leptin and Syndrome

Neuronal circuits within the hypothalamus play a critical role in the homeostatic regulation of body weight. By disrupting the development or function of these circuits, human monogenic disorders cause hyperphagia (increased food intake), neuroendocrine abnormalities, impaired sympathetic nervous system activation, and obesity. Some genetic disorders also cause maladaptive behaviors such as anxiety, autism, emotional lability, and aggression, highlighting the role of the specific molecules expressed by these hypothalamic neurons in the regulation of innate behaviors that are essential to survival. These findings inform understanding of a wide range of clinical disorders and highlight the challenges associated with targeting these hypothalamic pathways for weight loss therapy.

Topics: Appetite; Body Weight; Humans; Hypothalamus; Leptin; Obesity; Syndrome

Lipodystrophy syndromes (LS) constitute a group of rare diseases of the adipose tissue, characterized by a complete or selective deficiency of the fat mass. These disorders are associated with important insulin resistance, cardiovascular and metabolic comorbidities that impact patient's survival and quality of life. Management is challenging and includes diet, physical activity, and specific pharmacological treatment of LS-associated comorbidities. Because of a common pathophysiology involving decreased concentration of the adipokine leptin, efforts have been made to develop therapeutic strategies with leptin replacement therapy. Metreleptin, a recombinant human leptin analogue, has been proposed in hypoleptinemic patients since the beginning of 2000's. The treatment leads to an improvement in metabolic parameters, more important in generalized than in partial LS forms. In this review, the current knowledge about the development of the drug, its outcomes in the treatment of lipodystrophic patients as well as the peculiarities of its use will be presented.

Topics: Autoimmune Diseases; Bone and Bones; Dyslipidemias; Fatty Liver; Glucose; Humans; Hyperglycemia; Hypertension; Kidney; Leptin; Lipid Metabolism; Lipodystrophy; Quality of Life; Recombinant Proteins; Reproduction; Syndrome

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

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

Neural circuits in the hypothalamus play a key role in the regulation of human energy homeostasis. A critical circuit involves leptin-responsive neurons in the hypothalamic arcuate nucleus (the infundibular nucleus in humans) expressing the appetite-suppressing neuropeptide proopiomelanocortin (POMC) and the appetite-stimulating Agouti-related peptide. In the fed state, the POMC-derived melanocortin peptide α-melanocyte-stimulating hormone stimulates melanocortin-4 receptors (MC4Rs) expressed on second-order neurons in the paraventricular nucleus of the hypothalamus (PVN). Agonism of MC4R leads to reduced food intake and increased energy expenditure. Disruption of this hypothalamic circuit by inherited mutations in the genes encoding leptin, the leptin receptor, POMC, and MC4R can lead to severe obesity in humans. The characterization of these and closely related genetic obesity syndromes has informed our understanding of the neural pathways by which leptin regulates energy balance, neuroendocrine function, and the autonomic nervous system. A broader understanding of these neural and molecular mechanisms has paved the way for effective mechanism-based therapies for patients whose severe obesity is driven by disruption of these pathways.

Topics: Energy Metabolism; Humans; Hypothalamus; Leptin; Obesity; Pro-Opiomelanocortin; Receptor, Melanocortin, Type 4; Receptors, Leptin; Syndrome

The aim of this article is to provide an in depth review of the rare genetic and syndromic forms of childhood obesity. The authors demonstrate the complexity and inter-relationships of the leptin-melanocortin signaling pathway and its central nervous system and systemic effects. Authors highlight the clinical distinctive features of genetic/syndromic causes for childhood obesity, in particular, relative shorter height to their genetic potential, developmental challenges and in some instances, ophthalmological and retina changes. They outline specific genetic testing and treatment options available for these conditions.

Topics: Child; Genetic Testing; Humans; Leptin; Melanocortins; Pediatric Obesity; Signal Transduction; Syndrome

The development of the syndrome of cancer cachexia and that of metastasis are related with a poor prognostic for cancer patients. They are considered multifactorial processes associated with a proinflammatory environment, to which tumour microenvironment and other tissues from the tumour bearing individuals contribute. The aim of the present review is to address the role of ghrelin, myostatin, leptin, HIF, IL-6, TNF-α, and ANGPTL-4 in the regulation of energy balance, tumour development, and tumoural cell invasion. Hypoxia induced factor plays a prominent role in tumour macro- and microenvironment, by modulating the release of proinflammatory cytokines.

Topics: Angiopoietin-Like Protein 4; Angiopoietins; Animals; Cachexia; Cytokines; Ghrelin; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Inflammation; Interleukin-6; Leptin; Myostatin; Neoplasm Metastasis; Neoplasms; Prognosis; Syndrome; Tumor Microenvironment; Tumor Necrosis Factor-alpha

The clinical manifestations of lipodystrophy syndromes (LS) are hypoleptinemia, hyperglycemia, insulin resistance, dyslipidemia and hepatic steatosis. Leptin replacement therapy (LRT) is effective at improving these pathologies. Currently, there are no data compiling the evidence from the literature, and demonstrating the effect of LRT in LS patients. A systematic review of the MEDLINE and Cochrane Library databases was conducted to identify studies assessing the effect of LRT on metabolic and hepatic endpoints in patients with LS not associated with highly active antiretroviral therapy (HAART) use. Standardized mean differences (SMD) and 95% confidence intervals of pooled results were calculated for overall changes in glucose homeostasis, lipid profile, and hepatic physiology, using an inverse-variance random-effects model. After screening, 12 studies were included for review. Meta-analysis of results from 226 patients showed that LRT decreased fasting glucose [0.75 SMD units (range 0.36-1.13), p=0.0001], HbA1c [0.49 (0.17-0.81), p=0.003], triglycerides [1.00 (0.69-1.31), p<0.00001], total cholesterol [0.62 (0.21-1.02), p=0.003], liver volume [1.06 (0.51-1.61), p=0.0002] and AST [0.41 (0.10-0.73) p=0.01]. In patients with non-HAART LS, LRT improves the outcome of several metabolic and hepatic parameters. Studies were limited by small populations and therefore large prospective trials are needed to validate these findings.

Topics: Antiretroviral Therapy, Highly Active; Blood Glucose; Cholesterol; Fatty Liver; Glycated Hemoglobin; Hormone Replacement Therapy; Humans; Insulin; Leptin; Lipodystrophy; Liver; Serum Albumin; Syndrome; Transaminases; Triglycerides

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

Obesity and its associated comorbidities represent one of the biggest public health challenges facing the world today. The heritability of body weight is high, and genetic variation plays a major role in determining the interindividual differences in susceptibility or resistance to the obesogenic environment. Here we discuss how genetic studies in humans have contributed to our understanding of the central pathways that govern energy homeostasis. We discuss how the arrival of technological advances such as next-generation sequencing will result in a major acceleration in the pace of gene discovery. The study of patients harboring these genetic variants has informed our understanding of the molecular and physiological pathways involved in energy homeostasis. We anticipate that future studies will provide the framework for the development of a more rational targeted approach to the prevention and treatment of genetically susceptible individuals.

Topics: Adaptation, Physiological; Animals; Body Weight; Dietary Fats; Energy Metabolism; Environment; Gene Dosage; Genetic Association Studies; Genome-Wide Association Study; Genomic Imprinting; Humans; Leptin; Melanocortins; Mice; Mice, Mutant Strains; Obesity; Receptor, Melanocortin, Type 4; Receptors, Leptin; Syndrome

Obesity is associated with increased morbidity and mortality from cardiovascular disease, diabetes mellitus and certain cancers. The prevalence of obesity is increasing rapidly throughout the world and is now recognized as a major global public-health concern. Although the increased prevalence of obesity is undoubtedly driven by environmental factors, the evidence that inherited factors profoundly influence human fat mass is equally compelling. Twin and adoption studies indicate that up to 70% of the interindividual variance in fat mass is determined by genetic factors. Genetic strategies can, therefore, provide a useful tool with which to dissect the complex (and often heterogeneous) molecular and physiologic mechanisms involved in the regulation of body weight. In this Review, we have focused our attention on monogenic disorders, which primarily result in severe, early-onset obesity. The study of these genetic disorders has provided a framework for our understanding of the mechanisms involved in the regulation of body weight in humans and how these mechanisms are disrupted in obesity. The genes affected in these monogenic disorders all encode ligands and receptors of the highly conserved leptin-melanocortin pathway, which is critical for the regulation of food intake and body weight.

Topics: Drug Resistance; Genetic Predisposition to Disease; Humans; Leptin; Ligands; Melanocortins; Models, Biological; Mutation; Obesity; Pro-Opiomelanocortin; Receptors, Leptin; Receptors, Melanocortin; Signal Transduction; Syndrome

This review critically reappraises recent scientific evidence concerning central leptin insufficiency versus leptin resistance formulations to explain metabolic and neural disorders resulting from subnormal or defective leptin signaling in various sites in the brain. Research at various fronts to unravel the complexities of the neurobiology of leptin is surveyed to provide a comprehensive account of the neural and metabolic effects of environmentally imposed fluctuations in leptin availability at brain sites and the outcome of newer technology to restore leptin signaling in a site-specific manner. The cumulative new knowledge favors a unified central leptin insufficiency syndrome over the, in vogue, central resistance hypothesis to explain the global adverse impact of deficient leptin signaling in the brain. Furthermore, the leptin insufficiency syndrome delineates a novel role of leptin in the hypothalamus in restraining rhythmic pancreatic insulin secretion while concomitantly enhancing glucose metabolism and non-shivering thermogenic energy expenditure, sequelae that would otherwise promote fat accrual to store excess energy resulting from consumption of energy-enriched diets. A concerted effort should now focus on development of newer technologies for delivery of leptin or leptin mimetics to specifically target neural pathways for remediation of diverse ailments encompassing the central leptin insufficiency syndrome.

Topics: Animals; Humans; Leptin; Metabolic Diseases; Nervous System Diseases; Obesity; Syndrome

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

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

Topics: Agouti-Related Protein; Diagnosis, Differential; Energy Metabolism; Feeding Behavior; Ganglia, Autonomic; Humans; Hypothalamic Area, Lateral; Hypothalamic Diseases; Intercellular Signaling Peptides and Proteins; Leptin; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Proteins; Syndrome; Ventromedial Hypothalamic Nucleus

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: 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

Cachexia is among the most debilitating and life-threatening aspects of cancer. Associated with anorexia, fat and muscle tissue wasting, psychological distress, and a lower quality of life, cachexia arises from a complex interaction between the cancer and the host. This process results from a failure of the adaptive feeding response seen in simple starvation and includes cytokine production, release of lipid-mobilizing and proteolysis-inducing factors, and alterations in intermediary metabolism. Cytokines play a pivotal role in long-term inhibition of feeding by mimicking the hypothalamic effect of excessive negative feedback signaling from leptin, a hormone secreted by adipose tissue, which is an integral component of the homeostatic loop of body weight regulation. The two major options for pharmacological therapy have been either progestational agents or corticosteroids. However, knowledge of the mechanisms of cancer anorexia-cachexia syndrome continues to lead to effective therapeutic interventions for several aspects of the syndrome. These include antiserotonergic drugs, gastroprokinetic agents, branched-chain amino acids, eicosapentanoic acid, cannabinoids, melatonin, and thalidomide, all of which act on the feeding-regulatory circuitry to increase appetite and inhibit tumor-derived catabolic factors to antagonize tissue wasting and/or host cytokine release. The outcomes of drug studies in cancer cachexia should focus on the symptomatic and quality-of-life advantages rather than simply on nutritional end points, since the survival of cachexia cancer patients may be limited to weeks or months due to the incurable nature of the underlying malignancy. As weight loss shortens the survival time of cancer patients and decreases their performance status, effective therapy would extend patient survival and improve quality of life.

Topics: Adipose Tissue; Agouti Signaling Protein; Anorexia; Anti-Anxiety Agents; Anti-Inflammatory Agents, Non-Steroidal; Antidepressive Agents; Appetite Stimulants; Cachexia; Cytokines; Energy Metabolism; Gastrointestinal Agents; Glucocorticoids; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Neoplasms; Neuropeptide Y; Patient Care Team; Progesterone; Signal Transduction; Starvation; Syndrome

This chapter presents the current state of knowledge in the field of the genetics of human obesity. The molecular approach has proved to be powerful in defining new syndromes associated with obesity. The pivotal role of leptin and melanocortin pathways has been recognized, but only in rare cases of obesity. In the more common form of obesity a multitude of polymorphisms located in genes and candidate regions throughout the genome regulate an individual's susceptibility to weight gain in a permissive environment. The effects are often uncertain and the results not always confirmed. Combining these single nucleotide polymorphisms and defining the associated risks for obesity will be a real challenge in the future. It is now necessary to integrate data of various origins (environment, genotype, expression) to clarify this field.

Topics: Body Mass Index; Child; Environment; Genetic Linkage; Genome, Human; Glutamate Decarboxylase; Humans; Isoenzymes; Leptin; Melanocortins; Mutation; Obesity; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Pro-Opiomelanocortin; Receptor, Melanocortin, Type 4; Receptors, Melanocortin; Risk Factors; Syndrome

Until relatively recently, the small number of identifiable inherited human diseases associated with marked obesity were complex, pleiotropic developmental disorders, the molecular basis for which were entirely obscure. The molecular basis for many of these complex syndromes, such as Bardet Beidl syndrome, has been revealed, providing novel insights into processes essential for human hypothalamic function and energy balance. In addition to these discoveries, which were the fruits of positional cloning, the molecular constituents of the signaling pathways responsible for the control of mammalian energy homeostasis have been identified, largely through the study of natural or artificial mutations in mice. We discuss the increasing number of human disorders that result from genetic disruption of the leptin-melanocortin pathways that have been identified. Practical implications of these findings for genetic counseling, prognostication, and even therapy have already emerged.

Topics: Adolescent; Animals; Child; Child, Preschool; Developmental Disabilities; DNA Mutational Analysis; Energy Metabolism; Genetic Counseling; Genetic Diseases, Inborn; Homeostasis; Humans; Leptin; Mice; Mice, Obese; Obesity; Obesity, Morbid; Phenotype; Prognosis; Receptor, Melanocortin, Type 4; Signal Transduction; Syndrome

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

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

Genetic factors are involved in the regulation of body weight and in determining individual responses to environmental factors such as diet and exercise. The identification and characterization of monogenic obesity syndromes have led to an improved understanding of the precise nature of the inherited component of severe obesity and has had undoubted medical benefits, whilst helping to dispel the notion that obesity represents an individual defect in behaviour with no biological basis. For individuals at highest risk of the complications of severe obesity, such findings provide a starting point for providing more rational mechanism-based therapies, as has successfully been achieved for one disorder, congenital leptin deficiency.

Topics: alpha-MSH; Bardet-Biedl Syndrome; Cell Cycle Proteins; Child; Child, Preschool; Endocrine System Diseases; Female; Fibrous Dysplasia, Polyostotic; Fragile X Syndrome; Humans; Leptin; Male; Membrane Proteins; Obesity; Prader-Willi Syndrome; Pro-Opiomelanocortin; Proprotein Convertase 1; Proteins; Receptor, Melanocortin, Type 4; Receptors, Cell Surface; Receptors, Leptin; Syndrome; Vesicular Transport Proteins; WAGR Syndrome

The obesity hypoventilation syndrome, which is defined as a combination of obesity and chronic hypoventilation, utimately results in pulmonary hypertension, cor pulmonale, and probable early mortality. Since the classical description of this syndrome nearly fifty years ago, research has led to a better understanding of the pathophysiologic mechanisms involved in this disease process, and to the development of effective treatment options. However, recent data indicate the obesity hypoventilation syndrome is under-recognized, and under-treated. Because obesity has become a national epidemic, it is critical that physicians are able to recognize and treat obesity-associated diseases. This article reviews current definitions of the obesity hypoventilation syndrome, clinical presentation and diagnosis, present understanding of the pathophysiology, and treatment options.

Topics: Humans; Hypoventilation; Leptin; Obesity; Respiration, Artificial; Respiratory System; Sleep Apnea, Obstructive; Syndrome; Weight Loss

Over the past decade, we have witnessed a major increase in the scale of scientific activity devoted to the study of energy balance and obesity. This explosion of interest has, to a large extent, been driven by the identification of genes responsible for murine obesity syndromes and the novel physiological pathways revealed by those genetic discoveries. We and others recently have identified several single-gene defects causing severe human obesity. Many of these defects have occurred in molecules identical or similar to those identified as a cause of obesity in rodents. This chapter will consider the human monogenic obesity syndromes that have been characterized to date and discuss how far such observations support the physiological role of these molecules in the regulation of human body weight and neuroendocrine function.

Topics: Energy Metabolism; Heterozygote; Humans; Leptin; Mutation; Obesity; Phenotype; Pro-Opiomelanocortin; Proprotein Convertase 1; Receptor, Melanocortin, Type 4; Receptors, Cell Surface; Receptors, Leptin; Recombinant Proteins; Syndrome

Cancer anorexia-cachexia syndrome is observed in 80% of patients in the advanced stages of cancer and is a strong independent risk factor for mortality. Numerous cytokines produced by tumor and immune cells, interacting with the neuropeptidergic system, mediate the cachectic effect of cancer. Since there is currently no effective pharmacological treatment and the anorexia-cachexia syndrome continues to be defined biochemically, we review the role of cytokines and neuropeptides in this process.. Currently data suggest that cancer anorexia-cachexia syndrome results from a multifactorial process involving many mediators, including hormones (e.g. leptin), neuropeptides (e.g. neuropeptide Y, melanocortin, melanin-concentrating hormone and orexin) and cytokines (e.g. interleukin 1, interleukin 6, tumor necrosis factor alpha and interferon gamma). It is likely that close interrelation among these mediators exists in the hypothalamus, decreasing food intake and leading to cachexia.. In the pathogenesis of cancer anorexia, cytokines play a pivotal role influencing the imbalance of orexigenic and anorexigenic circuits that regulate the homeostatic loop of body-weight regulation, leading to cachexia. Interfering pharmacologically with cytokine expression or neural transduction of cytokine signals can be an effective therapeutic strategy in anorectic patients before they develop cancer anorexia-cachexia syndrome.

Topics: Animals; Anorexia; Cachexia; Cytokines; Ghrelin; Humans; Leptin; Neoplasms; Neuropeptides; Peptide Hormones; Syndrome

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

In health, growth hormone (GH) is secreted in a circadian rhythm with superimposed pulsatility. Temporal fluctuations of hormone concentrations are essential for physiological action, and loss of diurnal rhythm is important in the development of disease. GH feedback occurs through the hypothalamus and involves neuropeptides such as somatostatin, GH-releasing hormone, GH-releasing peptides and neuropeptide Y. In addition, the same neuropeptides are involved in the regulation of other hormone axes and biological systems, thus, establishing a link through which regulation by GH may occur. Clinical features of adult growth hormone deficiency (AGHD) include abnormal body composition, reduction in quality of life, osteoporosis and increased risk of cardiovascular mortality. In health, many of the factors which regulate these features demonstrate circadian rhythmicity and pulsatility. Furthermore, AGHD is associated with abnormalities in the periodic variation of such controlling factors. GH replacement therapy, administered in the form of timed, intermittent subcutaneous injections, results in improvement of many of the clinical effects of AGHD, and is associated with normalization of the temporal fluctuations. Currently, there remains scope for further investigation of the effects of AGHD and subsequent GHR on the circadian rhythmicity of many hormones and systems; and additional studies are required to understand the physiological significance of the changes observed to date.

Topics: Adult; Blood Pressure; Cardiovascular Diseases; Circadian Rhythm; Drug Administration Schedule; Feedback, Physiological; Female; Growth Hormone; Human Growth Hormone; Humans; Hypopituitarism; Hypothalamo-Hypophyseal System; Injections, Subcutaneous; Insulin-Like Growth Factor I; Leptin; Male; Osteoporosis; Parathyroid Hormone; Pulsatile Flow; Quality of Life; Receptors, Somatotropin; Syndrome

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

The recent rapid rise in the incidence of obesity has prompted investigations into understanding the hormonal and neuronal pathways involved in body weight homeostasis in order to devise novel therapeutic strategies. The early enthusiasm for the adipocyte hormone leptin as a regulator of fat mass was largely discarded because of the apparent development of leptin resistance, as seen in obese subjects with elevated blood leptin levels. We postulated that this leptin ineffectiveness may be caused by a lack of leptin availability at target sites in the hypothalamus. To test this hypothesis, we used viral vectors to introduce the leptin gene into the brain for a sustained supply of leptin in the hypothalamus. A single injection of recombinant adeno-associated virus encoding the leptin gene (rAAV-lep) into the third cerebroventricle prevented the aging-associated gradual increase in body weight and adiposity in adult rats for 6 months of the experiment. When administered to prepubertal rats, significantly lower body weight gain and adiposity were maintained for up to 10 months of the experiment. In addition, obesity was prevented in rats introduced to a high-fat diet and also reversed in obese-prone rats maintained on a high-fat diet. Body weight homeostasis and loss of adiposity by leptin gene therapy was achieved by an increase in energy expenditure, and when the rAAV-lep titer was increased, there was also a voluntary reduction in food intake. Importantly, this therapy reduced blood levels of insulin, triglycerides and free fatty acids, the pathophysiologic correlates of the metabolic syndrome. Thus, the long-term beneficial effects of central leptin gene therapy may herald the development of newer therapeutic strategies to control the epidemic of obesity and related metabolic disorders.

Topics: Adenoviridae; Age Factors; Animals; Dependovirus; Dietary Fats; Energy Metabolism; Genetic Therapy; Genetic Vectors; Ghrelin; Humans; Leptin; Metabolic Diseases; Obesity; Peptide Hormones; Syndrome

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

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

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

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

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

Obesity is a multifactorial disease combining the effects of genetic predisposition with very powerful environmental risk factors. Recent genetic studies have demonstrated that there is a continuum between different forms of human obesity. SINGLE GENE FACTORS: In certain cases, mainly cases of very severe obesity with childhood onset, a single gene would play a permissive role allowing environmental factors to have major impact. Rare mutations of the leptin gene and its receptor, proopiomelanocortin, or more frequently, melanocortin receptor 4 mutations, are evidence of the existence of an obesity gene. Inactivity of this gene would be sufficient to produce early onset anomalous eating habits. COMMON OBESITY: The more common forms of obesity are however polygenic. The strong environmental pressure exceeds the capacity for homeostatic adaptation of genetically predisposed persons, leading to an energy imbalance favoring fat storage. WHICH GENES? Certain candidate genes, such as decoupling genes, beta-3 adrenergic receptor genes, or regulator regions of the leptin gene, play a minor role in the constitution or aggravation of overweight. Recently, "whole genome" explorations in obese families have localized major obesity genes on chromosomes 2, 5, 10, 11, and 20. Identification of these genes with positional cloning and functional genomic techniques will be helpful in better understanding the molecular determinants of obesity and better defining targets for new therapies.

Topics: Animals; Humans; Leptin; Mice; Mutation; Obesity; Phenotype; Syndrome

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

Obesity is a multifactoral condition. Environmental risk factors related to sedentary lifestyle and unlimited access to food apply constant pressure in subjects with a genetic make-up predisposing to gaining weight. Recent genetic studies have demonstrated a continuum among the different forms of human obesity: certain cases, mainly very severe forms beginning in childhood, are monogenic conditions transmitted by recessive inheritance, the environment simply playing a permissive role. Other more frequent mutations, such as mutation of the melanocortin receptor 4 gene, have variable expression, but inactivity is sufficient to lead to early eating disorders. The common forms of obesity are however polygenic. The extreme pressure of the modern environment over-runs the capacity of homeostatic adaptation in individuals genetically predisposed to obesity, leading to an energy imbalance favoring energy storage in the form of fat; Certain candidate genes such as decoupling proteins, adrenergic beta-3 receptor, or regions regulating the leptin gene play a minor role in the development or aggravation of obesity. Recently, "whole genome" screening in families of obese subjects has localized major obesity genes on chromosomes 2, 5, 10, 11 and 20. Their identification using techniques of positional cloning and functional genomics will help better understand the molecules determining obesity and define targets for future therapy.

Topics: Chromosome Mapping; Diet; Genetic Predisposition to Disease; Humans; Leptin; Mutation; Obesity; Phenotype; Pro-Opiomelanocortin; Receptors, Adrenergic, beta-3; Risk Factors; Syndrome

Progressive wasting is common in many types of cancer and is one of the most important factors leading to early death in cancer patients. Weight loss is a potent stimulus to food intake in normal humans and animals. The persistence of anorexia in cancer patients, therefore, implies a failure of this adaptive feeding response, although the weight loss in the patients differs from that found in simple starvation. Tremendous progress has been made in the last 5 years with regard to the regulation of feeding and body weight. It has been demonstrated that leptin, a hormone secreted by adipose tissue, is an integral component of the homeostatic loop of body weight regulation. Leptin acts to control food intake and energy expenditure via neuropeptidergic effector molecules within the hypothalamus. Complex interactions among the nervous, endocrine, and immune systems affect the loop and induce behavioral and metabolic responses. A number of cytokines, including tumor necrosis factor-alpha, interleukins 1 and 6, IFN-gamma, leukemia inhibitory factor, and ciliary neurotrophic factor have been proposed as mediators of the cachectic process. Cytokines may play a pivotal role in long-term inhibition of feeding by mimicking the hypothalamic effect of excessive negative feedback signaling from leptin. This could be done by persistent stimulation of anorexigenic neuropeptides such as corticotropin-releasing factor, as well as by inhibition of the neuropeptide Y orexigenic network that consists of opioid peptides and galanin, in addition to the newly identified melanin-concentrating hormone, orexin, and agouti-related peptide. Information is being gathered, although it is still insufficient, on such abnormalities in the hypothalamic neuropeptide circuitry in tumor-bearing animals that coincide with the development of anorexia and cachexia. Characterization of the feeding-associated gene products have revealed new biochemical pathways and molecular targets for pharmacological intervention that will likely lead to new treatments. Although therapeutic intervention using neuropeptide agonists/antagonists is now directed at obesity treatment, it may also have an effect on treating cancer anorexia-cachexia, especially when combined with other agents that have effects on muscle and protein breakdown.

Topics: Animals; Anorexia; Body Weight; Cachexia; Humans; Leptin; Neoplasms; Neuropeptides; Proteins; Syndrome

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

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

Malnutrition-inflammation complex syndrome and anorexia, common conditions in maintenance dialysis patients, are strongly associated with higher mortality and hospitalization and lower quality of life (QoL) in this population. Megestrol acetate, 800 mg/day, has been shown to increase appetite and food intake and to mitigate inflammation in cachectic AIDS and cancer patients, leading to weight gain, but it is also associated with side effects at this dose.. We evaluated the efficacy of the oral solution of megestrol acetate in half of its conventional dose in improving the nutritional state and inflammation in 10 hypoalbuminemic dialysis patients (albumin < 3.7 g/dL). Six women and 4 men, ages 60.2 years, took 400 mg of megestrol acetate solution daily for 16 weeks. Anthropometry, dual energy x-ray absorptiometry, 24-hour diet recalls, and biochemical measurements of nutrition and inflammation, including serum C-reactive protein and leptin, were performed.. At the end of the 16 weeks of intervention, weight and body mass index increased by 9%, body fat proportion by 31%, and triceps skinfold by 40% (P < .01). Serum albumin increased from 3.0 to 3.3 g/dL and continued to increase significantly to 3.6 g/dL after 3 months postintervention (P = .03). Serum leptin increased from 5.2 to 10.7 ng/mL (P = .09). Daily protein and energy intake increased progressively up to 27% to 42% by the end of the trial (P < or = .01). In 8 patients without acute infection, serum C-reactive protein declined from 1.24 to 0.78 mg/L (P = .06). QoL and appetite were reported to be improved. No major side effects were observed, and all 10 patients completed the 16 weeks of daily intake of megestrol acetate without interruption.. Megestrol acetate oral solution in half of its conventional dose is safe and improves the nutritional state, inflammation, and anorexia in maintenance dialysis patients. Larger-scale placebo-controlled randomized studies are needed to confirm the beneficial effects of 400 mg/day of megestrol acetate in dialysis patients.

Topics: Adult; Aged; Aged, 80 and over; Anorexia; Anthropometry; Body Composition; Body Mass Index; Body Weight; C-Reactive Protein; Dietary Proteins; Energy Intake; Female; Humans; Hypoalbuminemia; Inflammation; Kidney Failure, Chronic; Leptin; Male; Megestrol Acetate; Middle Aged; Nutritional Status; Prospective Studies; Protein-Energy Malnutrition; Renal Dialysis; Serum Albumin; Syndrome; Treatment Outcome

Topics: Autonomic Nervous System Diseases; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Female; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Syndrome

To describe baseline characteristics and follow-up data in patients with lipodystrophy syndromes treated with metreleptin in a national reference network, in a real-life setting.. Clinical and metabolic data from patients receiving metreleptin in France were retrospectively collected, at baseline, at 1 year and at the latest follow-up during treatment.. In this real-life setting study, metabolic outcomes are improved by metreleptin therapy in patients with GLD. The therapeutic indication for metreleptin needs to be clarified in patients with PLD.

Topics: Adolescent; Adult; Humans; Leptin; Lipodystrophy; Lipodystrophy, Congenital Generalized; Middle Aged; Retrospective Studies; Syndrome; Young Adult

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

Topics: Adipose Tissue; Diagnostic Techniques, Endocrine; Hormone Replacement Therapy; Humans; Hypoglycemic Agents; Insulin-Like Growth Factor I; Japan; Leptin; Lipodystrophy; Syndrome

A high prevalence of obesity in fibromyalgia syndrome (FMS) predisposes patients to metabolic changes. It is not clear how the clinical manifestations of the disease affect metabolism. This study aimed to investigate leptin, growth hormone (GH), and insulin-like growth factor (IGF-1) levels in FMS, and their relationship with body mass index (BMI) and disease severity.. This case-control study included 60 patients with FMS and 42 age- and sex-matched healthy controls. BMIs were recorded for all participants. The disease severity was assessed using the Fibromyalgia Impact Questionnaire (FIQ) and a visual analog scale (VAS). The serum levels of leptin, GH, and IGF-1 of all participants were measured using specific enzyme-linked immunosorbent assays.. Both groups had similar age (p = 0.058), sex (p = 0.25), and BMI (p = 0.29) distribution. The mean age of the FMS and the control groups was 40.7 ± 10.8 years and 36.2 ± 13.6 years, respectively. The mean BMI was 26.7 kg/m. We found that leptin (high), GH (low), and IGF-1 (low) levels were statistically different, together with being independent of disease severity (FIQ, VAS), and correlated with BMI in the FMS group. These findings may be related with hypothalamo-pituitary axis dysfunction, BMI, and energy metabolism.

Topics: Adult; Body Mass Index; Case-Control Studies; Female; Fibromyalgia; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Leptin; Male; Middle Aged; Syndrome

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

Celia's encephalopathy (progressive encephalopathy with/without lipodystrophy, PELD) is a recessive neurodegenerative disease that is fatal in childhood. It is caused by a c.985C>T variant in the BSCL2/seipin gene that results in an aberrant seipin protein. We evaluated neurological development before and during treatment with human recombinant leptin (metreleptin) plus a dietary intervention rich in polyunsaturated fatty acids (PUFA) in the only living patient. A 7 years and 10 months old girl affected by PELD was treated at age 3 years with metreleptin, adding at age 6 omega-3 fatty acid supplementation. Her mental age was evaluated using the Battelle Developmental Inventory Screening Test (BDI), and brain PET/MRI was performed before treatment and at age 5, 6.5, and 7.5 years. At age 7.5 years, the girl remains alive and leads a normal life for her mental age of 30 months, which increased by 4 months over the last 18 months according to BDI. PET images showed improved glucose uptake in the thalami, cerebellum, and brainstem. This patient showed a clear slowdown in neurological regression during leptin replacement plus a high PUFA diet. The aberrant BSCL2 transcript was overexpressed in SH-SY5Y cells and was treated with docosahexaenoic acid (200 µM) plus leptin (0.001 mg/ml) for 24 h. The relative expression of aberrant BSCL2 transcript was measured by qPCR. In vitro studies showed significant reduction (32%) in aberrant transcript expression. This therapeutic approach should be further studied in this devastating disease.

Topics: Brain Diseases; Cell Line, Tumor; Child; Diet; Fatty Acids, Unsaturated; Female; GTP-Binding Protein gamma Subunits; Humans; Leptin; Lipodystrophy; Syndrome

We investigated how cytokines are implicated with overtraining syndrome (OTS) in athletes during a prolonged period of recovery. Plasma IL-6, IL-10, TNF-α, IL-1β, adipokine leptin, and insulin like growth factor-1 (IGF-1) concentrations were measured in overtrained (OA: 5 men, 2 women) and healthy control athletes (CA: 5 men, 5 women) before and after exercise to volitional exhaustion. Measurements were conducted at baseline and after 6 and 12 months. Inflammatory cytokines did not differ between groups at rest. However, resting leptin concentration was lower in OA than CA at every measurement (P < 0.050) but was not affected by acute exercise. Although IL-6 and TNF-α concentrations increased with exercise in both groups (P < 0.050), pro-inflammatory IL-1β concentration increased only in OA (P < 0.050) and anti-inflammatory IL-10 was greater in CA (P < 0.001). In OA, exercise-related IL-6 and TNF-α induction was enhanced during the follow-up (P < 0.050). IGF-1 decreased with exercise in OA (P < 0.050); however, no differences in resting IGF-1 were observed. In conclusion, low leptin level at rest and a pro-inflammatory cytokine response to acute exercise may reflect a chronic maladaptation state in overtrained athletes. In contrast, the accentuation of IL-6 and TNF-α responses to acute exercise seemed to associate with the progression of recovery from overtraining.

Topics: Adult; Body Fat Distribution; Body Mass Index; Case-Control Studies; Cytokines; Female; Heart Rate; Humans; Insulin-Like Growth Factor I; Interleukin-10; Interleukin-1beta; Interleukin-6; Leptin; Male; Oxygen Consumption; Physical Conditioning, Human; Syndrome; Tumor Necrosis Factor-alpha

Recombinant methionyl human leptin (metreleptin) therapy was shown to improve hyperglycaemia, dyslipidaemia and insulin sensitivity in patients with lipodystrophic syndromes, but its effects on insulin secretion remain controversial. We used dynamic intravenous (i.v.) clamp procedures to measure insulin secretion, adjusted to insulin sensitivity, at baseline and after 1 year of metreleptin therapy, in 16 consecutive patients with lipodystrophy, diabetes and leptin deficiency. Patients, with a mean [± standard error of the mean (s.e.m.)] age of 39.2 (±4) years, presented with familial partial lipodystrophy (n = 11, 10 women) or congenital generalized lipodystrophy (n = 5, four women). Their mean (± s.e.m.) BMI (23.9 ± 0.7 kg/m(2) ), glycated haemoglobin levels (8.5 ± 0.4%) and serum triglycerides levels (4.6 ± 0.9 mmol/l) significantly decreased within 1 month of metreleptin therapy, then remained stable. Insulin sensitivity (from hyperglycaemic or euglycaemic-hyperinsulinaemic clamps, n = 4 and n = 12, respectively), insulin secretion during graded glucose infusion (n = 12), and acute insulin response to i.v. glucose adjusted to insulin sensitivity (disposition index, n = 12), significantly increased after 1 year of metreleptin therapy. The increase in disposition index was related to a decrease in percentage of total and trunk body fat. Metreleptin therapy improves not only insulin sensitivity, but also insulin secretion in patients with diabetes attributable to genetic lipodystrophies.

Topics: Adult; Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Hypolipidemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Lamin Type A; Leptin; Lipodystrophy; Male; Mutation; Syndrome; Triglycerides

Monogenic and syndromic obesity are rare diseases with variable manifestation. Therefore diagnosis is difficult and often delayed.. The purpose of this work was to develop a clinical diagnostic algorithm for earlier diagnosis.. Available publications for clinical symptoms and molecular defects of monogenic and syndromic obesity cases were evaluated.. Monogenic and syndromic obesity can be expected in cases with early manifestation before the age of 5 years and a BMI above 40 or above the 99th percentile. Syndromic cases are mostly associated with a low IQ and dwarfism. Monogenic cases are associated with additional endocrine defects. Measurement of serum leptin proves the treatable leptin deficiency. Sequencing of the melanocortin-4 receptor gene (MC4R) allows diagnosis of the most frequent monogenic form of obesity. Treatment with a melanocyte-stimulating hormone (MSH) analog can be expected in the future. Early treatment of children with Prader-Willi syndrome can prevent severe obesity.. Because in some cases treatment is available, monogenic and syndromic obesity should be diagnosed early. Based on the disease symptoms, serum leptin, and MC4R sequencing, a diagnostic algorithm is proposed, which can be used to diagnose cases of morbid obesity.

Topics: Child, Preschool; Female; Genetic Markers; Genetic Predisposition to Disease; Genetic Testing; Humans; Infant, Newborn; Leptin; Male; Obesity, Morbid; Polymorphism, Single Nucleotide; Receptor, Melanocortin, Type 4; Symptom Assessment; Syndrome

Diencephalic syndrome is a rare condition associated with central nervous system tumors. The most common presentation is secondary failure to thrive with proper caloric intake and no statural impairment. Despite the importance of this syndrome, little is known of its pathophysiology. Some reports have documented changes in human growth hormone and insulin levels at the onset, whereas others have described endocrine disorders of hypothalamic insufficiency resulting from surgery of the tumor. It has been suggested that the hormonal changes described, such as increased human growth hormone and ghrelin or decreased insulin and leptin levels, are related to a patient's BMI. These findings support the role of these 4 hormones as indicators of the patient's nutritional status but not as mediators or potential therapeutic targets of the disease. We report the case of an infant who initially presented with tumor progression and, after chemotherapy, progressive weight gain and reduced tumor size. Because he presented no hormonal deficiencies or obesity after therapy, we were able to analyze his hormonal status uninfluenced by effects of metabolic treatment or excess weight. Although ghrelin and leptin levels have been related to nutritional status, our patient's leptin levels fell when tumor size decreased and weight increased: an extraordinary finding because leptin concentration is expected to increase with weight gain. This paradoxical response suggests that leptin may be dysregulated in diencephalic syndrome or that the diencephalic astrocytoma may have had an effect on leptin secretion.

Topics: Astrocytoma; Biomarkers; Humans; Hypothalamic Neoplasms; Infant; Leptin; Male; Syndrome

To investigate the characteristic changes in serum estradiol and leptin levels in patients with cerebral-cardiac syndrome (CCS) induced by subarachnoid hemorrhage (SAH).. Ninety-six female patients with early stage of SAH (within 48 h of onset), who were admitted in our department between February 2008 and February 2014, were included in this study. Clinical conditions of patients were rated using Hunt-Hess scale. Serum levels of estradiol, leptin and echocardiography were determined in patients with various neurological injuries as well as in post-SAH patients and patients with SAH-induced CCS.. No significant differences (p > 0.05) were observed in the levels of estradiol or leptin between patients with different Hunt-Hess grades. While serum levels of estradiol and leptin were significantly elevated in SAH and CCS patients compared to normal controls (p < 0.05) but the elevated levels were more profound in CCS patients. Meanwhile there were also variable extents of left ventricular expansion and decrease of ejection fraction in CCS patients, with the same trends of estradiol and leptin.. Thus the results show that a significant increase in estradiol and leptin levels occurred in post-SAH CCS patients.

Topics: Adult; Aged; Cerebrovascular Disorders; Estradiol; Female; Heart Diseases; Humans; Leptin; Middle Aged; Subarachnoid Hemorrhage; Syndrome; Ultrasonography

Cold Syndrome and Hot Syndrome are thousand-year-old key therapeutic concepts in traditional Chinese medicine (TCM), which depict the loss of body homeostasis. However, the scientific basis of TCM Syndrome remains unclear due to limitations of current reductionist approaches. Here, we established a network balance model to evaluate the imbalanced network underlying TCM Syndrome and find potential biomarkers. By implementing this approach and investigating a group of chronic superficial gastritis (CSG) and chronic atrophic gastritis (CAG) patients, we found that with leptin as a biomarker, Cold Syndrome patients experience low levels of energy metabolism, while the CCL2/MCP1 biomarker indicated that immune regulation is intensified in Hot Syndrome patients. Such a metabolism-immune imbalanced network is consistent during the course from CSG to CAG. This work provides a new way to understand TCM Syndrome scientifically, which in turn benefits the personalized medicine in terms of the ancient medicine and complex biological systems.

Topics: Adult; Biomarkers; Chemokine CCL2; Chronic Disease; Cluster Analysis; Diagnosis, Differential; Energy Metabolism; Female; Gastric Mucosa; Gastritis; Gastritis, Atrophic; Gene Expression Profiling; Gene Regulatory Networks; Humans; Immunity; Immunohistochemistry; Inflammation; Leptin; Male; Medicine, Chinese Traditional; Middle Aged; Models, Genetic; Principal Component Analysis; Syndrome

The association of motilin, ghrelin, leptin, gastrin, pepsinogen (PG) I and II with cancer chemotherapy-associated dyspepsia syndrome (CADS) was investigated in 35 patients with breast cancer receiving first cycle of 5-fluorouracil, cyclophosphamide, epirubicin (FEC60) chemotherapy.. The onset of dyspeptic symptoms on days 3 and 10 after chemotherapy identified patients with and without CADS. Gastrointestinal symptoms were scored with the Gastrointestinal Symptom Scoring Rate (GSRS) questionnaire. Gastrointestinal peptides were evaluated by enzyme-linked immunosorbent assay.. Twenty-one patients (60%) had CADS. The area under the curve (AUC) of ghrelin was higher, whereas that of PGI, PGII and motilin were lower in patients with CADS compared to those without. In patients with CADS, the AUC of PGI and PGII negatively correlated with the GSRS indigestion cluster.. Impairment of gastrointestinal motility suggested by low motilin concentrations and mucosal damage mirrored by an increase of ghrelin seem to be involved in the onset of CADS in patients during chemotherapy for breast cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma, Ductal, Breast; Chemotherapy, Adjuvant; Cyclophosphamide; Dyspepsia; Epirubicin; Female; Fluorouracil; Follow-Up Studies; Gastrins; Gastrointestinal Motility; Gastrointestinal Tract; Ghrelin; Humans; Leptin; Middle Aged; Motilin; Neoplasm Staging; Pepsinogen A; Pepsinogen C; Peptide Fragments; Prognosis; Prospective Studies; Syndrome

To observe the difference in fatty degree, glucose-lipid disorder and adipose-hormones between diet induced obesity (DIO) rats and diet induced obesity resistance (DIO-R) rats, and to explore the effect and acting mechanism of Chinese drugs for strengthening Pi (CD-SP) and those for both strengthening Pi and dissolving phlegm (CD-SPDP) in inhibiting obesity.. Excepting eight rats allocated in the blank control group, the other 54 rats were fed with high-lipid forage for 12 weeks to establish models of obesity. Finally, 30 DIO rats and 8 DIO-R rats (shown by their body weight) were obtained. The DIO rats were divided into three groups, which were given gastric perfusion, respectively, with normal saline (Group A), CD-SP (Group B), and CD-SPDP (Group C). Fourteen weeks later, the animals' body weight (BW), length (BL), blood levels of fasting insulin (FIn), fasting glucose (FBG), triglyceride (TG), cholesterol (TC), leptin (LP), neuropeptide Y (NPY), C-reactive protein (CRP), tumor necrosis factor-alpha(TNF-alpha), adiponectin (AN), and resistin (RS) were measured; insulin resistance index (IRI) was calculated, and the degree of obesity and lipid content in abdominal cavity of rats were estimated. Moreover, the levels of LP, CRP, TNF-alpha, AN and RS in homogenate of rats' adipose tissues (ATH) were determined.. After 12 weeks of high-lipid diet, the BW of DIO rats was higher than that of normal or DIO-R rats. After a 14-week continuous high-lipid diet feeding, in DIO rats, BW, lipid coefficient (LC), and IRI were significantly increased (P<0.01); serum levels of TNF-alpha, LP and AN were lower, NPY was higher, while the ATH levels of LP and AN were lower and TNF-alpha was higher in DIO rats than in DIO-R rats (P<0.05 or P<0.01); blood levels of FBG and lipids in DIO rats showed an increasing trend but was statistically insignificant (P>0.05); no significant difference was found in serum levels of CRP and RS due to the overly high data dispersion. Comparisons of the 3 DIO groups showed that BW, body weight index (BWI), LC and IRI were significantly lowered after treatment (P<0.01) in Group C, while these indexes were not significantly different between Group A and B; the serum levels of TNF-alpha, LP, and AN increased, NPY decreased in Group B and C, ATH levels of LP and AN increased, and TNF-alpha decreased in the two groups; but NPY, LP, and AN in blood and ATH were higher in Group C than those in Group B (P<0.05 or P<0.01).. CD-SPDP could inhibit DIO and IR, showing that the effect is better than that of CD-SP, and its mechanism is related to promotion of LP and AN secretion and elevation of serum NPY.

Topics: Adipokines; Animals; Blood Glucose; C-Reactive Protein; Diet, Atherogenic; Dietary Fats; Drug Evaluation, Preclinical; Drugs, Chinese Herbal; Leptin; Male; Neuropeptide Y; Obesity; Random Allocation; Rats; Rats, Wistar; Syndrome; Tumor Necrosis Factor-alpha

We investigated the association between esophageal cancer and cachexia-anorexia syndrome (CAS) of the alimentary tract and leptin, an adipocytokine crucial for body weight regulation, a modulator of inflammatory/immune response, implication of which in cancer and CAS development remains debatable. Circulating leptin was measured in 135 esophageal cancer patients (51 non-cachectic and 84 cachectic) and 83 controls (63 non-cachectic and 20 cachectic) and referred to cancer stage, CAS, and inflammatory and nutritional indices. Leptin was down-regulated in cancer patients and cachectic controls as compared to non-cachectic controls, with more pronounced hypoleptinemia in advanced cancers. Leptin correlated directly with BMI, TNF-alpha, albumin, and hemoglobin and indirectly with IL-6, IL-8, and hsCRP. The correlations, except for hsCRP, were more pronounced in females. BMI alone (females) and BMI and hsCRP (males) were independent predictors of leptin explaining over 60% of its variability. Following adjustment for BMI and gender, cancer-related CAS but not cancer itself negatively affected leptin. Leptin and BMI were independently associated with cancer-related and non-malignant CAS with diagnostic accuracy of 93% in identifying subjects with CAS. Pro-inflammatory, angiogenic and mitogenic properties of leptin do not seem to be important for esophageal cancer development but hypoleptinemia, independently from co-occurring reduction of adiposity, appears to be strongly associated with esophageal cancer-related CAS and non-malignant CAS of the alimentary tract.

Topics: Adenocarcinoma; Anorexia; Body Mass Index; C-Reactive Protein; Cachexia; Carcinoma, Squamous Cell; Down-Regulation; Esophageal Neoplasms; Female; Gastrointestinal Tract; Hemoglobins; Humans; Inflammation; Interleukin-6; Interleukin-8; Leptin; Male; Serum Albumin; Syndrome; Tumor Necrosis Factor-alpha

This study systematically assessed the weight management effects of a novel experimental DNA-customized nutraceutical, LG839 (LifeGen, Inc., La Jolla, CA, USA).. A total of 1058 subjects who participated in the overall D.I.E.T. study were genotyped and administered an LG839 variant based on polymorphic outcomes. A subset of 27 self-identified obese subjects of Dutch descent, having the same DNA pattern of four out of the five candidate genes tested (chi-square analysis) as the entire data set, was subsequently evaluated. Simple t tests comparing a number of weight management parameters before and after 80 days of treatment with LG839 were performed.. Significant results were observed for weight loss, sugar craving reduction, appetite suppression, snack reduction, reduction of late night eating (all P<0.01), increased perception of overeating, enhanced quality of sleep, increased happiness (all P<0.05), and increased energy (P<0.001). Polymorphic correlates were obtained for a number of genes (LEP, PPAR-gamma2, MTHFR, 5-HT2A, and DRD2 genes) with positive clinical parameters tested in this study. Of all the outcomes and gene polymorphisms, only the DRD2 gene polymorphism (A1 allele) had a significant Pearson correlation with days on treatment (r=0.42, P=0.045).. If these results are confirmed in additional rigorous, controlled studies, we carefully suggest that DNA-directed targeting of certain regulator genes, along with customized nutraceutical intervention, provides a unique framework and strategic modality to combat obesity.

Topics: Anti-Obesity Agents; Appetite; Cross-Sectional Studies; Dietary Supplements; Feeding Behavior; Genotype; Humans; Hyperphagia; Leptin; Methylenetetrahydrofolate Reductase (NADPH2); Obesity; Polymorphism, Genetic; PPAR gamma; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D2; Retrospective Studies; Reward; Syndrome; Weight Loss

Topics: Animals; Arcuate Nucleus of Hypothalamus; Critical Illness; Disease Models, Animal; Euthyroid Sick Syndromes; Fasting; Gene Expression; Homeostasis; Humans; Hypothalamus; Intensive Care Units; Leptin; Mice; Rabbits; Rats; Syndrome; Thyroid Hormones

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Humans; Hypoventilation; Leptin; Obesity; Respiration, Artificial; Respiratory System; Sleep Apnea, Obstructive; Syndrome; Weight Loss

Leptin is a protein produced by adipose tissue that circulates to the brain and interacts with receptors in the hypothalamus to inhibit eating. In obese humans, serum leptin is up to four times higher than in lean subjects, indicating that human obesity is associated with a central resistance to the weight-lowering effects of leptin. Although the leptin-deficient mouse (ob/ob) develops obesity hypoventilation syndrome (OHS), in humans with OHS, serum leptin is a better predictor of awake hypercapnia in obesity than the body mass index (BMI). This suggests that central leptin resistance may promote the development of OHS in humans. We speculated that the reversal of OHS by regular non-invasive ventilation (NIV) therapy decreases leptin levels.. The aim of this study was to investigate whether ventilatory treatment of OHS would alter circulating leptin concentrations.. We measured fasting serum leptin levels, BMI, spirometry and arterial blood gases in 14 obese hypercapnic subjects undergoing a diagnostic sleep study.. The average age of the subjects was (mean +/- SE) 62 +/- 13 years, BMI 40.9 +/- 2.2 kg/m(2), PaCO(2) 6.7 +/- 0.2 kPa, PaO(2 )8.9 +/- 0.4 kPa and total respiratory disturbance index 44 +/- 35 events/hour. Subjects were clinically reviewed after a median of 2.3 years (range 1.6-3) with repeat investigations. Nine patients were regular NIV users and 5 were non-users. NIV users had a significant reduction in serum leptin levels (p = 0.001), without a change in BMI. In these patients, there was a trend towards an improved daytime hypercapnia and hypoxemia, while in the 5 non-users, no changes in serum leptin, BMI or arterial blood gases occurred.. Regular NIV use reduces serum leptin in OHS. Leptin may be a modulator of respiratory drive in patients with OHS.

Topics: Body Mass Index; Carbon Dioxide; Continuous Positive Airway Pressure; Female; Humans; Hypercapnia; Hypoventilation; Hypoxia; Leptin; Male; Middle Aged; Obesity; Oxygen; Polysomnography; Positive-Pressure Respiration; Prospective Studies; Sleep Apnea, Obstructive; Syndrome

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

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

Topics: Adolescent; Androgens; Bone Density; Bone Development; Child; Estrogens; Female; Genetic Predisposition to Disease; Hormones; Humans; Leptin; Male; Osteoporosis; Phenotype; Puberty; Sex Factors; Syndrome

Adiponectin has been suggested to play a role in the etiopathogenesis of at least some forms of insulin resistance, in part based on a strong correlation between plasma levels of adiponectin and measures of insulin sensitivity.. The objective of the study was to establish whether this relationship is maintained at extreme levels of insulin resistance.. This was a cross-sectional study in a university teaching hospital of subjects recruited from the United Kingdom and the United States.. Participants included 75 subjects with a range of syndromes of severe insulin resistance and 872 nondiabetic controls.. Fasting plasma insulin, adiponectin, and leptin were measured.. Unexpectedly, subjects with mutations in the insulin receptor, despite having the most severe degree of insulin resistance, had elevated plasma adiponectin [median 24.4 mg/liter; range 6.6-36.6 (normal adult range for body mass index 20 kg/m(2) = 3-19 mg/liter)], whereas all other subjects had low adiponectin levels (median 2.0 mg/liter; range 0.12-11.2). Plasma leptin in all but one subject with an insulin receptoropathy was low or undetectable [median 0.5 ng/ml; range 0-16: normal adult range for body mass index of < 25 kg/m(2) = 2.4-24.4 (female) and 0.4-8.3 ng/ml (male)].. We conclude that the relationship between plasma adiponectin and insulin sensitivity is complex and dependent on the precise etiology of defective insulin action and that the combination of high plasma adiponectin with low leptin may have clinical utility in patients with severe insulin resistance as a marker of the presence of a genetic defect in the insulin receptor.

Topics: Adiponectin; Adolescent; Adult; Body Mass Index; Child; Child, Preschool; Fasting; Female; Humans; Infant; Infant, Newborn; Insulin; Insulin Resistance; Leptin; Male; Mutation; Receptor, Insulin; Syndrome

In spite of the increasing information that has recently been accumulated on the involvement of ghrelin and leptin in the control of energy balance, the relationship between ghrelin and leptin and the growth hormone (GH)-insulin-like growth factor 1 (IGF-1) axis in the pathological condition characterized by GH deficiency has been poorly clarified. Therefore, we performed this study to examine the correlation of the plasma levels of ghrelin and leptin with the anthropometric and biochemical markers in GH-deficient (GHD) adults as compared to their healthy cohorts.. In 60 male adults (GHD; n = 12, healthy control; n = 48, average age: 54 years), we investigated the correlations between the serum leptin and ghrelin levels with the anthropometric and biochemical factors in the control group, as compared to the GHD patients. The diagnosis of GH deficiency was made when peak response for serum GH was <5 microg/L to a GH-provocative test (L-dopa test). All subjects underwent assessment of waist circumference, body mass index (BMI) and percentage body fat for their body composition. Plasma ghrelin, leptin, insulin, GH and IGF-1 were measured.. Groups were matched for age, BMI, waist circumference and percent of body fat. Ghrelin and leptin levels were not significantly different between the two groups. There was no correlation between the peak GH level or the GHAUC and the ghrelin concentrations in the GHD subjects. Plasma leptin correlated positively with percentage of body fat, total cholesterol and LDL-cholesterol, but it had no correlation with the peak GH or area under the curve for growth hormone (GHAUC) in the GHD subjects. Plasma ghrelin concentrations were not correlated with the biochemical and anthropometric markers in the subjects with GHD, and ghrelin showed no significant differences in the GHD and control subjects. Leptin concentrations were positively correlated with body fat, but they were not correlated with the levels of either IGF-1 or GH in the GHD patients.. It is possible that ghrelin concentrations appeared normal in the GHD subjects because of the opposing influences of increased adiposity, which reduce ghrelin secretion, and GHD, which may increase it. Further studies are needed to clarify these controversies about the relation of ghrelin and leptin with the GH and IGF-1 levels.

Topics: Adult; Aged; Biomarkers; Body Mass Index; Female; Ghrelin; Growth Hormone; Humans; Insulin-Like Growth Factor I; Korea; Leptin; Male; Middle Aged; Peptide Hormones; Syndrome

McKusick-Kaufman syndrome (MKS) is an autosomal recessive disorder characterized by post-axial polydactyly, congenital heart defects and hydrometrocolpos, a congenital structural abnormality of female genitalia. Mutations in the MKKS gene have also been shown to cause some cases of Bardet-Biedl syndrome (BBS) which is characterized by obesity, pigmentary retinopathy, polydactyly, renal abnormalities and hypogenitalism with secondary features of hypertension and diabetes. Although there is overlap in clinical features between MKS and BBS, MKS patients are not obese and do not develop retinopathy or have learning disabilities. To further explore the pathophysiology of BBS and the related disorder MKS, we have developed an Mkks(-/-) mouse model. This model shows that the absence of Mkks leads to retinal degeneration through apoptosis, failure of spermatozoa flagella formation, elevated blood pressure and obesity. The obesity is associated with hyperphagia and decreased activity. In addition, neurological screening reveals deficits in olfaction and social dominance. The mice do not have polydactyly or vaginal abnormalities. The phenotype of the Mkks(-/-) mice closely resembles the phenotype of other mouse models of BBS (Bbs2(-/-) and Bbs4(-/-)). These observations suggest that the complete absence of MKKS leads to BBS while the MKS phenotype is likely to be due to specific mutations.

Topics: Abnormalities, Multiple; Alleles; Animals; Bardet-Biedl Syndrome; Blood Pressure; Disease Models, Animal; Genes, Recessive; Humans; Leptin; Male; Mice; Mice, Knockout; Models, Genetic; Obesity; Phenotype; Proteins; Retinal Degeneration; Social Dominance; Sperm Tail; Syndrome

The Berardinelli-Seip congenital lipodystrophy (BSCL) syndrome is characterized by a near-total congenital absence of fat and predisposition to develop diabetes mellitus. We have previously reported that 22 patients from 16 consanguineous pedigrees living in the northeastern region of Brazil had a homozygous 669insA mutation in the Seipin gene (BSCL2 locus), while all of the 10 investigated subjects from the southeastern region were homozygous for a 1036 bp deletion in the AGPAT2 gene (BSCL1 locus). In this study, we compared the serum insulin and insulin resistance (HOMA), leptin, triglyceride and fasting glucose levels in individuals of these two genetically distinct clusters of BSCL subjects. The onset of diabetes was also estimated. The fasting glucose and triglyceride levels were not significantly different in these groups. Significant differences were detected for leptin, insulin and insulin resistance. BSCL1 patients presented lower serum leptin levels compared to BSCL2 patients. BSCL2 subjects had earlier onset of diabetes and higher insulin levels. In agreement, BSCL2 patients were more insulin resistant, as detected by HOMA. These results indicate phenotypic heterogeneity between BSCL1 and BSCL2 Brazilian subjects.

Topics: Adolescent; Adult; Blood Glucose; Brazil; Child; Consanguinity; Diabetes Mellitus, Lipoatrophic; Female; Glucose; GTP-Binding Protein gamma Subunits; Homozygote; Humans; Insulin; Leptin; Male; Mutation; Phenotype; Polymorphism, Restriction Fragment Length; Syndrome; Time Factors; Triglycerides

Recombinant methionyl human leptin (r-metHuLeptin) therapy has shown clear efficacy in the treatment of severe insulin resistance associated with lipodystrophy syndromes and low leptin levels. We treated two siblings with Rabson-Mendenhall syndrome (severe insulin resistance and presumed insulin receptor mutations). The brother and sister, aged 13 and 11 yr, respectively, had severe acanthosis nigricans, insulin resistance, and diabetes. Both were taking 2000 mg metformin and 2 mg rosiglitazone daily; the brother was also taking 300 U regular insulin daily. In contrast to our lipoatrophic patients treated with r-metHuLeptin, these two patients had a higher percent body fat and low-normal fasting triglycerides [42 mg/dl (0.37 mmol/liter), male sibling, and 33 mg/dl (0.47 mmol/liter), female sibling]. The siblings were treated with r-metHuLeptin therapy for 10 months and demonstrated a 40-60% decrease in fasting serum glucose and insulin levels and improved glycosylated hemoglobin. There was corresponding improvement in glucose and insulin tolerance during leptin therapy. This is the first report of a partial, but significant, effect of r-metHuLeptin administration in patients with extreme insulin resistance with a presumed insulin receptor mutation and low serum triglyceride levels.

Topics: Adolescent; Adolescent Development; Blood Glucose; Child; Child Development; Fasting; Female; Glucose Tolerance Test; Glycated Hemoglobin; Growth; Humans; Hypothalamo-Hypophyseal System; Insulin; Insulin Resistance; Leptin; Male; Pilot Projects; Syndrome

Generalized lipodystrophy is characterized by adipose tissue absence, hypoleptinemia, hypertriglyceridemia, insulin resistance, diabetes, hepatomegaly, and nonalcoholic steatohepatitis. In the course of recruiting patients for treatment with recombinant leptin, we were struck by the frequency and severity of proteinuria. We evaluated 25 patients with generalized lipodystrophy. Eighteen were treated with recombinant leptin, and we have followed 15 on leptin for 4-36 months. We followed renal parameters at baseline and during follow-up visits. Renal biopsies were performed as clinically indicated. At baseline, 22 of 25 patients (88%) had elevated urine albumin excretion (>30 mg/24 h), 15 (60%) had macroalbuminuria (>300 mg/24 h), and five (20%) had nephrotic-range proteinuria (>3500 mg/24 h). Twenty-three (92%) had elevated creatinine clearance (>125 ml/min.1.73 m(2)). Eleven of 15 patients (73%) treated with recombinant leptin exhibited reduction in proteinuria, associated with reduction of hyperfiltration. Four patients who did not improve are discussed individually. Renal biopsy findings were remarkable for focal segmental glomerulosclerosis in four patients, membranoproliferative glomerulonephritis in two patients, and diabetic nephropathy in one patient. In conclusion, generalized lipodystrophy is associated with proteinuria and unique renal pathologies, including focal segmental glomerulosclerosis and membranoproliferative glomerulonephritis. The majority treated with recombinant leptin demonstrated reduction in proteinuria and hyperfiltration.

Topics: Adolescent; Adult; Aged; Biopsy; Child; Creatinine; Diabetic Nephropathies; Female; Glomerulonephritis, Membranoproliferative; Glomerulosclerosis, Focal Segmental; Humans; Kidney; Kidney Diseases; Leptin; Lipodystrophy; Male; Middle Aged; Proteinuria; Recombinant Proteins; Syndrome

To explore the mechanism of acupuncture in treating obesity complicated with climacteric syndrome (OCCS).. Thirty female OCCS patients were treated by acupuncture, combination of body and auricular acupuncture, according to the treating principle based on syndrome differentiation. The changes in symptoms, signs, obesity index, Kupperman index, vegetative nerve system equilibrium index (Y value), levels of estradiol (E2), luteinizing hormone (LH), follicle stimulating hormone (FSH), gonadotropin releasing hormone (GnRH), leptin (LP), insulin (INS), nitric oxide (NO), nitric oxide synthase (NOS) and insulin activation index (IAI) in patients were observed.. The obesity index, Kupperman index, Y value, and levels of LH, FSH, GnRH, LP, and INS increased, while levels of E2, NO, NOS and IAI decreased in OCCS patients. After acupuncture treatment, in the same time of obtaining promising effect in reducing weight, reversing effect was shown in all the above-mentioned parameters (P < 0.05 or P < 0.01) .. Acupuncture has favorable regulatory effect on Kupperman index, Y value, E2, LH, FSH, GnRH, NO, NOS, LP, INS and IAI in OCCS patients, its effect in improving the hypothalamic-pituitary-gonad axis, vegetative nerve function and vasomotor dysfunction, and adjusting the resistance to leptin and insulin may be the important mechanisms.

Topics: Acupuncture Therapy; Climacteric; Ear, External; Estradiol; Female; Follicle Stimulating Hormone; Humans; Insulin; Leptin; Luteinizing Hormone; Middle Aged; Nitric Oxide; Obesity; Syndrome

The phenotypic expression of partial lipodystrophy is present in two familial syndromes: familial partial lipodystrophy type 1 (FPLD1), with fat loss from the extremities, and central obesity and FPLD type 2, with fat loss from the extremities, abdomen, and thorax. The latter disorder is associated with mutations in the LMNA gene. FPLD1 is thought to be rare. Here, we report 13 subjects with FPLD1, suggesting that this syndrome is more common than previously thought.. Fasting glucose, plasma lipids, leptin, HbA(1c), and anthropomorphic measurements were evaluated in 13 subjects with clinical features of FPLD1 and are compared with two age-matched control groups, with and without diabetes.. Only women with clinical features of FPLD1 have been identified. Although they lack extremity and gluteal subcutaneous fat, they do have truncal obesity. Skinfold thickness on the arm and leg was significantly less than that in control subjects. The ratio of skinfold thickness from abdomen to thigh was significantly higher in subjects, suggesting an easy method for identifying affected patients. FPLD1 subjects also had components of the metabolic syndrome, including hypertension, insulin resistance, and severe hypertriglyceridemia resulting in pancreatitis. Premature coronary artery disease was present in 31% of subjects. None of the subjects had coding mutations in the LMNA gene or in the gene coding for peroxisome proliferator-activated receptor (PPAR)-gamma.. FPLD1 is more common than previously described, but the diagnosis is often missed. Early recognition and intensive treatment of hyperlipidemia and diabetes in FPLD1 is important for prevention of pancreatitis and early cardiovascular disease.

Topics: Anthropometry; Body Composition; Exons; Female; Humans; Lamin Type A; Leptin; Lipodystrophy; Obesity; Receptors, Cytoplasmic and Nuclear; Skinfold Thickness; Syndrome; Transcription Factors; Washington; White People

Topics: Humans; Hypoventilation; Leptin; Obesity; Sleep Apnea Syndromes; Syndrome

Launois-Bensaude Syndrome (LBS) is a very rare cause of obesity, characterized by a symmetrical accumulation of a very large number of lipomata in different regions of the body, excluding the face, the forearms, and the shanks. Obesity is known to be closely associated with insulin resistance, hyperleptinemia, and obstructive sleep apnea (OSA). We were interested in studying whether these conditions are also present in patients with obesity due to LBS with a similar frequency as in patients with "simple" truncal obesity.. We performed polysomnography and hyperinsulinemic euglycemic clamp studies and measured serum leptin in three patients with LBS and in six patients with "simple" truncal obesity, matched for sex and body mass index (LBS group, 36.39 kg/m(2); controls, 35.82 kg/m(2)).. Polysomnography revealed severe OSA in one LBS patient with marked "horsecollar lipomata." In the other LBS patients, no OSA could be demonstrated. The leptin levels of the two groups were comparable (LBS group, 36.39 microg/liter; controls, 37.18 microg/liter) and the insulin responsiveness index was also comparable in the two groups (LBS group, 3.47 micromol/kg. minute; controls, 3.79 micromol/kg. minute).. Patients with LBS demonstrated similar metabolic features in terms of insulin sensitivity and hyperleptinemia as patients with "simple" truncal obesity. LBS is not strictly associated with OSA.

Topics: Adult; Aged; Body Mass Index; Glucose Clamp Technique; Humans; Hyperinsulinism; Insulin Resistance; Leptin; Lipomatosis, Multiple Symmetrical; Male; Middle Aged; Obesity; Sleep Apnea, Obstructive; Syndrome; Tomography, X-Ray Computed; Uric Acid

To develop and to characterize a human preadipocyte cell strain with high capacity for adipose differentiation serving as a model for studying human adipocyte development and metabolism in vitro.. Cells were derived from the stromal cells fraction of subcutaneous adipose tissue of an infant with Simpson-Golabi-Behmel syndrome (SGBS). Adipose differentiation was induced under serum-free culture conditions by exposure to 10 nM insulin, 200 pM triiodothyronine, 1 microM cortisol and 2 microM BRL 49653, a PPAR gamma agonist.. During the differentiation process SGBS cells developed a gene expression pattern similar to that found in differentiating human preadipocytes with a characteristic increase in fat cell-specific mRNAs encoding lipoprotein lipase (LPL), glycero-3-phosphate dehydrogenase (GPDH), GLUT4, leptin and others. Differentiated SGBS cells exhibited an increase in glucose uptake upon insulin stimulation and in glycerol release upon catecholamine exposure. SGBS adipocytes were morphologically, biochemically and functionally identical to in vitro differentiated adipocytes from healthy subjects. However, while preadipocytes from healthy control infants rapidly lost their capacity to differentiate after a few cell divisions in culture, SGBS cells maintained their differentiation capacity over many generations: upon appropriate stimulation 95% of SGBS cells of generation 30 developed into adipocytes. A mutation in the glypican 3 gene was not detected in the patient. Thus, it remains unclear whether the molecular alteration in SGBS cells is also responsible for the high differentiation capacity and further investigations are required.. The human cell strain described here provides an almost unlimited source of human preadipocytes with high capacity for adipose differentiation and may, therefore, represent a unique tool for studying human fat cell development and metabolism. International Journal of Obesity (2001) 25, 8-15

Topics: Adipocytes; Adipose Tissue; Cell Differentiation; Cell Division; Cells, Cultured; Female; Gene Expression; Glypicans; Growth Disorders; Heparan Sulfate Proteoglycans; Humans; Infant; Insulin; Karyotyping; Leptin; Male; Models, Biological; Receptors, Cytoplasmic and Nuclear; Rosiglitazone; Syndrome; Thiazoles; Thiazolidinediones; Transcription Factors

Alstrom syndrome is a very rare autosomal recessive inherited disorder. Only 50 cases have been reported since the syndrome was first described in 1959. This syndrome is characterized by obesity, impaired glucose tolerance with insulin resistance, retinal degeneration, neurosensory deafness, acanthosis nigricans, hepatic dysfunction, and some endocrine disorders. The index case of this report was a 12-year-old girl who became blind at the age of 6 years as the result of progressively impaired vision. At the age of 12, diabetes mellitus was diagnosed and acanthosis nigricans presented in the neck, axilla, and groin regions. Her 10-year-old brother had similar symptoms. Electroretinography and audiometry disclosed generalized pigmentary epithelial change, decreased to absent cone and rod responses, and moderate sensorineural hearing loss in both siblings. Biochemistry and oral glucose tolerance tests showed diabetes mellitus, dyslipidemia, and hepatic dysfunction in the index case. Elevations of insulin, C-peptide, and leptin concentrations were found in both siblings. Insulin resistance was also demonstrated in both siblings using the modified insulin suppression test with constant infusion of somatostatin and exogenous insulin.

Topics: Acanthosis Nigricans; Child; Deafness; Female; Humans; Insulin Resistance; Leptin; Liver Diseases; Male; Retinal Degeneration; Syndrome

Neuropeptide Y (NPY) is involved in the central regulation of appetite, sexual behavior, and reproductive function. We have previously shown that chronic infusion of NPY into the lateral ventricle of normal rats produced an obesity syndrome characterized by hyperphagia, hyperinsulinism and collapse of reproductive function. We further demonstrated that acute inhibition of LH secretion in castrated rats was preferentially mediated by the NPY receptor subtype 5 (Y(5)). In the present study, the effects of chronic, central infusion of NPY, or the mixed Y2-Y5 agonist PYY(3-36), were evaluated both in normal male C57BL/6J mice and Sprague-Dawley rats. After a 7-day infusion to male mice, both NPY and PYY(3-36) at 5 nmol per day, induced marked hyperphagia leading to significant increases in body and fat pad weights. Furthermore, both compounds markedly reduced several markers of the reproductive axis. In the rat study, PYY(3-36) was more active than NPY to inhibit the pituitary-testicular axis, confirming the importance of the Y5 subtype for such effects. In the mouse, chronic NPY infusion induced a sustained increase in corticosterone and insulin secretion. Plasma leptin levels were also markedly increased possibly explaining the observed reduction in gene expression for hypothalamic NPY. Gene expression for hypothalamic POMC was reduced in the NPY- or PYY(3-36)-infused mice, suggesting that NPY exacerbated food intake by both acting through its own receptor(s), and reducing the satiety signal driven by the POMC-derived alpha-MSH. The present study in the mouse suggests in analogy with available rat data, that constant exposure to elevated NPY in the hypothalamic area unabatedly enhances food intake leading to an obesity syndrome including increased adiposity, insulin resistance, hypercorticism, and hypogonadism, reminiscent of the phenotype of the ob/ob mouse, that displays elevated hypothalamic NPY secondary to lack of leptin negative feedback action.

Topics: Animals; Hyperphagia; Hypogonadism; Insulin Resistance; Lateral Ventricles; Leptin; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Obesity; Peptide Fragments; Peptide YY; Rats; Rats, Sprague-Dawley; Syndrome

Topics: Humans; Hyperinsulinism; Hypertension; Insulin Resistance; Leptin; Obesity; Syndrome

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

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

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

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

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

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

Leptin is a recently identified hormone produced by the adipocyte ob gene which acts as a negative feedback signal critical to the normal control of food intake and body weight. A number of proinflammatory cytokines, such as interleukin (IL) 1alpha, IL-6, tumor necrosis factor (TNF) alpha and interferon (IFN) gamma, have been proposed as mediators of cancer cachexia. These data suggest that abnormalities in leptin production/release or in its feedback mechanism play a role in cancer patients. To elucidate this we studied the relationship between total serum leptin and serum cytokines IL-1alpha, IL-6, TNFalpha as well as the production of leptin and cytokines by peripheral blood mononuclear cells (PBMC) isolated from cancer patients. Sixteen advanced cancer patients (mainly stage IV) with tumors at different sites were included in the study. The serum levels of leptin in cancer patients were significantly lower than those of healthy individuals at all times (7 a.m., noon, 3 p.m.). No significant differences were found in circadian rhythm between patients and controls. Serum levels of IL-1alpha, IL-6, and TNFalpha were significantly higher in cancer patients than in healthy individuals. An inverse correlation between serum levels of leptin and IL-6 was found in cancer patients. The production in culture of leptin by unstimulated PBMCs and those stimulated by phytohemagglutinin M or by phorbol myristate acetate isolated from cancer patients was very low; no differences were observed in comparison with leptin production by PBMCs from healthy individuals.

Topics: Adult; Aged; Anorexia; Body Mass Index; Cachexia; Cytokines; Female; Humans; Leptin; Leukocytes, Mononuclear; Lymphocyte Activation; Male; Matched-Pair Analysis; Middle Aged; Neoplasms; Syndrome

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

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

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

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

This cross-sectional study aimed to evaluate the relationship between leptin and the cluster of abnormalities often referred to as the metabolic syndrome. The serum leptin concentration, body mass index (BMI), percent body fat, total fat mass (FM), waist and hip circumference, waist to hip ratio (WHR), prevalence of hypertension, and triglyceride (TG), lipoprotein, and uric acid concentration were determined in 86 type 2 diabetic (n = 59) and healthy (n = 27) subjects. Multiple regression analyses showed that the estimates of total body obesity (BMI, percent body fat, and total FM), sex, and serum uric acid concentration are independently associated with the serum leptin concentration. The finding of a positive correlation between serum leptin and uric acid levels suggests that leptin could be a pathogenic factor responsible for hyperuricemia in obesity.

Topics: Adipose Tissue; Analysis of Variance; Body Constitution; Body Mass Index; Case-Control Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Humans; Hypertension; Leptin; Linear Models; Lipoproteins; Male; Middle Aged; Obesity; Proteins; Sex Factors; Syndrome; Triglycerides; Uric Acid

Investigators first described the night-eating syndrome (NES), which consists of morning anorexia, evening hyperphagia, and insomnia, in 1955, but, to our knowledge, this syndrome has never been subjected to careful clinical study.. To characterize NES on the basis of behavioral characteristics and neuroendocrine data.. A behavioral observational study was conducted between January 1996 and June 1997 in a weight and eating disorders program at the University of Pennsylvania. A neuroendocrine study was conducted from May through August 1997 at the Clinical Research Center of the University Hospital, Tromso, Norway.. The behavioral study included 10 obese subjects who met criteria for NES and 10 matched control subjects. The neuroendocrine study included 12 night eaters and 21 control subjects. Behavioral study subjects were observed for 1 week on an outpatient basis, and neuroendocrine study subjects were observed during a 24-hour period in the hospital.. The behavioral study measured timing of energy intake, mood level, and sleep disturbances. The neuroendocrine study measured circadian levels of plasma melatonin, leptin, and cortisol.. In the behavioral study, compared with control subjects, night eaters had more eating episodes in the 24 hours (mean [SD], 9.3 [0.6] vs 4.2 [0.2]; P<.001) and consumed significantly more of their daily energy intake at night than did control subjects (56% vs 15%; P<.001). They averaged 3.6 (0.9) awakenings per night compared with 0.3 (0.3) by controls (P<.001). In night eaters, 52% of these awakenings were associated with food intake, with a mean intake per ingestion of 1134 (1197) kJ. None of the controls ate during their awakenings. In the neuroendocrine study, compared with control subjects, night eaters had attenuation of the nocturnal rise in plasma melatonin and leptin levels (P<.001 for both) and higher circadian levels of plasma cortisol (P = .001).. A coherent pattern of behavioral and neuroendocrine characteristics was found in subjects with NES.

Topics: Adult; Anorexia; Circadian Rhythm; Feeding and Eating Disorders; Feeding Behavior; Female; Humans; Hydrocortisone; Hyperphagia; Leptin; Male; Melatonin; Neurosecretory Systems; Obesity; Poisson Distribution; Proteins; Regression Analysis; Sleep Initiation and Maintenance Disorders; Statistics, Nonparametric; Syndrome

Hepatic steatosis and nonalcoholic steatohepatitis (NASH) have been associated with obesity, non insulin-dependent diabetes mellitus and hyperlipidemia. The present study was designed in order to evaluate whether patients with steatosis/NASH presented common features with the metabolic syndrome.. In 30 patients with nonalcoholic fatty liver the prevalence of hypertension and diabetes; the glucose/insulin profile, lipid profile, and serum leptin were evaluated and correlated with body composition and energy expenditure, assessed by bioimpedance spectroscopy and indirect calorimetry, respectively. Results were compared with a group of eight controls.. Obesity was present in 80% of patients, hypertension in 50% and non insulin dependent diabetes in 33%. Glucose metabolism was altered in 69%, with elevated insulin in 14 patients. Serum leptin, higher in women, was increased in patients: 33.9 +/- 38.9 vs 9.6 +/- 6.9 ng/ml, P< 0.05. There was a correlation between insulin and leptin, both of which correlated with body mass index, fat mass and percentage of body fat. Dyslipidaemia was found in 80% of patients: 45% presented low high density lipoproteins cholesterol, 58% high low density lipoproteins and 38% elevated very low density lipoproteins.. There is a strong association between nonalcoholic fatty liver and features of the metabolic syndrome, suggesting a simultaneous insulin resistance and decreased sensitivity to leptin.

Topics: Adult; Blood Glucose; Body Composition; Calorimetry, Indirect; Case-Control Studies; Diabetes Mellitus, Type 2; Energy Metabolism; Fatty Liver; Female; Humans; Hypertension; Insulin; Leptin; Male; Middle Aged; Obesity; Prevalence; Prospective Studies; Syndrome

In humans, production of the adipocyte-derived peptide leptin has been linked to adiposity, insulin, and insulin sensitivity. We therefore considered that alterations in plasma leptin concentrations could constitute an additional component of a metabolic syndrome of cardiovascular risk. To explore this hypothesis, we employed factor analysis, a multivariate statistical technique that allows reduction of large numbers of highly intercorrelated variables to composite, biologically meaningful factors. Seventy-four men [age, 48.4+/-1.3 years (mean+/-SEM); body mass index (BMI), 25.6+/-0.3 kg/m2] who were free of coronary heart disease and diabetes underwent anthropometric measurements (subscapular-to-triceps [S:T] and subscapular-to-biceps [S:B] skinfold thickness ratios, measurement of fasting plasma leptin, and an intravenous glucose tolerance test (IVGTT) for assessment of insulin sensitivity. Plasma leptin concentrations were correlated with BMI (r=0.57, P<0.001), S:T (r=0.34, P=0.003), S:B (r=0.37, P<0.001), systolic and diastolic blood pressures (both r=0.24, P=0.044), fasting triglycerides (r=0.31, P=0.007), serum uric acid (r=0.35, P=0.003), fasting glucose (r=0.32, P=0.003) and insulin (r=0.33, P=0.004), and IVGTT insulin (r=0.63, P<0.001). A negative correlation was observed between leptin and insulin sensitivity (r=-0.32, P=0.006). No significant correlations emerged between plasma leptin concentrations and age, high density lipoprotein cholesterol, or IVGTT glucose. In multivariate regression analyses, BMI (standardized coefficient [SC]=0.40, P=0.001), fasting insulin (SC=0.23, P=0.036), and IVGTT insulin (SC=0.51, P<0.001) emerged as independent predictors of plasma leptin concentrations (R2=0.56, P<0.001). After adjustment for BMI, only IVGTT insulin emerged as a significant predictor of plasma leptin concentrations (SC=0.56, P<0.001, R2=0.45, P<0.001). Factor analysis of plasma leptin concentrations and the variables that are considered relevant to the insulin resistance syndrome revealed a clustering of plasma leptin concentrations with a factor dominated by insulin resistance and high IVGTT insulin, separate from a high IVGTT glucose/central obesity factor and a high triglyceride/low high density lipoprotein cholesterol factor. Together, these factors accounted for 55.9% of the total variance in the dataset. In conclusion, interindividual variations in plasma leptin concentrations are strongly related to the principal components of the insuli

Topics: Blood Pressure; Body Mass Index; Cardiovascular Diseases; Glucose Tolerance Test; Humans; Insulin; Leptin; Male; Middle Aged; Multivariate Analysis; Proteins; Risk Factors; Syndrome

Leptin levels in subjects with android obesity with the insulin resistance syndrome (syndrome X, 5H) are in general elevated, as compared with non-obese subjects and correlate with the BMI, with the percentage of body fat, WHR, IRI levels and sex (they are higher in women), as it is the case in the general population. In the elevated leptin level in syndrome 5H (association of hyperinsulinism, hyperglycaemia-NIDDM, hyperlipoproteinaemia with android obesity, arterial hypertension and hirsutism in females with the polycystic ovaries syndrome) participate in a significant way also elevated basal IRI and cortisol levels as well as an elevated postprandial IRI response during oGTT despite the fact that leptin and endothelin-1 levels do not rise significantly during oGTT despite hyperinsulinaemia. Leptin levels were however higher in men (liminally significant in women) with an hyperinsulinaemic response during oGTT, as compared with probands with a normal insulin response. Optimal insulin and glucocorticoid levels are the prerequisite for a rise of leptin because proadipocytes in vitro begin to produce leptin as soon as insulin is added to the medium and this effect is trebled, if cortisol is added. It appears that the insulin and leptin resistance in syndrome 5H are parallel phenomena which potentiate each other. Elevated insulin and cortisol levels maintain elevated leptin levels which in turn enhances the insulin resistance in muscles and at the same time has an impact on the IRI response to postprandial hyperglycaemia. In the background of this insulin and leptin resistance in the majority of subjects with the 5H syndrome there is apparently no actual molecular defect of the hormone and its receptors in target tissues but a possible defect in mechanisms of postreceptor transduction of the hormonal signal. In the hormonal resistance participate moreover also two general and non-specific mechanisms such as: 1. increased consumption or uptake of hormonal receptors by elevated levels of the appropriate hormone ("down regulation" phenomenon), 2. disorders of paracrine endothelial mechanisms of the vascular wall which determine via the control of the inflow in the regional microcirculation the availability of insulin, leptin and metabolic substrates to target tissues. Impaired vasodilatation reserves and the development of paradoxical vascular spasms in response to stimuli which normally cause vasodilatation (strain, administration of acetylcholine, histamine,

Topics: Adult; Female; Glucose Tolerance Test; Humans; Hydrocortisone; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Proteins; Syndrome