCPTP, as well as to study the effect of their five-day administration (i.p., 10 mg/kg/day) to Wistar rats with diet-induced obesity on body weight and fat, metabolic and hormonal parameters, and gene expression of phosphatase and insulin and leptin receptors in the liver. It has been shown that PI04 is a mild, low selective inhibitor of both phosphatases (PTP1B, IC50=3.42(2.60-4.51) μM; TCPTP, IC50=4.16(3.49-4.95) μM), while PI06 and PI07 preferentially inhibit PTP1B (IC50=3.55 (2.63-4.78) μM) and TCPTP (IC50=1.45(1.18-1.78) μM), respectively. PI04 significantly reduced food intake, body weight and fat, attenuated hyperglycemia, normalized glucose tolerance, basal and glucose-stimulated levels of insulin and leptin, and insulin resistance index. Despite the anorexigenic effect, PI06 and PI07 were less effective, having little effect on glucose homeostasis and insulin sensitivity. PI04 significantly increased the expression of the PTP1B and TCPTP genes and decreased the expression of the insulin and leptin receptor genes. PI06 and PI07 had little effect on these indicators. Thus, PI04, the inhibitor of PTP1B and TCPTP phosphatases, restored metabolic and hormonal parameters in obese rats with greater efficiency than inhibitors of PTP1B (PI06) and TCPTP (PI07). This indicates the prospect of creating mixed PTP1B/TCPTP inhibitors for correction of metabolic disorders.. Funktsional'nye narusheniia pri ozhirenii vo mnogom obuslovleny snizheniem chuvstvitel'nosti tkaneĭ k insulinu i leptinu. Odnim iz puteĭ ee vosstanovleniia iavliaetsia ingibirovanie proteinfosfotirozinfosfatazy 1B (PTP1B) i T-kletochnoĭ proteinfosfotirozinfosfatazy (TCPTP) — negativnykh reguliatorov insulinovogo i leptinovogo signalinga. Nesmotria na progress v razrabotke ingibitorov étikh fosfataz kommercheskie preparaty na ikh osnove ne razrabotany, a mekhanizmy deĭstviia malo izucheny. Tsel' raboty sostoiala v issledovanii vliianiia novykh proizvodnykh 4-okso-1,4-digidrotsinnolina (PI04, PI06, PI07) na aktivnost' PTP1B i TCPTP, a takzhe v izuchenii vliianiia ikh piatidnevnogo vnutribriushinnogo vvedeniia (10 mg/kg/sutki) krysam Wistar s indutsirovannym dietoĭ ozhireniem na massu tela i zhira, metabolicheskie i gormonal'nye pokazateli, ékspressiiu genov fosfataz i retseptorov insulina i leptina v pecheni. Pokazano, chto PI04 iavliaetsia miagkim nizkoselektivnym ingibitorom obeikh fosfataz (PTP1B, IC50=3,42(2,60–4,51) mkM; TCPTP, IC50=4,16(3,49–4,95) mkM), v to vremia kak PI06 i PI07 predpochtitel'no ingibiruiut PTP1B (IC50=3,55(2,63–4,78) mkM) i TCPTP (IC50=1,45(1,18–1,78) mkM) sootvetstvenno. PI04 znachimo snizhal potreblenie korma, massu tela i zhira, oslablial giperglikemiiu, normalizoval tolerantnost' k gliukoze, bazovye i stimulirovannye gliukozoĭ urovni insulina i leptina, indeks insulinovoĭ rezistentnosti. Nesmotria na anoreksigennyĭ éffekt, PI06 i PI07 byli menee éffektivnymi, slabo vliiaia na gliukoznyĭ gomeostaz i chuvstvitel'nost' k insulinu. PI04 sushchestvenno povyshal ékspressiiu genov PTP1B i TCPTP i snizhal ékspressiiu genov retseptorov insulina i leptina. PI06 i PI07 slabo vliiali na éti pokazateli. Takim obrazom, PI04 — ingibitor fosfataz PTP1B i TCPTP — s bol'sheĭ éffektivnost'iu v sravnenii s ingibitorami PTP1B (PI06) i TCPTP (PI07) vosstanavlival metabolicheskie i gormonal'nye pokazateli u krys s ozhireniem, chto ukazyvaet na perspektivnost' sozdaniia smeshannykh PTP1B/TCPTP-ingibitorov dlia korrektsii metabolicheskikh rasstroĭstv.

Topics: Animals; Enzyme Inhibitors; Glucose; Insulin; Insulin Resistance; Leptin; Obesity; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatase, Non-Receptor Type 2; Rats; Rats, Wistar; T-Lymphocytes; Tyrosine

We aimed to investigate the metabolic effects of HIIT exercise on PCOS patients and how it affects adiponectin, vaspin and leptin.. Twenty women with PCOS were included in the study and were divided into two groups. HIIT program was applied for 10 PCOS and Medium Intensity Continuous Training (MICT) program was applied for other 10 PCOS. At the beginning and at the end of the study, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), triglyceride(TG), insulin, Adiponectin, Leptin, Vaspin levels of both PCOS groups were evaluated.. When PCOS patients by performed HIIT exercise for 12 weeks, we found that the levels of leptin and vaspin did not change while adiponectin levels increased. Moreover serum levels of insulin, TG, total cholesterol, LDL-C decreased but levels of HDL-C increased.. HIIT increased in the adiponectin levels in women with PCOS and provided more weight loss.

Topics: Adiponectin; Body Mass Index; Case-Control Studies; Female; High-Intensity Interval Training; Humans; Insulin; Insulin Resistance; Leptin; Polycystic Ovary Syndrome; Serpins

Links between resistin, insulin resistance (IR), and resistin-stimulated cytokine signaling remain unknown in Mexican-Americans. A Mexican-American cohort was examined to determine (1) relationships between circulating resistin and IR, (2) resistin's associations with cytokines and demographic and anthropometric variables, and (3) similar measurements with other adipokines.. For cross sectional analyses, 953 adults (367 males and 586 females) in the Cameron County Hispanic Cohort (CCHC) were stratified into three groups: normal glucose tolerance, prediabetes, and diabetes mellitus. Differences in resistin and other adipokine levels were examined using linear regression via unadjusted model (Model 1), model adjusted for cytokines (Model 2), and model further adjusted for demographic and anthropometric variables (Model 3).. HOMA-IR increased with worsening glucose tolerance (p < 0.0001). In all models, resistin significantly decreased as glucose tolerance deteriorated. Model 3 resistin was positively associated with IL-1β (p = 0.0252) and IL-8 (p < 0.0001), inversely associated with TNF-α (p = 0.0352), but nonsignificantly associated with IL-6 (p = 0.8671). Model 3 leptin was significantly lower in diabetes mellitus compared to other groups (p < 0.005) and positively associated with female sex (p < 0.0001), age (p = 0.024), and BMI (p < 0.0001), without significant cytokine associations. Adiponectin displayed no significant associations with glucose tolerance, but was significantly associated with sex, BMI, and lipids (Model 3).. Resistin unexpectedly decreased as IR increased while supporting evidence of a resistin-stimulated cytokine pathway in this Mexican-American cohort. Leptin fell with elevated IR after adjusting for cytokines, demographic and anthropometric variables. Adiponectin nonsignificantly decreased as IR increased while showing significant associations with sex, BMI, and lipids.

Topics: Adipokines; Adult; Cohort Studies; Female; Glucose Tolerance Test; Humans; Insulin Resistance; Leptin; Linear Models; Male; Mexican Americans; Multivariate Analysis; Resistin

ER stress and activation of the unfolded protein response in the periphery as well as the central nervous system have been linked to various metabolic abnormalities. Chemically lowering protein kinase R-like ER kinase (PERK) activity within the hypothalamus leads to decreased food intake and body weight. However, the cell populations required in this response remain undefined. In the current study, we investigated the effects of proopiomelanocortin-specific (POMC-specific) PERK deficiency on energy balance and glucose metabolism. Male mice deficient for PERK in POMC neurons exhibited improvements in energy balance on a high-fat diet, showing decreased food intake and body weight, independent of changes in glucose and insulin tolerances. The plant-based inhibitor of PERK, celastrol, increases leptin sensitivity, resulting in decreased food intake and body weight in a murine model of diet-induced obesity (DIO). Our data extend these observations by demonstrating that celastrol-induced improvements in leptin sensitivity and energy balance were attenuated in mice with PERK deficiency in POMC neurons. Altogether, these data suggest that POMC-specific PERK deficiency in male mice confers protection against DIO, possibly providing a new therapeutic target for the treatment of diabetes and metabolic syndrome.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Diet, High-Fat; Eating; eIF-2 Kinase; Endoplasmic Reticulum Stress; Energy Metabolism; Glucose; Insulin Resistance; Leptin; Male; Mice; Mice, Knockout; Neurons; Obesity; Pentacyclic Triterpenes; Pro-Opiomelanocortin

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

To predict the presence of breast cancer by using a pattern recognition network with optimal features based on routine blood analysis parameters and anthropometric data.. Sensitivity, specificity, accuracy, Matthews correlation coefficient (MCC), and Fowlkes-Mallows (FM) index of each model were calculated. Glucose, insulin, age, homeostatic model assessment, leptin, body mass index (BMI), resistin, adiponectin, and monocyte chemoattractant protein-1 were used as predictors.. Pattern recognition network distinguished patients with breast cancer disease from healthy people. The best classification performance was obtained by using BMI, age, glucose, resistin, and adiponectin, and in a model with two hidden layers with 11 and 100 neurons in the neural network. The accuracy, sensitivity, specificty, FM index, and MCC values of the best model were 94.1%, 100%, 88.9%, 94.3%, and 88.9%, respectively.. Breast cancer diagnosis was succesfully predicted using only five features. A model using a pattern recognition network with optimal feature subsets proposed in this study could be used to improve the early detection of breast cancer.

Topics: Adiponectin; Body Mass Index; Breast Neoplasms; Female; Humans; Insulin; Insulin Resistance; Leptin; Resistin

To investigate the effects of an interdisciplinary intervention on biomarkers of inflammation and their relationship with fibroblast growth factor 21 (FGF21) concentrations in women with overweight and obesity.. Thirty-one women were enrolled in a 12-week interdisciplinary weight loss program delivered by a team comprising an endocrinologist, nutritionist and exercise physiologist. Body composition; anthropometric measures; metabolic and inflammatory markers including adiponectin, leptin, and atrial natriuretic peptide (ANP) were assessed at baseline and post-therapy. The homeostasis model assessment of insulin resistance (HOMA-IR) and the homeostasis model assessment of adiponectin (HOMA-AD) were calculated. The participants were divided into two groups: those with increased FGF21, and those with decreased FGF21.. Changes in FGF21 concentrations were different among the women participating in the weight loss program, with some having increased levels and some reduced levels. Furthermore, improvements in adiponectin and the adiponectin/leptin ratio were found only in the group with increased FGF21 concentration.

Topics: Adiponectin; Adult; Biomarkers; Body Mass Index; Female; Fibroblast Growth Factors; Humans; Insulin Resistance; Leptin; Obesity; Overweight; Weight Reduction Programs

Dietary intervention is a common tactic employed to curtail the current obesity epidemic. Changes in nutritional status alter metabolic hormones such as insulin or leptin, as well as the insulin-like growth factor (IGF) system, but little is known about restoration of these parameters after weight loss in obese subjects and if this differs between the sexes, especially regarding the IGF system. Here male and female mice received a high fat diet (HFD) or chow for 8 weeks, then half of the HFD mice were changed to chow (HFDCH) for 4 weeks. Both sexes gained weight (p < 0.001) and increased their energy intake (p < 0.001) and basal glycemia (p < 0.5) on the HFD, with these parameters normalizing after switching to chow but at different rates in males and females. In both sexes HFD decreased hypothalamic NPY and AgRP (p < 0.001) and increased POMC (p < 0.001) mRNA levels, with all normalizing in HFDCH mice, whereas the HFD-induced decrease in ObR did not normalize (p < 0.05). All HFD mice had abnormal glucose tolerance tests (p < 0.001), with males clearly more affected, that normalized when returned to chow. HFD increased insulin levels and HOMA index (p < 0.01) in both sexes, but only HFDCH males normalized this parameter. Returning to chow normalized the HFD-induced increase in circulating leptin (p < 0.001), total IGF1 (p < 0.001), IGF2 (p < 0.001, only in females) and IGFBP3 (p < 0.001), whereas free IGF1 levels remained elevated (p < 0.01). In males IGFBP2 decreased with HFD and normalized with chow (p < 0.001), with no changes in females. Although returning to a healthy diet improved of most metabolic parameters analyzed, fIGF1 levels remained elevated and hypothalamic ObR decreased in both sexes. Moreover, there was sex differences in both the response to HFD and the switch to chow including circulating levels of IGF2 and IGFBP2, factors previously reported to be involved in glucose metabolism. Indeed, glucose metabolism was also differentially modified in males and females, suggesting that these observations could be related.

Topics: Animals; Blood Glucose; Diet, High-Fat; Energy Intake; Female; Hypothalamus; Insulin Resistance; Insulin-Like Growth Factor Binding Protein 2; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Sex Characteristics; Weight Loss

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

Recently, inflammation have been proposed as one of the mechanisms underlying the patology of drug-resistant epilepsy (DRE). Ketogenic diet (KD) is one of the therapeutic methods used in DRE. There are some data that adipokines may modulate inflammatory processes and their concentrations are influenced by KD. Therefore, the aim of this study was to evaluate the influence of KD on serum leptin, chemerin and resistin in children with DRE.. A cross-sectional observational study performed on 72 subjects aged 3-9 years, divided into 3 groups: 24 children with DRE treated with KD, 26 treated with valproic acid (VPA), and a control group of 22 children.. Anthropometric measurements (weight, heigth, BMI, waist to hip circumerences ratio) were performed in all participants. Biochemical tests included serum fasting glucose, insulin, beta-hydroxybutyric acid, lipid profile, alanine aminotransferase and aspartate aminotransferase activities and blood gasometry. Serum levels of leptin, chemerin and resistin were assayed using commercially available ELISA tests.. Serum levels of leptin and chemerin in the KD group were significantly lower and resistin - higher in comparison to patients receiving VPA and the control group. In children treated with the KD, leptin concentrations correlate with insulin levels and HOMA-IR scores. Chemerin levels in this group, in contrast, show negative correlation with body mass and height expressed as standard deviation scores from the mean for age and sex.. Modification of pro-inflammatory adipocytokine levels is potentially one of the mechanisms of anticonvulsant effects of KD in children with refractory epilepsy.

Topics: Adipokines; Adiponectin; Body Mass Index; Child; Cross-Sectional Studies; Diet, Ketogenic; Drug Resistant Epilepsy; Epilepsy; Humans; Insulin; Insulin Resistance; Leptin; Resistin

Sitting time (ST) is a serious global health issue and positively associated with cardiometabolic disease. The present study investigated associations between objectively measured ST, sedentary patterns, and cardiometabolic biomarkers in physically active young males.. Cross-sectional analysis was completed in 94 males 18-35 yr of age. Total ST, prolonged sedentary bouts (≥30 min with no interruption), and sedentary breaks (transitions from sitting/lying to standing/stepping) were assessed using activPAL. Lipids, insulin, C-peptide, C-reactive protein (CRP), vascular cellular adhesion molecule-1, intercellular adhesion molecule 1, E-selectin, P-selectin, leptin, resistin, and adiponectin were measured using assay kits. The expression of specific proteins related to endothelial dysfunction was determined using quantitative real-time polymerase chain reaction. Associations between total ST, prolonged sedentary bouts, and sedentary breaks with cardiometabolic biomarkers and total ST and levels of gene expression were assessed using generalized linear models.. Total ST was significantly associated with triglycerides (B = 1.814), insulin (B = 2.117), homeostasis model assessment of insulin resistance (B = 0.071), and E-selectin (B = 2.052). Leptin (B = 0.086), E-selectin (B = 1.623), and P-selectin (B = 2.519) were significantly associated with prolonged sedentary bouts, whereas leptin (B = -0.017) and CRP (B = -0.016) were associated with sedentary breaks. After adjustment for moderate to vigorous physical activity, the associations between triglycerides (B = 2.048) and total ST, and between CRP (B = -0.016) and sedentary breaks, remained significant. E-selectin mRNA levels (B = 0.0002) were positively associated with ST with or without adjustment for moderate to vigorous physical activity.. Total ST and prolonged sedentary bouts were positively associated with several cardiometabolic biomarkers, with interruptions in ST potentially contributing to reduced cardiometabolic risk in physically active young male adults.

Topics: Adiponectin; Adult; Biomarkers; C-Peptide; C-Reactive Protein; Cross-Sectional Studies; E-Selectin; Exercise; Humans; Insulin; Insulin Resistance; Leptin; Lipids; Male; P-Selectin; Resistin; Sedentary Behavior; Sitting Position; Standing Position; Time Factors; Vascular Cell Adhesion Molecule-1; Young Adult

Polyphenolic biologically active substances (BAS) including resveratrol (R) can exert beneficial effects on fat accumulation, blood pressure, glycemia, insulin sensitivity, and plasma lipid profile in patients with obesity, and associated diseases. The study aimed to determine the effect of R at a dose of 25 mg/kg body weight on the DBA/2J and DBCB mice with diet-induced obesity followed by the consumption high-fat high-carbohydrate diet (HFCD). Behavioral reactions (elevated plus maze [EPM]) and muscle tone (the strength of the forepaw grip) were tested, and plasma biochemical and immunological parameters were assessed. In the repeated EPM test, anxiety increased only in DBCB mice during the second trial. In DBCB mice treated with HFCD, the muscle tone decreased with the second trial; however, this effect was not observed in the background of R consumption. R decreased the level of triglycerides, diminished the activities of alanine and asparagine aminotransferases, which were elevated upon HFCD consumption. Ghrelin level increased after R consumption in mice of both genotypes. The leptin to ghrelin ratio was reduced in DBCB mice receiving R. Consumption of R increased IL-3 and IL-10 levels in both DBA/2J and DBCB mice. IL-12p70 level increased in DBCB mice in response to R. R addition to HFCD reduced several symptoms of dyslipidemia in highly sensitive tetrahybrid mice. The results obtained indicate the importance of a personalized (depending on the genotype) approach when any R prescription, among other BAS and dietary factors, are used in diet therapy for patients with low, moderate and high-risk obesity.

Topics: Animals; Antioxidants; Behavior, Animal; Diet, High-Fat; Dietary Carbohydrates; Dietary Fats; Elevated Plus Maze Test; Fructose; Ghrelin; Inflammation; Insulin Resistance; Interleukin-10; Interleukin-3; Leptin; Male; Mice; Mice, Inbred DBA; Obesity; Resveratrol; Triglycerides

Alopecia areata (AA) is considered an organ-specific autoimmune disease of hair follicles. Adipose tissue plays a role in lipid metabolism and glucose metabolism and secretes adipokines such as leptin and adiponectin. Dysregulation in the adipokine balance may be associated with metabolic syndrome. We aimed to determine serum adipokine levels in AA patients and compare them with healthy controls, and to determine whether there was metabolic syndrome and insulin resistance in the AA patients.. A total of 70 participants were included in the study. Patients were divided into two subgroups: patients with scalp hair loss were in subgroup 1 (AA1). Patients with beard and eyebrow hair loss were in subgroup 2 (AA2). Serum adiponectin, leptin, TNF-α, insulin, fasting glucose, TG, and HDL were analyzed.. Thirty-six (25 male, 11 female) patients with AA and 34 (18 male, 16 female) healthy subjects were included in the study. Metabolic syndrome was detected in three of the AA patients and in two of the healthy subjects. Serum leptin, adiponectin, TNF-α, TG, HDL, and insulin levels and HOMA-IR scores were not statistically significant in patients compared with control subjects, except fasting glucose levels (p = 0.035). However, serum leptin and adiponectin levels were significantly higher in AA1 (n = 25) subgroup compared with the control group (p = 0.029, p = 0.026 respectively). There was a statistically significant increase in the fasting glucose level, while there were no differences in other parameters between the AA2 (n = 11) subgroup and the control group.. To our knowledge, this is the first report indicating that adiponectin and leptin probably has a role in the pathogenesis of AA with scalp hair involvement.

Topics: Adiponectin; Alopecia Areata; Body Mass Index; Case-Control Studies; Female; Humans; Insulin Resistance; Leptin; Male; Scalp

Insulin resistance (IR) and lipotoxicity were evidenced as the major nonalcoholic steatohepatitis (NASH) initiators. However, absence of the effective treatment against NASH progression raised our aim to discover a new promising insulin modulator and NSH preventer.. Our study aimed to extract and prepare a nitriles rich fraction (NRF) from Diceratella elliptica (DC.) Jonsell, investigate its insulin-sensitizing & anti-NASH potentialities and address its molecular targets in IR-NASH pathogenesis.. NRF was prepared using natural autolysis method and compounds were identified. Then, seventy male Wistar rats were feed high fat diet (HFD) or normal pellets for 35 days. In day 14th, HFD rats were injected by Streptozotocin (STZ) once and treatment was started in day 21st with either NRF (30, 60 and 120 mg/kg; orally) or pioglitazone (PioG) (10 mg/kg; i.p) beside HFD. While, NRF-alone rats were treated with NRF (120 mg/kg; orally) beside the normal pellets. Body weight, glucose homeostasis, hepatopathological examinations were performed.. Gas liquid chromatography-mass spectrophotometry (GLC/MS) was used for compounds' identification while spectrophotometer was used for total glucosinolates (GLS) quantification. Also, the biochemical and molecular investigations concerned with liver lipotoxicity, oxidative stress, inflammation and insulin signaling pathway were investigated and confirmed with the computational prediction of the major compounds' targets.. Butenyl and benzyl GLS were the major along with other volatile compounds. NRF had significantly increased the insulin sensitivity and improved NASH-hisptopathology showing hepatoprotective effect. While, the fraction's anti-NASH potentiality was evidenced in the normalized hepatic steatosis markers, inflammation and oxidative stress key transcriptional factors resulting in induction of insulin receptor substrates (IRSs) phosphorylation and its downstream effectors.. NRF has reversed IR, stimulated leptin secretion and prevented NASH initiation showing promising anti-NASH and anti-fibrotic effects.

Topics: Animals; Brassicaceae; Diet, High-Fat; Glucosinolates; Insulin Resistance; Leptin; Liver; Male; NF-E2-Related Factor 2; NF-kappa B; Nitriles; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Pioglitazone; Plant Extracts; Rats, Wistar; Signal Transduction

Central kisspeptin action is well known in reproductive regulation; however, its peripheral action is not well understood. This study aimed to 1) compare serum or cerebrospinal fluid (CSF) kisspeptin levels between different body mass index (BMI) groups 2) compare the levels of kisspeptin between serum and CSF, and 3) determine correlations between serum or CSF kisspeptin levels with clinical, metabolic, and reproductive parameters. There were 40 male subjects undergoing operations with lumbar puncture anesthesia. Subgroup analysis was performed to compare between the normal (n = 12), overweight (n = 10), and obese groups (n = 17). One lean subject was recruited for correlation analysis. Serum kisspeptin levels were significantly higher in the obese group when compared to the normal weight and overweight groups even after adjusting for age or diastolic blood pressure (DBP) (p < 0.05 all). Serum leptin levels were significantly higher in the obese group when compared to the normal weight and overweight groups (p < 0.05 all). CSF kisspeptin levels were below the minimum detectable concentration for the assay (<0.06 ng/mL). Serum kisspeptin was positively correlated with body weight, BMI, plasma insulin, the homeostatic model assessment for insulin resistance (HOMA-IR), and serum leptin but was negatively correlated with plasma LH (p < 0.05 all). In conclusion, serum kisspeptin was related to obesity, leptin, insulin, and insulin resistance, while CSF kisspeptin was below the limits of detection. Thus, peripheral kisspeptin might have a role in metabolic regulation.

Topics: Adult; Anesthesia; Body Mass Index; Body Weight; Female; Humans; Insulin Resistance; Kisspeptins; Leptin; Male; Obesity; Overweight; Reproduction; Spinal Puncture

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

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

Leptin, adiponectin, secreted frizzled-related protein 5 (Sfrp5) and wingless-type family member 5a (Wnt5a) are novel adipokines that are involved in insulin sensitivity and atherosclerosis. The aim of the present study was to investigate the serum and periarterial adipose tissue leptin/adiponectin and Sfrp5/Wnt5a levels in patients with peripheral arterial occlusive disease (PAOD).. A total of 75 patients with PAOD and 39 control subjects were recruited. The serum concentrations of leptin, adiponectin, Sfrp5 and Wnt5a were measured by ELISAs, and the leptin, adiponectin, Sfrp5 and Wnt5a levels in the periarterial adipose tissue were observed by western blotting.. The serum Sfrp5 levels were significantly lower in the patients with PAOD than in the control subjects (p < 0.001) and Wnt5a levels were higher in the patients with PAOD (p < 0.001). The serum leptin levels were significantly higher in the patients with PAOD than in the control subjects (p < 0.001), and adiponectin levels were significantly lower in the patients with PAOD (p < 0.001). The serum Sfrp5 levels were associated with ABI (rs = 0.274; p = 0.018), Wnt5a (rs = -0.409; p < 0.001), adiponectin (rs = 0.244; p = 0.035) and Leptin/Adiponetin ratio (rs = -0.244; p = 0.037). The adiponectin and Sfrp5 protein levels were decreased in the periarterial adipose tissue of patients with PAOD compared with control subjects. The leptin and Wnt5a protein levels were increased in the periarterial adipose tissue of patients with PAOD compared with control subjects.. We demonstrated that the adiponectin and Sfrp5 levels in the serum and periarterial adipose tissue were significantly lower in the patients with PAOD than in the control subjects. The leptin and Wnt5a levels in the serum and periarterial adipose tissue were significantly higher in the patients with PAOD than in the control subjects.

Topics: Adaptor Proteins, Signal Transducing; Adiponectin; Adipose Tissue; Aged; Arterial Occlusive Diseases; Biomarkers; Body Mass Index; Case-Control Studies; Female; Humans; Insulin Resistance; Leptin; Male; Peripheral Arterial Disease; Wnt-5a Protein

Mice lacking SH2B1 and humans with variants of SH2B1 display severe obesity and insulin resistance. SH2B1 is an adapter protein that is recruited to the receptors of multiple hormones and neurotrophic factors. Of the four known alternatively spliced SH2B1 isoforms, SH2B1β and SH2B1γ exhibit ubiquitous expression, whereas SH2B1α and SH2B1δ are essentially restricted to the brain. To understand the roles for SH2B1α and SH2B1δ in energy balance and glucose metabolism, we generated mice lacking these brain-specific isoforms (αδ knockout [αδKO] mice). αδKO mice exhibit decreased food intake, protection from weight gain on standard and high-fat diets, and an adiposity-dependent improvement in glucose homeostasis. SH2B1 has been suggested to impact energy balance via the modulation of leptin action. However, αδKO mice exhibit leptin sensitivity that is similar to that of wild-type mice by multiple measures. Thus, decreasing the abundance of SH2B1α and/or SH2B1δ relative to the other SH2B1 isoforms likely shifts energy balance toward a lean phenotype via a primarily leptin-independent mechanism. Our findings suggest that the different alternatively spliced isoforms of SH2B1 perform different functions in vivo.

Topics: Adaptor Proteins, Signal Transducing; Animals; Brain; Energy Metabolism; Insulin Resistance; Leptin; Mice; Mice, Knockout; Obesity; Protein Isoforms

Fat mass distribution, especially in the abdominal visceral region, has been rarely evaluated in patients with PsA or psoriasis (PsO).. Patients with PsA and patients with PsO alone were evaluated and compared with control subjects (1:1 ratio in each patient group) matched for age, sex and BMI category. Body composition and fat distribution (android and visceral fat) were evaluated by DXA. Anthropometric measurements, disease activity and the systematic coronary risk evaluation (SCORE) cardiovascular risk were assessed. Metabolic parameters (insulin, homeostasis model assessment for insulin resistance), serum adipokines [total and high-molecular-weight adiponectin, leptin, resistin and retinol-binding protein-4 (RBP4)] were measured.. Data for 52 patients with PsA and 52 patients with PsO and their respective paired controls were analysed. Android fat and visceral fat were found to be significantly higher in patients with PsO compared with their controls, while these measurements did not differ between patients with PsA and their controls. By multivariate analysis, after adjusting for age, sex and BMI, visceral fat was higher in PsO patients compared with PsA patients (P = 0.0004) and the whole group of controls (P = 0.0013). Insulin levels and HOMA-IR were increased in both PsA and PsO groups. High-molecular-weight/total adiponectin ratio was decreased in patients with PsO. RBP4 was significantly higher in both PsA and PsO patients. In patients with PsO, visceral fat strongly correlated with SCORE (r = 0.61).. Visceral fat accumulates more in PsO alone than in PsA. Visceral adiposity may be a more pressing concern in PsO relative to PsA.. The ADIPSO study (Évaluation du tissu ADIpeux et des adipokines dans le PSOriasis et le rhumatisme psoriasique et analyse de ses relations avec le risque cardiovasculaire) is a case-control study conducted in Besançon, France, and is registered on ClinicalTrials.gov under the number NCT02849795.

Topics: Adipokines; Age Factors; Arthritis, Psoriatic; Body Composition; Body Mass Index; Case-Control Studies; Female; Heart Disease Risk Factors; Humans; Insulin; Insulin Resistance; Intra-Abdominal Fat; Leptin; Male; Middle Aged; Multivariate Analysis; Obesity, Abdominal; Psoriasis; Resistin; Retinol-Binding Proteins, Plasma; Sex Factors

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

Blood glucose and insulin homeostasis is disrupted during the progression of type 2 diabetes. Insulin levels and action are regulated by both peripheral and central responses that involve the intestine and microbiome. The intestine and its microbiota process nutrients and generate molecules that influence blood glucose and insulin. Peripheral insulin regulation is regulated by gut-segment-dependent nutrient sensing and microbial factors such as short-chain fatty acids and bile acids that engage G-protein-coupled receptors. Innate immune sensing of gut-derived bacterial cell wall components and lipopolysaccharides also alter insulin homeostasis. These bacterial metabolites and postbiotics influence insulin secretion and insulin clearance in part by altering endocrine responses such as glucagon-like peptide-1. Gut-derived bacterial factors can promote inflammation and insulin resistance, but other postbiotics can be insulin sensitizers. In parallel, activation of small intestinal sirtuin 1 increases insulin sensitivity by reversing high fat-induced hypothalamic insulin resistance through a gut-brain neuronal axis, whereas high fat-feeding alters small intestinal microbiome and increases taurochenodeoxycholic acid in the plasma and the dorsal vagal complex to induce insulin resistance. In summary, emerging evidence indicates that intestinal molecular signaling involving nutrient sensing and the host-microbe symbiosis alters insulin homeostasis and action. Gut-derived host endocrine and paracrine factors as well as microbial metabolites act on the liver, pancreas, and the brain, and in parallel on the gut-brain neuronal axis. Understanding common nodes of peripheral and central insulin homeostasis and action may reveal new ways to target the intestinal host-microbe relationship in obesity, metabolic disease, and type 2 diabetes.

Topics: Administration, Intranasal; Animals; Central Nervous System; Endocrinology; Gastrointestinal Microbiome; Glucose; History, 20th Century; History, 21st Century; Homeostasis; Humans; Insulin; Insulin Resistance; Intestines; Leptin; Microbiota

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

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

Low-density lipoprotein receptor-related protein 1 (LRP1) is a member of LDL receptor family that plays a key role in systemic glucose and lipid homeostasis. LRP1 also regulates energy balance in the hypothalamus by mediating leptin's anorexigenic action, although the underlying neurocircuitry involved is still unclear. Because GABAergic neurons are a major mediator of hypothalamic leptin action, we studied the role of GABAergic LRP1 in energy balance and leptin action using mice lacking LRP1 in Vgat- or AgRP-expressing neurons (Vgat-Cre; LRP1

Topics: Agouti-Related Protein; Animals; Eating; Energy Metabolism; Female; GABAergic Neurons; Glucose; Homeostasis; Insulin Resistance; Leptin; Low Density Lipoprotein Receptor-Related Protein-1; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Receptors, Leptin

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

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

Whether HAIR-AN syndrome and polycystic ovarian syndrome (PCOS) are distinct entities or represent a phenotypic spectrum of the same syndrome is still unclear. HAIR-AN syndrome is characterized by high insulin resistance, obesity, and hyperinsulinemia as compared to PCOS and could represent adipose tissue dysfunction as the primary pathophysiologic trigger. This study was undertaken to study the role of adipose tissue dysfunction in HAIR-AN syndrome and PCOS using adipocytokines as surrogate markers of "adiposopathy.". A cross-sectional observational study was conducted at a tertiary care hospital over a period of 1 year. Serum adiponectin, leptin, IL-6, and TNF-α levels were measured in 30 women with HAIR-AN syndrome and in 30 women with PCOS. Correlations between adipocytokines, inflammatory markers, serum testosterone, and serum insulin were determined. Data analysis was performed using the SPSS version 23.0 (IBM SPSS Statistics Inc., Chicago, IL, USA) software program.. Women with HAIR-AN syndrome had significantly higher hyperandrogenemia, hyperinsulinemia, and insulin resistance as compared to PCOS women. They also had high leptin levels and lower adiponectin levels (p < 0.001). However, the levels of inflammatory markers (TNF-α and IL-6) were similar in both the groups (p > 0.05). Serum adiponectin showed a negative correlation with HOMA-IR and testosterone levels, while leptin showed a positive correlation with both in HAIR-AN patients while no such correlation was found in the PCOS group.. The significantly raised adipocytokines in HAIR-AN syndrome patients as compared to PCOS patients indicates the primary role of adipose tissue dysfunction ("adiposopathy") in the pathogenesis of HAIR-AN syndrome while only a minor role, if any, in PCOS. Both these syndromes stand as distinct entities pathogenically with an overlapping phenotype.

Topics: Acanthosis Nigricans; Adiponectin; Adipose Tissue; Adolescent; Adult; Asian People; Cross-Sectional Studies; Female; Humans; Hyperandrogenism; India; Insulin Resistance; Interleukin-6; Leptin; Polycystic Ovary Syndrome; Tumor Necrosis Factor-alpha; Young Adult

Adiponectin has been reported to be associated with lower skeletal muscle mass and skeletal strength and may be involved in skeletal muscle regulation along with myostatin. This study aims to evaluate the association between serum adiponectin and myostatin levels and identify independent factors using body composition and metabolic parameters in patients with obesity.. Overall, 148 patients (age, 45.9 ± 14.3 years, body mass index, 37.2 ± 8.0 kg/m2) who initially visited the outpatient clinic of obesity between November 2013 and November 2019 were included. Body composition was measured using InBody 720 and dual energy X-ray absorptiometry. In addition, muscle strength, vascular function, and metabolic parameters were measured. Serum levels of adiponectin, leptin, myostatin, and irisin were measured from blood samples.. The serum adiponectin level was 2.9 μg/mL (1.7-4.1 μg/mL), and the serum myostatin level was 2398.4 pg/mL (1,777.1-2952.5 pg/mL). The stepwise regression analysis revealed less leg strength, homeostasis model assessment of insulin resistance, and C-reactive protein as an independent predictor of serum adiponectin levels based on the significance of the univariate analysis (R2 = 0.190, P < 0.001). A high appendicular lean mass/body weight, reactive hyperemia index, and irisin were independent factors for serum myostatin levels (R2 = 0.260, P < 0.001).. The serum adiponectin level was associated with less muscle strength. Although serum myostatin was associated with a high appendicular lean mass, it is possible that myostatin was regulated by the percentage of body weight from appendicular lean mass.

Topics: Absorptiometry, Photon; Adiponectin; Adult; Body Composition; Body Mass Index; Body Weight; C-Reactive Protein; Correlation of Data; Cross-Sectional Studies; Female; Fibronectins; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Muscle Strength; Muscle, Skeletal; Myostatin; Obesity

No study has previously investigated insulin resistance in collegiate baseball players. The purposes of this study were to examine: 1) the insulin resistance; and 2) the usefulness of the adiponectin/leptin (A/L) ratio compared with the homeostasis model assessment of insulin resistance (HOMA-IR) for assessing insulin resistance in collegiate baseball players.. Twenty collegiate baseball players with abdominal obesity (AO group) defined by a waist circumference (WC) ≥85 cm, 65 lean baseball players with a WC<85 cm (L group), and 20 controls who were sedentary for at least 1 year (C group) were compared. The Body Mass Index, WC, systolic and diastolic blood pressures, fasting plasma glucose, total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, apolipoprotein B, insulin, leptin, adiponectin, and high-sensitivity C-reactive protein (hs-CRP) were measured.. The AO group had a significantly higher insulin level, HOMA-IR, and leptin level, and lower A/L ratio than the L and C groups. The AO group had a significantly higher prevalence of insulin resistance (50%) than the L (14%) group. The A/L ratio was significantly negatively correlated with body weight, Body Mass Index, WC, triglycerides, triglycerides/HDL-C ratio, apolipoprotein B, hs-CRP, insulin, HOMA-IR, and leptin, and positively correlated with HDL-C, whereas HOMA-IR was significantly positively correlated with body weight, Body Mass Index, WC, systolic and diastolic blood pressures, fasting plasma glucose, and insulin, and negatively correlated with adiponectin and the A/L ratio. In the forward stepwise multiple regression analysis, WC, triglycerides, and hs-CRP were the significant determinants for the A/L ratio, whereas diastolic blood pressure and WC were the significant determinants for HOMA-IR. This model explained 53.7% of the variance in the A/L ratio and 13.6% of the variance in HOMA-IR.. The present study suggested that the baseball players with abdominal obesity had a significantly higher prevalence of insulin resistance than the lean baseball group. The A/L ratio may be more useful than HOMA-IR to accurately assess insulin resistance in male collegiate baseball players.

Topics: Adiponectin; Athletes; Baseball; Blood Glucose; Body Mass Index; Humans; Insulin; Insulin Resistance; Japan; Leptin; Male; Triglycerides

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

Topics: Adipogenesis; Adiponectin; Alanine Transaminase; Animals; Aspartate Aminotransferases; Body Weight; Citrus; Diet, High-Fat; Fermented Foods; Fruit; Gene Expression Regulation; Insulin Resistance; Leptin; Lipid Metabolism; Lipids; Lipogenesis; Liver; Male; Mice; Mice, Inbred C57BL; Obesity

To examine the effects of myo-inositol supplementation during lactation in male and female rats on metabolic parameters and its potential to reverse metabolic alterations associated with a moderate gestational calorie restriction.. The offspring of control and 25% gestational calorie-restricted rats are supplemented with myo-inositol or vehicle throughout lactation and exposed to a Western diet (WD) from 5 to 7 months of age. Blood parameters are measured and gene expression and protein levels in retroperitoneal white adipose tissue (rWAT) and liver are analyzed. In male offspring, but not in females, myo-inositol supplementation resulted in lower fasting triglyceride and insulin levels and HOMA-IR at 7 months, and reversed the alterations in these parameters due to gestational calorie restriction. The expression pattern of key genes in metabolism in rWAT and liver support the beneficial effect of myo-inositol supplementation in reversing metabolic alterations programmed by gestational calorie restriction in male rats.. Myo-inositol supplementation at physiological doses during lactation improves metabolic health and prevents the programmed trend to develop insulin resistance and hypertriglyceridemia in male rats acquired by inadequate fetal nutrition and exacerbated by a diabetogenic diet in adulthood. The absence of clear effects in females deserves further investigation.

Topics: Adipose Tissue, White; Animals; Body Weight; Caloric Restriction; Dietary Supplements; Eating; Energy Metabolism; Female; Gene Expression Regulation; Inositol; Insulin Resistance; Lactation; Leptin; Male; Obesity; Pregnancy; Rats, Wistar; Sex Factors; Triglycerides

To observe the effect of electroacupuncture (EA) on Leptin and Leptin receptor (OB-Rb) of insulin resistant obese (OIR) rats, so as to explore its possible mechanism for obesity.. Twenty-four Wistar rats were randomly divided into normal, model and EA groups, with 8 rats in each group. The OIR model was established by feeding the rats with high-fat diet for 8 weeks. EA (2 Hz, 1 mA) was applied to "Zhongwan" (CV12), "Guanyuan" (CV4), "Zusanli" (ST36) and "Fenglong" (ST40) for 30 min, once every other day for 8 weeks. At the 6th week of intervention, glucose contents of intraperitoneal glucose tolerance test (IPGTT) and intraperitoneal insulin tolerance test (IPITT) were measured. After 8 weeks' intervention, the body weight and food intake were recorded. Serum total cholesterol (TC) and total triglyceride (TG) were assayed by using an automatic biochemical analyzer. The expression levels of Leptin and OB-Rb proteins in the small intestine and hypothalamus were detected by Western blot.. Following modeling, the body weight, food intake, IPGTT, IPITT, the contents of serum TC and TG, and the expressions of Leptin protein in small intestine and hypothalamus were significantly up-regulated (. EA can improve insulin resis-tance by up-regulating the OB-Rb protein expression and enhancing the binding force of Leptin and OB-Rb.

Topics: Acupuncture Points; Animals; Electroacupuncture; Insulin Resistance; Leptin; Obesity; Rats; Rats, Wistar

Increased visceral adipose tissue (VAT) is associated with metabolic dysfunction, while subcutaneous adipose tissue (SAT) is considered protective. The mechanisms underlying these differences are not fully elucidated. This study aimed to investigate molecular differences in VAT and SAT of male Wistar rats fed a cafeteria diet (CD) or a standard rodent diet (STD) for three months. The expression of fatty acid metabolism genes was analysed by quantitative real-time PCR. Global and gene-specific DNA methylation was quantified using the Imprint® Methylated DNA Quantification Kit and pyrosequencing, respectively. Bodyweight, retroperitoneal fat mass, insulin resistance, leptin and triglyceride concentrations and adipocyte hypertrophy were higher in CD- compared to STD-fed rats. The expression of solute carrier family 27 member 3 (Slc27a3), a fatty acid transporter, was 9.6-fold higher in VAT and 6.3-fold lower in SAT of CD- versus STD-fed rats. Taqman probes confirmed increased Slc27a3 expression, while pyrosequencing showed Slc27a3 hypomethylation in VAT of CD- compared to STD-fed rats. The CD decreased global methylation in both VAT and SAT, although no depot differences were observed. Dysregulated fatty acid influx in VAT, in response to a CD, provides insight into the mechanisms underlying depot-differences in adipose tissue expansion during obesity and metabolic disease.

Topics: Adipose Tissue; Animals; Body Weight; Diabetes Mellitus, Type 2; Diet; Diet, High-Fat; DNA Methylation; Fatty Acid Transport Proteins; Insulin; Insulin Resistance; Intra-Abdominal Fat; Leptin; Male; Metabolic Diseases; Obesity; Rats; Rats, Wistar; Subcutaneous Fat

AMP-activated protein kinase (AMPK) plays a crucial role in the regulation of energy homeostasis in both peripheral metabolic organs and the central nervous system. Recent studies indicated that

Topics: AMP-Activated Protein Kinases; Animals; Coumaric Acids; Glucose; Homeostasis; Hypothalamus; Insulin Resistance; Leptin; Mice; Pro-Opiomelanocortin; Signal Transduction

Kisspeptin, neuropeptide involved in puberty beginning and regulation of pituitary-gonadal axis, has been shown to stimulate antioxidant defenses in murine models. Its levels are greater in females than males and also in obese prepubertal girls. Therefore, our aim was to evaluate sex-related differences in prepubertal obese patients and the relationships of Kisspeptin with metabolic/hormonal parameters.. We studied Kisspeptin concentrations in 54 children (22 males and 32 females, Tanner stage 1), 5-12 ys, classified according to Cole's criteria into 17 overweight and 37 obese; 25 normal-weight children, aged 6-12 years, were studied as controls. We evaluated metabolic (glucose and insulin levels after oral glucose load, total- LDL- HDL-cholesterol, triglycerides, uric acid) and hormonal (fT3, fT4, TSH, IGF-1, leptin) parameters. Moreover, total antioxidant capacity (TAC) was evaluated by spectrophotometric method, using the system H202-metmyoglobin-ABTS. Kisspeptin levels were measured by RIA.. We did not find significant differences between obese and normal-weight children, but obese males presented significantly lower levels than females. Kisspeptin did not correlate with BMI, HOMA-IR, Insulin peak levels and TAC; a significant correlation was found between Kisspeptin and fT3 (r2=0.25; p=0.003) in the obese group; leptin levels, significantly greater in obese vs. overweight and control children, significantly correlated with TAC (r2=0.39; p=0.03).. These data suggest that both hormones could modulate antioxidants, Kisspeptin indirectly via influence on thyroid hormones, and Leptin by a direct effect. This mechanism seems to be sex-related, not attributable to peripheral steroid levels. Further studies can clarify the complex interrelationship between central and peripheral Kisspeptin secretion and oxidative stress in children obesity.

Topics: Antioxidants; Body Mass Index; Case-Control Studies; Child; Child, Preschool; Female; Humans; Insulin Resistance; Kisspeptins; Leptin; Male; Pediatric Obesity; Sex Characteristics; Spectrophotometry

Insulin resistance is an essential characteristic of type 2 diabetes mellitus (T2DM), which can be induced by glucotoxicity and adipose chronic inflammation. Mesenchymal stem cells (MSCs) and their exosomes were reported to ameliorate T2DM and its complications by their immunoregulatory and healing abilities. Exosomes derived from MSCs contain abundant molecules to mediate crosstalk between cells and mimic biological function of MSCs. But the role of exosomes derived from human umbilical cord mesenchymal stem cells (hUC-MSCs) in insulin resistance of human adipocytes is unclear. In this study, exosomes were harvested from the conditioned medium of hUC-MSCs and added to insulin-resistant adipocytes. Insulin-stimulated glucose uptake was measured by glucose oxidase/peroxidase assay. The signal pathway involved in exosome-treated adipocytes was detected by RT-PCR and Western blotting. The biological characteristics and function were compared between hUC-MSCs and human adipose-derived mesenchymal stem cells (hAMSCs). The results showed that hAMSCs had better adipogenic ability than hUC-MSCs. After induction of mature adipocytes by adipogenesis of hAMSC, the model of insulin-resistant adipocytes was successfully established by TNF-α and high glucose intervention. After exosome treatment, the insulin-stimulated glucose uptake was significantly increased. In addition, the effect of exosomes could be stabilized for at least 48 h. Furthermore, the level of leptin was significantly decreased, and the mRNA expression of sirtuin-1 and insulin receptor substrate-1 was significantly upregulated after exosome treatment. In conclusion, exosomes significantly improve insulin sensitivity in insulin-resistant human adipocytes, and the mechanism involves the regulation of adipokines.

Topics: Adipocytes; Cell Differentiation; Cells, Cultured; Exosomes; Glucose; Humans; Insulin; Insulin Resistance; Leptin; Mesenchymal Stem Cells; Sirtuin 1; Tumor Necrosis Factor-alpha; Umbilical Cord

The relationship between insulin resistance (IR) and hepatic steatosis (fatty liver) is well known; however, the extent to which the satiety hormone leptin acts as a confounder or mediator in this relationship is uncertain. We examined whether the association between IR and hepatic steatosis is mediated by leptin in Colombian adolescents with excess adiposity.. A total of 122 adolescents (mean age: 13.4 years; 68% girls) participated in the study. We assessed body composition, hepatic steatosis (as defined by the controlled attenuation parameter [CAP]), cardiometabolic risk factors (body mass index, waist circumference, body composition), biochemical variables (leptin, insulin, glucose, lipid profile, cardiometabolic Z-score, transaminases, etc.), and physical fitness (cardiorespiratory fitness and grip strength). Partial correlation, regression, and mediation analyses were conducted using the Barron and Kenny framework.. The findings are clinically relevant to consider leptin levels as a surrogate marker of insulin sensitivity when assessing youths with excess adiposity and/or suspected Nonalcoholic hepatic steatosis or nonalcoholic fatty liver disease (NAFLD).

Topics: Adiposity; Adolescent; Age Factors; Biomarkers; Child; Colombia; Cross-Sectional Studies; Female; Humans; Insulin Resistance; Leptin; Male; Non-alcoholic Fatty Liver Disease; Pediatric Obesity; Risk Assessment; Risk Factors

Studies on the association between adiponectin and leptin and anxiety and depression among postmenopausal women are limited. Therefore, the present study specifically evaluates the mutual relationships between adiponectin and leptin and anxiety and depression in postmenopausal women.. In this cross-sectional study, a total of 190 women aged 40-65 years were enrolled. Depression symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D), and anxiety symptoms were evaluated using the Hamilton Anxiety Rating Scale (HAM-A). Fasting specimens were collected to measure sex hormone, glucose, insulin, and adipokine levels. Multiple linear regression analysis was performed to evaluate the associations between depression and anxiety and adipocyte-derived hormones.. The study was performed in a hospital medical center.. Among 190 enrolled postmenopausal women, Spearman's rank correlation analysis revealed significant correlations between CES-D and HAM-A (r = 0.715, P < 0.0001), between CES-D and adiponectin (p = 0.009) and leptin (p = 0.015), and between HAM-A and adiponectin (p = 0.01) and leptin (p = 0.001). The subjects with CES-D ≥ 16 and with HAM-A ≥ 18 had higher adiponectin levels than those with CES-D < 16 and HAM-A < 18, respectively. After adjusting for age, body mass index, exercise, alanine amino transferase and parameters of lipid profiles, Log adiponectin levels were found to be significantly associated with both CES-D and HAM-A, and Log leptin levels were only significantly associated with HAM-A.. The data show that adiponectin and leptin levels are significantly associated with depression and anxiety symptoms. These results suggest that higher adiponectin and lower leptin levels may serve as potential markers related to anxiety and mood in postmenopausal women. More future research that is designed to deal with the important confounders (e.g., population heterogeneity) is needed to investigate comprehensively on these associations.

Topics: Adipocytes; Adipokines; Adiponectin; Adult; Aged; Anxiety; Body Mass Index; Cross-Sectional Studies; Depression; Female; Humans; Insulin; Insulin Resistance; Leptin; Obesity; Postmenopause

Denervation of renal sympathetic nerves (RDN) is an invasive endovascular procedure introduced as an antihypertensive treatment with a potential beneficial effect on insulin resistance (IR). We have previously demonstrated a reduction in blood pressure (BP) six months after RDN, but severe hepatic and peripheral IR, assessed by glucose tracer and two step hyperinsulinemic-euglycemic clamp (HEC), did not improve. The aim of the current study was to evaluate IR and adipokines profiles in relation to BP and arterial stiffness changes two years after RDN.. In 20 non-diabetic patients with true treatment-resistant hypertension, ambulatory and office BP were measured after witnessed intake of medications prior to, six and 24 months after RDN. Arterial stiffness index (AASI) was calculated from ambulatory BP. Insulin sensitivity (IS) was assessed using an oral glucose tolerance test (OGTT), the Homeostasis Model Assessment (HOMA-IR), HOMA-Adiponectin Model Assessment (HOMA-AD), the Quantitative Insulin Sensitivity Check Index (QUICKI), the Triglyceride and Glucose Index (TyG) and the Leptin-to-Adiponectin Ratio (LAR). These surrogate indices of IS were compared with tracer/HEC measurements to identify which best correlated in this group of patients.. All measured metabolic variables and IS surrogate indices remained essentially unchanged two years after RDN apart from a significant increase in HOMA-AD. OGTT peak at 30 min correlated best with reduction in endogenous glucose release (EGR) during low insulin HEC (r = -0.6, p = 0.01), whereas HOMA-IR correlated best with whole-body glucose disposal (WGD) (r = -0.6, p = 0.01) and glucose infusion rate (r = -0.6, p = 0.01) during high insulin HEC. BP response was unrelated to IS prior to RDN. Nocturnal systolic BP and arterial stiffness before RDN correlated positively with a progression in hepatic IR at six-month follow-up.. IR, adiponectin and leptin did not improve two years after RDN. There was no correlation between baseline IS and BP response. Our study does not support the notion of a beneficial metabolic effect of RDN in patients with treatment resistant hypertension.

Topics: Adiponectin; Biomarkers; Blood Glucose; Blood Pressure; Denervation; Female; Follow-Up Studies; Glucose Clamp Technique; Glucose Tolerance Test; Health Status Indicators; Humans; Hypertension; Insulin; Insulin Resistance; Kidney; Leptin; Male; Middle Aged; Postoperative Period; Time Factors; Treatment Outcome; Vascular Stiffness

Pro- and anti-inflammatory adipokines have been regarded as potential markers of obesity and cardiometabolic comorbidities. However, few studies have evaluated this association in children. We aimed to evaluate the relationship between adipokine concentrations and cardiometabolic risk markers in Brazilian schoolchildren. This was a cross-sectional study with 378 children aged 8-9 years from Viçosa, Minas Gerais, Brazil. We measured adipokines (leptin, retinol-binding protein 4, adiponectin, and chemerin) and cardiometabolic risk markers (fasting glucose, HOMA-IR, lipid profile, and blood pressure). Cardiometabolic risk markers were compared by quintiles of adipokines with linear regression adjusted for potential confounders. Leptin was positively associated with diastolic blood pressure (P = 0.03) and HOMA-IR (P = 0.01), and retinol-binding protein 4 was positively associated with total cholesterol (P = 0.04). Each standard deviation of leptin and retinol-binding protein 4 was associated to, respectively, a 0.1 (95%CI: 0.1; 0.2), 0.3 (95%CI: 0.1; 0.6), and 2.5 (95%CI: 0.1; 4.9) units increase in diastolic blood pressure, HOMA-IR, and total cholesterol. Adiponectin was negatively associated with diastolic blood pressure (P = 0.01) and HOMA-IR (P = 0.01), and chemerin was negatively associated with glucose (P = 0.001). Each standard deviation of adiponectin and chemerin was associated to, respectively, a -0.1 (95%CI: -0.2; -0.1), -0.2 (95%CI: -0.3; -0.1), and -1.2 (95%CI: -1.9; -0.5) units decrease in diastolic blood pressure, HOMA-IR, and glucose.Conclusion: Pro- and anti-inflammatory adipokines were positively and negatively associated with cardiometabolic risk markers, respectively, among schoolchildren, indicating this relationship may be identified at earlier ages. What is Known: • Although leptin, retinol-binding protein 4, and adiponectin are well-known adipokines, a consensus regarding their relationship with cardiometabolic risk markers, especially in schoolchildren, has not yet been reached. • Chemerin is an adipokine that has been studied recently. Yet, due to its dependence on the target cell type, its functions are still a controversial topic. What is New: • Leptin was positively associated with diastolic blood pressure and HOMA-IR, and retinol-binding protein 4 was positively associated with total cholesterol. • Adiponectin was negatively associated with diastolic blood pressure and HOMA-IR, and chemerin was negatively associated with glucose.

Topics: Adipokines; Adiponectin; Anti-Inflammatory Agents; Body Mass Index; Brazil; Cardiovascular Diseases; Chemokines; Child; Cross-Sectional Studies; Humans; Insulin Resistance; Leptin

Polycystic ovary syndrome (PCOS) is a complex reproductive endocrinopathy among reproductive-aged women and related with body mass and insulin resistance. Adipocytokines produced by adipose tissue seems to take part in the hormonal and metabolic alterations that arise in PCOS. Fat mass and obesity associated (FTO) gene is linked with body mass index (BMI) and diabetes. Aims - To investigate the association between fat mass related adipocytokines and single nucleotide polymorphisms (SNPs) (rs9939609 T/A) in the FTO gene in women with PCOS. Study design - Cross-sectional study MATERIAL AND METHODS: FTO+rs9939609 gene polymorphism and serum spexin, adiponectin and leptin levels were determined in 91 PCOS women and 86 healthy controls. Study participants were subdivided according to BMI and comparisons were made within each group.. Serum spexin levels were not differed between study groups. Serum levels of adiponectin were found to be decreased in PCOS women with BMI lower than 25 kg/m2 (10.1 ± 5.6 vs 14.1 ± 9.1, p = 0.015). Serum leptin levels were elevated in obese PCOS women compared to healthy control group (2197.9 ± 596.3 pg/mL vs 1535.9 ± 812.1 pg/mL, p = 0.001). The prevalence of A risk allele of SNP rs9939609 was more frequent in PCOS patients than in the control group. PCOS risk was found to increase 3 times more in AA genotype when compared with TT genotype (OR = 3.04 95% CI: 1.243-7.309; p = 0.013).. Serum adiponectin and leptin levels may serve as independent markers for PCOS diagnosis. Moreover, the FTO+rs9939609 gene polymorphism increase susceptibility to PCOS development independent from serum adipocytokine levels.

Topics: Adiponectin; Adult; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Body Mass Index; Case-Control Studies; Cross-Sectional Studies; Female; Genotype; Humans; Insulin Resistance; Leptin; Peptide Hormones; Polycystic Ovary Syndrome; Polymorphism, Single Nucleotide

We aimed to examine prospective associations between circulating fatty acids in early pregnancy and incident gestational diabetes mellitus (GDM) among Chinese pregnant women.. Analyses were based on two prospective nested case-control studies conducted in western China (336 GDM cases and 672 matched controls) and central China (305 cases and 305 matched controls). Fasting plasma fatty acids in early pregnancy (gestational age at enrollment: 10.4 weeks(s.d., 2.0)) and 13.2 weeks (1.0), respectively) were determined by gas chromatography-mass spectrometry, and GDM was diagnosed based on the International Association of Diabetes in Pregnancy Study Groups criteria during 24-28 weeks of gestation. Multiple metabolic biomarkers (HOMA-IR (homeostatic model assessment for insulin resistance), HbA1c, c-peptide, high-sensitivity C-reactive protein, adiponectin, leptin, and blood lipids) were additionally measured among 672 non-GDM controls at enrollment.. Higher levels of saturated fatty acids (SFAs) 14:0 (pooled odds ratio, 1.41 for each 1-s.d. increase; 95% CI: 1.25, 1.59) and 16:0 (1.19; 1.05, 1.35) were associated with higher odds of GDM. Higher levels of n-6 polyunsaturated fatty acid (PUFA) 18:2n-6 were strongly associated with lower odds of GDM (0.69; 0.60, 0.80). In non-GDM pregnant women, higher SFAs 14:0 and 16:0 but lower n-6 PUFA 18:2n-6 were generally correlated with unfavorable metabolic profiles.. We documented adverse associations of 14:0 and 16:0 but a protective association of 18:2n-6 with GDM among Chinese pregnant women. Our findings highlight the distinct roles of specific fatty acids in the onset of GDM.

Topics: Adiponectin; Adult; Blood Glucose; C-Peptide; C-Reactive Protein; Case-Control Studies; China; Diabetes, Gestational; Fasting; Fatty Acids; Fatty Acids, Monounsaturated; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Female; Glycated Hemoglobin; Humans; Insulin Resistance; Leptin; Pregnancy; Prospective Studies; Risk Factors; Young Adult

The hypothalamus is a critical regulator of glucose metabolism and is capable of correcting diabetes conditions independently of an effect on energy balance. The small GTPase Rap1 in the forebrain is implicated in high-fat diet-induced (HFD-induced) obesity and glucose imbalance. Here, we report that increasing Rap1 activity selectively in the medial hypothalamus elevated blood glucose without increasing the body weight of HFD-fed mice. In contrast, decreasing hypothalamic Rap1 activity protected mice from diet-induced hyperglycemia but did not prevent weight gain. The remarkable glycemic effect of Rap1 was reproduced when Rap1 was specifically deleted in steroidogenic factor-1-positive (SF-1-positive) neurons in the ventromedial hypothalamic nucleus (VMH) known to regulate glucose metabolism. While having no effect on body weight regardless of sex, diet, and age, Rap1 deficiency in the VMH SF1 neurons markedly lowered blood glucose and insulin levels, improved glucose and insulin tolerance, and protected mice against HFD-induced neural leptin resistance and peripheral insulin resistance at the cellular and whole-body levels. Last, acute pharmacological inhibition of brain exchange protein directly activated by cAMP 2, a direct activator of Rap1, corrected glucose imbalance in obese mouse models. Our findings uncover the primary role of VMH Rap1 in glycemic control and implicate Rap1 signaling as a potential target for therapeutic intervention in diabetes.

Topics: Animals; Blood Glucose; Diet, High-Fat; Gene Knockdown Techniques; Homeostasis; Hyperglycemia; Hypothalamus; Insulin; Insulin Resistance; Leptin; Mice; Neurons; Obesity; rap1 GTP-Binding Proteins; Steroidogenic Factor 1; Ventromedial Hypothalamic Nucleus

Adipose tissue distribution and glucose metabolism differ between men and women. Few studies have investigated sex differences in adipose tissue insulin resistance (adipose-IR). Herein, we investigated sex differences in adipose-IR in adults ranging from overweight to obese and the potential factors associated with sex differences in adipose-IR.. A total of 424 adults had their body mass index (BMI), adipose-IR, and sex hormones evaluated. Based on BMI, males and females were assigned to 4 groups.. In total, males (n = 156) had higher adipose-IR than females with similar BMI levels (n = 268) (P < 0.05). Adipose-IR progressively increased from overweight to class III obesity in both males and females (all P < 0.0001); however, only in the class III obesity group was the adipose-IR significantly higher in males than in females (P = 0.025). There were significant differences in testosterone between males and females (all P < 0.01); testosterone levels were negatively correlated with adipose-IR (r = -0.333, P < 0.001) in males but positively correlated with adipose-IR (r = 0.216, P < 0.001) in females. For the logistic regression analysis, testosterone was an independent protective factor against adipose-IR in males, with an odds ratio of 0.858 (B = -0.153 [95% CI, 0.743-0.991], P = 0.037).. Adipose-IR reflects the progressive deterioration in adipose tissue insulin sensitivity from overweight to obesity in both males and females. Males with class III obesity have more severe adipose-IR than similarly obese females. The sex difference is associated with testosterone, and low testosterone levels may contribute to more severe adipose-IR in obese males.

Topics: Adipose Tissue; Adult; Blood Glucose; Body Mass Index; Cross-Sectional Studies; Female; Humans; Insulin; Insulin Resistance; Leptin; Male; Obesity; Overweight; Sex Characteristics; Testosterone

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

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

Systemic inflammation has been documented in obstructive sleep apnea (OSA). However studies on childhood OSA and systemic inflammation are limited. This study aimed to determine the relation between OSA in overweight/obese children and various inflammatory markers.. In this cross sectional study, we enrolled 247 overweight/ obese children from pediatric outpatient services. We evaluated demographic and clinical details, anthropometric parameters, body composition and estimation of inflammatory cytokines such as interleukin (IL) 6, IL-8, IL-10, IL-17, IL-18, IL-23, macrophage migration inhibitory factor (MIF), high sensitive C-reactive protein (Hs-CRP), tumor necrosis factor-alpha (TNF-α), plasminogen activator inhibitor-1 (PAI-1) and leptin levels. Overnight polysomnography was performed.. A total of 247 children (190 with OSA and 57 without OSA) were enrolled. OSA was documented on polysomnography in 40% of patients. We observed significantly high values body mass index, waist circumference (WC), % body fat, fasting blood glucose (FBG), alanine transaminase (ALT), alkaline phosphate, fasting insulin and HOMA-IR in children with OSA. Inflammatory markers IL-6, IL-8, IL-17, IL-18, MIF, Hs CRP, TNF- α, PAI-1, and leptin levels were significantly higher in OSA patients (p<0.05). There was strong positive correlation of IL-6, IL-8, IL-17, IL-23, MIF, Hs CRP, TNF-A, PAI-1 and leptin with BMI, % body fat, AHI, fasting Insulin, triglyceride, FBG, WC, HOMA-IR, AST and ALT.. Children with OSA have increased obesity, insulin resistance and systemic inflammation. Further studies are require to confirm our findings and evaluate their utility in diagnosis of OSAs, assessing severity and possible interventions.

Topics: Biomarkers; Blood Glucose; Body Mass Index; C-Reactive Protein; Child; Cross-Sectional Studies; Cytokines; Female; Humans; Inflammation; Insulin; Insulin Resistance; Leptin; Male; Overweight; Pediatric Obesity; Sleep Apnea, Obstructive

Familial partial lipodystrophy type 3 (FPLD3) is a very rare autosomal dominant genetic disorder which is caused by mutations in the peroxisome proliferator activated receptor gamma (. This case highlights the importance of early recognition of FPLD syndromes otherwise frequently observed as difficult-to-classify and manages diabetes cases, in order to prevent cardiovascular complications. Metreleptin may be an effective treatment for FPLD3.

Topics: Diabetes Mellitus, Type 1; Diagnostic Errors; Female; Glycated Hemoglobin; Humans; Insulin Resistance; Leptin; Lipodystrophy, Familial Partial; Liver; Middle Aged; Mutation; Triglycerides

The aim of the study was to investigate the association of adipokines (resistin, leptin and adiponectin) with obesity, insulin resistance (IR) and inflammation in type 2 diabetes mellitus (T2DM). A total of 284 patients with T2DM were included. Concentrations of resistin, leptin, adiponectin, and inflammatory markers [high sensitivity C-reactive protein (hsCRP), tumor necrosis factor α (TNF-α), and interleukin 6 (IL-6)] were measured and homeostatic model assessment for IR (HOMA-IR) index was calculated. Resistin correlated negatively with estimated glomerular filtration rate (eGFR) and positively with hsCRP, TNF-α, IL-6, and white blood cell count (WBC). Leptin correlated positively with HOMA-IR, whereas adiponectin correlated negatively. Leptin also correlated positively with body mass index (BMI), waist circumference, IL-6, WBC and negatively with eGFR. Adiponectin correlated negatively with waist circumference, WBC, and eGFR. Multivariate logistic regression indicated lower eGFR and higher WBC and IL-6 as independent predictive factors of resistin concentration above the upper quartile (CAQ3), whereas female sex and higher BMI and HOMA-IR of leptin CAQ3, and lower HOMA-IR and older age of adiponectin CAQ3. In conclusion, in contrast to leptin and adiponectin, in T2DM patients, resistin is not associated with BMI and IR, but with inflammation and worse kidney function.

Topics: Adipokines; Adiponectin; Adult; Aged; Aged, 80 and over; Biomarkers; Body Mass Index; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Inflammation; Insulin Resistance; Kidney Function Tests; Leptin; Male; Middle Aged; Prognosis; Prospective Studies; Resistin

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

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

Lipodystrophy syndromes are rare disorders of deficient adipose tissue, low leptin, and severe metabolic disease, affecting all adipose depots (generalized lipodystrophy, GLD) or only some (partial lipodystrophy, PLD). Left ventricular (LV) hypertrophy is common (especially in GLD); mechanisms may include hyperglycemia, dyslipidemia, or hyperinsulinemia.. Determine effects of recombinant leptin (metreleptin) on cardiac structure and function in lipodystrophy.. Open-label treatment study of 38 subjects (18 GLD, 20 PLD) at the National Institutes of Health before and after 1 (N = 27), and 3 to 5 years (N = 23) of metreleptin. Outcomes were echocardiograms, blood pressure (BP), triglycerides, A1c, and homeostasis model assessment of insulin resistance.. In GLD, metreleptin lowered triglycerides (median [interquartile range] 740 [403-1239], 138 [88-196], 211 [136-558] mg/dL at baseline, 1 year, 3-5 years, P < .0001), A1c (9.5 ± 3.0, 6.5 ± 1.6, 6.5 ± 1.9%, P < .001), and HOMA-IR (34.1 [15.2-43.5], 8.7 [2.4-16.0], 8.9 [2.1-16.4], P < .001). Only HOMA-IR improved in PLD (P < .01). Systolic BP decreased in GLD but not PLD. Metreleptin improved cardiac parameters in patients with GLD, including reduced posterior wall thickness (9.8 ± 1.7, 9.1 ± 1.3, 8.3 ± 1.7 mm, P < .01), and LV mass (140.7 ± 45.9, 128.7 ± 37.9, 110.9 ± 29.1 g, P < .01), and increased septal e' velocity (8.6 ± 1.7, 10.0 ± 2.1, 10.7 ± 2.4 cm/s, P < .01). Changes remained significant after adjustment for BP. In GLD, multivariate models suggested that reduced posterior wall thickness and LV mass index correlated with reduced triglycerides and increased septal e' velocity correlated with reduced A1c. No changes in echocardiographic parameters were seen in PLD.. Metreleptin attenuated cardiac hypertrophy and improved septal e' velocity in GLD, which may be mediated by reduced lipotoxicity and glucose toxicity. The applicability of these findings to leptin-sufficient populations remains to be determined.

Topics: Adolescent; Adult; Blood Pressure; Cardiomegaly; Echocardiography; Female; Glycated Hemoglobin; Humans; Hypertrophy, Left Ventricular; Insulin Resistance; Leptin; Lipodystrophy; Lipodystrophy, Congenital Generalized; Male; Middle Aged; National Institutes of Health (U.S.); Prospective Studies; Triglycerides; United States; Ventricular Septum; Young Adult

One of the therapeutic approaches in the treatment of obesity is the use of histamine H. Histamine ligands were selected based on the preliminary studies which included determination of intrinsic activity and selected pharmacokinetic parameters. Female Wistar rats were fed palatable feed for 28 days and simultaneously the tested compounds were administered intraperitoneally at a dose of 10 mg/kg b.w./day. Rats' weight was evaluated daily and calories intake was evaluated once per week. At the end of experiment insulin and glucose tolerance tests was performed. Plasma levels of cholesterol, triglycerides, leptin, insulin, glucose, C-peptide and CRP were also determined. In order to rule out false-positive results the influence of tested compounds on spontaneous activity of rats was monitored.. Animals fed palatable feed and treated with KSK-61 or KSK-63 compounds showed the slowest weight gain which was comparable to the one observed in control animals. Both compounds with the highest pharmacological activity have also similar pharmacokinetic properties with quite long half-life and high volume of distribution indicating that they can freely cross most biological barriers. Some compounds, especially KSK-63, compensated for metabolic disorders.. The presented study proves that search among the active histamine H

Topics: Adipose Tissue; Animals; Body Weight; C-Peptide; Carrier Proteins; Cholesterol; Energy Intake; Feeding Behavior; Female; Glucose Tolerance Test; Histamine Agonists; Histamine Antagonists; Injections, Intraperitoneal; Insulin; Insulin Resistance; Leptin; Ligands; Metformin; Models, Animal; Obesity; Rats, Wistar; Receptors, Histamine H3; Triglycerides

Exposure to fine particulate matter (PM

Topics: Adipose Tissue; Air Pollution; Animals; Aortic Diseases; Atherosclerosis; Diet, High-Fat; Gene Expression Regulation; Inflammation; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Particulate Matter; Superoxide Dismutase

BackgroundIt is increasingly recognized that intestinal cells can store lipids after a meal, yet the effect of this phenomenon on lipid absorption patterns in insulin resistance remains unknown.MethodsThe kinetics of meal fat appearance were measured in insulin-sensitive (IS, n = 8) and insulin-resistant (IR, n = 8) subjects after sequential, isotopically labeled lunch and dinner meals. Plasma dynamics on triacylglycerol-rich (TAG-rich) lipoproteins and plasma hormones were analyzed using a nonlinear, non-steady state kinetic model.ResultsAt the onset of dinner, IS subjects showed an abrupt plasma appearance of lunch lipid consistent with the "second-meal effect," followed by slower appearance of dinner fat in plasma, resulting in reduced accumulation of dinner TAG of 48% compared with lunch. By contrast, IR subjects exhibited faster meal TAG appearance rates after both lunch and dinner. This effect of lower enterocyte storage between meals was associated with greater nocturnal and next-morning hyperlipidemia. The biochemical data and the kinetic analysis of second-meal effect dynamics are consistent with rapid secretion of stored TAG bypassing lipolysis and resynthesis. In addition, the data are consistent with a role for the diurnal pattern of plasma leptin in regulating the processing of dietary lipid.ConclusionThese data support the concept that intestinal lipid storage may be physiologically beneficial in IS subjects.Trial registrationClinicalTrials.gov NCT02020343.FundingThis study was supported by a grant from the American Diabetes Association (grant 1-13-TS-12).

Topics: Adult; Body Fat Distribution; Dietary Fats; Feeding Behavior; Female; Humans; Insulin Resistance; Insulin Secretion; Intestinal Absorption; Intestines; Leptin; Lipid Metabolism; Lipoproteins; Male; Triglycerides

Topics: Adult; Animals; Anti-Mullerian Hormone; Female; Humans; Hyperinsulinism; Insulin Resistance; Insulin Secretion; Leptin; Polycystic Ovary Syndrome; Rats; Young Adult

Detailed data on adipokines and body composition during and after pregnancy in women of different BMI categories are lacking. Furthermore, adipokine regulation during pregnancy and the factors contributing to gestational insulin resistance are not completely understood. The objective was to longitudinally determine adipokine levels, body composition, and insulin sensitivity during and after pregnancy in women of healthy weight (HW) and with obesity (OB), and identify factors associated with insulin resistance.. Women (30 HW, 19 OB) underwent blood sampling and body composition examination, by air-displacement plethysmography, longitudinally during pregnancy (trimesters 1, 2, 3) and after pregnancy (6, 12, 18 months postpartum). Serum leptin, soluble leptin receptor (sOB-R), and adiponectin levels were measured and free leptin index (FLI) and homeostatic model assessment of insulin resistance (HOMA-IR) determined.. Fat mass and leptin increased during pregnancy in the HW (p < 0.01) but not in the OB group. sOB-R increased during pregnancy in both groups (p < 0.001). Thus, FLI was unchanged in HW throughout pregnancy but reduced in OB (p = 0.001), although consistently higher in OB. Adiponectin decreased in both groups during pregnancy (p < 0.001 for HW, p = 0.01 for OB). After pregnancy, adiponectin increased in both groups, but more markedly in OB where it reached trimester 1 levels. Multivariable regression identified FLI as the variable most strongly associated with HOMA-IR in all trimesters, but not after pregnancy.. Leptin, sOB-R, adiponectin, and FLI undergo marked changes during and after pregnancy with differences in women of different BMI. We suggest that leptin activity is regulated by its soluble receptor and that this is an important factor for optimizing fat mass and insulin sensitivity during pregnancy.

Topics: Adipokines; Adult; Body Composition; Body Weight; Female; Gestational Weight Gain; Humans; Insulin Resistance; Leptin; Obesity; Pregnancy; Pregnancy Complications

An original model of diabetes linked to carbohydrate and lipid intake is presented and applied to predict the effects on biomarkers of various diets. The variables (biomarkers) are concentrations of fasting plasma glucose, insulin, leptin, glucagon, non-esterified fatty acids (NEFA) and very low density lipoprotein triglyceride (VLDLTG), as well as muscle lipids, hepatic lipids, pancreatic lipids, fat mass and mass of β-cells. The model predicts isocaloric high carbohydrate low fat (HCLF) diet and low carbohydrate high fat (LCHF) diet trajectories to health which vary in fat mass by at most a few kilograms at steady state. The LCHF trajectories to health are faster than isocaloric HCLF trajectories with respect to fat mass loss, although these trajectories may be slower initially if parameters are adjusting from HCLF values. On LC diets, leptin sensitivity and VLDLTG clearance are thought to increase. Increasing leptin sensitivity and VLDLTG clearance is predicted to lower lipids including fat mass and VLDLTG. The model predicts that changes in VLDLTG due to a change in diet happen rapidly, approaching steady state values after a few weeks, reflecting leptin sensitivity and VLDLTG clearance which are much harder to measure. The model predicts that if only insulin sensitivity increases on a LC diet, steady state fat mass would increase slightly. If leptin and insulin sensitivities increase concurrently, the combined effect could be a decrease in fat mass, consistent with the fact that increasing insulin sensitivity is often associated with fat mass loss in trials. The model predicts trajectories to fat type II diabetes with hypertriglyceridemia due to high carbohydrate moderate fat diets, on which insulin rises before falling, as ectopic fat deposits increase; made fatter and more diabetic by higher lipid consumption. It predicts trajectories to non-diabetic states with raised fat mass, VLDLTG and muscle, hepatic and pancreatic lipids due to moderate carbohydrate high fat diets. The model predicts paths to lean type II diabetes, on a diet of moderate energy but low β-cell replication rate or high death rate.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Diet; Humans; Insulin; Insulin Resistance; Leptin; Lipid Metabolism; Lipoproteins, VLDL; Models, Theoretical; Triglycerides

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

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

Low weight in early infancy is a known risk factor for cardio-metabolic syndrome in adult life. However, little is known either about developmental programming in subjects of normal birthweight or about events between the ages which separate early programming and the occurrence of disease at late adulthood. We tested the hypothesis that circulating concentrations of leptin, adiponectin and insulin in young, healthy adults, born with a birth size within the normal range, are influenced by early life growth patterns. In an observational study of 188 healthy volunteers aged 18-25 years (97 males, 91 females) we investigated the association of metabolic function with their birth size, their growth during childhood and their body composition. High plasma leptin in early adulthood, a risk factor for cardio-metabolic syndrome, was associated with low weight at age 2 years (correlation coefficient controlled for adult weight = -0.21, P < 0.01). It was also positively associated with pre-prandial insulin and with HOMA (Homeostasis Model Assessment) insulin resistance. Leptin, leptin-adiponectin ratio and insulin correlated with lean mass, fat mass and percent fat (P < 0.0001). In conclusion, high leptin in early adulthood was associated with both low weight at age 2 years and insulin resistance. We speculate that high leptin is developmentally programmed and can contribute to the association between low weight in early infancy and increased cardio-metabolic risk in adulthood in healthy subjects.

Topics: Adiponectin; Adolescent; Adult; Birth Weight; Body Weight; Child Development; Child, Preschool; Female; Humans; Infant; Insulin; Insulin Resistance; Leptin; Male; Young Adult

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

Leptin is associated with cardiovascular risk factors (e.g. hypertension, insulin resistance, kidney disease and excess body weight). Experimental studies showed that leptin might affect serum uric acid, by modulation of the uric acid excretion. However, there are few observational data on the relationship between leptin and uric acid in the general population. Therefore, the aim of the present study was to evaluate the relationship between leptin and uric acid and its excretion in a large middle-aged male general population.. A sample of 930 adult male individuals (mean age: 52 years) without therapy for high uric acid was included in the analysis (the Olivetti Heart Study).. Uric acid was significantly and positively associated with blood pressure, BMI, waist circumference, insulin resistance, C-reactive protein and leptin (p < 0.01), while inversely with renal function (p = 0.01). The multivariate analysis confirmed the association between leptin and uric acid after adjustment for potential confounders (p < 0.01). After division for adiposity, this trend was confirmed separately for normal weight and excess body weight participants. Moreover, leptin was inversely associated with excretion of uric acid (p < 0.01), also in multivariate analysis (p = 0.03).. The results of this study indicate a positive association between circulating leptin levels and uric acid, independently of potential confounders, both in normal and excess body weight men. Furthermore, an inverse association between leptin and uric acid excretion was detected.

Topics: Adult; Blood Pressure; Body Mass Index; C-Reactive Protein; Humans; Hypertension; Insulin Resistance; Kidney; Kidney Function Tests; Leptin; Male; Middle Aged; Obesity; Overweight; Risk Factors; Uric Acid; Waist Circumference

There is growing evidence that type 2 diabetes or insulin resistance is linked to cognitive impairment. We recently confirmed altered lipid composition, down-regulation of insulin receptor expression and impaired basal synaptic transmission in the hippocampus of our transgenic murine model of adipocyte insulin resistance (AtENPP1-Tg). Here we evaluated whether the correction of adipose tissue dysfunction [via the subcutaneous transplantation of mesenchymal stem cells (MSC)] can improve the hippocampal synaptic transmission in AtENPP1-Tg mice versus their wildtype littermates. Animals were simply randomized to receive MSC, then weighed weekly for 12 weeks. At euthanasia, we assessed leptin in the collected serum and hippocampal synaptic high-frequency stimulation long-term potentiation (HFS-LTP) using brain slices. MSC transplantation normalized AtENPP1-Tg body and epididymal fat weights and was associated with increased leptin levels, a sign of adipocyte maturation. More importantly, transplantation restored the deficiency observed in AtENPP1-Tg HFS-LTP, the cellular readout of memory. Our results further corroborate the role of adipocyte maturation arrest in adipose tissue and highlight a role for the adipose tissue in modulating hippocampal cellular mechanisms. Further studies are warranted to explore the mechanisms for the MSC-induced improvement of hippocampal HFS-LTP.

Topics: Adipose Tissue; Animals; Diabetes Mellitus, Type 2; Diet, High-Fat; Fatty Acids, Nonesterified; Hippocampus; Humans; Insulin Resistance; Leptin; Long-Term Potentiation; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Mice, Transgenic; Phosphoric Diester Hydrolases; Pyrophosphatases; Synaptic Transmission

Hidradenitis suppurativa (HS) is a chronic inflammatory disease associated with insulin resistance (IR), metabolic syndrome and increased cardiovascular risk. Adipokines are biologically active, pleotropic molecules which have been involved in the development of IR and in the pathogenesis of several chronic inflammatory conditions. The aim of the present study was to analyze serum concentrations of adiponectin, leptin, resistin and visfatin in patients with HS, and investigate their possible associations with IR, HS risk and disease severity. This case-control study enrolled 137 non-diabetic individuals (76 HS-patients and 61 age and sex-matched controls). Serum concentrations of adiponectin, leptin, resistin and visfatin, and the homeostasis model assessment of IR (HOMA-IR) were measured in all the participants. Serum adiponectin concentrations were found to be significantly lower, and leptin, resistin and visfatin levels were significantly higher in HS-patients than in controls. These differences remained significant even after adjusting for age, sex and body mass index, except for leptin. In a multivariate regression analysis, HOMA-IR was inversely correlated with adiponectin and positively associated with resistin levels. Furthermore, serum levels of resistin and visfatin were independently associated with HS risk. However, we found no association between serum levels of adipokines and HS severity. Our results suggest that reduced adiponectin and increased resistin serum levels may be surrogate biomarkers for IR in patients with HS. Moreover, resistin and visfatin might be independent risk factors for the development of HS.

Topics: Adiponectin; Adult; Biomarkers; Case-Control Studies; Cross-Sectional Studies; Cytokines; Female; Hidradenitis Suppurativa; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Resistin; Risk Factors; Severity of Illness Index

This study aimed to determine, in women with gestational diabetes (GDM), the changes in insulin sensitivity (Matsuda Insulin Sensitivity Index; IS. IS. A total of 27 women completed all assessments. Compared with T1, IS. In women with GDM, delivery was associated with improvement in both insulin sensitivity and insulin production within the first few days. Improvement in insulin production persisted for 6-12 weeks, but insulin sensitivity deteriorated slightly. These changes in glucose metabolism were not associated to changes in lipids, leptin, inflammation markers or body weight.. ClinicalTrials.gov NCT02082301.

Topics: Adipokines; Adiponectin; Adult; Blood Glucose; C-Reactive Protein; Diabetes, Gestational; Female; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Leptin; Postpartum Period; Pregnancy; Young Adult

The adipokine omentin-1 has been suggested to be inversely associated with obesity and insulin resistance in humans. We studied the relationships between omentin-1, parameters of fat mass, insulin resistance, lipids and blood pressure in children with obesity in a longitudinal study.. We analysed omentin-1 concentrations in 23 normal-weight children and in 82 children with obesity participating in a one-year lifestyle intervention. In the children with obesity, omentin-1, bioactive and conventional leptin, thyroid hormones (thyroid-stimulating hormone, free thyroxine 4, free triiodothyronine), body mass index, waist circumference, body fat based on skin-fold measurements and bioimpedance analyses, lipids, insulin resistance as homeostatic model assessment of insulin resistance (HOMA-IR) and blood pressure were determined at baseline and 1 year later. Furthermore, we measured omentin-1 concentrations 1 year after the end of the lifestyle intervention.. The omentin-1 concentrations were significantly (P = .008) lower in children with obesity compared to normal-weight children (296 ± 108 ng ml. Our data do support the hypothesis that omentin-1 is reversibly decreased in obesity and is a link between obesity and insulin resistance.

Topics: Adipose Tissue; Blood Pressure; Child; Cross-Sectional Studies; Cytokines; Female; Germany; GPI-Linked Proteins; Humans; Insulin Resistance; Lectins; Leptin; Lipids; Longitudinal Studies; Male; Obesity

It is imperative to develop markers for risk stratification and detection of cardiometabolic comorbidities in children with obesity. The adipokines leptin and adiponectin are both involved in fat mass regulation and the development of obesity-related disorders; furthermore, their ratio (leptin/adiponectin ratio) is suggested to be associated with insulin resistance and cardiometabolic risk.. To evaluate associations between fasting serum concentrations of the adipokines (total leptin and adiponectin as well as the L/A ratio) and cardiometabolic comorbidities in children with overweight/obesity.. A total of 2258 children with overweight/obesity or normal weight aged 6 to 18 years were studied. Differences in anthropometrics and adipokine concentrations were tested using Wilcoxon rank-sum test. Associations between the adipokines and cardiometabolic risk were tested using Spearman's correlation and logistic regression, adjusted for age and body mass index SD score (BMI-SDS).. Compared to normal weight children; children with overweight/obesity exhibited higher leptin concentrations, lower adiponectin concentrations, and higher L/A ratios. After adjusting for age and degree of obesity, girls with overweight/obesity in the upper quartile range for the L/A ratio, when compared with girls in the lower quartile range, were more likely to have insulin resistance (odds ratio [OR]: 7.78 [95% confidence interval [CI], 3.78-16.65]), dysglycemia (OR: 3.08 [95% CI, 1.35-7.31]), and dyslipidemia (OR: 2.53 [95% CI, 1.18-5.59]); while boys were more likely to have insulin resistance (OR: 4.45 [95% CI, 2.03-10.10]).. Independent of the degree of obesity, leptin, adiponectin, and the L/A ratio were associated with insulin resistance and other cardiometabolic comorbidities in children with overweight/obesity, but the L/A ratio exhibited stronger associations than the respective adipokines.

Topics: Adiponectin; Adolescent; Biomarkers; Child; Cohort Studies; Female; Humans; Insulin Resistance; Leptin; Male; Pediatric Obesity

Although the associations between first-episode psychosis (FEP) and metabolic abnormalities on one side, and childhood trauma (CT) and risk of developing psychosis on the other are both well established, evidence on the relationship between CT and metabolic dysregulation in terms of abnormal glucose metabolism is very limited. We tested whether, already at illness onset, FEP patients with a history of CT show dysregulation of a broad range of glucose metabolism markers. In particular, in 148 FEP patients we evaluated serum concentrations of c-peptide, insulin, plasminogen-activator-inhibitor-1 (PAI-1), resistin, visfatin, glucagon, glucagon-like peptide-1 (GLP-1), gastric-inhibitor-peptide (GIP), leptin, and ghrelin. We also assessed CT with the Childhood Experience of Care and Abuse Questionnaire, and stressful life events (SLEs) with a semi-structured interview. Psychopathology, cannabis and tobacco habits, Body Mass Index (BMI) were recorded. Serum concentrations of markers were analyzed from peripheral blood. Ninety-five patients (56 % males, mean age 29.5) reported CT. Multivariate models showed that CT is associated only with the concentrations of c-peptide and insulin after adjusting for age, sex, BMI and SLEs. FEP patients who had experienced CT showed higher c-peptide and insulin serum concentrations. Our study reports that CT might be associated with the metabolic abnormalities in the first stage of psychosis, suggesting that a thorough anamnestic evaluation at psychosis onset that would include the history of CT could be helpful for clinicians in order to implement early programmes of healthy lifestyle education and to guide choice of therapeutic interventions for trauma.

Topics: Adult; Adverse Childhood Experiences; Antipsychotic Agents; Biomarkers; C-Peptide; Female; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Plasminogen Activator Inhibitor 1; Psychotic Disorders; Resistin

Although novel pharmacological options for the treatment of type 2 diabetes mellitus (DM2) have been observed to modulate the functionality of several key organs in glucose homeostasis, successful regulation of insulin resistance (IR), body weight management, and pharmacological treatment of obesity remain notable problems in endocrinology. Leptin may be a pivotal player in this scenario, as an adipokine which centrally regulates appetite and energy balance. In obesity, excessive caloric intake promotes a low-grade inflammatory response, which leads to dysregulations in lipid storage and adipokine secretion. In turn, these entail alterations in leptin sensitivity, leptin transport across the blood-brain barrier and defects in post-receptor signaling. Furthermore, hypothalamic inflammation and endoplasmic reticulum stress may increase the expression of molecules which may disrupt leptin signaling. Abundant evidence has linked obesity and leptin resistance, which may precede or occur simultaneously to IR and DM2. Thus, leptin sensitivity may be a potential early therapeutic target that demands further preclinical and clinical research. Modulators of insulin sensitivity have been tested in animal models and small clinical trials with promising results, especially in combination with agents such as amylin and GLP-1 analogs, in particular, due to their central activity in the hypothalamus.

Topics: Animals; Diabetes Mellitus, Type 2; Humans; Hypothalamus; Insulin Resistance; Leptin; Obesity

To investigate the relationships among serum resistin, adiponectin, and leptin and microvascular complications in patients with type 2 diabetes mellitus (T2DM).. A total of 120 patients with T2DM were divided into non-microangiopathy and microangiopathy groups. Sixty age- and sex-matched healthy subjects were used as a normal control (NC) group. Body height, body mass, waist circumference, and blood pressure were determined, and waist/hip ratio (WHR), body mass index, blood glucose, lipids, resistin, leptin, adiponectin, free fatty acids (FFA), high-sensitivity C-reactive protein (hs-CRP), fasting insulin, hemoglobin A1c, and homeostatic model assessment of insulin resistance (HOMA-IR) were compared among the three groups.. Serum levels of resistin, leptin, FFA, and hs-CRP were significantly higher and levels of adiponectin were significantly lower in patients in the non-microangiopathy (n = 60) and microangiopathy groups (n = 60) compared with the NC group (n = 60). Serum resistin and leptin levels in patients with T2DM were positively correlated with WHR, hs-CRP, FFA, HOMA-IR, and triglycerides, but negatively correlated with high-density lipoprotein-cholesterol (HDL-C). Serum adiponectin levels in patients with T2DM were negatively correlated with WHR, hs-CRP, FFA, HOMA-IR, and triglycerides, but positively correlated with HDL-C.. Serum resistin, adiponectin, and leptin levels correlate with the occurrence of T2DM and microvascular complications.

Topics: Adiponectin; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Leptin; Resistin; Vascular Diseases

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

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

Data on resveratrol-(trans-3,5,4'-trihydroxystilbene)-induced caloric-restriction-(CR)-mimicking effects in mice receiving a high-fat diet (HFD) are contradictory. It is hypothesized that this can possibly stem from different bioactivities of resveratrol (RSV) microbial metabolites.. C57BL/6Rj mice are fed an ad-libitum HFD supplemented with RSV or its metabolites, dihydroresveratrol (DHR) and lunularin (LUN) (≈28 mg (dihydro)stilbene kg. Decelerated carbohydrate breakdown by RSV may have contributed to the moderate impact of dietary RSV on mouse insulin sensitivity (lowered fasting and post-glucose-bolus insulin levels).

Topics: Animals; Bibenzyls; Body Composition; Caloric Restriction; Dietary Supplements; Gene Expression Regulation; Glucose Tolerance Test; Glycoside Hydrolase Inhibitors; Insulin; Insulin Resistance; Leptin; Liver; Male; Metabolome; Mice, Inbred C57BL; Phenols; Resveratrol; Stilbenes

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

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

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin secreted from enteroendocine K cells after nutrient ingestion. Fat strongly induces GIP secretion, and GIP hypersecretion is involved in high-fat diet-induced obesity and insulin resistance. Aging also induces GIP hypersecretion, but its effect on body weight gain and insulin sensitivity remains unclear. In the present study, we investigated the effect of GIP on age-related body weight gain and insulin resistance using GIP-knockout homozygous (GIP-/-) and heterozygous (GIP+/-) mice, which have entirely absent and 50% reduced GIP secretion compared to wild-type (WT) mice, respectively. Under 12% fat-containing normal diet feeding condition, body weight was significantly lower in GIP-/- mice compared to that in WT and GIP+/- mice from 38 weeks of age, while there was no significant difference between WT and GIP+/- mice. Visceral and s.c. fat mass were also significantly lower in GIP-/- mice compared to those in WT and GIP+/- mice. During oral glucose tolerance test, blood glucose levels did not differ among the three groups. Insulin levels were significantly lower in GIP-/- mice than those in WT and GIP+/- mice. During insulin tolerance test, GIP-/- mice showed higher insulin sensitivity than that of WT and GIP+/- mice. Adiponectin mRNA levels were increased and leptin mRNA levels tended to be decreased in adipose tissue of GIP-/- mice. These results demonstrate that GIP is involved in age-related obesity and insulin resistance and that inhibition of GIP secretion alleviates age-related fat mass gain and insulin resistance under carbohydrate-based diet feeding condition.

Topics: Adiponectin; Adipose Tissue; Age Factors; Animals; Diet; Diet, High-Fat; Enteroendocrine Cells; Gastric Inhibitory Polypeptide; Gene Expression; Glucose Tolerance Test; Insulin; Insulin Resistance; Leptin; Male; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Obesity

The present study was designed to elucidate the underlying mechanisms of Bao Gui capsule (BGC) against hyperandrogenism, insulin resistance and leptin resistance of PCOS. Letrozole was used to induce a PCOS model in rats, which were then randomly divided into four groups (n=9): Control, Model, high‑dose BGC (BGC‑H) and low‑dose BGC (BGC‑L) group. Serum levels of follicle‑stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T), estradiol (E2), insulin, leptin, and interleukin (IL)‑1β, IL‑6 and tumor necrosis factor‑α (TNF‑α) in the hypothalamus were determined by ELISA. Protein levels of cytochrome P450c17α and cytochrome P450 aromatase (P450arom) in ovaries were determined by immunohistochemistry and western blot analysis. Additionally, the expression of GLUT4 in uterus and muscle tissue, and NF‑κB, IKKβ and SOCS3 mRNA levels in the hypothalamus were evaluated. BGC significantly reduced body weight gain and decreased serum levels of LH/FSH, T, log T/E2, insulin and leptin compared with the PCOS model rats. Furthermore, BGC markedly reduced the expression of P450c17α and significantly increased the expression of P450arom in ovaries, and increased the expression of GLUT4 in uterus and muscle tissues. BGC also effectively reduced the level of IL‑6 and TNF‑α, and the expression of IKKβ, NF‑κB and SOCS3 in the hypothalamus of PCOS model rats. These results suggest that BGC may effectively improve hyperandrogenism, insulin resistance, endometrial receptivity and the low‑grade chronic inflammation in the hypothalamus.

Topics: Animals; Cytokines; Drugs, Chinese Herbal; Endometrium; Estradiol; Female; Follicle Stimulating Hormone; Glucose Transporter Type 4; Hyperandrogenism; Hypothalamus; Insulin; Insulin Resistance; Leptin; Luteinizing Hormone; Phytotherapy; Plant Preparations; Polycystic Ovary Syndrome; Rats; Testosterone; Uterus

Loss of ovarian hormones leads to increased adiposity and insulin resistance (IR), increasing the risk for cardiovascular and metabolic diseases. The purpose of this study was to investigate whether the molecular mechanism behind the adverse systemic and adipose tissue-specific metabolic effects of ovariectomy requires loss of signaling through estrogen receptor alpha (ERα) or estrogen receptor β (ERβ). We examined ovariectomized (OVX) and ovary-intactwild-type (WT), ERα-null (αKO), and ERβ-null (βKO) female mice (age ~49 weeks; n = 7-12/group). All mice were fed a phytoestrogen-free diet (<15 mg/kg) and either remained ovary-intact (INT) or were OVX and followed for 12 weeks. Body composition, energy expenditure, glucose tolerance, and adipose tissue gene and protein expression were analyzed. INT αKO were ~25% fatter with reduced energy expenditure compared to age-matched INT WT controls and βKO mice (all P < 0.001). Following OVX, αKO mice did not increase adiposity or experience a further increase in IR, unlike WT and βKO, suggesting that loss of signaling through ERα mediates OVX-induced metabolic dysfunction. In fact, OVX in αKO mice (i.e., signaling through ERβ in the absence of ERα) resulted in reduced adiposity, adipocyte size, and IR (P < 0.05 for all). βKO mice responded adversely to OVX in terms of increased adiposity and development of IR. Together, these findings challenge the paradigm that ERα mediates metabolic protection over ERβ in all settings. These findings lead us to suggest that, following ovarian hormone loss, ERβ may mediate protective metabolic benefits.

Topics: Adiponectin; Adipose Tissue, White; Adiposity; Animals; Body Composition; Energy Metabolism; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Gene Expression; Humans; Insulin Resistance; Leptin; Mice, Inbred C57BL; Mice, Knockout; Ovariectomy; Signal Transduction

Objective The aim of this study was to investigate polycystic ovary syndrome (PCOS) and to explore the relationship between body fat percentage and metabolic markers. Subjects and methods Sedentary women were assigned to PCOS (N = 60) and CONTROL (N = 60) groups. Each group was subdivided into three subgroups according to body fat percentage (22-27%, 27-32% and 32-37%). The protocol consisted of assessments of glucose, insulin, androgens, follicle stimulating hormone (FSH), luteinizing hormone (LH), 17-hydroxyprogesterone (17-OHP), leptin, adiponectin, tumor necrosis factor (TNF-α) and interleukin-6 (IL-6). Results The PCOS subgroups showed higher concentrations of androgens, LH and 17-OHP. Leptin showed direct relationship with increased body fat percentage, whereas adiponectin showed the inverse effect. However, both were unaffected by PCOS. TNF-α and IL-6 were higher in PCOS women and showed a direct relationship with increased body fat percentage. Glucose showed direct relationship with body fat percentage, whereas insulin presented higher values in PCOS women and direct relationship with increased body fat percentage. Conclusions Our findings indicate that PCOS and body fat percentage directly influence concentrations of insulin, TNF-α and IL-6, whereas leptin and adiponectin are influenced only by the increase in body fat percentage in these women. Arch Endocrinol Metab. 2020;64(1):4-10.

Topics: 17-alpha-Hydroxyprogesterone; Adiponectin; Adipose Tissue; Adolescent; Adult; Androgens; Biomarkers; Body Mass Index; Case-Control Studies; Female; Follicle Stimulating Hormone; Glucose; Humans; Insulin; Insulin Resistance; Interleukin-6; Leptin; Luteinizing Hormone; Metabolic Diseases; Polycystic Ovary Syndrome; Risk Factors; Sedentary Behavior; Tumor Necrosis Factor-alpha; Young Adult

Unhealthy dietary practices, sedentary life style and lack of physical exercise in developing countries like India are major contributors of metabolic syndrome like obesity and diabetes. Obesity in Indians is defined at Body Mass Index (BMI, kg/m. A preliminary study performed to explore ramification of obesity on metabolic profile of adipose tissue and adipose derived stem cells (ADSC) from control and obese Indians.. Adipose tissue/lipoaspirates from both control (BMI ≤ 23) subjects, and non-diabetic obese Indians subjects (BMI ≥ 25), were scrutinized for expressions of lipogenic genes, inflammatory mediators, stored adipokine levels, and insulin signaling proteins. Further, hADSC were isolated and immune-phenotyped from both the subject groups. Comparative assessments between chADSC and ohADSC were carried out for growth kinetics, expressions of pluripotent genes, adipogenic transcriptional factors, RUNX2, inflammatory mediators (IM), insulin signaling proteins, adipogenic and osteogenic differentiation.. Adipose tissue of obese subjects depicted high leptin and resistin levels with reduced adiponectin levels. Expressions of IM and insulin signaling proteins were elevated compared to those of control subjects. hADSC of obese subjects demonstrated diminished proliferation, altered pluripotent genes, aggravated inflammation, adipogenesis with reduced osteogenesis. hADSC of obese had established insulin resistance compared to those of control subjects.. This is the first study that describes hADSC of metabolically obese Indians have insulin resistance at lower BMI compared to Caucasians exemplifying plausible role in diminishing stemness of hADSC. Study alarms Indians to restore healthy dietary habits and assess quality of hADSC in regenerative therapy.

Topics: Adipokines; Adiponectin; Adipose Tissue; Adolescent; Adult; Body Mass Index; Cell Differentiation; Cell Proliferation; Core Binding Factor Alpha 1 Subunit; Female; Humans; India; Inflammation Mediators; Insulin; Insulin Resistance; Leptin; Lipogenesis; Male; Mesenchymal Stem Cells; Metabolome; Middle Aged; Myogenic Regulatory Factor 5; Obesity; Osteogenesis; Phenotype; Resistin; Signal Transduction; Transcription Factors; Young Adult

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

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

Hyperleptinemia per se is sufficient to promote leptin resistance in the obese state. Leptin sensitivity can be restored by reducing circulating leptin levels within a physiologically healthy range and is a viable antiobesity and antidiabetic strategy. However, a previous study suggests that partial leptin deficiency favors diet-induced obesity and related metabolic disorders in mice, arguing that a lower leptin level may indeed promote diet-induced obesity and its associated metabolic disorders. Here, we aim to elucidate what the impact of partial leptin deficiency is on fat mass and insulin sensitivity.. We used two different mouse models of partial leptin deficiency: an adipocyte-specific congenital heterozygous leptin knockout mouse line (LepHZ) and the well-established whole body heterozygous leptin knockout mouse (OBHZ). The metabolic studies of OBHZ and LepHZ mice were performed both on normal carbohydrate-rich chow diet and on a high-fat diet (HFD). Male and female mice were included in the study to account for sex-specific differences. Body weight, food intake, glucose tolerance, and insulin tolerance were tested. Histology of adipose tissue and liver tissue allowed insights into adipose tissue inflammation and hepatic triglyceride content. Immunohistochemistry was paired with RT-PCR analysis for expression levels of inflammatory markers.. Both OBHZ and LepHZ mice displayed reduced circulating leptin levels on the chow diet and HFD. On chow diet, male OBHZ and LepHZ mice showed elevated fat mass and body weight, while their glucose tolerance and insulin sensitivity remained unchanged. However, the inability in partially leptin-deficient mice to fully induce circulating leptin during the development of diet-induced obesity results in reduced food intake and leaner mice with lower body weight compared to their littermate controls. Importantly, a strong reduction of adipose tissue inflammation is observed along with improvements in insulin sensitivity and enhanced glucose tolerance. Additionally, partial leptin deficiency protects the mice from fatty liver and liver fibrosis. Chronically HFD-fed OBHZ and LepHZ mice remain more sensitive to exogenous leptin injection, as reflected by their reduced food intake upon an acute leptin treatment.. In response to HFD feeding, the inability to upregulate leptin levels due to partial leptin deficiency protects mice from diet-induced obesity and metabolic dysregulation. Thus, in an obesogenic environment, maintaining lower leptin levels is highly beneficial for both obesity and diabetes management. Chronic leptin reduction represents a viable preventive strategy whose efficacy awaits clinical testing.

Topics: Adipose Tissue; Adipose Tissue, White; Animals; Body Composition; Body Weight; Diet, High-Fat; Fatty Liver; Female; Insulin; Insulin Resistance; Leptin; Liver; Male; Metabolic Diseases; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Obesity

Waist-to-height ratio has been shown to be an important indicator of cardiometabolic risk. There are few studies evaluating this measure against existing measures of adiposity and cardiometabolic markers in early childhood. The objectives were: (i) to determine in young children the ability of waist-to-height ratio, BMI z-score, weight for length, and sum of skin fold thickness to predict cardiometabolic risk and (ii) to examine this association at ages 1, 3 and 5 years.. Prospective cohort study.. A university hospital in Toronto, Ontario.. Infants at 1 (n 406), 3 (n 112) and 5 years of age (n 94) born to mothers with and without gestational diabetes mellitus.. Weight for length and BMI z-score demonstrated the strongest correlations with biochemical measures compared to waist-to-height ratio, including leptin (at 5 years, weight for length z-score: ρ = 0·65, P < 0·001; BMI z-score: ρ = 0·67, P < 0·001) and measures of insulin resistance (at 3 years, weight for length z-score: ρ = 0·25, P = 0·02; BMI z-score: ρ = 0·24, P = 0·02). The magnitude of associations between anthropometric measures and biochemical measures strengthened over time. Weight for length and BMI z-scores were moderately correlated with overall measures of fat mass as measured by dual-energy X-ray absorptiometry (ρ = 0·65, P = 0·00; ρ = 0·61, P = 0·01).. Waist-to-height ratio was not superior to existing measures in predicting cardiometabolic risk in young children. BMI z-score is a preferred measure of adiposity between birth and 5 years of age.

Topics: Adiposity; Body Mass Index; Cardiovascular Diseases; Child, Preschool; Humans; Infant; Insulin Resistance; Leptin; Ontario; Prospective Studies; Risk Factors; Waist Circumference; Waist-Height Ratio

There is limited information on the effect of black beans (BB) as a source of protein and resistant starch on the intestinal microbiota. The purpose of the present work was to study the effect of cooked black beans with and without high fat and sugar (HF + S) in the diet on body composition, energy expenditure, gut microbiota, short-chain fatty acids, NF-κB, occluding and insulin signaling in a rat model and the area under the curve for glucose, insulin and incretins in healthy subjects. The consumption of BB reduced the percentage of body fat, the area under the curve of glucose, serum leptin, LPS, glucose and insulin concentrations and increased energy expenditure even in the presence of HF + S. These results could be mediated in part by modification of the gut microbiota, by increasing a cluster of bacteria in the Clostridia class, mainly

Topics: Animals; Body Fat Distribution; Butyrates; Clostridiales; Dietary Supplements; Endotoxemia; Energy Metabolism; Fabaceae; Gastrointestinal Microbiome; Glucose; Healthy Volunteers; Insulin Resistance; Leptin; Liver; Male; Models, Animal; Oxygenases; Rats, Wistar; Spondylitis, Ankylosing

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

It was reported that either orexigenic neuropeptide galanin or anorexigenic hormone leptin caught benefit insulin sensitivity through increasing the translocation of glucose transporter 4 (GLUT4) in patients with diabetes. To date, it is unknown whether galanin can potentiate the effect of leptin on alleviation of insulin resistance. Therefore, in the current study we sought to assess the combined effect of central leptin and galanin on insulin resistance in the adipose tissues of type 2 diabetic rats. Galanin and leptin were injected into the intracerebroventricle of the diabetic rats, respectively, or cooperatively once a day for 2 weeks. Then, several indexes of insulin resistance were examined. The results showed that glucose infusion rates in the hyperinsulinaemic-euglycaemic clamp test, plasma adiponectin content and GLUT4 translocation, as well as Akt phosphorylation in fat cells, were higher, not GLUT4 protein and GLUT4 mRNA expression, but HOMA index was lower in the galanin + leptin group than either one of them. Furthermore, treatment with MK-2206, an Akt inhibitor, blocked the combined effects of galanin + leptin on alleviation of insulin resistance. These results suggest that galanin can improve the leptin-induced mitigative effects on insulin resistance in the fat cells, and those provided new insights into the potential tactics for prevention and remedy of insulin resistance.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Animals; Body Weight; Deoxyglucose; Diabetes Mellitus, Experimental; Feeding Behavior; Galanin; Glucose Clamp Technique; Glucose Transporter Type 4; Hyperinsulinism; Insulin Resistance; Leptin; Male; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats, Wistar; RNA, Messenger

Topics: Adipose Tissue; Adiposity; Animals; Body Weight; Diet, High-Fat; Dietary Supplements; Eicosapentaenoic Acid; Energy Metabolism; Glucose; Insulin; Insulin Resistance; Leptin; Male; Mice, Inbred Strains; Motor Activity; Obesity; Oxygen Consumption; Triglycerides

Emerging evidence suggests that during gestation the in utero environment programs metabolism and can increase risk of obesity in adult offspring. Our aim was to study how alterations in maternal diets during gestation might alter body weight evolution, circulating leptin levels and caloric intake in offspring, leading to changes in body composition.. We fed gestating rats either a control diet (CD), high fat diet (HFD) or an isocaloric low protein diet (LPD), and examined the repercussions in offspring fed similar diets post-weaning on birth weight, body weight evolution, body composition, insulin sensitivity, glucose tolerance and in the relationship between plasma leptin concentration and caloric intake in offspring during growth and development.. Offspring from dams fed LPD maintained reduced body weight with greater % lean mass and consumed fewer calories despite having leptin levels similar to controls. On the other hand, offspring from dams fed a HFD were insulin resistant and maintained increased body weight and % fat mass, while consuming more calories than controls despite elevated leptin concentrations. Therefore the uterine environment, modulated primarily through maternal nutrition, modified the relationship between circulating leptin levels, body fat, and caloric intake in the offspring, and dams fed a HFD produced offspring with excess adiposity, insulin resistance, and leptin resistance into adulthood.. Our data indicates that in utero environmental factors affected by maternal diet program alterations in the set point around which leptin regulates body weight in offspring into adulthood contributing to obesity.

Topics: Adipose Tissue; Adiposity; Animals; Animals, Newborn; Birth Weight; Body Composition; Body Weight; Diet, High-Fat; Dietary Fats; Energy Intake; Female; Insulin Resistance; Lactation; Leptin; Male; Maternal Nutritional Physiological Phenomena; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Prenatal Nutritional Physiological Phenomena; Rats; Rats, Sprague-Dawley; Weaning

This study was conducted to evaluate the changing concentrations of metabolic hormones and metabolites in pregnant (P) and pseudopregnant (PP) rabbit does. Twenty-five New Zealand White rabbit does were submitted to artificial insemination (AI) and then classified as P (n = 15) or PP (n = 10). Blood samples were collected weekly until day 32 post AI. During pregnancy, leptin concentrations were greater on Days 14 and 21 (P < 0.05), while insulin was greater on days 21 and 32 post AI (P < 0.05) compared to PP does. The triiodothyronine/thyroxine (T3/T4) ratio was greater in the first and last week (P < 0.001); whereas, cortisol concentrations were greater in the last week of pregnancy and after parturition (P < 0.01) compared with that of PP does. Non-esterified fatty acids (NEFA) concentrations increased from day 7 until day 32 post AI (P < 0.05). Glucose concentrations were unchanged throughout pregnancy although concentrations were positively associated with litter size. These results indicate concentrations of hormones and metabolites change during pregnancy to ensure energy requirements are met for both the foetuses and the maternal tissues. Physiological hyperleptinemia, hyperinsulinemia, and changes in cortisol as well as thyroid hormones indicate there is an adaptation of metabolic functions induced by pregnancy. These adaptations could be mediated by gonadal steroids because changes mainly occur in the second half of pregnancy when the profile of the sex hormones differs between P and PP does.

Topics: Adaptation, Physiological; Animals; Energy Metabolism; Female; Homeostasis; Hydrocortisone; Insulin; Insulin Resistance; Leptin; Pregnancy; Pregnancy, Animal; Pseudopregnancy; Rabbits; Triiodothyronine

In the present study, we assessed the extent of mediation by low-grade systemic inflammation and adipokines in the association between abdominal adiposity and insulin resistance.. In this cross-sectional analysis of baseline measurements of the Netherlands Epidemiology of Obesity study, total body fat (TBF) was measured in all (n = 5772) participants who did not have missing data and neither used glucose-lowering medication, and abdominal subcutaneous adipose tissue (aSAT) and visceral adipose tissue (VAT) were assessed by MRI in a random subgroup (n = 2448). C-reactive protein (CRP), adiponectin, and leptin were considered as potential mediators, and insulin resistance was assessed by Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). Mediation by CRP, adiponectin, and leptin was studied by including the mediators to the fully adjusted linear regression model. Participants had a mean (SD) age of 56 (6) years, TBF of 36 (9) %, VAT of 119 (61) cm. Where leptin fully explained the aSAT-HOMA-IR association, the VAT-HOMA-IR association was only partly explained by leptin and adiponectin similarly in men and women.

Topics: Adiponectin; Adiposity; Age Factors; Biomarkers; C-Reactive Protein; Cross-Sectional Studies; Female; Humans; Insulin Resistance; Intra-Abdominal Fat; Leptin; Magnetic Resonance Imaging; Male; Middle Aged; Netherlands; Obesity, Abdominal; Prospective Studies; Risk Factors; Subcutaneous Fat

Joint damage in patients with diabetes mellitus (DM) is a common complication and is associated with the induction of metabolic inflammation against the background of increased catabolic processes in various joint structures. The aim of our work was to study the level of insulin, leptin, osteocalcin, as well as biochemical markers of connective tissue metabolism in patients with diabetes-associated osteoarthritis. We examined 77 patients who were divided into groups by type of diabetes, the presence and severity of diabetic arthropathy. The content of insulin and leptin, osteocalcin in the blood serum was determined by the enzyme immunoassay, the level of glycosaminoglycans, hydroxyproline, hyaluronidase, collagenase according to traditional biochemical methods. Among the examined patients, diabetic arthropathy was diagnosed in more than 70%. Patients with diabetic arthropathy significantly increased levels of insulin (with type 1 diabetes by 38.5%, with type 2 diabetes by 55.6%) and leptin (with type 1 diabetes by 43.8%, with type 2 diabetes by 53.7,%), the level of osteocalcin (only with type 1 diabetes by 53.9%) There is a direct correlation between the severity of joint damage and the level of insulin and leptin. The severity of arthopathy in patients with type 2 diabetes is directly correlated with indicators of insulin resistance. In patients with diabetes-associated osteoarthritis, indicators that characterize catabolic processes in the connective tissue (hydroxyproline free and collagenase (p<0.001) are increased. The chances of detecting arthropathy with type 1 diabetes increase 3.8 times with an increase in insulin levels, with an increase in leptin 1.3 times, in patients with type 2 diabetes, 2.6 and 1.2 times, respectively. For this sample, it was found that the development of arthropathy does not depend on the type of diabetes. In women with type 2 diabetes, the chances of developing arthropathy are six times higher. 4 times than men. An increase in insulin and leptin levels can serve as a marker for the presence and progression of arthropathy in patients with diabetes. Patients with arthropathies have increased levels of hydroxyproline and collagenase, which reflects an increase in catabolic processes in the connective tissue, which may be one of the mechanisms for the development of joint structures in patients with diabetes.

Topics: Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Insulin; Insulin Resistance; Leptin; Male; Osteoarthritis

Obesity leads a crucial importance in metabolic disorders, as well as type 2 diabetes mellitus. Our present study was designed to assess the potential role of irisin, adiponectin, leptin and gene polymorphism of PNPLA3, leptin and adiponectin as predictive markers of diabetes associated with obesity. One hundred eighty subjects were distributed to three groups including; healthy non-diabetic non obese volunteers as a control group, diabetic non obese group, and diabetic obese group (n = 60 for each group). Fasting blood samples of all groups were collected to determine fasting blood glucose, insulin levels, insulin resistance, total cholesterol, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triacylglycerol, irisin, adiponectin, leptin; as well as, polymorphism of PNPLA3, adiponectin and leptin. The results showed that glucose, insulin resistance, total cholesterol, irisin, leptin, LDL-C, triacylglycerol concentrations were significantly increased, however, insulin, HDL-C, adiponectin were significantly decreased in diabetic obese patients in relation to diabetic non-obese patients as well as in healthy volunteers. The polymorphism of PNPLA3 rs738409 was linearly related to irisin and leptin but was not related with circulating concentrations of adiponectin. We concluded that increased irisin and leptin levels can predict the insulin resistance in obese patients. Moreover, patients who have mutant genotype of PNPLA3 I148 gene (rs738409) C>G, ADIPOQ gene (rs266729) G>C and LEP gene (rs2167270) G>A showed a significant higher susceptibility rate for DM in obese people than those with wild type. This could be considered as an adjustable retort to counter the impact of obesity on glucose homeostasis.

Topics: Adiponectin; Adult; Diabetes Mellitus, Type 2; Female; Fibronectins; Genetic Markers; Genetic Predisposition to Disease; Humans; Insulin Resistance; Leptin; Lipase; Male; Membrane Proteins; Obesity; Polymorphism, Genetic; Young Adult

The study aimed to investigate association of circulating leptin, adiponectin, chemerin, and omentin-1 with metabolic syndrome (MetS) and cardio-metabolic risk factors in youths. Thirty eight young males were enrolled. Participants underwent anthropometric and blood pressure measures, and fasting blood sampling. Plasma leptin, adiponectin, chemerin, omentin-1 and insulin were measured by ELISA methods. Multiple linear regression models, adjusting for age, MetS traits, C-reactive protein (CRP) and homeostasis model assessment of insulin resistance (HOMA-IR), were applied to determine correlates for each adipokine. Eleven participants meet criteria of MetS. These individuals had higher leptin and chemerin and lower adiponectin plasma concentrations than those without MetS. Plasma leptin and chemerin were positively related, and adiponectin and omentin-1 were inversely related to cardio-metabolic traits. In multivariate models, predictors of leptin were age (β, 0.20, P = 0.01), abdominal obesity (β, 0.24, P = 0.06), raised blood pressure (β, 0.40, P = 0.01), raised triglycerides (β, 0.19, P = 0.01) and CRP (β, 0.31, P = 0.01). Chemerin was associated with abdominal obesity (β, 0.33, P = 0.09) and CRP (β, 0.29, P = 0.04), and adiponectin was associated with raised triglycerides (β, -0.26, P = 0.05), decreased HDL-C (β, -0.28, P = 0.06) and CRP (β, -0.48, P = 0.01). HOMA-IR (β, -0.39, P = 0.09) was the only predictor for omentin. MetS is associated with an altered plasma adipokines profile, with increased leptin and chemerin and decreased adiponectin circulating levels. These findings suggest a beneficial potential of adiponectin and omentin, but a detrimental potential of leptin and chemerin. Further research is needed to lighten the role of adipose tissue-derived adipokines in cardio-metabolic health.

Topics: Adipokines; Adipose Tissue; Adolescent; Adult; C-Reactive Protein; Humans; Insulin; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Obesity, Abdominal; Risk Factors; Triglycerides; Young Adult

Hyperuricaemia (HUA) significantly increases the risk of metabolic syndrome and is strongly associated with the increased prevalence of high serum free fatty acids (FFAs) and insulin resistance. However, the underlying mechanisms are not well established, especially the effect of uric acid (UA) on adipose tissue, a vital organ in regulating whole-body energy and FFA homeostasis. In the present study, we noticed that adipocytes from the white adipose tissue of patients with HUA were hypertrophied and had decreased UCP1 expression. To test the effects of UA on adipose tissue, we built both in vitro and in vivo HUA models and elucidated that a high level of UA could induce hypertrophy of adipocytes, inhibit their hyperplasia and reduce their beige-like characteristics. According to mRNA-sequencing analysis, UA significantly decreased the expression of leptin in adipocytes, which was closely related to fatty acid metabolism and the AMPK signalling pathway, as indicated by KEGG pathway analysis. Moreover, lowering UA using benzbromarone (a uricosuric agent) or metformin-induced activation of AMPK expression significantly attenuated UA-induced FFA metabolism impairment and adipose beiging suppression, which subsequently alleviated serum FFA elevation and insulin resistance in HUA mice. Taken together, these observations confirm that UA is involved in the aetiology of metabolic abnormalities in adipose tissue by regulating leptin-AMPK pathway, and metformin could lessen HUA-induced serum FFA elevation and insulin resistance by improving adipose tissue function via AMPK activation. Therefore, metformin could represent a novel treatment strategy for HUA-related metabolic disorders.

Topics: 3T3-L1 Cells; Adenylate Kinase; Adipocytes; Adipose Tissue, Beige; Adipose Tissue, White; Adult; Animals; Enzyme Activation; Fatty Acids, Nonesterified; Female; Humans; Hypertrophy; Hyperuricemia; Insulin Resistance; Leptin; Lipogenesis; Lipolysis; Male; Metformin; Mice; Mice, Inbred C57BL; Middle Aged; Signal Transduction; Triglycerides; Uric Acid

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

Obesity is a metabolic disorder that results from complex interactions between genetic predisposition and dietary factors. Interleukin-4 (IL-4), besides its role in immunity, has metabolic effects on insulin efficacy. We studied the effects of IL-4 on metabolic abnormalities in a mice model of obesity involving leptin deficiency and leptin resistance. Leptin-deficient 145E and leptin-resistant high-fat diet (HFD) mice showed lower levels of circulating IL-4. 145E and HFD mice showed a number of abnormalities: Obesity, hyperglycemia, hyperinsulinemia, insulin resistance, dyslipidemia, liver injury, and adiposity with concurrent inflammation, decreases in Akt, signal transducer and activator of transcription 3 (STAT3), and STAT6 phosphorylation in the hypothalamus, liver, and epididymal fat. Independent of leptin-deficient obesity and dietary obesity, a course of 8-week IL-4 supplementation improved obesity and impairment in Akt, STAT3, and STAT6 signaling. Amelioration of cytokine expression, despite variable extents, was closely linked with the actions of IL-4. Additionally, the browning of white adipocytes by IL-4 was found in epididymal white adipose tissues and 3T3-L1 preadipocytes. Chronic exercise, weight management, and probiotics are recommended to overweight patients and IL-4 signaling is associated with clinical improvement. Thus, IL-4 could be a metabolic regulator and antiobesity candidate for the treatment of obesity and its complications.

Topics: Adjuvants, Immunologic; Animals; Diet, High-Fat; Inflammation; Insulin Resistance; Interleukin-4; Leptin; Male; Metabolic Diseases; Mice; Mice, Inbred C57BL; Obesity

Browning of white adipose tissue (WAT) has been shown to reduce obesity and obesity-related complications, suggesting that factors that promote WAT browning may have applications in the development of therapeutic strategies for treating obesity. Here, we show that ablation of spinophilin (SPL), a ubiquitously expressed, multidomain scaffolding protein, increases metabolism and improves energy balance. Male and female SPL knockout (KO) and wild-type (WT) littermate controls were fed a chow diet or a high-fat diet (HFD). Body weight, hepatic steatosis, glucose and insulin tolerance, physical activity, and expression of browning genes in adipose tissues were measured and compared. Male SPL knockout (KO) mice fed a chow diet were significantly leaner, had lower body weights, and exhibited better glucose tolerance and insulin sensitivity than wild-type (WT) littermate controls. When fed an HFD, SPL KO mice were protected from increased body fat, weight gain, hepatic steatosis, hyperinsulinemia, and insulin resistance. Physical activity of SPL KO mice was markedly increased compared with WT controls. Furthermore, expression of the brown adipocyte marker, uncoupling protein-1 (UCP-1), and the mitochondrial activity markers, cd137 and c-idea, were significantly increased in visceral WAT (vWAT) of SPL KO mice, suggesting that SPL knockout protected the mice from HFD-induced obesity and its metabolic complications, at least in part, by promoting the browning of white adipocytes in vWAT. Our data identify a critical role of SPL in regulating glucose homeostasis, obesity, and adipocyte browning. These results suggest SPL may serve as a drug target for obesity and diabetes.

Topics: Adiponectin; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Diet, High-Fat; Energy Metabolism; Fatty Liver; Female; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microfilament Proteins; Nerve Tissue Proteins; Obesity; Physical Exertion

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

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

Anthocyanins (ACNs) are polyphenols that might reduce pathological processes associated with type 2 diabetes mellitus and other chronic diseases, but their bioavailability is still controversial. In this study, the metabolic activity of oral delivery of ACN-loaded niosomes was investigated and evaluated in a diet-induced obesity (DIO) mice model.. ACNs extracted from Vaccinium Meridionale by the supercritical fluid extraction method were loaded in niosomes. The niosomal formulation was physically characterized and further administrated in drinking water to obese, insulin resistant mouse. We evaluated the effect of ACN loaded niosomes on hyperglycemia, glucose and insulin intolerance and insulin blood levels in C57BL/6 J mice fed with a high-fat diet.. The ACN-loaded particles were moderately monodisperse, showed a negative surface charge and 57% encapsulation efficiency. The ACN-loaded niosomes ameliorated the insulin resistance and glucose intolerance in the DIO mice model. Additionally, they reduced animal weight and plasma insulin, glucose, leptin and total cholesterol levels in obese mice.. ACN-loaded niosomes administration, as a functional drink, had a beneficial effect on the reversal of metabolic abnormalities associated with obesity.

Topics: Animals; Anthocyanins; Blood Glucose; Body Weight; Cholesterol; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Drug Compounding; Drug Liberation; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Liposomes; Male; Mice, Inbred C57BL; Mice, Obese; Nanocapsules; Obesity; Plant Extracts; Streptophyta

Our data about pathogenesis of hepatic steatosis after liver transplantation is scarce. This study aimed to investigate the association between serum adipokines and insulin resistance with hepatic steatosis in liver transplant recipients. We investigated the association between insulin resistance, serum adiponectin, insulin, and leptin with hepatic steatosis in a cohort of liver transplant recipients. Homeostatic model assessment of insulin resistance 2 (HOMA 2-IR) was used for estimation of insulin resistance. Hepatic steatosis was determined using ultrasound and controlled attenuation parameter (CAP). A total of 178 patients were included. 79 patients (44.4%) had hepatic steatosis. Serum adiponectin (OR: 0.912; 95% CI 0.869-0.957; P < 0.001), serum leptin (OR: 1.060; 95% CI 1.017-1.102; P = 0.005), HOMA2-IR (OR: 1.671; 95% CI 1.049-2.662; P = 0.031), and post-transplant diabetes mellitus (PTDM) (OR: 5.988; 95% CI 1.680-21.276; P = 0.006) were independently associated with hepatic steatosis after liver transplantation. CAP values were negatively correlated with serum adiponectin (P = 0.011) and positively correlated with serum insulin (P = 0.001), leptin (P < 0.001) and HOMA2-IR (P < 0.001). Insulin resistance and alterations in adipokines might have central role in pathogenesis of hepatic steatosis after liver transplantation and can be targeted for diagnostic and therapeutic purposes.

Topics: Adipokines; Adult; Body Mass Index; Fatty Liver; Female; Humans; Insulin Resistance; Leptin; Liver Transplantation; Male; Middle Aged; Risk Factors

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

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

In view of the association of Ramadan intermittent fasting with profound changes in lifestyle both in nondiabetic and diabetic patients, the aim of this study was to investigate the effect of Ramadan fasting on adiponectin, leptin and leptin to adiponectin ratio (LAR), growth hormone (GH), human-sensitive C-reactive protein (hs-CRP), and diabetic and metabolic syndrome factors in patients with Type 2 Diabetes Mellitus (Type 2 DM), their first-degree relatives (FDRs), and healthy controls.. This cohort study involved 98 Yemeni male subjects aged 30-70 years old: 30 Type 2 DM, 37 FDRs of Type 2 diabetic patients, and 31 healthy control subjects. Subjects' body mass index (BMI), waist circumference (WC), and blood pressure (BP) were measured, and venous blood samples were collected twice: the first samples were collected a couple of days prior to Ramadan fasting (baseline) and the second samples after 3 weeks of fasting.. Ramadan fasting did not affect BMI, WC, and BP in Type 2 DM and their FDRs with respect to the baseline levels prior to Ramadan, whereas triglyceride and cholesterol were borderline significantly decreased in Type 2 DM with no effect in FDRs. Fasting blood glucose was not affected in Type 2 DM but was significantly increased in FDRs and control groups, whereas glycated haemoglobin (HbA1c) was slightly decreased in Type 2 DM, FDRs, and healthy controls. C-peptide, insulin, and insulin resistance (HOMA-IR) were significantly increased in Type 2 DM and FDRs, with no effect in the control group, whereas. Ramadan intermittent fasting decreased adiponectin and increased leptin, LAR, insulin, and insulin resistance in both Type 2 DM and FDRs as well as decreased GH in both FDRs and healthy controls and increased hs-CRP in healthy controls. Moreover, Ramadan intermittent fasting neither worsens a patient's glycemic parameters nor improves it, with the exception of a slight improvement in HbA1c in Type 2 DM, FDRs, and healthy controls.

Topics: Adipokines; Adiponectin; Adult; Aged; Blood Glucose; Blood Pressure; Body Mass Index; C-Peptide; C-Reactive Protein; Cohort Studies; Diabetes Mellitus, Type 2; Fasting; Glycated Hemoglobin; Humans; Insulin; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Middle Aged; Triglycerides; Waist Circumference

Cholinergic neurons are distributed in brain areas containing growth hormone (GH)-responsive cells. We determined if cholinergic neurons are directly responsive to GH and the metabolic consequences of deleting the GH receptor (GHR) specifically in choline acetyltransferase (ChAT)-expressing cells.. Mice received an acute injection of GH to detect neurons co-expressing ChAT and phosphorylated STAT5 (pSTAT5), a well-established marker of GH-responsive cells. For the physiological studies, mice carrying ablation of GHR exclusively in ChAT-expressing cells were produced and possible changes in energy and glucose homeostasis were determined when consuming regular chow or high-fat diet (HFD).. The majority of cholinergic neurons in the arcuate nucleus (60%) and dorsomedial nucleus (84%) of the hypothalamus are directly responsive to GH. Approximately 34% of pre-ganglionic parasympathetic neurons in the dorsal motor nucleus of the vagus also exhibited GH-induced pSTAT5. GH-induced pSTAT5 in these ChAT neurons was absent in GHR ChAT knockout mice. Mice carrying ChAT-specific GHR deletion, either in chow or HFD, did not exhibit significant changes in body weight, body adiposity, lean body mass, food intake, energy expenditure, respiratory quotient, ambulatory activity, serum leptin levels, glucose tolerance, insulin sensitivity and metabolic responses to 2-deoxy-d-glucose. However, GHR deletion in ChAT neurons caused decreased hypothalamic Pomc mRNA levels in HFD mice.. Cholinergic neurons that regulate the metabolism are directly responsive to GH, although GHR signaling in these cells is not required for energy and glucose homeostasis. Thus, the physiological importance of GH action on cholinergic neurons still needs to be identified.

Topics: Acetylcholine; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Choline O-Acetyltransferase; Cholinergic Neurons; Diet, High-Fat; Energy Metabolism; Glucose; Growth Hormone; Hypothalamus; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Somatotropin; STAT5 Transcription Factor; Vagus Nerve

Women with polycystic ovary syndrome (PCOS) are at an increased risk of developing insulin resistance and abdominal obesity in the state of an improper diet balance. Leptin is a peptide considered to be a satiety hormone that plays an important role in the long-term energy balance, whereas ghrelin is a hormone that controls short-term appetite regulation and is considered a hunger hormone. The aim of the present study was to assess the relationship between serum leptin and ghrelin concentrations and the dietary macronutrient content in PCOS women. We examined 73 subjects: 39 women diagnosed with PCOS by the Rotterdam criteria and 34 healthy controls, matched by the body mass index. The subjects completed a consecutive three-day dietary diary to identify the macronutrient and micronutrient intake. Serum concentrations of leptin and total ghrelin were measured and homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. The studied groups did not differ significantly in terms of the intake of macronutrients (proteins, fats, and carbohydrates) and serum concentrations of ghrelin and leptin (all

Topics: Adult; Body Mass Index; Case-Control Studies; Diet Records; Dietary Fats; Eating; Energy Metabolism; Female; Ghrelin; Humans; Insulin Resistance; Leptin; Micronutrients; Nutrients; Polycystic Ovary Syndrome; Young Adult

Adipocytokines are numerous proteins secreted by adipose tissue predominantly. They regulate many key physiological processes in human body. High or low levels of thyroid hormones in various thyropathies may have influence on levels of various adipocytokines, especially adiponectin, resistin and visfatin. However, results of studies are controversial or miss. Perplexing influence could have associate diseases of metabolic character (e. g. insulin resistance and type 2 diabetes mellitus or developing atherosclerosis).

Topics: Adipokines; Adiponectin; Adipose Tissue; Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Leptin

Although the hypothalamus is crucial for peripheral metabolism control, the signals in specific neurons involved remain poorly understood. The aim of our current study was to explore the role of the hypothalamic gene mothers against decapentaplegic homolog 7 (Smad7) in peripheral glucose disorders.. We studied glucose metabolism in high-fat diet (HFD)-fed mice and middle-aged mice with Cre-mediated recombination causing 1) overexpression of Smad7 in hypothalamic proopiomelanocortin (POMC) neurons, 2) deletion of Smad7 in POMC neurons, and 3) overexpression of protein kinase B (AKT) in arcuate nucleus (ARC) in Smad7 overexpressed mice. Intracerebroventricular (ICV) cannulation of insulin was used to test the hypothalamic insulin sensitivity in the mice. Hypothalamic primary neurons were used to investigate the mechanism of Smad7 regulating hypothalamic insulin signaling.. We found that Smad7 expression was increased in POMC neurons in the hypothalamic ARC of HFD-fed or middle-aged mice. Furthermore, overexpression of Smad7 in POMC neurons disrupted the glucose balance, and deletion of Smad7 in POMC neurons prevented diet- or age-induced glucose disorders, which was likely to be independent of changes in body weight or food intake. Moreover, the effect of Smad7 was reversed by overexpression of AKT in the ARC. Finally, Smad7 decreased AKT phosphorylation by activating protein phosphatase 1c in hypothalamic primary neurons.. Our results demonstrated that an excess of central Smad7 in POMC neurons disrupts glucose balance by attenuating hypothalamic insulin signaling. In addition, we found that this regulation was mediated by the activity of protein phosphatase 1c.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Diet, High-Fat; Energy Metabolism; Gene Expression; Gene Expression Regulation; Glucose; Hypothalamus; Insulin; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Neurons; Obesity; Pro-Opiomelanocortin; Proto-Oncogene Proteins c-akt; Signal Transduction; Smad7 Protein

Patients with rheumatoid arthritis (RA) have an increased risk of cardiovascular (CV) disease. Adiponectin is involved in the metabolism of glucose and lipids with favourable effects on CV disease, especially its high molecular weight (HMW) isoform. Body composition changes are described in RA with various phenotypes including obesity. The effects of tocilizumab on serum adiponectin and body composition, especially fat mass, in patients with RA are not well determined.. Patients with active RA despite previous csDMARDs and/or bDMARDs and who were tocilizumab naïve were enrolled in a multicentre open-label study. They were evaluated at baseline, 1, 3, 6 and 12 months. Clinical assessment included body mass index (BMI) and anthropometric measurements. Lipid and metabolic parameters, serum adiponectin (total and HMW), leptin, resistin and ghrelin were measured at each time point. Body composition (lean mass, fat mass, % fat, fat in the android and gynoid regions) was evaluated at baseline, 6 and 12 months.. One hundred seven patients were included. Both total and HMW adiponectin significantly increased from baseline to month 3, peaking respectively at month 3 (p = 0.0105) and month 1 (p < 0.0001), then declining progressively until month 6 to 12 and returning to baseline values. Significant elevation in HMW adiponectin persisted at month 6 (p = 0.001). BMI and waist circumference significantly increased at month 6 and 12, as well as lean mass at month 6 (p = 0.0097). Fat mass, percentage fat and android fat did not change over the study period. Lipid parameters (total cholesterol and LDL cholesterol) increased while glycaemia, insulin and HOMA-IR remained stable. Serum leptin, resistin and ghrelin did not change during follow-up.. Tocilizumab treatment in RA patients was associated with a significant increase in total and HMW adiponectin, especially at the onset of the treatment. Tocilizumab also induced a significant gain in lean mass, while fat mass did not change. These variations in adiponectin levels during tocilizumab treatment could have positive effects on the CV risk of RA patients. In addition, tocilizumab may have an anabolic impact on lean mass/skeletal muscle.. The ADIPRAT study was a phase IV open-label multicentre study retrospectively registered on ClinicalTrials.gov under the number NCT02843789 (date of registration: July 26, 2016).

Topics: Adiponectin; Antibodies, Monoclonal, Humanized; Arthritis, Rheumatoid; Body Mass Index; Humans; Insulin Resistance; Leptin; Molecular Weight

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

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

Copeptin and nesfatin-1 have recently been identified as novel peptides that play a role in the pathogenesis of obesity-related insulin resistance in adults. However, the relationship between them has not yet been elucidated, and their circulating levels in children with obesity have not been adequately studied. Therefore, the current study aimed to investigate whether their levels are altered in Chinese children with obesity, as well as to determine the correlation of these 2 peptides with each other, with insulin resistance, and with other biochemical parameters.. A total of 156 children were enrolled in this study, including 101 children with obesity and 55 lean controls. Anthropometric parameters and clinical data of all subjects were collected, and circulating tumor necrosis factor-α, adiponectin, leptin, copeptin, and nesfatin-1 levels were measured using ELISA.. Serum copeptin and nesfatin-1 levels were significantly elevated in children with obesity and children with insulin resistance compared to control subjects. In addition, nesfatin-1 and copeptin levels were found to be significantly positively correlated with one another by Pearson's correlation and partial correlation. In multiple regression analysis using nesfatin-1 or copeptin as the dependent parameter, a significant correlation was observed between nesfatin-1 and copeptin, and associations between each of them with homeostasis model assessment of insulin resistance (HOMA-IR) were detected.. These novel findings shed light on the possible interplay role of these 2 molecules in obesity-related insulin resistance.

Topics: Adiponectin; Anthropometry; Biomarkers; Case-Control Studies; Child; China; Female; Glycopeptides; Humans; Insulin Resistance; Leptin; Male; Nucleobindins; Pediatric Obesity; Regression Analysis

Aging and chronic glucocorticoid excess share a number of critical features, including the development of central obesity, insulin resistance and osteoporosis. Previous studies have shown that skeletal glucocorticoid signalling increases with aging and that osteoblasts mediate the detrimental skeletal and metabolic effects of chronic glucocorticoid excess. Here, we investigated whether endogenous glucocorticoid action in the skeleton contributes to metabolic dysfunction during normal aging.. As they aged, wild-type mice became obese and insulin-resistant. In contrast, HSD2. Skeletal glucocorticoid signalling is critical for the development of leptin resistance, obesity and insulin resistance during aging. These findings underscore the skeleton's importance in the regulation of body weight and implicate osteoblastic/osteocytic glucocorticoid signalling in the aetiology of aging-related obesity and metabolic disease.

Topics: Adipose Tissue; Age Factors; Aging; Animals; Arcuate Nucleus of Hypothalamus; Body Composition; Body Weight; Bone and Bones; Brain; Female; Glucocorticoids; Glucose; Hypothalamus; Insulin; Insulin Resistance; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Mice, Transgenic; Obesity; Signal Transduction; Thermogenesis

The aim of the study was to evaluate the main and interactive effects of chromium(III) propionate complex (Cr3) supplementation and different iron supply on the carbohydrate metabolism, lipid profile and other selected biochemical parameters of rats. The experiment was carried out in a two-factor design, in which rats were fed a diet with different proportions of Fe(III) and Cr(III) for six weeks. Fifty-four healthy female Wistar rats were divided into nine experimental groups with different Fe(III) levels, i.e. adequate-control group (45 mg/kg)-100% recommended daily dietary dose of Fe for rodents, deficient (5 mg/kg) and oversupply (180 mg/kg-400%). At the same time they were supplemented with Cr(III) of doses 1 (adequate), 50 and 500 mg/kg of diet. The activity and concentrations of most biochemical parameters were measured with standard enzymatic, kinetic, and colorimetric methods. HOMA-IR and QUICKI indexes were calculated according to appropriate formulas. It was found that there was an interactive effect of high Cr(III) doses and different Fe(III) levels in the diet on the carbohydrate metabolism and insulin resistance indexes. The presented results suggested that iron deficient diet fed animals led to insulin resistance; however, an effect is attenuated by Cr(III) supplementation at high doses. There were no significant changes in the rats' lipid profile (except for the high density lipoprotein cholesterol (HDL-C) level) and most of the other biochemical parameters, such as the leptin, aspartate aminotransferase (AST),

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Blood Urea Nitrogen; Carbohydrate Metabolism; Chromium; Creatinine; Dietary Supplements; Drug Interactions; Female; Insulin Resistance; Iron, Dietary; Leptin; Lipid Metabolism; Micronutrients; Rats, Wistar

Positive selection in Europeans at the 2q21.3 locus harboring the lactase gene has been attributed to selection for the ability of adults to digest milk to survive famine in ancient times. However, the 2q21.3 locus is also associated with obesity and type 2 diabetes in humans, raising the possibility that additional genetic elements in the locus may have contributed to evolutionary adaptation to famine by promoting energy storage, but which now confer susceptibility to metabolic diseases. We show here that the miR-128-1 microRNA, located at the center of the positively selected locus, represents a crucial metabolic regulator in mammals. Antisense targeting and genetic ablation of miR-128-1 in mouse metabolic disease models result in increased energy expenditure and amelioration of high-fat-diet-induced obesity and markedly improved glucose tolerance. A thrifty phenotype connected to miR-128-1-dependent energy storage may link ancient adaptation to famine and modern metabolic maladaptation associated with nutritional overabundance.

Topics: Adipocytes, Brown; Adiposity; Alleles; Animals; Cell Differentiation; Cell Line; Cells, Cultured; Diet, High-Fat; Energy Metabolism; Epigenesis, Genetic; Genetic Loci; Glucose; Homeostasis; Humans; Hypertrophy; Insulin Resistance; Leptin; Male; Mammals; Metabolic Diseases; Mice, Inbred C57BL; Mice, Obese; MicroRNAs; Obesity; Oligonucleotides; Species Specificity

What is the central question of this study? Studies reported the efficacy of metformin as a promising drug for preventing or treating of metabolic diseases. Nutrient stresses during neonatal life increase long-term risk for cardiometabolic diseases. Can early metformin treatment prevent the malprogramming effects of early overfeeding? What is the main finding and its importance? Neonatal metformin treatment prevented early overfeeding-induced metabolic dysfunction in adult rats. Inhibition of early hyperinsulinaemia and adult hyperphagia might be associated with decreased metabolic disease risk in these animals. Therefore, interventions during infant development offer a key area for future research to identify potential strategies to prevent the long-term metabolic diseases. We suggest that metformin is a potential tool for intervention.. Given the need for studies investigating the possible long-term effects of metformin use at crucial stages of development, and taking into account the concept of metabolic programming, the present work aimed to evaluate whether early metformin treatment might program rats to resist the development of adult metabolic dysfunctions caused by overnutrition during the neonatal suckling phase. Wistar rats raised in small litters (SLs, three pups per dam) and normal litters (NLs, nine pups per dam) were used as models of early overfeeding and normal feeding, respectively. During the first 12 days of suckling, animals from SL and NL groups received metformin, whereas the controls received saline injections. Food intake and body weight were monitored from weaning until 90 days of age, when biometric and biochemical parameters were assessed. The metformin treatment decreased insulin concentrations in pups from SL groups, and as adults, these animals showed improvements in glucose tolerance, insulin sensitivity, body weight gain, white fat pad stores and food intake. Low-glucose insulinotrophic effects were observed in pancreatic islets from both NL and SL groups. These results indicate that early postnatal treatment with metformin inhibits early overfeeding-induced metabolic dysfunctions in adult rats.

Topics: Adipose Tissue, White; Animals; Animals, Newborn; Blood Glucose; Body Composition; Body Weight; Female; Insulin; Insulin Resistance; Islets of Langerhans; Leptin; Male; Metabolic Diseases; Metformin; Obesity; Overnutrition; Rats; Rats, Wistar; Weight Gain

Recent evidence suggests that insulin resistance may play an important role in the pathogenesis of Alzheimer's disease (AD). In this study, the probable role of insulin resistance in the pathogenesis of AD was investigated in patients with Type 2 Diabetes Mellitus (T2DM).. Serum amyloid beta (Aβ) (1-42), insulin like growth factor-1 (IGF-1), sirtuin1 (SIRT1) and leptin protein levels were measured in serum samples of control (n = 26), probable AD (n = 26), and probable AD+T2DM patients (n = 12) using ELISA method. Mini mental state examination (MMSE) was performed to the patient and control groups.. Serum IGF-1 significantly increased in the probable AD+T2DM group as compared to the control and probable AD groups (p ˂ 0.05). The levels of serum leptin significantly decreased in the probable AD and AD+T2DM groups as compared to the control (p ˂ 0.05). There were no statistically significant differences in serum Aβ (1-42) and SIRT1 levels among groups (p > 0.05).. The significant decrease in serum leptin levels in AD patients may indicate that it may be a therapeutic marker in AD. The level of serum Aβ peptide and SIRT1 proteins can vary depending on the stage of the disease. Therefore, this study should be supported by more comprehensive studies in terms of the number of patients in advanced stage (Tab. 1, Fig. 4, Ref. 29).

Topics: Alzheimer Disease; Amyloid beta-Peptides; Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Leptin; Sirtuin 1

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

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

The prevalence of obesity-related disorders has been steadily increasing over the past couple of decades. Diseases that were once only detected in adults are now prevalent in children, such as hyperlipidemia. The adipose tissue-derived hormonal factor C1q TNF Related Protein 3 (CTRP3) has been linked to triglyceride regulation especially in animal models. However, the relationship between circulating CTRP3 levels and obesity-related disorders in human subjects is controversial. CTRP3 can circulate in different oligomeric complexes: trimeric (<100 kDa), middle molecular weight (100-300 kDa), and high molecular weight (HMW) oligomeric complexes (>300 kDa). Previous work has identified that it is not the total amount of CTRP3 present in the serum, but the specific circulating oligomeric complexes that appear to be indicative of the relationship between CTRP3 and serum lipids levels. However, this work has not been examined in children. Therefore, the purpose of this study was to compare the levels of different oligomeric complexes of CTRP3 and circulating lipid levels among young children (aged 7-10 years).. Morphometric data and serum samples were collected and analyzed from a cross-sectional population of 62 children of self-identified Hispanic origin from a community health center, between 2015 and 2016. Serum analysis included adiponectin, insulin, leptin, ghrelin, glucagon, C-reactive peptide, triglyceride, cholesterol, IL-6, TNF, and CTRP3. Correlation analyses were conducted to explore the relationships between CTRP3 and other biomarkers.. Total CTRP3 concentrations were significantly positively correlated with total cholesterol and HDL cholesterol. Whereas, HMW CTRP3 was not significantly associated with any variable measured. Conversely, the middle molecular weight (MMW) CTRP3 was negatively correlated with triglycerides levels, and very low-density lipoprotein (VLDL), insulin, and body mass index (BMI). The negative correlations between MMW CTRP3 and triglycerides and VLDLs were particularly strong (r2 = -0.826 and -0.827, respectively).. Overall, these data indicate that the circulating oligomeric state of CTRP3 and not just total CTRP3 level is important for understanding the association between CTRP3 and metabolic diseases. Further, this work indicates that MMW CTRP3 plays an important role in triglyceride and VLDL regulation which requires further study.

Topics: Adiponectin; Biomarkers; Body Mass Index; Child; Female; Humans; Insulin; Insulin Resistance; Leptin; Male; Obesity; Triglycerides; Tumor Necrosis Factors

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

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

Topics: Animals; Diet; Diet, High-Fat; Dietary Supplements; Dose-Response Relationship, Drug; Eating; Energy Metabolism; Female; Folic Acid; Gene Expression; Hypothalamus; Insulin Resistance; Lactation; Leptin; Parturition; Phenotype; Pregnancy; Rats; Rats, Wistar; Tetrahydrofolates; Weaning; Weight Gain

The prepubertal stage is a critical period of body fat development, in which leptin and insulin re sistance has been associated, however, there are few studies in normal-weight prepubescents. Ob jective: To assess the relationship between leptin and body composition and insulin resistance in a group of normal-weight prepubescents.. Analytical cross-sectional study with 128 healthy prepubescents of normal weight, aged between 6 and 10 years. Height, weight, body mass index (BMI), body fat percentage (BFP), waist circumference (WC), and hip circumference (HC) were measured. Plasma leptin (ng/mL) and insulin (mU/L) were evaluated by immunoassay and glycemia (mmol/L) by enzymatic method. HOMA-IR was calculated. A comparison study and correlation analysis by sex were performed.. Females presented higher values than males of leptin (6.8 ± 5 vs 3.3 ± 3.7; p = 0.000), insulin (7.1 ± 4.5 vs 5.2 ± 2.5; p = 0.016), BFP (22.4 ± 4.3 vs 18.6 ± 3.9; p = 0.000), and HC (67 ± 5.7 vs 65.0 ± 4.5; p = 0.019), and a lower waist/hip ratio (0.84 ± 0.04 vs 0.88 ± 0.04; p = 0.000). Leptin correlations with anthropometric variables were significant in both sexes, with greater association in females. The association of HOMA-IR with leptin was similar in both sexes.. in normal-weight prepubescents aged between 6-10 years, there are sex differences in adiposity and leptin levels not associated with differences in BMI or insulin resistance. The greater association of leptin with adiposity in girls could be related to a high rate of adipogenesis induced by this hormone.

Topics: Adiposity; Blood Glucose; Body Composition; Body Height; Body Mass Index; Body Weight; Child; Cross-Sectional Studies; Female; Humans; Ideal Body Weight; Insulin; Insulin Resistance; Leptin; Male; Sex Characteristics; Sex Factors

There exists little human neuroscience research to explain why some individuals lose their appetite when they become depressed, while others eat more. Answering this question may reveal much about the various pathophysiologies underlying depression. The present study combined neuroimaging, salivary cortisol, and blood markers of inflammation and metabolism collected prior to scanning. We compared the relationships between peripheral endocrine, metabolic, and immune signaling and brain activity to food cues between depressed participants experiencing increased (N = 23) or decreased (N = 31) appetite and weight in their current depressive episode and healthy control participants (N = 42). The two depression subgroups were unmedicated and did not differ in depression severity, anxiety, anhedonia, or body mass index. Depressed participants experiencing decreased appetite had higher cortisol levels than subjects in the other two groups, and their cortisol values correlated inversely with the ventral striatal response to food cues. In contrast, depressed participants experiencing increased appetite exhibited marked immunometabolic dysregulation, with higher insulin, insulin resistance, leptin, CRP, IL-1RA, and IL-6, and lower ghrelin than subjects in other groups, and the magnitude of their insulin resistance correlated positively with the insula response to food cues. These findings provide novel evidence linking aberrations in homeostatic signaling pathways within depression subtypes to the activity of neural systems that respond to food cues and select when, what, and how much to eat. In conjunction with prior work, the present findings strongly support the existence of pathophysiologically distinct depression subtypes for which the direction of appetite change may be an easily measured behavioral marker.

Topics: Adolescent; Adult; Appetite; C-Reactive Protein; Depression; Female; Ghrelin; Humans; Hydrocortisone; Inflammation; Insulin; Insulin Resistance; Interleukin 1 Receptor Antagonist Protein; Interleukin-6; Leptin; Male; Middle Aged; Saliva; Young Adult

In Traditional Korean and Chinese medicine, the herbal remedy Yijin (Erchen)-Tang (YJT) is widely used to treat obesity-related disorders, and its therapeutic potential has been demonstrated in numerous studies. However, the systemic effect of YJT on obesity status and change of lipid metabolism by YJT still remains unknown.. This study aimed to investigate the therapeutic mechanism of the YJT on obesity by using lipidomics.. To evaluate the effects of treatment with YJT on obesity, C57BL/6 J mice were fed a high-fat and high-cholesterol (HFHC, 40% fat and 1% cholesterol) diet for 8 weeks and treated them with YJT for an additional 6 weeks. We then performed untargeted lipidomic analysis using ultra-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry mass spectroscopy coupled with multivariate statistical analysis.. YJT ameliorated obesity induced systemic inflammation and improved insulin resistance. Additionally, YJT protected against HFHC-diet-induced hepatic inflammation. To explore specific changes in lipid metabolism associated with the therapeutic effects of YJT, we performed untargeted lipid profiling of the plasma. Partial least squares-discriminant analysis (PLS-DA) score plots showed that YJT altered the lipid metabolic pattern of HFHC mice. In particular, ceramides and triglycerides with saturated fatty acids and monounsaturated fatty acids were significantly changed by YJT, which were significantly associated with insulin resistance, the AGE-RAGE signaling pathway in diabetic complications and adipocytokine signaling pathway in pathway enrichment analysis. Thus, we analyzed the changes in adipocytes and adipokine caused by YJT, and confirmed that YJT alleviated adipocytes inflammation and macrophage infiltration, and reversed HFHC-induced alterations in leptin and adiponectin levels in adipose tissue and plasma.. These data suggest that YJT ameliorates obesity-induced systemic inflammation and insulin resistance by regulating lipid metabolism, and demonstrated that lipidomic profiling is a useful method to investigate the therapeutic effects of herbal decoctions in traditional Korean and Chinese medicine.

Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Cholesterol; Diet, High-Fat; Insulin Resistance; Leptin; Lipid Metabolism; Lipidomics; Male; Medicine, Korean Traditional; Mice, Inbred C57BL; Obesity; Panniculitis; Plant Extracts; Triglycerides

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

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

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

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

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

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

The physiological role of leptin is thought to be a driving force to reduce food intake and increase energy expenditure. However, leptin therapies in the clinic have failed to effectively treat obesity, predominantly due to a phenomenon referred to as leptin resistance. The mechanisms linking obesity and the associated leptin resistance remain largely unclear. With various mouse models and a leptin neutralizing antibody, we demonstrated that hyperleptinemia is a driving force for metabolic disorders. A partial reduction of plasma leptin levels in the context of obesity restores hypothalamic leptin sensitivity and effectively reduces weight gain and enhances insulin sensitivity. These results highlight that a partial reduction in plasma leptin levels leads to improved leptin sensitivity, while pointing to a new avenue for therapeutic interventions in the treatment of obesity and its associated comorbidities.

Topics: Animals; Antibodies, Neutralizing; Eating; Energy Metabolism; Insulin; Insulin Resistance; Leptin; Mice; Mice, Inbred Strains; Obesity; Weight Loss; Weight Reduction Programs

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

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

The importance of hypothalamic leptin and insulin resistance in the development and maintenance of obesity remains unclear. The tyrosine phosphatases protein tyrosine phosphatase 1B (PTP1B) and T cell protein tyrosine phosphatase (TCPTP) attenuate leptin and insulin signaling and are elevated in the hypothalami of obese mice. We report that elevated PTP1B and TCPTP antagonize hypothalamic leptin and insulin signaling and contribute to the maintenance of obesity. Deletion of PTP1B and TCPTP in the hypothalami of obese mice enhances CNS leptin and insulin sensitivity, represses feeding, and increases browning, to decrease adiposity and improve glucose metabolism. The daily intranasal administration of a PTP1B inhibitor, plus the glucocorticoid antagonist RU486 that decreases TCPTP expression, represses feeding, increases browning, promotes weight loss, and improves glucose metabolism in obese mice. Our findings causally link heightened hypothalamic PTP1B and TCPTP with leptin and insulin resistance and the maintenance of obesity and define a viable pharmacological approach by which to promote weight loss in obesity.

Topics: Adipose Tissue, White; Administration, Intranasal; Animals; Blood-Brain Barrier; Cholestanes; Diet, High-Fat; Feeding Behavior; Gliosis; Glucocorticoids; Hypothalamus; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mifepristone; Obesity; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatase, Non-Receptor Type 2; Spermine; Weight Loss

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

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

Obesity and associated metabolic comorbidities represent a growing public health problem. In this study, we demonstrate the use of a newly created fusion gene of exendin-4 and α1-antitrypsin to control obesity and obesity-associated metabolic disorders including insulin resistance, fatty liver and hyperglycemia. The fusion gene encodes a protein with exendin-4 peptide placed at the N-terminus of human α-1 antitrypsin, and is named EAT. Hydrodynamic transfer of the EAT gene to mice prevents high-fat diet-induced obesity, insulin resistance and fatty liver development. In diet-induced obese mice, expression of EAT gene induces weight loss, improves glucose homeostasis, and attenuates hepatic steatosis. In ob/ob mice, EAT gene transfer suppresses body weight gain, maintains metabolic homeostasis, and completely blocks fatty liver development. Six-month overexpression of the EAT fusion gene in healthy mice does not lead to any detectable toxicity. Mechanistic study reveals that the resulting metabolic benefits are achieved by a reduced food take and down-regulation of transcription of pivotal genes responsible for lipogenesis and lipid droplet formation in the liver and chronic inflammation in visceral fat. These results validate the feasibility of gene therapy in preventing and restoring metabolic homeostasis under diverse pathologic conditions, and provide evidence in support of a new strategy to control obesity and related metabolic diseases.

Topics: Adiposity; alpha 1-Antitrypsin; Animals; Anti-Obesity Agents; Diet, High-Fat; Exenatide; Gene Expression Regulation; Genetic Vectors; Glucose; Insulin Resistance; Leptin; Male; Mice, Inbred C57BL; Mice, Obese; Non-alcoholic Fatty Liver Disease; Obesity; Protein Engineering; Recombinant Fusion Proteins; Weight Gain

Insulin resistance is an important clinical feature of metabolic syndrome, which includes obesity and type 2 diabetes. Increased adipose energy storage in obesity promote insulin resistance and other metabolic adverse effects. To identify a new link between adipocyte and insulin resistance, we performed targeted metabolite profiling of differentiated adipocytes and studied the association between adipogenic metabolites and insulin resistance. We found a correlation between 2-aminoadipic acid (2-AAA) and adipogenic differentiation. Also, circulatory 2-AAA was positively associated with obesity-related factors (fat mass, fat percent, waist circumference, BMI, BMI z-score, triglycerides, insulin, and HOMA-IR) at baseline and after 2 years in the children cohort study. Of these factors, increased BMI z-score and HOMA-IR were the primary independent factors associated with higher 2-AAA levels, and the baseline 2-AAA level was an indicator of the BMI z-score after 2 years. To validate the relationship between 2-AAA and obesity-related factors, we analyzed changes in 2-AAA levels following obesity intervention programs in two independent studies. In both studies, changes in 2-AAA levels during the intervention period were positively correlated with changes in the BMI z-score and HOMA-IR after adjusting for confounders. Moreover, the 2-AAA levels were increased in cell and mouse models of obesity-related insulin resistance. Excess 2-AAA levels led to impaired insulin signaling in insulin-sensitive cells (liver, skeletal muscle and adipose cells) and caused abnormal gluconeogenesis. Our results demonstrate that 2-AAA is associated with adipogenesis and insulin resistance. In this regard, 2-AAA could be a potential biomarker of obesity and obesity-related metabolic disorders.

Topics: 2-Aminoadipic Acid; Adipocytes; Adipogenesis; Adipose Tissue; Adiposity; Adolescent; Animals; Biomarkers; Blood Glucose; Body Mass Index; Cell Differentiation; Child; Cohort Studies; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Humans; Insulin; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Pediatric Obesity; Republic of Korea; Triglycerides; Waist Circumference

The flavonoid myricitrin exhibits various pharmacological and physiological effects. However, studies on the effects of myricitrin on obesity are limited. We hypothesized that dietary myricitrin would attenuate the adiposity and metabolic dysfunction that occur in obesity. To test this hypothesis, mice were randomly fed a high-fat diet (HFD) or HFD supplemented with myricitrin for 16 weeks. Myricitrin significantly reduced white adipose tissue (WAT) mass, adipocyte size, and plasma leptin levels, and also attenuated dyslipidemia. These changes appeared to result from increased energy expenditure and activation of the carnitine acyltransferase (CPT) and

Topics: Adipose Tissue, White; Adiposity; Animals; Diet, High-Fat; Dietary Supplements; Dyslipidemias; Fatty Liver; Flavonoids; Inflammation; Insulin Resistance; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Obesity

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

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

The present study was designed to evaluate the relationship between bone traits [bone mineral density (BMD) and trabecular bone score (TBS)] and the accumulation of fat in adipose tissues [abdominal subcutaneous (SAT), visceral (VAT), marrow (MAT) and intrahepatic lipids (IHL)], as well as insulin resistance, in subjects with Cushing's disease (CD). The study included control (C = 27), paired (P = 16) and Cushing's disease (CD = 10) groups, which underwent biochemical assessment, dual X-ray absorptiometry, TBS, and magnetic resonance imaging to determine fat deposits. The CD group showed higher serum levels of glucose and insulin, as well as HOMA-IR values, but lower circulatory levels of osteocalcin, in comparison to C and P. The CD group exhibited lower L1-L4 BMD than P (P = 1.059 ± 0.141 vs CD = 0.935 ± 0.093 g/cm2, p < 0.05) (Fig 1A). The lumbar spine BMD from the C group was similar to the other groups. TBS was lower in CD than in P and C (C = 1.512±0.077 vs P = 1.405±0.150 vs CD = 1.135±0.136; p<0.05); there was also significant difference between C and P (p<0.05). MAT, VAT, and IHL were higher in CD than in C and P (p<0.05). Considering all subjects, there was a positive association between TBS with both lumbar spine BMD (R2 = 0.45; p<0.0001) and osteocalcin (R2 = 0.44; p = 0.05). TBS was negatively associated with MAT (R2 = 0.49; p = 0.01), VAT (R2 = 0.55; p<0.05), and HOMA-IR (R2 = 0.44; p<0.01). MAT was positively related with VAT (R2 = 0.44; p<0.01) and IHL (R2 = 0.41; p<0.05). In CD, insulin resistance and adipose tissue dysfunction, including high MAT, are active players in bone deterioration, as confirmed by lower lumbar spine BMD and lower TBS. Thus, our findings point to an additional component of the already well-known complex mechanisms of osteoporosis associated with hypercortisolism.

Topics: Adiponectin; Adipose Tissue; Adult; Body Weight; Bone and Bones; Bone Density; Bone Marrow; Cancellous Bone; Humans; Insulin Resistance; Leptin; Linear Models; Lipids; Metabolic Syndrome; Pituitary ACTH Hypersecretion

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

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

To investigate the relationship between insulin resistance indices ["Revised quantitative insulin sensitivity check index" (RQUICKI; RQ), "Revised quantitative insulin sensitivity check index - β-hydroxybutyrate" (RQUICKI

Topics: 3-Hydroxybutyric Acid; Animals; Animals, Newborn; Cattle; Fatty Acids, Nonesterified; Female; Insulin; Insulin Resistance; Leptin; Male; Pregnancy

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

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

In obese patients, sleeve gastrectomy (SG) has shown mixed results on bile acid (BA) values. The aim of our study was to examine the potential ultra-early and early changes of the circulating total BA in relation with the changes of insulin resistance (IR) in obese patients submitted to laparoscopic SG.

Topics: Adult; Bile Acids and Salts; Female; Gastrectomy; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Obesity

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

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

Estrogens protect against diet-induced obesity in women and female rodents. For example, a lack of estrogens in postmenopausal women is associated with an increased risk of weight gain, cardiovascular diseases, low-grade inflammation, and cancer. Estrogens act with leptin to regulate energy homeostasis in females. Leptin-deficient mice (ob/ob) exhibit morbid obesity and insulin resistance. The gut microbiome is also critical in regulating metabolism. The present study investigates whether estrogens and leptin modulate gut microbiota in ovariectomized ob/ob (obese) or heterozygote (lean) mice fed high-fat diet (HFD) that received either 17β-Estradiol (E2) or vehicle implants. E2 attenuated weight gain in both genotypes. Moreover, both obesity (ob/ob mice) and E2 were associated with reduced gut microbial diversity. ob/ob mice exhibited lower species richness than control mice, while E2-treated mice had reduced evenness compared with vehicle mice. Regarding taxa, E2 was associated with an increased abundance of the S24-7 family, while leptin was associated with increases in Coriobacteriaceae, Clostridium and Lactobacillus. Some taxa were affected by both E2 and leptin, suggesting these hormones alter gut microbiota of HFD-fed female mice. Understanding the role of E2 and leptin in regulating gut microbiota will provide important insights into hormone-dependent metabolic disorders in women.

Topics: Animals; Diet, High-Fat; Estradiol; Feeding Behavior; Female; Gastrointestinal Microbiome; Insulin Resistance; Leptin; Mice; Mice, Obese; Weight Gain

To compare the effects of a palatable cafeteria diet on serum parameters and neuroinflammatory markers of young and aged female Wistar rats.. Three-month-old (young) and 18-month-old (aged) female Wistar rats had access to a cafeteria diet (Caf-Young, Caf-Aged) or a standard chow diet (Std-Young, Std-Aged).. The Caf-Young group showed a higher food consumption, weight gain, visceral fat depot, serum insulin and leptin levels, and the insulin resistance index (HOMA-IR) than the Std-Young group. The Caf-Aged group exhibited an increase in interleukin-1 levels in the cerebral cortex and hippocampus. The number of GFAP-positive cells did not differ between the groups, but there was a diet effect in the cerebral cortex and an age effect in the hippocampus. Phospho-tau expression did not differ between the groups.. The 3- and 18-month-old rats responded differently to a cafeteria diet. Insulin and leptin levels are elevated in young animals fed a cafeteria diet, whereas aged animals are prone to neuroinflammation (indicated by an increase in interleukin-1β levels). A combination of hypercaloric diet and senescence have detrimental effects on the inflammatory response in the brain, which may predispose to neurological diseases.

Topics: Aging; Animals; Blood Glucose; Brain; Cerebral Cortex; Diet, High-Fat; Encephalitis; Female; Hippocampus; Insulin; Insulin Resistance; Leptin; Neuroglia; Rats, Wistar; tau Proteins

Topics: Adult; Anthropometry; Antipsychotic Agents; Blood Glucose; Body Composition; Body Mass Index; Diabetes Mellitus, Type 2; Female; Glucose; Humans; Insulin; Insulin Resistance; Leptin; Male; Psychotic Disorders; Siblings; Signal Transduction; Triglycerides

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

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

Leptin (LPT) is associated with a number of cardiovascular risk factors, such as high blood pressure (BP), insulin resistance and excess in body weight. Some studies find an unfavorable cross-sectional association between LPT and renal disease, in particular in patients with already known kidney dysfunction. There are few data on the relationship between LPT and changes in renal function over time in subjects without evidence of kidney dysfunction. Hence, the aim of this study is to estimate the predictive role of LPT on the decline in renal function occurring in an 8-year follow-up observation of a sample of adult apparently healthy men (The Olivetti Heart Study). The study includes 319 untreated normotensive and nondiabetic men without clinical evidence of renal dysfunction (creatinine clearance-CrCl > 60 mL/min/1.73 m

Topics: Adult; Biomarkers; Blood Pressure; Body Mass Index; Cross-Sectional Studies; Female; Humans; Insulin Resistance; Kidney Diseases; Kidney Function Tests; Leptin; Male; Middle Aged; Prospective Studies; Risk Factors

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

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

(1) Examine associations of a branched-chain amino acid (BCAA) metabolite pattern with metabolic risk across adolescence; (2) use Least Absolute Shrinkage and Selection Operator (LASSO) to identify novel metabolites of metabolic risk.. We used linear regression to examine associations of a BCAA score with change (∆) in metabolic biomarkers over 5-year follow-up in 179 adolescents 8-14 years at baseline. Next, we applied LASSO, a regularized regression technique well suited for reduction of high-dimensional data, to identify metabolite predictors of ∆biomarkers.. In boys, the BCAA score corresponded with decreasing C-peptide, C-peptide-based insulin resistance (CP-IR), total cholesterol (TC), and low-density-lipoprotein cholesterol (LDL). In pubertal girls, the BCAA pattern corresponded with increasing C-peptide and leptin. LASSO identified asparagine as a predictor of decreasing C-peptide (β = -0.33) and CP-IR (β = -0.012), and acetyl-carnitine (β = 2.098), 4-hydroxyproline (β = -0.050), ornithine (β = -0.353), and α-aminoisobutyric acid (β = -0.793) as determinants of TC in boys. In girls, histidine was a negative determinant of TC (β = -0.033).. The BCAA pattern was associated with ∆glycemia and ∆lipids in a sex-specific manner. LASSO identified asparagine, which influences growth hormone secretion, as a determinant of decreasing C-peptide and CP-IR in boys, and metabolites on lipid metabolism pathways as determinants of decreasing cholesterol in both sexes.

Topics: Acetylcarnitine; Adolescent; Amino Acids, Branched-Chain; Aminoisobutyric Acids; Asparagine; Biomarkers; Blood Glucose; Body Composition; Body Mass Index; C-Peptide; Carnitine; Child; Cholesterol; Female; Humans; Hydroxyproline; Hyperglycemia; Insulin Resistance; Leptin; Male; Metabolome; Ornithine; Prospective Studies; Puberty; Regression Analysis; Risk Factors

Rates of obesity have been growing at alarming rates, compromising the health of the world population. Thus, the search for interventions that address the metabolic repercussions of obesity are necessary. Here we evaluated the metabolic and antioxidant effects of zinc and branched-chain amino acids (BCAA) supplementation on obese rats. Male Wistar rats were fed either a high-fat/high-fructose diet (HFD) or a standard diet (SD) for 19 weeks. From the fifteenth week until the end of the experiment, HFD- and SD-fed rats received zinc (6 mg/kg) or BCAA (750 mg/kg) supplementation. Body weight, abdominal fat, lipid profile, blood glucose, insulin, leptin, and hepatic transaminases were evaluated. In the liver, superoxide dismutase and catalase activities and lipid peroxidation were also analyzed. HFD-fed animals showed increased weight gain, abdominal fat pad, plasma insulin, leptin, and triglycerides levels in comparison with SD-fed rats. Zinc supplementation reduced all these parameters, suggesting a beneficial role for the treatment of obesity. BCAA, on the other hand, did not show any beneficial effect. Liver antioxidant enzymes and hepatic transaminases plasma levels did not change among groups. Lipid peroxidation was higher in HFD-fed rats and was not reverted by zinc or BCAA supplementation. In conclusion, zinc supplementation may be a useful strategy for the treatment of the metabolic dysfunction associated with obesity.

Topics: Amino Acids, Branched-Chain; Animals; Antioxidants; Blood Glucose; Diet, High-Fat; Dietary Supplements; Insulin; Insulin Resistance; Leptin; Lipid Peroxidation; Lipids; Male; Obesity; Random Allocation; Rats, Wistar; Zinc

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

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

Neuregulin 4 (Nrg4), a newly identified adipokine secreted by brown adipose tissue, is hypothesised to play a crucial role in metabolism. The present study aimed to evaluate the association between serum Nrg4 levels and non-alcoholic fatty liver disease (NAFLD) in children with obesity in China. A total of 123 children with obesity were included in this study. Anthropometric and biochemical parameters were measured in all subjects. NAFLD was diagnosed using ultrasonography. The serum levels of Nrg4, leptin and adiponectin were measured by enzyme-linked immunosorbent assay. NAFLD was identified in 58 children with obesity (47.2%). Serum Nrg4 levels were significantly lower in the NAFLD group (2.24 [1.20, 3.22] ng/mL) than in the control group (5.50 [2.45, 10.85] ng/mL) (p < 0.001). Serum Nrg4 levels were negatively correlated with most of the anthropometric and biochemical parameters (p < 0.05) but were positively correlated with high-density lipoprotein cholesterol (p < 0.05). In multiple stepwise regression analyses, serum Nrg4 levels were independently related with WHtR (β = -2.009, p = 0.048) and homeostasis model assessment of insulin resistance (β = -0.524, p = 0.005). Furthermore, a multivariable logistic regression analysis of NAFLD prediction by Nrg4 revealed an odds ratio of 0.129 (95% confidence interval: 0.028-0.587, p < 0.01). The receiver operating characteristic curve analysis of the diagnostic value of using serum Nrg4 levels to differentiate NAFLD in children with obesity showed that the area under the curve was 0.723; the cutoff for serum Nrg4 levels to have diagnostic value for predicting NAFLD in children with obesity was 3.39 ng/mL. Elevated Nrg4 is associated with a decreased risk of NAFLD in children with obesity.

Topics: Adolescent; Blood Glucose; Body Mass Index; Child; China; Female; Humans; Insulin; Insulin Resistance; Leptin; Lipids; Male; Neuregulins; Non-alcoholic Fatty Liver Disease; Pediatric Obesity; Risk Factors; ROC Curve; Waist Circumference; Waist-Height Ratio

A large part of the daily intake of children in the U.S. consists of snacks, with the average child consuming three snacks per day. Despite this, little research has been conducted to determine the metabolic and behavioral effects of snacking. Using a developing female rat model, our studies aimed to determine the effects of snacking during development before the protective effects of estrogen on weight gain would be relevant. Additionally, to determine if snack composition is important, we created one healthy and one unhealthy snacking group provided with chow and three snacks each in addition to a chow-only group. We found that both snacking groups experienced increased weight gain, elevated abdominal fat pad mass, prolonged leptin resistance into adulthood, and insulin insensitivity that was not observed in their non-snacking counterparts. These physiological differences were measured despite both snacking groups having a similar caloric intake as the chow-only group throughout the study. In addition to physiological changes, both snacking groups showed a preference for snacks over chow and ate more often during the inactive light phase than typical for rats, with the unhealthy snacking group presenting this behavioral change earlier than the healthy snacking group. Our results suggest that constant access to palatable snacks, which is often the case for children in western countries, alters feeding behaviors in relation to food choice and time of day when eating occurs. Snacking during development seemed to promote signs of metabolic syndrome in adulthood even when excess caloric intake was not observed. Our work further suggests that development is a vulnerable time for palatable snack presentation when prepubertal females lack the protective effects of estrogen and exhibit reduced leptin feedback on food intake. Thus snacking from weaning onward could be a contributor to the current childhood obesity crisis.

Topics: Abdominal Fat; Animals; Body Composition; Eating; Estrogens; Feeding Behavior; Female; Food Preferences; Glucose Tolerance Test; Insulin Resistance; Leptin; Rats; Rats, Long-Evans; Snacks; Weight Gain

Leptin (LPT) is associated with unfavourable cardio-metabolic risk profile. Although a number of studies have found a positive association between LPT and insulin resistance (IR), no observational study has evaluated a prospective association to detect a predictive role of LPT in IR. Therefore, the aim of this study was to estimate the role of LPT on the incidence of IR in an 8-year follow-up of a sample of adult men (The Olivetti Heart Study).. The study included 527 not diabetic men without IR (homeostasis model assessment - HOMA index < 2.77 UI) at baseline. Baseline LPT was significantly and positively associated with HOMA index, body mass index (BMI), waist circumference and blood pressure. At the end of the 8-year follow-up period, a positive and significant association was detected between baseline LPT and changes in HOMA index (r = 0.25, p < 0.01) and incidence of IR (OR: 2.6, 95%CI: 1.9-3.4). This trend was also confirmed after adjustment for potential confounders. In addition, the predictive value of LPT was found in subjects who had not experienced any weight increase over the years, and for normal weight and excess body weight participants, separately.. The results of this prospective study suggest a predictive role of circulating LPT levels on a reduction of insulin sensitivity over time, independently of main potential confounders, in non-diabetic men without IR at baseline. In addition, in normal weight individuals, LPT levels were associated with development of IR.

Topics: Adult; Aged; Biomarkers; Follow-Up Studies; Glucose Metabolism Disorders; Humans; Incidence; Insulin Resistance; Italy; Leptin; Male; Middle Aged; Prognosis; Prospective Studies; Risk Factors; Time Factors

Obesity is a continually growing pandemic leading to many diseases that affect the overall quality of life. The widely marketed Garcinia cambogia (GC) and Raspberry ketone (RK) were used in this study. Despite their known dietetic effect, however, the metabolomic/signaling pathways involved in this effect are not fully elucidated. Hence, our study comprehends the possible trajectories of their combination against obesity and insulin resistance in addition to exploring their combination merit.. Adult male Wistar rats were divided into 5 groups; viz., normal diet (ND), high fat fructose diet (HFFD), HFFD+GC (600mg/kg), HFFD+RK (55mg/kg) and HFFD+GC+RK. To assess our aim, we determined their effect on body weight, IPGTT, glucose homeostasis (glucose, insulin, HOMA IR), lipid profile parameters and SREBP-1c, oxidative stress markers, insulin and leptin signaling pathways (p-IRS-1/p-AKT/GLUT-4, and leptin/STAT-3), as well as liver and adipose tissue histopathology.. GC/RK combinationcaused weight loss, corrected the disturbed glucose and insulin homeostasis, raised serum levels of HDL anddecreased all other lipid profile parameters. They also increased Nrf-2 expression, ad GSH, as well as p-IRS-1/p-Akt/GLUT-4 cue, while they decreased MDA, leptin/STAT-3 and SREBP-1c content compared to the HFFD group. Furthermore, the GC/RK combination abolished apoptosis, fatty changes and inflammation in hepatocytes and decreased sclerotic blood vessels and congestion in adipose tissue.. Our study highlights the involvement ofp-IRS-1/p-Akt/GLUT-4, leptin/STAT-3 and SREBP-1c signaling trajectories in the beneficial combination of GC and RK, besides, the efficient rebalance of the redox status, insulin resistance and tissue fat deposition confirmed histopathologically.

Topics: Adiposity; Animals; Butanones; Diet, High-Fat; Fructose; Garcinia cambogia; Insulin Resistance; Leptin; Male; Obesity; Plant Extracts; Rats; Rats, Wistar; Signal Transduction

An observational, prospective, cohort study was performed to assess changes in insulin sensitivity and serum leptin level after a switch from a ritonavir-boosted PI (PI/r) to raltegravir or dolutegravir in HIV-infected adults on stable combination ART (cART).. Non-diabetic HIV-infected patients receiving suppressive cART including tenofovir disoproxil fumarate/emtricitabine plus one PI/r, who underwent a switch from the PI/r to raltegravir (group A) or dolutegravir (group B), were enrolled in the study. Serum levels of insulin, leptin and the homeostasis model assessment of insulin resistance (HOMA) index were evaluated during a 12 month follow-up.. Overall, 86 patients were enrolled: 45 patients were included in group A and 41 were included in group B. The mean age was 45.7 years and 74 (86%) patients were male. After 12 months of follow-up, a significant reduction in the mean concentration of leptin and insulin was reported both in group A [-0.61 ng/mL (P < 0.001) and -2.5 mIU/L (P = 0.008), respectively] and in group B [-0.54 ng/mL (P = 0.005) and -2.1 mIU/L (P = 0.017), respectively], without a significant difference between the groups. A significant and comparable reduction in the mean HOMA index was reported both in group A [-0.55 (P = 0.004)] and in group B [-0.49 (P < 0.001)], as well as a significant decrease in lipid levels.. In HIV-positive subjects on suppressive cART, the switch from a PI/r to raltegravir or dolutegravir led to a significant and comparable reduction in both HOMA index and serum leptin level, reflecting a similar and significant improvement in insulin sensitivity.

Topics: Adult; Antiretroviral Therapy, Highly Active; Biomarkers; Coinfection; Drug Substitution; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Oxazines; Piperazines; Prospective Studies; Pyridones; Raltegravir Potassium; Risk Factors; Ritonavir; Treatment Outcome; Viral Load

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

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

This study aimed to evaluate the longitudinal association of vitamin D status with glycaemia, insulin, homoeostatic model assessment of insulin resistance, adiponectin and leptin. A prospective cohort with 181 healthy, pregnant Brazilian women was followed at the 5th-13th, 20th-26th and 30th-36th gestational weeks. In this cohort, 25-hydroxyvitamin D (25(OH)D) plasma concentrations were analysed using liquid chromatography-tandem MS. Vitamin D status was categorised as sufficient or insufficient using the Endocrine Society Practice Guidelines (≥75/<75 nmol/l) and the Institute of Medicine (≥50/<50 nmol/l) thresholds. Linear mixed-effect regression models were employed to evaluate the association between vitamin D status and each outcome, considering interaction terms between vitamin D status and gestational age (P<0·1). At baseline, 70·7 % of pregnant women had 25(OH)D levels <75 nmol/l and 16 % had levels <50 nmol/l. Women with sufficient vitamin D status at baseline, using both thresholds, presented lower glycaemia than those with insufficient 25(OH)D. Pregnant women with 25(OH)D concentrations <75 nmol/l showed lower insulin (β=-0·12; 95 % CI -0·251, 0·009; P=0·069) and adiponectin (β=-0·070; 95 % CI -0·150, 0·010; P=0·085) concentrations throughout pregnancy than those with 25(OH)D levels ≥75 nmol/l. Pregnant women with 25(OH)D <50 nmol/l at baseline presented significantly higher leptin concentrations than those with 25(OH)D levels ≥50 nmol/l (β=-0·253; 95 % CI -0·044, 0·550; P=0·095). The baseline status of vitamin D influences the biomarkers involved in glucose metabolism. Vitamin D-sufficient women at baseline had higher increases in insulin and adiponectin changes throughout gestation than those who were insufficient.

Topics: Adipokines; Adiponectin; Adult; Blood Glucose; Brazil; Cohort Studies; Diabetes, Gestational; Diet; Female; Gestational Age; Humans; Insulin; Insulin Resistance; Leptin; Pregnancy; Pregnancy Complications; Prospective Studies; Vitamin D; Vitamin D Deficiency

Metabolic Syndrome (MetS) affects 35% of American adults > 40 yr and portends an increased risk for both atherosclerotic cardiovascular disease (ASCVD) and diabetes. The role of mast cells in the proinflammatory state of MetS is not well elucidated. We propose that mast cells in subcutaneous adipose tissue (SAT) of MetS patients without diabetes or clinical ASCVD contribute to insulin resistance and inflammation. Matched controls ( n = 15) and MetS ( n = 19) subjects were recruited from Sacramento, CA, and selected based on Adult Treatment Panel III criteria. SAT biopsy was performed on all subjects and processed for immunohistochemistry. The SAT sections were stained using Astra Blue stain and tryptase stain for mast cells. Fasting blood was obtained for chemistries and biomarkers. Abundance of mast cells (Astra Blue stain) in SAT of MetS subjects compared with controls was increased 2.5-fold ( P < 0.0001). Mast cells correlated positively and significantly with waist circumference, glucose, triglycerides, homeostatic model of assessment-insulin resistance (HOMA-IR), AT insulin resistance, leptin, interleukin (IL)-1β, IL-6, chemerin, p38 MAPK activity, and nuclear factor κB activity in circulating monocytes. Mast cells also correlated significantly with markers of fibrosis and angiogenesis. Tryptase staining of mast cells in AT revealed a significant increase ( P = 0.008) with similar correlations. We make the novel observation that there are increased mast cells in SAT of MetS, and these mast cells correlate with insulin resistance (hepatic and adipose tissue), inflammation, and AT fibrosis. Hence, these immune cells appear to occupy a pivotal role in the pathogenesis of MetS.

Topics: Adipose Tissue; Adult; Aged; Blood Glucose; Case-Control Studies; Chemokines; Female; Fibrosis; Humans; Inflammation; Insulin Resistance; Interleukin-1beta; Interleukin-6; Leptin; Male; Mast Cells; Metabolic Syndrome; Middle Aged; Monocytes; Neovascularization, Pathologic; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Subcutaneous Fat; Triglycerides; Waist Circumference; Young Adult

The aim of the study was to investigate whether altered adipose tissue secretion of various adipokines is secondary to obesity, hyperandrogenism, and hyperinsulinemia or intrinsic to polycystic ovary syndrome (PCOS). This cross-sectional study included 151 women diagnosed with PCOS by the Rotterdam criteria and 95 healthy women matched by age, body mass index (BMI), and waist-to-hip ratio (WHR). Clinical, biochemical, and hormonal characteristics were assessed. Serum concentrations of ghrelin and adiponectin were found to be significantly lower and concentrations of leptin and resistin significantly higher in women with PCOS than in healthy women matched by age, BMI, and WHR. A PCOS diagnosis made the largest contribution to predicting serum levels of leptin, adiponectin, resistin, and ghrelin in all stepwise multiple regression models, which included PCOS diagnosis, BMI, WHR, luteinizing hormone, total testosterone, free testosterone and homeostatic model assessment of insulin resistance as independent predictors. Leptin, adiponectin, ghrelin and resistin levels may serve as independent biomarkers for the diagnosis of PCOS.

Topics: Adiponectin; Adult; Biomarkers; Body Mass Index; Cross-Sectional Studies; Female; Ghrelin; Humans; Insulin Resistance; Leptin; Polycystic Ovary Syndrome; Resistin; Waist-Hip Ratio; Young Adult

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

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

Insulin and leptin may increase growth and proliferation of thyroid cells, underlying an association between type 2 diabetes and papillary thyroid cancer (PTC). Patients with extreme insulin resistance due to lipodystrophy or insulin receptor mutations (INSR) are treated with high-dose insulin and recombinant leptin (metreleptin), which may increase the risk of thyroid neoplasia.. The aim of this study was to analyze thyroid structural abnormalities in patients with lipodystrophy and INSR mutations and to assess whether insulin, IGF-1, and metreleptin therapy contribute to the thyroid growth and neoplasia in this population.. Thyroid ultrasound characteristics were analyzed in 81 patients with lipodystrophy and 11 with INSR (5 homozygous; 6 heterozygous). Sixty patients were taking metreleptin.. The prevalence of thyroid nodules in children with extreme insulin resistance (5 of 30, 16.7%) was significantly higher than published prevalence for children (64 of 3202; 2%), with no difference between lipodystrophy and INSR. Body surface area-adjusted thyroid volume was larger in INSR homozygotes vs heterozygotes or lipodystrophy (10.4 ± 5.1, 3.9 ± 1.5, and 6.2 ± 3.4 cm2, respectively. Three patients with lipodystrophy and one INSR heterozygote had PTC. There were no differences in thyroid ultrasound features in patients treated vs not treated with metreleptin.. Children with extreme insulin resistance had a high prevalence of thyroid nodules, which were not associated with metreleptin treatment. Patients with homozygous INSR mutation had thyromegaly, which may be a novel phenotypic feature of this disease. Further studies are needed to determine the etiology of thyroid abnormalities in patients with extreme insulin resistance.

Topics: Adolescent; Adult; Aged; Child; Cysts; Female; Humans; Insulin Resistance; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Leptin; Lipodystrophy; Male; MAP Kinase Signaling System; Middle Aged; Mutation; Receptor, Insulin; Syndrome; Thyroid Gland; Young Adult

The prevalence of obesity, metabolic syndrome and type 2 diabetes mellitus is increased among patients with severe mental disorders, and particularly use of second generation antipsychotic drugs is associated with metabolic side effects. Antipsychotics have been found to alter levels of adipokines which regulate insulin sensitivity, but their role in antipsychotic-associated insulin resistance is not established, and it is unclear whether adipokines affect insulin resistance independently of body mass index (BMI).. We included 1050 patients with severe mental disorders and 112 healthy controls aged 18-65 years from the Oslo area, Norway. Clinical variables, BMI and use of medication were assessed, fasting blood samples were obtained for calculation of the leptin/adiponectin ratio (L/A ratio) and estimate of insulin resistance using the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). Case-control analyses were followed by mediation analyses to evaluate the possible direct effect of antipsychotics on HOMA-IR and indirect effect mediated via the L/A ratio. This was performed both with and without adjustment for BMI, in the total sample and in an antipsychotic monotherapy subsample (N = 387).. BMI, L/A ratio and HOMA-IR were significantly higher in patients than controls (p < 0.001-p = 0.01). There was a significant direct effect from use of antipsychotics in general on HOMA-IR both without (b = 0.03, p = 0.007) and with adjustment for BMI (b = 0.03, p = 0.013), as well as a significant mediating effect via L/A ratio both without (b = 0.03, p < 0.001) and with adjustment for BMI (b = 0.01, p = 0.041). Use of olanzapine (b = 0.03, p < 0.001) or aripiprazole (b = 0.04, p < 0.001) in monotherapy showed significant effects on HOMA-IR mediated via L/A ratio.. The study suggests that use of antipsychotics may alter adipokine levels, and that increased L/A ratio may play a role in the development of insulin resistance associated with use of antipsychotics also independently of BMI.

Topics: Adipokines; Adult; Antipsychotic Agents; Blood Glucose; Body Mass Index; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Humans; Insulin; Insulin Resistance; Leptin; Male; Mental Disorders; Metabolic Syndrome; Middle Aged; Norway; Obesity

To investigate the association between visceral adipose tissue loss and insulin resistance and hyperleptinemia in adolescents with obesity submitted to interdisciplinary weight-loss therapy.. A total of 172 post-pubertal adolescents (body mass index greater than the 95th percentile of the Centers for Disease Control and Prevention reference growth charts) were recruited for the study. The adolescents were assigned to long-term weight-loss therapy. Body composition, visceral and subcutaneous fat, glucose metabolism, lipid profile, hepatic enzymes and leptin concentration were measured. After the therapy, the adolescents were allocated to three different groups according to the tertile of visceral fat reduction.. Positive effects on body composition were observed in all analysed groups independent of visceral fat reduction. It was found that visceral fat was an independent predictor of insulin resistance in the investigated population. Obese adolescents who lost a higher proportion of visceral adipose tissue (>1.8 cm) demonstrated improved metabolic and inflammatory parameters twice as much than those who presented smaller losses. Positive correlations between visceral fat reduction and glucose metabolism, lipid profile, hepatic enzymes and homeostasis model assessment of insulin resistance index were demonstrated.. The magnitude of the reduction in visceral fat was an independent predictor of insulin resistance, hyperleptinemia and metabolic disorders related to obese adolescents.

Topics: Adiposity; Adolescent; Age Factors; Biomarkers; Blood Glucose; Female; Health Status; Humans; Insulin; Insulin Resistance; Intra-Abdominal Fat; Leptin; Lipids; Male; Metabolic Syndrome; Pediatric Obesity; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Weight Loss; Young Adult

Protein tyrosine phosphatase 1B (PTP1B) has been considered as a validated biological target for type 2 diabetes treatment, but past endeavors to develop inhibitors of PTP1B into drugs have been unsuccessful. Two challenging aspects are selective inhibition and cell permeability. A structure-based strategy was employed to develop uncharged bromophenols as a new series of PTP1B inhibitors. The most potent compound 22 (LXQ46) inhibited PTP1B with an IC

Topics: Animals; Body Weight; Cell Line; Diabetes Mellitus, Type 2; Drug Evaluation, Preclinical; Enzyme Inhibitors; Insulin; Insulin Resistance; Leptin; Mice; Molecular Docking Simulation; Obesity; Phenols; Phosphorylation; Protein Conformation; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Proto-Oncogene Proteins c-akt; Safety; Signal Transduction

non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder in the western world. Although NAFLD prevalence is higher in patients with a BMI > 25 kg /m2, it is unclear if there are differences between overweight and obese patients. The associated biochemical, dietary and genetic parameters were compared between overweight and obese patients with NAFLD.. patients with biopsy-proven NAFLD (n = 203) were enrolled in a cross-sectional study. The MEDAS questionnaire was used to assess adherence to the Mediterranean diet. Biochemical, anthropometrical parameters and the I148M variant (rs738409) of the PNPLA3 gene and rs180069 of the TNF-α gene were evaluated.. overweight patients had higher serum adiponectin levels (22.5 ± 21.9 vs 11.2 ± 18.1 ng/ml; p < 0.05) and lower resistin (3.3 ± 1.7 vs 8.1 ± 8 ng/ml; p < 0.001) and leptin concentrations (22.9 ± 21.9 vs 55.8 ± 45 ng/ml; p < 0.001) than obese patients. Non-alcoholic steatohepatitis (NASH) was more frequent in the obese group (59.3% vs 41.3%; p = 0.02). The multivariate analysis showed adherence to the Mediterranean diet to be an independent protective factor for NASH and liver fibrosis in overweight patients (OR 0.7, 95% CI 0.5-0.8).. NASH was more prevalent in obese patients than in overweight subjects. HOMA-IR and adherence to the Mediterranean diet provided protection against fibrosis in overweight patients. Adherence to the Mediterranean diet was the only independent factor associated with NASH in these patients.

Topics: Adiponectin; Adult; Analysis of Variance; Biopsy, Needle; Body Mass Index; Cross-Sectional Studies; Diet, Mediterranean; Female; Humans; Insulin Resistance; Leptin; Lipase; Liver; Male; Membrane Proteins; Metabolic Syndrome; Middle Aged; Non-alcoholic Fatty Liver Disease; Obesity; Overweight; Polymorphism, Single Nucleotide; Prevalence; Resistin; Surveys and Questionnaires; Tumor Necrosis Factor-alpha

This study aims to investigate the correlation between oxidative stress and intra-abdominal fat (IAF) in obese young and middle-aged males.The present study included 136 male examinees in the Examination Center of the First Hospital of Qinhuangdao from October 10, 2015 to December 10, 2015. Then, clinical data, oxidative stress indices (8-iso-prostaglandin F2α [8-iso-PGF2α], malondialdehyde [MDA], and superoxide dismutase [SOD]), and IAF area were recorded. All subjects were assigned into 3 groups according to body mass index (BMI): obese group (BMI ≥ 28 kg/m, 43 subjects), overweight group (24 ≤ BMI < 28 kg/m, 46 subjects), and control group (BMI < 24 kg/m, 47 subjects). Then, statistical analysis was performed.There were significant differences in IAF area, leptin, adiponectin, 8-iso-PGF2α, MDA, SOD, fasting insulin (FINS), fasting blood glucose (FBG), and homeostasis model assessment-insulin resistance (HOMA-IR) among these 3 groups (P < .05). Male subjects in the obese group had higher leptin, 8-iso-PGF2α, MDA, FINS, and HOMA-IR levels, compared to subjects in the overweight and control groups. Furthermore, subjects in the overweight group had a larger IAF area and higher 8-iso-PGF2α, MDA, and FBG levels, when compared to controls. In addition, SOD was significantly lower in the obese and overweight groups than in the control group. However, there were no statistical differences in age, systolic and diastolic blood pressure, lipids, and islet β-cell secretion function (homeostasis model assessment-β) among these 3 groups (P ≥ .05). Moreover, the IAF area was positively correlated to 8-iso-PGF2α and MDA, and negatively correlated to SOD.Oxidative stress is significantly associated with the IAF area in obese males, and abdominal obesity could increase oxidative stress level and insulin resistance.

Topics: Adiponectin; Adult; Blood Glucose; Body Mass Index; Dinoprost; Humans; Insulin Resistance; Intra-Abdominal Fat; Leptin; Male; Malondialdehyde; Middle Aged; Obesity; Oxidative Stress; Superoxide Dismutase; Young Adult

"Accelerated aging," assessed by adult DNA methylation, predicts cardiovascular disease (CVD). Adolescent accelerated aging might predict CVD earlier. We investigated whether epigenetic age acceleration (assessed age, 17 years) was associated with adiposity/CVD risk measured (ages 17, 20, and 22 years) and projected CVD by middle age.. DNA methylation measured in peripheral blood provided two estimates of epigenetic age acceleration: intrinsic (IEAA; preserved across cell types) and extrinsic (EEAA; dependent on cell admixture and methylation levels within each cell type). Adiposity was assessed by anthropometry, ultrasound, and dual-energy x-ray absorptiometry (ages 17, 20, and 22 years). CVD risk factors [lipids, homeostatic model assessment of insulin resistance (HOMA-IR), blood pressure, inflammatory markers] were assessed at age 17 years. CVD development by age 47 years was calculated by Framingham algorithms. Results are presented as regression coefficients per 5-year epigenetic age acceleration (IEAA/EEAA) for adiposity, CVD risk factors, and CVD development.. In 995 participants (49.6% female; age, 17.3 ± 0.6 years), EEAA (per 5 years) was associated with increased body mass index (BMI) of 2.4% (95% CI, 1.2% to 3.6%) and 2.4% (0.8% to 3.9%) at 17 and 22 years, respectively. EEAA was associated with increases of 23% (3% to 33%) in high-sensitivity C-reactive protein, 10% (4% to 17%) in interferon-γ-inducible protein of 10 kDa, and 4% (2% to 6%) in soluble TNF receptor 2, adjusted for BMI and HOMA-IR. EEAA (per 5 years) results in a 4% increase in hard endpoints of CVD by 47 years of age and a 3% increase, after adjustment for conventional risk factors.. Accelerated epigenetic age in adolescence was associated with inflammation, BMI measured 5 years later, and probability of middle age CVD. Irrespective of whether this is cause or effect, assessing epigenetic age might refine disease prediction.

Topics: Absorptiometry, Photon; Adiponectin; Adolescent; Aging; Aging, Premature; Algorithms; Blood Pressure; Body Composition; Body Mass Index; C-Reactive Protein; Cardiovascular Diseases; Chemokine CXCL10; Cholesterol, HDL; Cholesterol, LDL; DNA Methylation; Epigenesis, Genetic; Female; Humans; Inflammation; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Interleukin-18; Leptin; Male; Middle Aged; Receptors, Tumor Necrosis Factor, Type II; Risk Assessment; Risk Factors; Western Australia; Young Adult

Growing evidence suggests an independent relationship between obstructive sleep apnea syndrome (OSAS) and metabolic syndrome (MS). Patients with OSAS always show clustering of metabolic components. However, the understanding of interplay between OSAS and metabolic components is still lacking.. Participants were consecutively enrolled from our sleep center during the period 2009-2013. Anthropometric variables, metabolic indicators, and sleep parameters were collected from all participants. The factor structure for MS in OSAS and non-OSAS was examined by confirmatory factor analysis.. The OSAS and non-OSAS demonstrated clustering of metabolic components. MS in patients with OSAS was strongly associated with insulin resistance (standardized factor loading = 0.93, p < 0.001), obesity (loading = 0.92, p < 0.001), and the lipid profile (loading = 0.72, p < 0.001). Furthermore, insulin resistance was correlated with obesity and lipid profile (r = 0.86, p < 0.001; r = 0.68, p < 0.001, respectively). Obesity and lipid profile were also highly correlated in OSAS (r = 0.66, p < 0.001). In non-OSAS, MS was strongly associated with insulin resistance, obesity, and lipid profile (loading = 0.95, p < 0.001; loading = 0.74, p < 0.001; loading = 0.68, p < 0.001, respectively). Insulin resistance was most strongly associated with fasting insulin (loading = 0.65, p < 0.001). Lipid profile was most strongly associated with TG (loading = 0.88, p < 0.001). Obesity was most strongly associated with BMI (loading = 0.80, p < 0.001).. OSAS is more prone to show clustering of metabolic components compared with non-OSAS. In particular, insulin resistance, obesity, and the lipid profile were independently and strongly correlated with MS in OSAS.

Topics: Adult; Body Mass Index; Female; Humans; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Middle Aged; Obesity; Polysomnography; Risk Factors; Sleep Apnea, Obstructive

Background: the aim of this study was to evaluate the intake of nutrients, anthropometric parameters, health indicators, adipokines and insulin levels in a population of young undergraduates. Method: in this study, 378 young undergraduates were invited to participate. Due to the inclusion criteria and their own decision of participating, 90 attended the anthropometric, health indicators: waist circumference (WC), waist to hip ratio (WHR), waist to height ratio (WHtR), and homeostatic model assessment-insulin resistance index (HOMA-IR) studies and completed the questionnaire of frequency of food intake; and 34 participants were selected to perform the determination of biochemical parameters, insulin and adipokines levels: leptin, IL-6, IL-8, tumor necrosis factor alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1) and hepatocyte growth factor (HGF). Results: according to WC, WHR and WHtR, obese population showed health, cardiovascular and metabolic risk. Overweight population showed cardiometabolic risk. In general, lipid intake was higher than 30%, being animal fat the most consumed. The levels of leptin (women: 17.2 ± 9.2, 28 ± 11.3, 36.8 ± 17.8; men: 4.3 ± 3.6, 9.5 ± 3.1, 24.6 ± 16.4 to lean overweight and obese, respectively) and insulin (women: 408 ± 182, 438 ± 187, 768 ± 167; men: 244 ± 88, 520 ± 256, 853 ± 590) increased along with body mass index (BMI), body fat percentage (BFP), visceral fat area (VFA), WC, WHR and WHtR. Lean (2.4 ± 1.3), overweight (2.2 ± 0.9) and obese (4.3 ± 1.1) women and overweight (2.8 ± 1.2) and obese (5.0 ± 3.1) men showed insulin resistance according to HOMA-IR. Significant correlation between leptin and HOMA-IR was found (p = 0.41). BMI, BFP, VFA, WC, and WHtR positively correlated with leptin (p = 0.67, 0.75, 0.66, 0.60, 0.67, respectively) and insulin (p = 0.37, 0.40, 0.48, 0.49, 0.42, respectively), while WHR only with insulin (p = 0.43). No significant differences were found in the other adipokines. Conclusion: the use of health indicators such VFA, WC, WHR, WHtR and HOMA-IR are useful tools in the determination of health, cardio vascular and metabolic risk and are correlated with levels of leptin and insulin in the studied population.. Introducción: el objetivo de este estudio fue evaluar la ingesta de nutrientes, parámetros antropométricos, indicadores de salud, adipocinas y niveles de insulina en una población de jóvenes universitarios con una dieta habitual. Método: en este estudio se invitó a participar a 378 jóvenes universitarios. Debido a los criterios de inclusión y su propia decisión de participar, 90 asistieron a los estudios antropométricos y de indicadores de salud: circunferencia de cintura (WC), índice de cadera cintura (WHR), índice de cintura-talla (WHtR) y modelo homeostático de evaluación-índice de resistencia a la insulina (HOMA-IR) y completaron el cuestionario de frecuencia de ingesta de alimentos. Treinta y cuatro participantes fueron seleccionados para realizar la determinación de los parámetros bioquímicos, niveles de insulina y adipocinas (leptina, IL-6, IL-8, factor de necrosis tumoral alfa [TNF-α], proteína quimioatractante de monocitos-1 [MCP-1] y factor de crecimiento hepático [HGF]). Resultados: de acuerdo con WC, WHR y WHtR, la población obesa mostró riesgo cardiovascular, metabólico y para la salud. La población con sobrepeso mostró riesgo cardiometabólico. En general, la ingesta de lípidos fue superior al 30% y la grasa animal fue la más consumida. Los niveles de leptina (mujeres: 17,2 ± 9,2, 28 ± 11,3, 36,8 ± 17,8; hombres: 4,3 ± 3,6, 9,5 ± 3,1, 24,6 ± 16,4 para delgados, sobrepeso y obesos, respectivamente) e insulina (mujeres: 408 ± 182, 438 ± 187, 768 ± 167; hombres: 244 ± 88, 520 ± 256, 853 ± 590) aumentaron junto con el índice de masa corporal (BMI), porcentaje de grasa corporal (BFP), área de grasa visceral (VFA), WC, WHR y WHtR. Las mujeres delgadas (2,4 ± 1,3), con sobrepeso (2,2 ± 0,9) y obesas (4,3 ± 1,1) y los hombres con sobrepeso (2,8 ± 1,2) y obesos (5,0 ± 3,1) mostraron resistencia a la insulina de acuerdo con HOMA-IR. Se encontró una correlación significativa entre leptina y HOMA-IR (p = 0,41). BMI, BFP, VFA, WC y WHtR correlacionaron positivamente con leptina (p = 0,67, 0,75, 0,66, 0,60 y 0,67, respectivamente) e insulina (p = 0,37, 0,40, 0,48, 0,49 y 0,42, respectivamente), mientras que el WHR solo con insulina (p = 0,43). No se encontraron diferencias significativas en las otras adipocinas. Conclusión: el uso de indicadores de salud como VFA, WC, WHR, WHtR y HOMA-IR es una herramienta útil en la determinación del riesgo metabólico, cardiovascular y de salud, y dichos indicadores correlacionaron con los niveles de leptina e insulina en

Topics: Adipokines; Adiposity; Anthropometry; Body Composition; Body Mass Index; Cross-Sectional Studies; Diet; Feeding Behavior; Female; Humans; Insulin Resistance; Leptin; Male; Obesity; Overweight; Sex Factors; Students; Waist Circumference; Waist-Hip Ratio; Young Adult

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

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

Obesity has become a global health-threat for every age group. It is well known that young mice (10-12 weeks of age) fed a western-type diet (WD) become obese and develop higher cholesterol levels and liver steatosis whereas insulin sensitivity is reduced. Less is known, however, about the effect of a WD on advanced-age mice. Therefore, 10 week-old (young) and 22 month-old (advanced-age), male C57BL/6JRj mice were kept on either a WD or a control diet (SFD) for 15 weeks. In contrast to young mice, advanced-age mice on WD did not show a higher body weight or adipose tissue (AT)-masses, suggesting a protection against diet-induced obesity. Furthermore, plasma adiponectin and leptin levels were not affected upon WD-feeding. A WD, however, did induce more hepatic lipid accumulation as well as increased hepatic expression of the macrophage marker F4/80, in advanced-age mice. There were no significant differences in mRNA levels of uncoupling protein-1 or F4/80 in brown AT (BAT) or of several intestinal integrity markers in colon suggesting that the protection against obesity is not due to excessive BAT or to impaired intestinal absorption of fat. Thus, advanced-age mice, in contrast to their younger counterparts, appeared to be protected against diet-induced obesity.

Topics: Adipose Tissue; Adipose Tissue, Brown; Age Factors; Animals; Diet, Western; Fatty Liver; Glucose; Insulin Resistance; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Obesity; Uncoupling Protein 1

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

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

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

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

Aromatase deficiency causes obesity and insulin resistance in aromatase knockout mice and humans with rare mutations of the aromatase gene (CYP19). Aromatase inhibitors are a commonly prescribed therapy for postmenopausal breast cancer.. We hypothesized that aromatase inhibitors induce obesity and insulin resistance when used in treatment of breast cancer.. Case-control study.. University teaching hospital.. Patients with postmenopausal breast cancer (n = 20) treated with aromatase inhibitors and 20 age-matched control subjects.. The primary outcome measure was insulin sensitivity index - Matsuda, derived from a 75-g oral glucose tolerance test. Body composition was assessed by dual energy x-ray absorptiometry and biopsy specimens of subcutaneous adipose tissue obtained for assessment of mRNA transcript levels. Data are reported as mean ± SEM (patients receiving inhibitors vs control group, respectively).. Aromatase inhibitor therapy was associated with significantly lower insulin sensitivity (5.15 ± 0.45 vs 6.80 ± 0.64; P = 0.041), higher peak insulin concentration after oral glucose tolerance test (693.4 ± 78.6 vs 527.6 ± 85.5 pmol/L; P = 0.035), greater percentage of body fat (38.4% ± 1.0% vs 34.6% ± 1.3%; P = 0.026), and higher plasma leptin concentration (23.5 ± 2.8 vs 15.5 ± 2.3 ng/mL; P = 0.035).. Women who received aromatase inhibitors for postmenopausal breast cancer had greater percentage body fat and insulin resistance compared with control subjects with no history of breast cancer.

Topics: Adipose Tissue; Adiposity; Aged; Aromatase Inhibitors; Breast Neoplasms; Case-Control Studies; Female; Follow-Up Studies; Glucose Tolerance Test; Gonadal Steroid Hormones; Humans; Insulin; Insulin Resistance; Leptin; Middle Aged; Postmenopause; Prognosis

Familial partial lipodystrophy type 2 (FPLD2) is characterized by insulin resistance, adipose atrophy of the extremities and central obesity. Due to the resemblance with Cushing's syndrome, we hypothesized a putative role of glucocorticoid in the pathogenesis of metabolic abnormalities in FPLD2.. To evaluate the phenotypic heterogeneity and glucocorticoid sensitivity in FPLD2 patients exhibiting the p.R482W or p.R644C LMNA mutations.. Prospective study with FPLD2 patients (n = 24) and controls (n = 24), who underwent anthropometric, body composition, metabolic profile and adipokines/cytokine plasma measurements. Plasma and salivary cortisol were measured in basal conditions and after 0.25, 0.5 and 1.0 mg of dexamethasone (DEX) given at 23:00 hours. Glucocorticoid receptor (GR) and 11βHSD isoforms expression were assessed by qPCR.. Familial partial lipodystrophy type 2 individuals presented increased waist and neck circumferences, decreased hip circumference, peripheral skinfold thickness and fat mass. Patients presented increased HOMA-IR, triglycerides, TNF-α, IL-1β, IL-6 and IL-10, and decreased adiponectin and leptin plasma levels. FPLD2 patients showed decreased ability to suppress the HPA axis compared with controls after 0.5 mg DEX. The phenotype was more pronounced in patients harbouring the p.R482W LMNA mutation. GRβ overexpression in PBMC was observed in female patients compared with female controls.. Familial partial lipodystrophy type 2 patients exhibited anthropometric, clinical and biochemical phenotypic heterogeneity related to LMNA mutation sites and to gender. LMNA mutations affecting both lamin A and lamin C lead to more severe phenotype. FPLD2 patients also showed blunted HPA axis response to DEX, probably due to the association of increased levels of proinflammatory cytokines with GRβ overexpression leading to a more severe phenotype in female.

Topics: Adiponectin; Body Composition; Dexamethasone; Female; Glucocorticoids; Humans; Hydrocortisone; Insulin Resistance; Interleukin-10; Interleukin-1beta; Interleukin-6; Lamin Type A; Leptin; Lipodystrophy, Familial Partial; Male; Mutation; Prospective Studies; Protein Isoforms; Receptors, Glucocorticoid; Tumor Necrosis Factor-alpha

To investigate the cord blood levels of adipokine and to assess their association with the fetal insulin resistance and fetal outcomes in newborns of gestational diabetic women (GDM). Methods: This cross-sectional study was performed in 40 GDM women and 40 healthy pregnant women (HPW) in the Department of Obstetrics and Gynecology at Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER) hospital in Puducherry, India, during the period from May 2016 to December 2017. Cord blood samples were collected at delivery from GDM and HPW groups. Cord plasma biochemical parameters such as insulin, C-peptide, adiponectin, leptin, resistin, and visfatin concentrations were measured. Leptin/adiponectin ratio (L/A), homeostasis model assessment of insulin resistance (HOMA2-IR), insulin sensitivity (HOMA2-%S) and beta cell function (HOMA2-%B) were calculated. The pregnancy outcomes such as birth weight (BW), Ponderal index and Apgar scores of the baby were measured. Results: The BW and Ponderal index of the baby were found to be significantly higher in GDM newborns compared to HPW newborns. Cord plasma insulin, C-peptide, HOMA2 -IR, visfatin, leptin, and L/A ratio were significantly higher whereas adiponectin level was lower in GDM compared to HPW. A significant positive correlation was observed between L/A ratio and fetal HOMA2-IR. Conclusion: Altered adipokine levels with increased L/A ratio was observed among the new-borns of Indian gestational diabetic mothers. There was an association between increased L/A ratio, insulin resistance and increased Ponderal index among the new-borns.

Topics: Adipokines; Apgar Score; Biomarkers; Birth Weight; C-Peptide; Cross-Sectional Studies; Diabetes, Gestational; Female; Fetal Blood; Humans; India; Infant, Newborn; Insulin; Insulin Resistance; Leptin; Nicotinamide Phosphoribosyltransferase; Pregnancy; Pregnancy Outcome; Resistin

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

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

The consumption of diets rich in fat and refined sugars is recognized to be one of the causes of lifestyle disorders, and dietary fibres are being advocated to ameliorate the complications associated with these disorders. In the present study, the effects of two soluble fermentable fibres, viz., gum acacia and inulin on the progression of adiposity, insulin resistance, and the expression of genes related to metabolism were examined in C57BL/6 mice fed a high-fat and sucrose diet for 18 weeks. The feeding of either type of fibre resulted in decrease in body weight, epididymal fat mass, adipocyte size, hyperlipidaemia, hyperglycaemia and hyperinsulinemia. In the fibre-fed groups, the expressions of adiponectin and glucose transporter 4 in the epididymal fat increased significantly, while the expressions of leptin, interleukin 6 and tumor necrosis factor alpha decreased significantly. Moreover, the expressions of genes related to beta-oxidation, viz., carnitine palmitoyltransferase 1, peroxisome proliferator-activated receptor gamma co-activator 1β, and peroxisome proliferator-activated receptor alpha in the liver tissue of the fibre-fed groups enhanced significantly. Furthermore, due to the feeding of either type of fibre, the expressions of zonula occludens 1 and fasting-induced adipose factor in the distal ileum and proglucagon in the colon increased significantly. From the results of the present study, it can be concluded that the beneficial effects of the fibres are mediated due to enhanced energy expenditure, improved intestinal integrity, and reduced inflammation.

Topics: Adiponectin; Adiposity; Animals; Carnitine O-Palmitoyltransferase; Diet, High-Fat; Dietary Sucrose; Glucose Transporter Type 4; Gum Arabic; Humans; Insulin; Insulin Resistance; Inulin; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity

This study aimed to examine changes in the insulin secretory response in early pregnancy, while accounting for changes in insulin sensitivity.. This is a secondary analysis of a previously conducted longitudinal physiological study. In 34 women, insulin secretory response (by IVGTT) and insulin sensitivity (by euglycaemic clamp) were assessed prior to pregnancy, in early pregnancy (12-14 weeks gestation) and in late pregnancy (34-36 weeks gestation). Using mixed-effects models, we compared insulin secretory response and sensitivity in early pregnancy to the same variables prior to pregnancy and in late pregnancy, with adjustment for age, obesity status and gestational diabetes mellitus (GDM). We examined changes in insulin secretory response after adjustment for insulin sensitivity using both multivariate modelling and the disposition index (DI). We explored the relationship between insulin secretory response and circulating hormones.. The insulin secretory response increased from prior to pregnancy to early pregnancy (unadjusted mean [SD] first-phase insulin response 465.1 [268.5] to 720 [358.2], p < 0.0001) and from early pregnancy to late pregnancy (to 924 [494.6], p = 0.01). Insulin sensitivity increased from prior to pregnancy to early pregnancy (insulin sensitivity index 0.10 [0.04] to 0.12 [0.05], p = 0.001) and decreased in late pregnancy (to 0.06 [0.03], p < 0.0001). Accounting for changes in insulin sensitivity, using either multivariate modelling or the DI, did not attenuate the early-pregnancy augmentation of insulin secretory response. Leptin was positively associated with insulin secretory response, independent of insulin sensitivity and adiposity (p = 0.004). Adjustment for leptin attenuated the observed augmentation of insulin secretory response in early pregnancy (adjusted mean change 121.5, p = 0.13).. The insulin secretory response increases markedly in early pregnancy, prior to and independent of changes in insulin sensitivity. Circulating hormones may mediate this metabolic adaptation. Identifying mediators of this physiological effect could have therapeutic implications for treating hyperglycaemia during and outside of pregnancy.

Topics: Adult; Age Factors; Blood Glucose; Body Mass Index; Cytokines; Diabetes, Gestational; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Leptin; Longitudinal Studies; Multivariate Analysis; Obesity; Pregnancy; Pregnancy Complications; Pregnancy Trimester, First; Pregnancy Trimester, Third; Prospective Studies; Tumor Necrosis Factor-alpha

The adipocyte expansion is a critical process with implications in the pathogenesis of obesity associated metabolic syndrome. Impaired adipogenesis leads to dysfunctional, hypertrophic adipocytes, local inflammation and peripheric insulin resistance.. We assessed the relationship between the adipogenic differentiation capacity of the subcutaneous adipose derived stem cells (ASCs), evaluated by total lipid accumulation, and the metabolic and hormonal profile in a group of obese female patients proposed for bariatric surgery (N = 20) versus normal weight female controls (N = 7).. The lipid accumulation (measured as optical density at 492 nm) of ASCs during their differentiation to adipocytes was significantly lower in ASCs isolated from obese patients as compared to ASCs isolated from normal weight patients (0.49 ± 0.1 vs. 0.71 ± 0.1, p < 0.001). Significant negative correlations between lipid accumulation in adipogenic differentiated ASCs and plasma concentrations of triglycerides (p < 0.01), insulin (p < 0.001), HOMA-IR (p < 0.01), adiponectin (p < 0.05) and leptin/adiponectin ratio (p < 0.05) were found in obese group.. In severely obese female patients, the abnormal adipogenesis is related to insulin resistance and leptin/adiponectin ratio. The abnormal lipid accumulation in the mature adipocyte derived from obese ASCs could possible predict the further development of type 2 diabetes mellitus in severely obese patients and influence the selection of patients for bariatric surgery.

Topics: Adiponectin; Adult; Bariatric Surgery; Cell Differentiation; Cells, Cultured; Female; Fluorescent Antibody Technique; Humans; Insulin Resistance; Leptin; Metabolic Syndrome; Middle Aged; Obesity; Subcutaneous Fat

Metabolic Syndrome (MetS) is a common global disorder that predisposes to both Type 2 diabetes mellitus (T2DM) and cardiovascular disease (ASCVD). Adipose tissue (AT) contributes significantly to increased inflammation and insulin resistance (IR) in MetS which appear to be the crucial underpinnings of MetS. Compared to macrophages and lymphocytes in human subcutaneous AT (SAT), there is sparse data on the role of other immune cells, especially eosinophils (EOS). In this study, we investigated the abundance of EOS in the SAT of 19 patients with MetS without diabetes, ASCVD, smoking or any inflammatory condition, and matched controls.. SAT EOS were quantified by immunohistochemistry.. Both circulating and SAT EOS were significantly increased 2-fold in MetS and correlated with each other. Circulating EOS correlated significantly with triglycerides (TG), high-sensitivity CRP, leptin, and IL-6. SAT EOS correlated significantly with plasma glucose, TG, FFA, adipose-IR, leptin, IL-6, endotoxin, chemerin and inversely with adiponectin. They also correlated with SAT markers of fibrosis: collagen and Sirius red staining of SAT.. We make the novel and seminal observation that eosinophils are increased in SAT of MetS patients, and are associated with the pro-inflammatory state. Hence, in humans, they appear to contribute to the dysregulation of SAT biology in MetS.

Topics: Adipose Tissue; Adult; Biomarkers; C-Reactive Protein; Eosinophils; Female; Humans; Inflammation; Insulin Resistance; Interleukin-6; Leptin; Male; Metabolic Syndrome; Middle Aged; Subcutaneous Fat; Triglycerides

Pregnancy increases sympathetic nerve activity (SNA), although the mechanisms responsible for this remain unknown. We tested whether insulin or leptin, two sympathoexcitatory hormones increased during pregnancy, contribute to this. Transport of insulin across the blood-brain barrier in some brain regions, and into the cerebrospinal fluid (CSF), was increased, although brain insulin degradation was also increased. As a result, brain and CSF insulin levels were not different between pregnant and non-pregnant rats. The sympathoexcitatory responses to insulin and leptin were abolished in pregnant rats. Blockade of arcuate nucleus insulin receptors did not lower SNA in pregnant or non-pregnant rats. Collectively, these data suggest that pregnancy renders the brain resistant to the sympathoexcitatory effects of insulin and leptin, and that these hormones do not mediate pregnancy-induced sympathoexcitation. Increased muscle SNA stimulates glucose uptake. Therefore, during pregnancy, peripheral insulin resistance coupled with blunted insulin- and leptin-induced sympathoexcitation ensures adequate delivery of glucose to the fetus.. Pregnancy increases basal sympathetic nerve activity (SNA), although the mechanism responsible for this remains unknown. Insulin and leptin are two sympathoexcitatory hormones that increase during pregnancy, yet, pregnancy impairs central insulin- and leptin-induced signalling. Therefore, to test whether insulin or leptin contribute to basal sympathoexcitation or, instead, whether pregnancy induces resistance to the sympathoexcitatory effects of insulin and leptin, we investigated α-chloralose anaesthetized late pregnant rats, which exhibited increases in lumbar SNA (LSNA), splanchnic SNA and heart rate (HR) compared to non-pregnant animals. In pregnant rats, transport of insulin into cerebrospinal fluid and across the blood-brain barrier in some brain regions increased, although brain insulin degradation was also increased; brain and cerebrospinal fluid insulin levels were not different between pregnant and non-pregnant rats. Although i.c.v. insulin increased LSNA and HR and baroreflex control of LSNA and HR in non-pregnant rats, these effects were abolished in pregnant rats. In parallel, pregnancy completely prevented the actions of leptin with respect to increasing lumbar, splanchnic and renal SNA, as well as baroreflex control of SNA. Blockade of insulin receptors (with S961) in the arcuate nucleus, the site of action of insulin, did not decrease LSNA in pregnant rats, despite blocking the effects of exogenous insulin. Thus, pregnancy is associated with central resistance to insulin and leptin, and these hormones are not responsible for the increased basal SNA of pregnancy. Because increases in LSNA to skeletal muscle stimulates glucose uptake, blunted insulin- and leptin-induced sympathoexcitation reinforces systemic insulin resistance, thereby increasing the delivery of glucose to the fetus.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Baroreflex; Female; Insulin; Insulin Resistance; Leptin; Peptides; Pregnancy; Rats; Rats, Sprague-Dawley; Receptor, Insulin; Sympathetic Nervous System

We investigated whether there are similar serum alterations in schizophrenia and major depressive disorder (MDD). We investigated serum analytes in two epidemiological studies on schizophrenia (N = 121) and MDD (N = 1172) versus controls. Serum analytes (N = 109) were measured with a multi-analyte profiling platform and analysed using linear regression models, adjusted for site, age, gender, ethnicity, anti-inflammatory agents, smoking, cardiovascular disease and diabetes, and adjusted for multiple comparisons. An increase in leptin and insulin levels was observed for both schizophrenia patients (Cohen's d (d): 0.26 and 0.65, respectively) and MDD patients (d: 0.29 and 0.12, respectively) compared to their respective controls. Lower angiopoietin-2 levels were seen in both schizophrenia (d: -0.22) and MDD (d: -0.13). Four analytes differed in only schizophrenia patients (increased levels of C-peptide and prolactin, and decreased levels of CD5 antigen-like and sex hormone binding globulin) and one analyte differed in only MDD patients (increased angiotensinogen levels) compared to their respective controls. Restricting analyses to patients with a current episode of disease showed even more marked elevations of insulin and leptin. Our results suggest the presence of insulin and leptin resistance as cross-disorder mechanisms that could contribute to the higher somatic comorbidity and decreased life-span seen in both disorders.

Topics: Adolescent; Adult; Case-Control Studies; Depressive Disorder, Major; Female; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Proteomics; Schizophrenia; Young Adult

Circadian rhythms are an inherent property of physiological processes and can be disturbed by irregular environmental cycles, including artificial light at night (ALAN). Circadian disruption may contribute to many pathologies, such as hypertension, obesity, and type 2 diabetes, but the underlying mechanisms are not understood. Our study investigated the consequences of ALAN on cardiovascular and metabolic parameters in spontaneously hypertensive rats, which represent an animal model of essential hypertension and insulin resistance. Adult males were exposed to a 12 h light - 12 h dark cycle and the ALAN group experienced dim light at night (1-2 lx), either for 2 or 5 weeks. Rats on ALAN showed a loss of light-dark variability for systolic blood pressure, but not for heart rate. Moreover, a gradual increase of systolic blood pressure was recorded over 5 weeks of ALAN. Exposure to ALAN increased plasma insulin and hepatic triglyceride levels. An increased expression of metabolic transcription factors,

Topics: Animals; Blood Pressure; Circadian Rhythm; Dose-Response Relationship, Radiation; Heart Rate; Insulin; Insulin Resistance; Leptin; Light; Male; Rats; Rats, Inbred SHR

Prolonged exposure to glucocorticoids (GCs) causes various metabolic derangements. These include obesity and insulin resistance, as inhibiting glucose utilization in adipose tissues is a major function of GCs. Although adipose tissue distribution and glucose homeostasis are sex-dependently regulated, it has not been evaluated whether GCs affect glucose metabolism and adipose tissue functions in a sex-dependent manner. In this study, high-dose corticosterone (rodent GC) treatment in C57BL/6J mice resulted in nonfasting hyperglycemia in male mice only, whereas both sexes displayed hyperinsulinemia with normal fasting glucose levels, indicative of insulin resistance. Metabolic testing using stable isotope-labeled glucose techniques revealed a sex-specific corticosterone-driven glucose intolerance. Corticosterone treatment increased adipose tissue mass in both sexes, which was reflected by elevated serum leptin levels. However, female mice showed more metabolically protective adaptations of adipose tissues than did male mice, demonstrated by higher serum total and high-molecular-weight adiponectin levels, more hyperplastic morphological changes, and a stronger increase in mRNA expression of adipogenic differentiation markers. Subsequently, in vitro studies in 3T3-L1 (white) and T37i (brown) adipocytes suggest that the increased leptin and adiponectin levels were mainly driven by the elevated insulin levels. In summary, this study demonstrates that GC-induced insulin resistance is more severe in male mice than in female mice, which can be partially explained by a sex-dependent adaptation of adipose tissues.

Topics: Adipokines; Adiponectin; Adipose Tissue; Animals; Blood Glucose; Corticosterone; Female; Gene Expression Regulation; Glucose; Homeostasis; Insulin; Insulin Resistance; Leptin; Male; Mice; Proto-Oncogene Proteins c-akt; Sex Factors

Ceramides contribute to the lipotoxicity that underlies diabetes, hepatic steatosis, and heart disease. By genetically engineering mice, we deleted the enzyme dihydroceramide desaturase 1 (DES1), which normally inserts a conserved double bond into the backbone of ceramides and other predominant sphingolipids. Ablation of DES1 from whole animals or tissue-specific deletion in the liver and/or adipose tissue resolved hepatic steatosis and insulin resistance in mice caused by leptin deficiency or obesogenic diets. Mechanistic studies revealed ceramide actions that promoted lipid uptake and storage and impaired glucose utilization, none of which could be recapitulated by (dihydro)ceramides that lacked the critical double bond. These studies suggest that inhibition of DES1 may provide a means of treating hepatic steatosis and metabolic disorders.

Topics: Animals; Ceramides; Diet, High-Fat; Fatty Liver; Gene Deletion; Insulin Resistance; Leptin; Membrane Proteins; Mice; Mice, Mutant Strains; Oxidoreductases; Sphingolipids

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

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

Severe obesity is associated with fatigue, however, the effects of weight loss after bariatric surgery on particular dimensions of fatigue are unknown. In a secondary analysis of a prospective cohort study of women undergoing roux-en-y gastric bypass (RYGB) we explored relationships among multiple dimensions of fatigue and improving adiposity, insulin resistance and inflammation.. Before, and 1 and 6 months after RYBG, dimensions of fatigue were assessed using the validated, self-report, Multidimensional Fatigue Inventory. Total, abdominal visceral (VAT) and subcutaneous (SAT) adiposity, insulin sensitivity (Si and HOMA) and plasma concentrations of leptin, C-reactive protein (CRP) and interleukin-6 (Il-6) were measured using air displacement plethysmography, computed tomography, glucose tolerance testing and enzyme-linked immunoassay. Associations were assessed using Spearman correlations and linear regression.. At baseline, the majority of our female participants (N = 19, body mass index, 46.5 kg/m. In the 6 months after RYGB, fatigue improved, especially physical fatigue. Decreases in mental fatigue were strongly associated with decreases in visceral adiposity. Nevertheless, the biologic mechanisms underlying changes in these specific fatigue dimensions remain undetermined.

Topics: Adiposity; Adult; Anastomosis, Roux-en-Y; Body Mass Index; C-Reactive Protein; Fatigue; Female; Humans; Inflammation; Insulin Resistance; Interleukin-6; Leptin; Mental Fatigue; Middle Aged; Motivation; Obesity, Abdominal; Obesity, Morbid; Prospective Studies; Self Report; Treatment Outcome

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

We investigated the biomarkers of insulin action as well as changes in free fatty acids and lactate concentration after an acute soccer session pre and post training with caloric-restricted diet versus diet alone in type 2 diabetes (T2D) patients.. Fifty-one middle-aged (61.1 ± 6.4 years) T2D patients were randomly allocated to the soccer+diet group (SDG) or the diet group (DG). The control group comprised T2D patients observing a caloric-restricted diet who did not receive soccer training. Over 12 weeks, SDG performed 3 × 40 min per week of soccer training.. The first soccer session for SDG induced acute increases in blood lactate (1.4 ± 0.1-6.0 ± 0.7 mmol/l, P < 0.05) and glucagon levels (112.1 ± 6.2-142.9 ± 8.0 pg/ml, P < 0.05), whereas glucose and insulin levels remained unchanged. Moreover, this session showed suppressed insulin levels as well as higher free fatty acids, lactate levels and glucagon/insulin ratio compared to DG (p < 0.05). After 12 weeks, a baseline decrease was observed in glucagon, leptin and lactate levels in SDG and DG (p < 0.05), whereas HOMA-IR, Adipo-IR and glucose levels were lower only in SDG (p < 0.05). At the last soccer training session, the blood lactate response was significantly lower than for the first session (4.0 ± 0.4 vs 6.0 ± 0.7 mmol/l). At 48 h pre intervention, a decrease was observed in leptin levels (p < 0.05), which remained lower post intervention. The positive correlation between leptin and insulin, and the lower levels after training, could be attributed to the improved insulin sensitivity along with the weight loss observed in both groups (~3.4 kg for DG and 3.7 kg for SDG).. Acute soccer sessions markedly improved insulin action markers in T2D patients, while the cumulative effects enhanced insulin sensitivity and decreased risk factors associated with cardiovascular disease after 12 weeks of intervention better than caloric-restricted diet.

Topics: Aged; Biomarkers; Blood Glucose; Body Composition; Diabetes Mellitus, Type 2; Diet, Reducing; Exercise Therapy; Female; Glucagon; Humans; Insulin; Insulin Resistance; Lactic Acid; Leptin; Male; Middle Aged; Physical Conditioning, Human; Soccer; Treatment Outcome

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

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

Maternal metabolic syndrome during gestation and lactation leads to several Se-status-related metabolic changes in offspring. MS leads to hepatomegaly, liver oxidation, resistance to insulin challenges and selenoptroteins expression upregulation, producing an energy imbalance in hepatocytes. As Se is necessary for correct heart function, Se deposits are depleted and selenoproteins expression downregulated in heart; this depletion being related to cardiovascular damage. Recently, selenoproteins have been directly implicated in the central endocrine regulation of appetite and energy homeostasis.. To obtain information about how Se is involved in regulating endocrine peripheral energy balance during MS process, two experimental groups of dam rats were used: control (Se: 0.1 ppm) and MS (Fructose 65% and Se: 0.1 ppm). At the end of lactation (21d old), the pups' appetite profile, tissular Se deposits and peptides from gastrointestinal tract (including pancreas), leptin, skeletal growth markers and cytokines in serum were measured.. MS-exposed pups present changes in Se homeostasis, appetite profile and endocrine energy balance signals related to impaired insulin secretion and high leptin serum values. This profoundly affects the pups' growth profile since muscle and bones are in catabolic process and brown adipose tissue (BAT) mass decreases.. These results indicate that the pups are suffering a process similar to diabetes type 1 which appeared when dams received low Se dietary supply and they point to Se as an important marker and key treatment for these disorders during gestation and lactation that affect future adult health.

Topics: Animals; Biomarkers; Endocrine System Diseases; Energy Metabolism; Female; Fetal Development; Homeostasis; Insulin Resistance; Leptin; Male; Maternal Nutritional Physiological Phenomena; Metabolic Syndrome; Oxidative Stress; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Selenium

Obesity is a complex disorder that is influenced by genetic and environmental factors. DNA methylation is an epigenetic mechanism that is involved in development of obesity and its metabolic complications. The aim of this study was to investigate the association between the RANKL and c-Fos gene methylation on obesity with body mass index (BMI), lipid parameters, homeostasis model assessment of insulin resistance (HOMA-IR), plasma leptin, adiponectin and resistin levels. The study included 68 obese and 46 non-obese subjects. Anthropometric parameters, including body weight, body mass index, waist circumference, and waist-hip ratio, were assessed. Serum glucose, triglycerides (TG), total cholesterol, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), plasma leptin, adiponectin and resistin levels were measured. Methylation status of RANKL and c-Fos gen were evaluated by MS-HRM. Statistically significant differences were observed between obese patients and the controls with respect to RANKL and c-Fos gene methylation status (p < 0.001). Also, statistically significant importance was observed RANKL gene methylation and increased level of leptin in obese subjects (p = 0.0081). At the same time, statistically significant association between methylation of c-Fos and increased level of adiponectin was observed in obese patients (p = 0.03) On the other hand, decreased level of resistin was observed where the c-Fos was unmetyladed in controls (p = 0.01). We conclude that methylation of RANKL and c-Fos genes have significant influences on obesity and adipokine levels. Based on literature this was the first study which shows the interactions between RANKL and c-Fos methylation and obesity.

Topics: Adiponectin; Adult; Anthropometry; Body Mass Index; Cholesterol, HDL; Cholesterol, LDL; DNA Methylation; Epigenesis, Genetic; Female; Gene Expression Regulation; Genes, fos; Humans; Insulin Resistance; Leptin; Male; Obesity; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Signal Transduction; Triglycerides

An imbalance of omega (n)-3 and n-6 polyunsaturated fatty acids (PUFA) during critical periods of development may have adverse effects on the health of the newborn in later life.. We hypothesized that breastmilk with higher n-6 to n-3 PUFA ratio will have higher inflammatory cytokines and initiate cellular events similar to insulin resistance and obesity.. Breastmilk was collected from healthy women who gave natural birth at full term. Breastmilk fatty acids were measured using gas chromatography; samples were pooled based on the n-6 to n-3 PUFA ratio (high, medium and low), and soluble cytokines were measured. Pooled samples were used to treat 3T3-L1 cells; mRNA expression of diacylglycerol acyltransferase2, stearoyl-CoA desaturase-1, leptin and RPLPO was measured.. Breastmilk with a higher ratio of n-6 to n-3 PUFA showed higher pro-inflammatory cytokines; there was a direct correlation between n-6 PUFA and pro-inflammatory cytokines. Breastmilk with a higher ratio of n-6 to n-3 PUFA increased the expression of genes involved in lipogenesis.. Pro-inflammatory cytokines in breastmilk are associated with higher levels of n-6 PUFA in breastmilk and has the capacity to alter adipose tissue metabolism to likely predispose the newborn to a higher risk of obesity in later life.

Topics: 3T3-L1 Cells; Adipocytes; Adipose Tissue; Animals; Cytokines; Diacylglycerol O-Acyltransferase; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Female; Humans; Insulin Resistance; Leptin; Lipogenesis; Mice; Milk, Human; Obesity; Real-Time Polymerase Chain Reaction; Ribosomal Proteins; Stearoyl-CoA Desaturase

Sedentarism is a risk factor for mortality that is independent of physical exercise. As indicated in the literature, there is negative compensation of non-exercise physical activity due to exercise training. The aim was to investigate potential predictor variables of physical activity compensation in post-menopausal women beginning aerobic physical exercise training.. One hundred and three post-menopausal women (mean age, 58.31±5.33 years) were eligible for the study. Metabolic markers were measured (plasma leptin, insulin, glucose), together with cardiovascular parameters and body composition. Daily physical activity was recorded objectively. Following baseline measurements, participants walked at moderate intensity on 4 days/week, for 13 weeks.. Baseline mean intensity of daily physical activity and leptin-to-fat mass ratio (L/FMkg) were independently and negatively correlated with variations in non-exercise physical activity. High L/FMkg was associated with negative compensation of non-exercise physical activity due to aerobic physical exercise. The same was shown for participants starting their exercise training who showed high daily physical activity.. Knowledge of both L/FMkg and baseline spontaneous physical activity of participants in exercise training are important to programme physical exercise interventions and to prevent negative non-exercise physical activity compensation due to exercise training.

Topics: Anthropometry; Blood Glucose; Body Composition; Exercise; Female; Humans; Insulin; Insulin Resistance; Leptin; Middle Aged; Pilot Projects; Postmenopause; Walking

The leptin gene was transferred into the liver of streptozocin- and high fat diet-induced type 2 diabetic (T2D) mice by hydrodynamic-based gene delivery. The food intake, water consumption, glucose concentration, and triglyceride and total cholesterol levels of T2D mice were significantly decreased. Meanwhile, plasma leptin was remarkably increased after gene transfer for 2, 3, 5, and 7 days, while plasma adiponectin was also significantly increased at day 2. To understand the mechanism of action of leptin on T2D mice, gene expressions related to glycometabolism and energy metabolism in the liver, epididymal adipose tissue, hypothalamus, and muscle were measured. The mRNA expression levels of adiponectin receptor 1 (ADR1), glucose transporter 4 (GLUT4), glucose-6-phosphase, and peroxisome proliferator-activated receptor γ in the liver, leptin, adiponectin, and hormone-sensitive lipase in adipose tissue, leptin, leptin-receptor, ADR1 in the hypothalamus, and ADR1, GLUT4, and insulin 1 in the gastrocnemius significantly increased. Moreover, the hepatic glycogen of the leptin-gene-treated group was significantly increased in comparison to the control group. Meanwhile, the significant decrease of forkhead box O1, adiponectin receptor 2, and peroxisome proliferator-activated receptor α in the liver, and agouti-related protein and proopiomelanocortin genes in the hypothalamus were also observed. In fat tissue and hypothalamus, leptin and adiponectin protein levels were also significantly increased, whereas the neuropeptide Y protein level was significantly decreased. These results indicated that the leptin gene transfer could improve the symptoms of T2D mice by regulating the leptin-hypothalamus signaling pathway and improving the insulin resistance of the peripheral tissues of T2D mice.

Topics: Animals; Biomarkers; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Genetic Therapy; Humans; Hypothalamus; Insulin Resistance; Leptin; Liver; Mice; Signal Transduction; Transfection

Methods of body composition analysis are now widely used to characterize health status, i.e., nutritional status, metabolic rates, and cardiometabolic risk factors. However, the functional correlates of individual body components have not been systematically analyzed. In this study, we have used a two-compartment model, which was assessed by air displacement plethysmography. Detailed body composition was measured by whole body magnetic resonance imaging in a healthy population of 40 Caucasians, aged 65-81 yr (20 men; body mass index range: 18.6-37.2 kg/m

Topics: Aged; Aged, 80 and over; Body Composition; Energy Metabolism; Female; Geriatric Assessment; Hand Strength; Humans; Inflammation; Insulin Resistance; Leptin; Magnetic Resonance Imaging; Male; Whole Body Imaging

Care of premature infants often requires parental and caregiver separation, particularly during hypoxic and hypothermic episodes. We have established a neonatal rat model of human prematurity involving maternal-neonatal separation and hypoxia with spontaneous hypothermia prevented by external heat. Adults previously exposed to these neonatal stressors show a sex difference in the insulin and glucose response to arginine stimulation suggesting a state of insulin resistance. The current study used this cohort of adult rats to evaluate insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR)], plasma adipokines (reflecting insulin resistance states), and testosterone. The major findings were that daily maternal-neonatal separation led to an increase in body weight and HOMA-IR in adult male and female rats and increased plasma leptin in adult male rats only; neither prior neonatal hypoxia (without or with body temperature control) nor neonatal hypothermia altered subsequent adult HOMA-IR or plasma adiponectin. Adult male-female differences in plasma leptin were lost with prior exposure to neonatal hypoxia or hypothermia; male-female differences in resistin were lost in the adults that were exposed to hypoxia and spontaneous hypothermia as neonates. Exposure of neonates to daily hypoxia without spontaneous hypothermia led to a decrease in plasma testosterone in adult male rats. We conclude that neonatal stressors result in subsequent adult sex-dependent increases in insulin resistance and adipokines and that our rat model of prematurity with hypoxia without hypothermia alters adult testosterone dynamics.

Topics: Adiponectin; Animals; Animals, Newborn; Anxiety, Separation; Biomarkers; Blood Glucose; Female; Hypothermia; Hypoxia; Insulin; Insulin Resistance; Leptin; Male; Maternal Deprivation; Rats, Sprague-Dawley; Resistin; Sex Factors; Testosterone

Various fat depots including visceral (VAT), subcutaneous adipose tissue (SAT) or liver fat content (LFC) were supposed to have different influences on various entities including adipokine levels as well as insulin resistance/sensitivity. Therefore, the aim of the study was to investigate the associations of SAT, VAT and LFC with the levels of leptin and vaspin as well as insulin resistance in a general non-diabetic population.. In total, 1825 participants of the Study of Health in Pomerania were characterized according to body fat compartments and LFC determined by magnetic resonance imaging. Of those subjects, insulin resistance (HOMA-IR) and insulin sensitivity ([ISI(comp)) were determined in 981 participants and adipokines were assessed in 698 using enzyme-linked immunosorbent assay. Analyses of variance and linear regression models adjusted for age, sex, smoking, height, physical inactivity and alcohol consumption were used for analysis.. Using the residual method to assess independently the effect of the various fat depots, a strong positive association of SAT (beta per standard deviation (s.d.) increase 0.54 (95% confidence interval (CI) 0.47-0.60)) but not VAT (beta 0.01 (95% CI -0.08 to 0.09)) and LFC (beta 0.01 (95% CI -0.06 to 0.08)) with log2-leptin levels was found independent of the HOMA-IR status. Moreover, a positive association of LFC (beta 0.17 (95% CI 0.07-0.26)) with log2-vaspin levels becomes apparent, which were mostly driven by subjects with a low HOMA-IR. With respect to HOMA-IR and ISI(comp) index, pronounced positive and inverse associations to all fat markers were revealed, respectively, with the strongest relation found for SAT and LFC.. SAT and LFC were identified as predominant sites associated with leptin and vaspin levels, respectively. Residual analysis pointed towards a general adverse effect of disproportional triglyceride storage across physiological despots, in particular in ectopic sides such as the liver, with markers of insulin resistance.

Topics: Adult; Age Distribution; Aged; Alcohol Drinking; Biomarkers; Body Mass Index; Enzyme-Linked Immunosorbent Assay; Female; Germany; Health Surveys; Humans; Insulin Resistance; Leptin; Liver; Magnetic Resonance Imaging; Male; Middle Aged; Sedentary Behavior; Serpins; Sex Distribution; Smoking; Subcutaneous Fat; Young Adult

Surgical treatment for primary hyperparathyroidism (PHPT) improves bone metabolism. Osteocalcin (OC) and its undercarboxylated form (ucOC) are associated with bone and energy metabolism. Osteopontin (OPN), a multifunctional protein expressed in bone, is involved in resorption, along with β-carboxyl-terminal cross-linking telopeptide of type 1 collagen (β-CTX), and osteoprotegerin (OPG). Our aim was to investigate these biomarkers of bone metabolism in patients with PHPT.. We examined 30 individuals with PHPT, in a clinical research facility, before and 1 month following parathyroidectomy. Circulating levels of OC, ucOC, OPN, β-CTX, and OPG were examined as bone biomarkers along with inflammatory markers (e.g., interleukin-6 [IL-6], lipocalin-2), insulin resistance (i.e., homeostasis model assessment for insulin resistance [HOMA-IR]), adiposity (i.e., leptin, adiponectin), PTH, calcium, 25-hydroxyvitamin D, creatinine, and demographics.. The lower 1-month postoperative OPN and ucOC levels in PHPT seem to indicate reduced bone resorption. Decreased ucOC levels may also suggest lower energy demands postoperatively.

Topics: Adiponectin; Aged; Female; Follow-Up Studies; Humans; Hyperparathyroidism, Primary; Insulin Resistance; Interleukin-6; Leptin; Male; Middle Aged; Osteocalcin; Osteopontin; Osteoprotegerin; Parathyroidectomy

Dietary methionine restriction (MR) produces concurrent increases in energy intake and expenditure, but the proportionately larger increase in energy expenditure (EE) effectively limits weight gain and adipose tissue accretion over time. Increased hepatic fibroblast growth factor-21 (FGF21) is essential to MR-dependent increases in EE, but it is unknown whether the downregulation of hepatic stearoyl-coenzyme A desaturase-1 (SCD1) by MR could also be a contributing factor. Global deletion of SCD1 mimics cold exposure in mice housed at 23 °C by compromising the insular properties of the skin. The resulting cold stress increases EE, limits fat deposition, reduces hepatic lipids, and increases insulin sensitivity by activating thermoregulatory thermogenesis. To examine the efficacy of MR in the absence of SCD1 and without cold stress, the biological efficacy of MR in Scd1

Topics: Adiponectin; Animals; Cold Temperature; Diet; Down-Regulation; Energy Intake; Energy Metabolism; Fibroblast Growth Factors; Insulin; Insulin Resistance; Leptin; Liver; Male; Methionine; Mice; Mice, Knockout; Stearoyl-CoA Desaturase; Thermogenesis; Triglycerides; Uncoupling Protein 1

Resistance at the brain receptors for leptin and insulin has been associated with increased feeding, obesity and cognitive impairments. The causal agent for central resistance is unknown but could be derived from the blood. Here we postulate whether hypertriglyceridemia, the major dyslipidemia of the metabolic syndrome, could underlie central leptin and insulin resistance.. We used radioactively labeled triglycerides to measure blood-brain barrier (BBB) penetration, western blots to measure receptor activation, and feeding and cognitive tests to assess behavioral endpoints.. Human CSF was determined to contain triglycerides, a finding previously unclear. The radioactive triglyceride triolein readily crossed the BBB and centrally administered triolein and peripherally administered lipids induced in vivo leptin and/or insulin resistance at hypothalamic receptors. Central triolein blocked the satiety effect of centrally administered leptin. Decreasing serum triglycerides with gemfibrozil improved both learning and memory inversely proportionate to triglyceride levels.. Triglycerides cross the blood-brain barrier rapidly, are found in human cerebrospinal fluid, and induce central leptin and insulin receptor resistance, decreasing satiety and cognition.

Topics: Aged; Animals; Antigens, CD; Blood-Brain Barrier; Cognition; Female; Gemfibrozil; Humans; Insulin Resistance; Leptin; Male; Maze Learning; Receptor, Insulin; Satiety Response; Triglycerides; Triolein

Loss of white adipose tissue (WAT), associated with type 1 diabetes (DM1), contributes to increased chronic systemic inflammation.. The aim of this study was to investigate the effects of leucine supplementation and resistance training (RT) in attenuating WAT loss and improving inflammatory parameters and glucose metabolism in DM1 rats.. Thirty-two male Wistar rats were distributed into four groups: DA (sedentary and supplemented with non-essential amino acids (NEAA)), DL (sedentary and supplemented with leucine), DTA (submitted to RT and supplemented with NEAA) and DTL (submitted to RT and supplemented with leucine). DM1 was induced by streptozotocin (STZ). An 8-week period of RT consisted of climbing a ladder with a progressively increased load, and supplementation was offered in the feed.. Glycemia, polyphagia and polydipsia were lower in DL, DTA and DTL groups compared with the DA group by approximately 20% ( p<.0001), 28% ( p=.004) and 64% ( p<.0001), respectively. Weight of total WAT and retroperitoneal adipose tissue (RPAT) were higher by approximately 21% ( p=.01) and 54% ( p=.0004), respectively, in DL, DTA and DTL groups compared with DA. However, gene expression of adiponectin and leptin in RPAT was only increased by RT (DTA and DTL) compared with DA and DL by approximately 93% ( p<.0001) and 78% ( p=.0002), respectively. Similarly, the levels of adiponectin in the serum, tissue IL-10 (RPAT) and serum IL-10 were only increased in DTA and DTL compared with DA and DL by approximately 31% ( p=.03), 45% ( p=.0009) and 35% ( p=.003), respectively.. Both interventions, isolated or together, reduced hyperglycemia and excessive loss of WAT, but RT was the main factor responsible for attenuating inflammation.

Topics: Adiponectin; Adipose Tissue, White; Adiposity; Animals; Anti-Inflammatory Agents, Non-Steroidal; Combined Modality Therapy; Diabetes Mellitus, Type 1; Dietary Supplements; Gene Expression Regulation; Hyperglycemia; Inflammation Mediators; Insulin Resistance; Intra-Abdominal Fat; Leptin; Leucine; Male; Random Allocation; Rats, Wistar; Resistance Training; Weight Loss

Obesity and metabolic syndrome (MeS) are more frequently observed in bipolar patients than the general population. This may result from the differences of adipocytokines and ghrelin levels in bipolar disorder.. We evaluated the leptin, adiponectin, resistin and ghrelin levels in bipolar patients (n = 30) in manic episode and in a control group (n = 30). After treatment, the same patients were evaluated again during the euthymic episode. We also measured the insulin, glucose, insulin resistance (HOMA), trygliceride (TG), total cholesterol (TCHOL), high density lipoprotein cholesterol (HDL) and low density lipoprotein cholesterol (LDL) in relation to the (MeS).. When controlling for age, BMI and glucose, leptin levels were higher in the bipolar disorder manic episode group (BD-ME) and bipolar euthymic episode group (BD-EE) than the control group; resistin levels were higher in the BD-ME compared to the control group and it had a positive correlation with Young Mania Rating Scale (YMRS). After treatment, ghrelin levels were higher in the BD-EE compared to the BD-ME group. There was no difference among the groups with respect to adiponectin.. The present results point that high leptin, resistin and ghrelin levels may be involved in the early pathophysiological process which can lead to later obesity and MeS in patients with bipolar disorder.

Topics: Adiponectin; Adult; Bipolar Disorder; Blood Glucose; Female; Ghrelin; Humans; Insulin; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Middle Aged; Obesity; Resistin; Young Adult

Insulin and leptin resistance are highly involved in metabolic syndrome and non-alcoholic fatty liver disease (NAFLD). Presently, no approved treatment is available. Actein is isolated from the rthizomes of Cimicifuga foetida, a triterpene glycoside, exhibiting important biological properties, such as anti-inflammatory, anti-cancer, and anti-oxidant activity. However, its effects on metabolic syndrome are poorly understood. The aims of the study were mainly to investigate the molecular mechanisms regulating insulin and leptin resistance, and lipogenic action of actein in high fat diet-fed mice. Our data indicated that actein-treated mice displayed lower body weight, epididymal and subcutaneous fat mass, as well as serum lipid levels. Also, improved insulin and leptin resistance were observed in actein-treated groups. Liver inflammation and fibrosis triggered by high fat diet were decreased for actein administration. Moreover, hepatic lipid accumulation was also reduced by actein along with reductions of hepatic de novo lipogenesis-linked signals in actein-treated rodents with high fat diet. High fat diet-induced activation of insulin receptor substrate 1/Forkhead box protein O1 (IRS1/FOXO1), Janus kinase 2 gene/signal transducer and activator of transcription (JAK2/STAT3) and Protein Kinase B/Glycogen synthase kinase 3 beta (AKT/GSK3β) pathways in liver was inhibited by actein, a potential mechanism by which hyperinsulinemia, hyperleptindemia and dyslipidemia were attenuated. Thus, the findings above might be of nutritional and therapeutic importance for the treatment of NAFLD.

Topics: Animals; Cell Line; Diet, High-Fat; Dyslipidemias; Fatty Liver; Humans; Inflammation; Insulin; Insulin Resistance; Leptin; Lipid Metabolism; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Saponins; Triterpenes

Topics: Animals; Blood Glucose; Diethylhexyl Phthalate; Glucose Metabolism Disorders; Insulin; Insulin Resistance; Leptin; Liver; Male; Plasticizers; Rats; Rats, Wistar; Receptor, Insulin; Receptors, Leptin

Increased parathyroid hormone (PTH) is commonly associated with obesity, and its role in the pathogenesis of obesity-related glucometabolic abnormalities is uncertain. We aimed to explore the relationships of PTH with glucose/insulin homeostasis parameters before and after bariatric surgery-induced weight loss, and whether they depend or not on 25-hydroxyvitamin D (25OHD) status.. We included 42 subjects (27 women, aged 40 ± 5 years, BMI 48.5 ± 7.3 kg/m. Weight loss was accompanied by significant reduction of PTH levels (77.9 ± 19.1 vs. 60.5 ± 13.4 pg/ml; p = 0.005), without concomitant modification of 25OHD status. Both baseline PTH and its postoperative percent change resulted associated, with baseline fat mass (β = 0.615, p = 0.003) and its concurrent postoperative reduction (r = 0.419; p = 0.006), but neither with glucose homeostasis parameters nor their respective variations after weight loss. Interestingly, leptin reduction after weight loss was independently related to PTH change (β = 0.396, p = 0.015) and IGF-1 levels (β = 0.176, p = 0.059).. Circulating PTH decreases with fat mass reduction independent of 25OHD status, but it  is not associated with improvement of insulin resistance and related metabolic parameters. Leptin and PTH may mediate the cross-talk between adipose tissue and parathyroid glands, which possibly contributes to bone adaptation to excess body weight.

Topics: Adult; Bariatric Surgery; Blood Glucose; Body Mass Index; Calcium; Female; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Obesity, Morbid; Parathyroid Hormone; Vitamin D; Weight Loss

Insulin resistance (IR) has become a major threat to public health due to its role in metabolic syndrome. Inflammation associated with IR is an interesting area of biomedical research in recent years and is expected to affect insulin signalling pathway via downregulating glucose transporters. In the present study, we evaluate the potential of punicic acid (PA), a nutraceutical found in pomegranate seed oil, against TNF-α induced alteration in 3T3-L1 adipocytes on glucose metabolism, endocrine function and inflammation. IR was induced in 3T3-L1 adipocytes by treating with TNF-α (10 ng/mL) and various concentrations of PA (5, 10, 30 μM) were incubated simultaneously. After 24 h, we found that TNF-α treatment increased mRNA expression of SOCS3, PTP1B and a decrease in IRS1 causing diminished glucose uptake. Further, it showed significantly increased transcriptional activity of NFκB and leptin secretion while PA maintained leptin levels normal. Additionally, PA prevented the over-expression of phosphorylated JNK in a dose dependent manner during IR. PA also ameliorated significantly the upregulation of proinflammatory cytokines. From the results, we conclude that PA is effective to ameliorate TNF-α induced IR and also we recommend the intake of PA for control and management of IR and its associated complications.

Topics: 3T3-L1 Cells; Adipocytes; Adiponectin; Animals; Biological Transport; Cytokines; Drug Synergism; Glucose; Glucose Transporter Type 4; Inflammation; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; JNK Mitogen-Activated Protein Kinases; Leptin; Linolenic Acids; Mice; Phosphorylation; PPAR gamma; Protein Tyrosine Phosphatase, Non-Receptor Type 1; RNA, Messenger; Signal Transduction; Suppressor of Cytokine Signaling 3 Protein; Transcription Factor RelA; Tumor Necrosis Factor-alpha; Up-Regulation

Leptin plays a role in the control of breathing, acting mainly on central nervous system; however, leptin receptors have been recently shown to be expressed in the carotid body (CB), and this finding suggests a physiological role for leptin in the regulation of CB function. Leptin increases minute ventilation in both basal and hypoxic conditions in rats. It increases the frequency of carotid sinus nerve discharge in basal conditions, as well as the release of adenosine from the CB. However, in a metabolic syndrome animal model, the effects of leptin in ventilatory control, carotid sinus nerve activity and adenosine release by the CB are blunted. Although leptin may be involved in triggering CB overactivation in initial stages of obesity and dysmetabolism, resistance to leptin signalling and blunting of responses develops in metabolic syndrome animal models.. Leptin plays a role in the control of breathing, acting mainly on central nervous system structures. Leptin receptors are expressed in the carotid body (CB) and this finding has been associated with a putative physiological role of leptin in the regulation of CB function. Since, the CBs are implicated in energy metabolism, here we tested the effects of different concentrations of leptin administration on ventilatory parameters and on carotid sinus nerve (CSN) activity in control and high-fat (HF) diet fed rats, in order to clarify the role of leptin in ventilation control in metabolic disease states. We also investigated the expression of leptin receptors and the neurotransmitters involved in leptin signalling in the CBs. We found that in non-disease conditions, leptin increases minute ventilation in both basal and hypoxic conditions. However, in the HF model, the effect of leptin in ventilatory control is blunted. We also observed that HF rats display an increased frequency of CSN discharge in basal conditions that is not altered by leptin, in contrast to what is observed in control animals. Leptin did not modify intracellular Ca

Topics: Adenosine; Animals; Carotid Body; Carotid Sinus; Diet, High-Fat; Hypoxia; Insulin Resistance; Leptin; Male; Pulmonary Ventilation; Rats, Wistar; Receptors, Leptin; Respiration

Physical exercise is an efficient therapeutical tool in the management of insulin resistance (IR) and related metabolic diseases. Leptin, the well-known obesity hormone and the absence of which leads to IR, showed controversial effects on IR as research continues. Thus, in this study, a detailed investigation of the effect of leptin on exercise-mediated improvement of insulin sensitivity and its underlying mechanism was carried out. Using a rat model of chronic or acute swimming exercise training, we found that serum leptin increased 1 h after either acute exercise or the last session of chronic exercise, when impaired insulin action was observed in previous reports. However, chronic exercise reducd basal serum leptin levels and promoted insulin sensitivity compared with sedentary controls or rats subjected to one bout of aerobic exercise. Our animal results indicated the potential linkage between leptin and insulin sensitivity, which is further investigated in the skeletal muscle L6 cells. Leptin treatment in L6 cells promoted the basal levels of insulin signaling as well as glucose uptake, while blocking JAK2 signaling with either pharmacological intervention (JAK2 inhibitor AG490) or genetic manipulation (siRNA knockdown) decreased the basal levels of insulin signaling. Furthermore, leptin treatment inhibited insulin-stimulated insulin signaling and glucose uptake, while blocking JAK2 signaling restored leptin-attenuated insulin sensitivity. Taken together, our results demonstrated that reduced serum leptin, at least in part, contributes to exercise-mediated improvement of insulin sensitivity, indicating JAK2 as a potent therapeutical target of insulin resistance.

Topics: Animals; Blood Glucose; Insulin; Insulin Resistance; Janus Kinase 2; Leptin; Male; Oncogene Protein v-akt; Phosphorylation; Physical Conditioning, Animal; Physical Exertion; Rats; Rats, Sprague-Dawley