leptin and Hyperinsulinism

Homozygous leptin (LEP) and leptin receptor (LEPR) variants lead to childhood-onset obesity.. To present new cases with LEP and LEPR deficiency, report the long-term follow-up of previously described patients, and to define, based on all reported cases in literature, genotype-phenotype relationships.. Our cohort included 18 patients (LEP = 11, LEPR = 7), 8 of whom had been previously reported. A systematic literature review was conducted in July 2022. Forty-two of 47 studies on LEP/LEPR were selected.. Of 10 new cases, 2 novel pathogenic variants were identified in LEP (c.16delC) and LEPR (c.40 + 5G > C). Eleven patients with LEP deficiency received metreleptin, 4 of whom had been treated for over 20 years. One patient developed loss of efficacy associated with neutralizing antibody development. Of 152 patients, including 134 cases from the literature review in addition to our cases, frameshift variants were the most common (48%) in LEP and missense variants (35%) in LEPR. Patients with LEP deficiency were diagnosed at a younger age [3 (9) vs 7 (13) years, P = .02] and had a higher median body mass index (BMI) SD score [3.1 (2) vs 2.8 (1) kg/m2, P = 0.02], which was more closely associated with frameshift variants (P = .02). Patients with LEP deficiency were more likely to have hyperinsulinemia (P = .02).. Frameshift variants were more common in patients with LEP deficiency whereas missense variants were more common in LEPR deficiency. Patients with LEP deficiency were identified at younger ages, had higher BMI SD scores, and had higher rates of hyperinsulinemia than patients with LEPR deficiency. Eleven patients benefitted from long-term metreleptin, with 1 losing efficacy due to neutralizing antibodies.

Topics: Humans; Hyperinsulinism; Leptin; Multicenter Studies as Topic; Pediatric Obesity; Polymorphism, Single Nucleotide; Receptors, Leptin

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

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

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

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

Children with Down syndrome (DS) are more likely to be overweight or obese than the general population of youth without DS.. To review the prevalence of overweight and obesity and their determinants in youth with DS. The health consequences and the effectiveness of interventions were also examined.. A search using MEDLINE, Embase, Web of Science, Scopus, CINAHL, PsycINFO, SPORTDiscus, LILACS, and COCHRANE was conducted. From a total of 4280 studies, we included 45 original research articles published between 1988 and 2015.. The combined prevalence of overweight and obesity varied between studies from 23% to 70%. Youth with DS had higher rates of overweight and obesity than youths without DS. Likely determinants of obesity included increased leptin, decreased resting energy expenditure, comorbidities, unfavorable diet, and low physical activity levels. Obesity was positively associated with obstructive sleep apnea, dyslipidemia, hyperinsulinemia, and gait disorder. Interventions for obesity prevention and control were primarily based on exercise-based programs, and were insufficient to achieve weight or fat loss.. Population-based research is needed to identify risk factors and support multi-factorial strategies for reducing overweight and obesity in children and adolescents with DS.

Topics: Adolescent; Child; Diet; Down Syndrome; Dyslipidemias; Energy Metabolism; Exercise; Exercise Therapy; Humans; Hyperinsulinism; Leptin; Obesity; Overweight; Prevalence; Risk Factors; Sleep Apnea, Obstructive

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

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

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

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

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

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

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

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

Obesity is associated to significant disturbances in endocrine function. Hyper insulinemia and insulin resistance are the best known changes in obesity, but their mechanisms and clinical significance are not clearly established. Adipose tissue is considered to be a hormone-secreting endocrine organ; and increased leptin secretion from the adipocyte, a satiety signal, is a well-established endocrine change in obesity. In obesity there is a decreased GH secretion. Impairment of somatotropic function in obesity is functional and may be reversed in certain circumstances. The pathophysiological mechanism responsible for low GH secretion in obesity is probably multifactorial. There are many data suggesting that a chronic state of somatostatin hypersecretion results in inhibition of GH release. Increased FFA levels, as well as a deficient ghrelin secretion, probably contribute to the impaired GH secretion. In women, abdominal obesity is associated to hyperandrogenism and low sex hormone-binding globulin levels. Obese men, particularly those with morbid obesity, have decreased testosterone and gonadotropin levels. Obesity is associated to an increased cortisol production rate, which is compensated for by a higher cortisol clearance, resulting in plasma free cortisol levels that do not change when body weight increases. Ghrelin is the only known circulating orexigenic factor, and has been found to be decreased in obese people. In obesity there is also a trend to increased TSH and free T3 levels.

Topics: Adiponectin; Adipose Tissue; Endocrine System; Female; Ghrelin; Gonadal Steroid Hormones; Human Growth Hormone; Humans; Hydrocortisone; Hyperinsulinism; Leptin; Male; Obesity; Sex Hormone-Binding Globulin; Somatostatin; Thyroid Hormones

The sympathetic nervous system is activated in human obesity and in the analogous experimental obesity produced by overfeeding. The causes remain uncertain and may be multiple. The consequences include hypertension, probably attributable to activation of the sympathetic outflow to the kidneys, and, more disputed, insulin resistance. The pattern of sympathetic activation in normal-weight and obesity-related hypertension differs in terms of the firing characteristics of individual sympathetic fibers (increased rate of nerve firing in normal-weight hypertensives, increased number of active fibers firing at a normal rate in obesity-hypertension) and the sympathetic outflows involved. The underlying mechanisms and the adverse consequences of the two modes of sympathetic activation may differ. Should antihypertensive drug therapy in obesity-hypertension specifically target the existing neural pathophysiology? Such an approach can be advocated on theoretical grounds. Perhaps more important is the requirement that chosen antihypertensives do not cause weight gain or insulin resistance.

Topics: Adrenergic beta-3 Receptor Agonists; Humans; Hyperinsulinism; Hypertension; Leptin; Obesity; Risk Factors; Sleep Apnea, Obstructive; Sympathetic Nervous System; Weight Loss

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

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

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

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

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

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

Histamine H3 receptors (H3Rs) are autoreceptors that negatively regulate the release of histamine and other neurotransmitters such as norepinephrine, dopamine, and acetylcholine in the central nervous system (CNS). Consistent with the wide-spread projection of histaminergic neurons from the lateral hypothalamus, H3Rs are widely distributed in the CNS and are believed to play a variety of physiological roles, including regulation of feeding, arousal, cognition, pain, and endocrine systems. To further understand the physiological roles of H3Rs in vivo, we produced H3R knockout (H3R-/-) mice and found that H3R-/- mice displayed hyperphagia and late-onset obesity associated with hyperinsulinemia and leptinemia, the fundamental marks of metabolic syndromes. A series of non-imidazole H3R antagonists/inverse agonists with improved selectivity and potency have been developed and were found to regulate feeding and body weight gain in laboratory animals. Taken together, these observations suggest that H3Rs are involved in the regulation of feeding behavior and body weight. Several H3R inverse agonists targeting cognitive disorders and dementia have entered clinical trials. These trials will give critical information about the physiological functions of H3Rs in humans.

Topics: Animals; Feeding Behavior; Histamine Antagonists; Hyperinsulinism; Hyperphagia; Leptin; Mice; Mice, Knockout; Obesity; Receptors, Histamine H3

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

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

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

Obesity is strongly associated with hypertension and cardiovascular disease. Several central and peripheral abnormalities that can explain the development or maintenance of high arterial pressure in obesity have been identified. These include activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system. Obesity is also associated with endothelial dysfunction and renal functional abnormalities that may play a role in the development of hypertension. The continuing discovery of mechanisms regulating appetite and metabolism is likely to lead to new therapies for obesity-induced hypertension. Better understanding of leptin signaling in the hypothalamus and the mechanisms of leptin resistance should facilitate therapeutic approaches to reverse the phenomenon of selective leptin resistance. Other hunger and satiety signals such as ghrelin and peptide YY are potentially attractive therapeutic strategies for treatment of obesity and its complications. These recent discoveries should lead to novel strategies for treatment of obesity and hypertension.

Topics: Adiponectin; Aldosterone; Animals; Appetite; Endothelium, Vascular; Energy Metabolism; Ghrelin; Humans; Hyperinsulinism; Hypertension; Intercellular Signaling Peptides and Proteins; Kidney; Leptin; Mice; Mice, Mutant Strains; Mineralocorticoid Receptor Antagonists; Obesity; Peptide Hormones; Peptide YY; Receptors, Cell Surface; Receptors, Leptin; Renin-Angiotensin System; Repressor Proteins; Satiation; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Sympathetic Nervous System; Transcription Factors

A role for the sympathetic nervous system in hypertension has been looked for in relation to the 'metabolic syndrome' with associations between body weight, insulin sensitivity and hypertension. By use of microneurography human sympathetic responses to hypoglycaemia, normoglycaemic hyperinsulinaemia and food intake have been studied. A strong but differentiated influence of insulin-induced hypoglycaemia comprises increase in muscle sympathetic nerve activity (MSNA) and the sudomotor part of skin sympathetic nerve activity (SSNA), whereas vasoconstrictor SSNA is inhibited. Responses to infusion of 2-deoxy-D-glucose are identical, suggesting central nervous system glucopenia and not insulin to be the causative factor. Insulin infusion during normoglycaemia evokes a moderate increase in MSNA; SSNA and blood pressure does not change. After glucose ingestion MSNA displays a sustained increase, which is only partly elicited by insulin. A significant albeit weaker increase occurs after pure protein or fat meals, and after glucose ingestion in C-peptide-negative diabetic patients, with no insulin secretion. In healthy elderly people the MSNA response to food intake is weak, because of a high outflow already at rest; this is suggested to explain postprandial hypotension in the elderly, a paradoxical mechanism behind clinical autonomic failure. A pathophysiological role of MSNA in the metabolic syndrome with hypertension has been speculated. An association between obesity and elevated level of MSNA at rest is established; observed relationships to chronic insulin levels and hypertension are less unanimous. The adipose tissue regulating hormone leptin has become one focus of interest in ongoing attempts to elucidate a possible role of the human sympathetic nervous system in the 'metabolic syndrome' and hypertension.

Topics: Adaptation, Physiological; Adipose Tissue; Eating; Glucose; Hemodynamics; Humans; Hyperinsulinism; Hypoglycemia; Hypotension; Insulin; Leptin; Muscles; Obesity; Peripheral Nerves; Skin Physiological Phenomena; Sympathetic Nervous System; Vasodilation

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

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

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

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

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

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

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

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

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

Obesity is often accompanied with hypertension and increases cardiovascular events. Japanese new guideline on identification of obesity includes a modified BMI categories and a method of detection of visceral fat obesity in Japanese. Hyper-insulinemia and leptin released from adipose tissue play an important role in the development of hypertension in obese patients. Insulin and leptin increase sympathetic tone which results in sodium retention and hyper-responsiveness of blood vessels. As leptin has also a direct vasodilative and diuretic action, its effect on blood pressure is bidirectional. Life style modification, especially diet and physical exercise are important to obtain the body weight loss and the improvement of insulin resistance. Dynamic exercise at the level of fifty percent of max VO2 for 30 to 60 minutes over three times a week should be recommended for hypertensive patients with obesity. ACE inhibitors improve the hypersympathetic tone and impaired insulin sensitivity in obese patients. Calcium antagonist is also useful for these patients.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Diet; Exercise; Humans; Hyperinsulinism; Hypertension; Insulin; Leptin; Life Style; Obesity; Practice Guidelines as Topic

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

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

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

Topics: Adenosine Triphosphate; Allosteric Regulation; Amino Acid Motifs; Amino Acid Sequence; Amino Acid Substitution; Animals; ATP-Binding Cassette Transporters; Blood Glucose; Chromosomes, Human, Pair 11; Drosophila Proteins; GTP-Binding Proteins; Humans; Hyperinsulinism; Hypoglycemic Agents; Infant, Newborn; Insulin; Insulin Secretion; Intercellular Signaling Peptides and Proteins; Ion Channel Gating; Ion Transport; Islets of Langerhans; Leptin; Membrane Potentials; Models, Molecular; Molecular Sequence Data; Mutagenesis, Site-Directed; Peptides; Phosphorylation; Potassium; Potassium Channels; Potassium Channels, Inwardly Rectifying; Protein Conformation; Protein Processing, Post-Translational; Receptors, Drug; Structure-Activity Relationship; Sulfonylurea Compounds; Sulfonylurea Receptors; Transcription, Genetic

Serum levels of the adipocyte hormone leptin are increased in proportion to body fat stores as a result of increased production in enlarged fat cells from obese subjects. In vitro studies indicate that insulin and glucocorticoids work directly on adipose tissue to upregulate in a synergistic manner leptin mRNA levels and rates of leptin secretion in human adipose tissue over the long term. Thus, the increased leptin expression observed in obesity could result from the chronic hyperinsulinemia and increased cortisol turnover. Superimposed upon the long-term regulation, nutritional status can influence serum leptin over the short term, independent of adiposity. Fasting leads to a gradual decline in serum leptin that is probably attributable to the decline in insulin and the ability of catecholamines to decrease leptin expression, as observed in both in vivo and in vitro studies. In addition, increases in serum leptin occur approximately 4-7 h after meals. Increasing evidence indicates that insulin, in concert with permissive effects of cortisol, can increase serum leptin over this time frame and likely contributes to meal-induced increases in serum leptin. Further research is required to elucidate the cellular and molecular mechanisms underlying short- and long-term nutritional and hormonal regulation of leptin production and secretion.

Topics: Adipocytes; Adipose Tissue; Catecholamines; Fasting; Glucocorticoids; Humans; Hydrocortisone; Hyperinsulinism; In Vitro Techniques; Insulin; Leptin; Nutritional Status; Obesity; RNA, Messenger; Time Factors; Up-Regulation

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

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

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

The article summarizes the endocrinology axis in relation to leptin in the obesity. There is a glucocorticoid hypothesis in the obesity origin. Human plasma leptin levels are elevated in Cushing's syndrome and there is a robust leptin secretory responses to dexamethasone. Obesity impacts on reproductive function in man and women. Leptin levels are higher in women than in men and a critical blood leptin level is necessary to trigger reproductive ability in women. The relationship between body mass index and circulating leptin varies during the course of spontaneous cycles in women, the best correlation occurring during the luteal phase when progesterone and leptin concentrations are highest. Obesity is associated with a decrease in growth hormone (GH) and reversible with weight loss. The influence of body composition on GH secretion in the obesity may be mediated through leptin, acting as a peripheral signal from adipose tissue. Thyroid dysfunction appear not associated with alterations in serum leptin levels. There is a significant relationship between insulin and leptin, but it is not immediate, since type 2 diabetics show similar leptin levels to those of nondiabetic humans of the same body mass index.

Topics: Adult; Animals; Body Mass Index; Cushing Syndrome; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Human Growth Hormone; Humans; Hyperinsulinism; Hypertension; Hypothalamo-Hypophyseal System; Insulin; Leptin; Male; Menstrual Cycle; Mice; Mice, Obese; Middle Aged; Obesity; Pituitary-Adrenal System; Progesterone; Rats; Reproduction; Sex Factors

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

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

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

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

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

Metformin treatment (1000-2000 mg/day) over 6 months in pubertal children and/or adolescents with obesity and hyperinsulinism is associated with a reduction in body mass index (BMI) and the insulin resistance index (HOMA-IR). We aimed to ascertain if long-term treatment (24 months) with lower doses of metformin (850 mg/day) normalizes the endocrine-metabolic abnormalities, improves body composition, and reduces the carotid intima-media thickness (cIMT) in pre-puberal and early pubertal children with obesity.. A pilot double-blind, placebo-controlled trial was conducted on 18 pre-puberal and early pubertal (Tanner stage I-II) children with obesity and risk markers for metabolic syndrome. Patients were randomly assigned (1:1) to receive metformin (850 mg/day) or placebo for 24 months. Clinical, biochemical (insulin, lipids, leptin, and high-sensitivity C-reactive protein [hsCRP]), and imaging (body composition [dual-energy X-ray absorptiometry and magnetic resonance imaging]) parameters as well as cIMT (ultrasonography) were assessed at baseline and at 6, 12, and 24 months.. The 12-month treatment tend to cause a reduction in weight standard deviation scores (SDS), BMI-SDS, leptin, leptin-to-high-molecular-weight (HMW) adiponectin ratio, hsCRP, cIMT, fat mass, and liver fat in metformin-treated children compared with placebo. The effect of metformin on the reduction of BMI-SDS, leptin, leptin-to-HMW adiponectin ratio, hsCRP, and liver fat seemed to be maintained after completing the 24 months of treatment. No changes in insulin sensitivity (HOMA-IR) or adverse effects were detected.. In this pilot study, metformin treatment in pre-puberal and early pubertal children with obesity seemed to improve body composition and inflammation markers. Our data encourage the development of future fully powered trials using 850 mg/day metformin in young children, highlighting its excellent tolerance and potential long-term benefits.

Topics: Adolescent; Body Mass Index; Body Weight; C-Reactive Protein; Carotid Intima-Media Thickness; Child; Double-Blind Method; Female; Humans; Hyperinsulinism; Insulin; Leptin; Male; Metabolic Syndrome; Metformin; Obesity; Pilot Projects; Spain; White People

Resistin and the proinflammatory cytokines, such as TNF- α , IL-6, and IL-1 β , produced by adipocytes, and macrophages, are considered to be important modulators of chronic inflammation contributing to the development of obesity and atherosclerosis. Human monocyte-enriched mononuclear cells, from ten healthy individuals, were exposed to high concentrations of insulin, leptin, and glucose (alone or in combination) for 24 hours in vitro. Resistin, TNF- α , IL-6, and IL-1 β production was examined and compared to that in untreated cells. High insulin and leptin concentrations significantly upregulated resistin and the cytokines. The subsequent addition of high glucose significantly upregulated resistin and TNF- α mRNA and protein secretion, while it did not have any effect on IL-6 or IL-1 β production. By comparison, exposure to dexamethasone reduced TNF- α , IL-6, and IL-1 β production, while at this time point it increased resistin protein secretion. These data suggest that the expression of resistin, TNF- α , IL-6, and IL-1 β from human mononuclear cells, might be enhanced by the hyperinsulinemia and hyperleptinemia and possibly by the hyperglycemia in metabolic diseases as obesity, type 2 diabetes, and atherosclerosis. Therefore, the above increased production may contribute to detrimental effects of their increased adipocyte-derived circulating levels on systemic inflammation, insulin sensitivity, and endothelial function of these patients.

Topics: Adult; Anti-Inflammatory Agents; Atherosclerosis; Cells, Cultured; Cytokines; Dexamethasone; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Gene Expression Regulation; Glucose; Humans; Hyperglycemia; Hyperinsulinism; Hypoglycemic Agents; Inflammation Mediators; Insulin; Leptin; Leukocytes, Mononuclear; Male; Obesity; Resistin; RNA, Messenger; Sweetening Agents

Puberty is part of a critical window in which adiposity and its correlates can be fine-tuned toward reproduction, which implies that puberty provides an opportunity to reprogram a misprogramming that occurred in early life. We tested this hypothesis in low-birthweight (LBW) girls with precocious pubarche (PP), who are at risk for hyperinsulinemic body adiposity during and beyond puberty.. LBW girls with PP (n = 38; mean age 8 years) were randomized to remain untreated or to receive metformin across puberty (425 mg/d for 2 years, then 850 mg/d for 2 years); subsequently, all girls were monitored for 1 year without intervention. Here we report on the latter year.. The benefits of metformin were mostly maintained during the posttreatment year so that, after 5 years, metformin therapy was associated with more lean mass; with less total, visceral, and hepatic fat; with lower circulating levels of androgens and leptin; and with elevated levels of high-molecular-weight adiponectin and undercarboxylated osteocalcin.. In LBW girls with PP, pubertal metformin therapy was followed by a favorable adipokine profile and by a reduction of total, visceral, and hepatic adiposity beyond puberty.

Topics: Adiposity; Adolescent; Body Weight; Child; Comorbidity; Female; Follow-Up Studies; Humans; Hyperinsulinism; Hypoglycemic Agents; Infant, Low Birth Weight; Infant, Newborn; Intra-Abdominal Fat; Leptin; Liver; Magnetic Resonance Imaging; Metformin; Puberty, Precocious

Leptin, particularly in its free form, is deeply involved in the regulation of energy balance. Insulin was suggested to influence plasmatic leptin levels and soluble leptin receptor in humans. However, this study indicates that metformin treatment, although improving insulin levels, does not exert a significant effect on either total leptin level or free leptin index in obese women with hyperinsulinemia and PCOS.

Topics: Adult; Female; Humans; Hyperinsulinism; Hypoglycemic Agents; Insulin; Leptin; Metformin; Obesity; Polycystic Ovary Syndrome

Insulin, ghrelin, neuropeptide Y (NPY) and leptin interact in the regulation of energy homeostasis. Most of these signals are altered in polycystic ovary syndrome (PCOS), which is characterized by a high prevalence of obesity. The present study was conducted to evaluate ghrelin-NPY and ghrelin-leptin interplays in relation to insulin secretion in obese PCOS subjects.. Pilot prospective study.. Seven obese PCOS women and seven age-weight matched controls.. Hormonal measurements, oral glucose tolerance test (OGTT) and a ghrelin test (1 microg/kg i.v. bolus). PCOS patients repeated the clinical work-up after 4 months of metformin treatment (1500 mg/day orally).. At baseline, PCOS women showed a significantly higher insulinaemic response to the OGTT compared to controls (P < 0.05). In basal conditions, PCOS women exhibited lower NPY levels than controls (P < 0.01). Ghrelin injection markedly increased NPY in controls (P < 0.01), whereas PCOS women showed a deeply blunted NPY response to the stimulus (area under the curve--AUC-NPY: P < 0.01 vs. controls.). Metformin treatment induced a significant decrease in insulin levels (P < 0.01) and the concomitant recovery of NPY secretory capacity in response to ghrelin (AUC-NPY: P < 0.05 vs. baseline) in PCOS women. Leptin levels, which were similar in the two groups, were not modified by ghrelin injection; metformin did not affect this pattern.. Hyperinsulinaemia seems to play a pivotal role in the alteration of NPY response to ghrelin in obese PCOS women. This derangement could be implicated in the physiopatology of obesity in these patients.

Topics: Adult; Female; Ghrelin; Glucose Tolerance Test; Humans; Hyperinsulinism; Hypoglycemic Agents; Insulin; Leptin; Metformin; Neuropeptide Y; Obesity; Pilot Projects; Polycystic Ovary Syndrome; Signal Transduction; Young Adult

Lack of leptin is implicated in insulin resistance and other metabolic abnormalities in generalized lipodystrophy; however, the efficacy, safety, and underlying mechanisms of leptin-replacement therapy in patients with generalized lipodystrophy remain unclear.. Seven Japanese patients with generalized lipodystrophy, two acquired and five congenital type, were treated with the physiological replacement dose of recombinant leptin during an initial 4-month hospitalization followed by outpatient follow-up for up to 36 months.. The leptin-replacement therapy with the twice-daily injection dramatically improved fasting glucose (mean +/- SE, 172 +/- 20 to 120 +/- 12 mg/dl, P < 0.05) and triglyceride levels (mean +/- SE, 700 +/- 272 to 260 +/- 98 mg/dl, P < 0.05) within 1 wk. The leptin-replacement therapy reduced insulin resistance evaluated by euglycemic clamp method and augmented insulin secretion at glucose tolerance test with different responses between acquired and congenital types. Improvement of the fatty liver was also observed. The efficacy and safety of the once-daily injection were comparable to those of the twice-daily injection. The leptin-replacement therapy ameliorated macro- and microalbuminuria and showed no deterioration of neuropathy and retinopathy of these patients. The leptin-replacement therapy is beneficial to diabetic complications and lipodystrophic ones. Two patients developed antileptin antibodies but not neutralizing antibodies. The therapy was well tolerated, and its effects were maintained for up to 36 months without any notable adverse effects such as hypoglycemia, high blood pressure, or reduction of bone mineral density.. The present study demonstrates the efficacy and safety of the long-term leptin-replacement therapy and possible mechanisms of leptin actions in patients with generalized lipodystrophy.

Topics: Adolescent; Adult; Albuminuria; Blood Glucose; Child; Diabetes Complications; Fatty Liver; Female; Follow-Up Studies; Glucose Clamp Technique; Glucose Tolerance Test; Hormone Replacement Therapy; Humans; Hyperinsulinism; Injections, Subcutaneous; Insulin Resistance; Leptin; Lipodystrophy; Male; Time Factors; Treatment Outcome; Triglycerides

To determine the effect of hyperinsulinemia on food intake and plasma concentrations of glucose and food intake regulatory hormones in men after a glucose drink.. Cross-sectional clinical intervention study of the effect of a glucose drink on food intake regulation.. Thirty-three normoinsulinemic (NI) (body mass index (BMI)=25.3+/-0.6; age=41.4+/-2.4) and 32 hyperinsulinemic (HI) men (BMI=29.5+/-0.6; age=43.4+/-2.6).. Food intake was measured from a pizza meal 1 h after subjects consumed either a noncaloric sweetened drink or a glucose-containing drink (75 g/300 ml) in random order on two occasions. On another occasion, blood samples were taken every 30 min for 2 h after the glucose drink.. Fasting insulin in the HI and NI men was 65+/-3 (mean+/-s.e.m.) and 26+/-1.5 pmol/l, respectively. Food intake at the pizza meal was reduced by the glucose drink (P<0.01), but more so in HI (-9.7+/-4.1 %) than NI men (-5.4+/-3.4 %) (P=0.06). The increase in plasma insulin and cholecystokinin (CCK) after the glucose drink was greater and the plasma concentrations of leptin were higher, and ghrelin and adiponectin were lower in HI men than in NI men (P<0.05).. These results support epidemiological data suggesting that hyperinsulinemia, at least in the early stages, may provide resistance to weight gain, possibly through physiological mechanisms of food intake control.

Topics: Adiponectin; Administration, Oral; Adolescent; Adult; Aged; Appetite Regulation; Blood Glucose; Cholecystokinin; Cross-Sectional Studies; Ghrelin; Glucose; Humans; Hyperinsulinism; Insulin; Leptin; Male; Middle Aged

Leptin resistance is a hallmark of obesity, but its etiology is unknown, and its clinical measurement is elusive. Leptin-sensitive subjects have normal resting energy expenditure (REE) at a low leptin concentration, while leptin-resistant subjects have a normal REE at a higher leptin concentration; thus, the ratio of REE:Leptin may provide a surrogate index of leptin sensitivity. We examined changes in REE and leptin in a cohort of 17 obese subjects during experimental weight loss therapy with the insulin-suppressive agent octreotide-LAR, 40 mg i.m. q28d for 6 months. Six subjects lost significant weight (>10%) and BMI (>-3 kg/m(2)) with a 34% decline in leptin and a 46% decrease in insulin area under the curve (IAUC) to oral glucose tolerance testing. These subjects maintained their pretreatment REE, and thus exhibited a rise in REE:Leptin, while the other 11 showed minimal changes in each of these parameters. For the entire cohort, the change in IAUC correlated negatively with the change in REE:Leptin. These results suggest that the REE:Leptin ratio, while derivative, may serve as a useful clinical indicator of changes in leptin sensitivity within obese subjects. They also support the possibilities that hyperinsulinemia may be a proximate cause of leptin resistance, and that reduction of insulinemia may promote weight loss by improving leptin sensitivity.

Topics: Adult; Blood Glucose; Body Mass Index; Energy Metabolism; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Leptin; Obesity; Octreotide; Weight Loss

Patients with highly active antiretroviral therapy-associated lipodystrophy (HAART+LD+) have high plasminogen activator inhibitor-1 (PAI-1) concentrations for unknown reasons. We determined whether (1). plasma PAI-1 antigen concentrations are related to liver fat content (LFAT) independently of the size of other fat depots and (2) rosiglitazone decreases PAI-1 and LFAT in these patients.. In the cross-sectional study, 3 groups were investigated: 30 HIV-positive patients with HAART+LD+, 13 HIV-positive patients without lipodystrophy (HAART+LD-), and 15 HIV-negative subjects (HIV-). In the treatment study, the HAART+LD+ group received either rosiglitazone (8 mg, n=15) or placebo (n=15) for 24 weeks. Plasma PAI-1 was increased in HAART+LD+ (28+/-2 ng/mL) compared with the HAART+LD- (18+/-3, P<0.02) and HIV- (10+/-3, P<0.001) groups. LFAT was higher in HAART+LD+ (7.6+/-1.7%) than in the HAART+LD- (2.1+/-1.1%, P<0.001) and HIV- (3.6+/-1.2%, P<0.05) groups. Within the HAART+LD+ group, plasma PAI-1 was correlated with LFAT (r=0.49, P<0.01) but not with subcutaneous or intra-abdominal fat or serum insulin or triglycerides. In subcutaneous adipose tissue, PAI-1 mRNA was 2- to 3-fold higher in the HAART+LD+ group than in either the HAART+LD- or HIV- group. Rosiglitazone decreased LFAT, serum insulin, and plasma PAI-1 and increased serum triglycerides but had no effect on intra-abdominal or subcutaneous fat mass or PAI-1 mRNA.. Plasma PAI-1 concentrations are increased in direct proportion to LFAT in HAART+LD+ patients. Rosiglitazone decreases LFAT, serum insulin, and plasma PAI-1 without changing the size of other fat depots or PAI-1 mRNA in subcutaneous fat. These data suggest that liver fat contributes to plasma PAI-1 concentrations in these patients.

Topics: Adipose Tissue; Adult; Antiretroviral Therapy, Highly Active; Cross-Sectional Studies; Female; HIV Infections; Humans; Hyperinsulinism; Hypertriglyceridemia; Interleukin-6; Leptin; Lipodystrophy; Liver; Male; Middle Aged; Organ Specificity; Plasminogen Activator Inhibitor 1; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Rosiglitazone; Subcutaneous Tissue; Thiazolidinediones; Transcription Factors

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

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

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

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

Hyperinsulinemia and insulin resistance are common features of obesity in humans and experimental animals. It has been demonstrated that metformin, an antihyperglycemic agent, decreases hyperinsulinemia and insulin resistance leading to decreased adiposity in obese and non-insulin-dependent diabetes mellitus (NIDDM) adults. To evaluate the antiobesity effect of metformin, we conducted a randomized double-blind placebo controlled trial in 24 hyperinsulinemic nondiabetic obese adolescents (body mass index [BMI] >30 kg/m(2)). All subjects were placed on a low-calorie (1,500 kcal for women and 1,800 kcal for men) meal plan. After an initial 1-week lead-in period, 12 subjects (mean +/- SE for age and BMI, 15.6 +/- 0.4 and 41.2 +/- 1.8, respectively) received metformin (850 mg twice daily) for 8 weeks, and 12 subjects (mean +/- SE for age and BMI, 15.7 +/- 0.5 and 40.8 +/- 1.4, respectively) received placebo. Compared to the placebo group, the metformin group had greater weight loss (6.5% +/- 0.8% v 3.8 +/- 0.4%, P <.01), greater decrease in body fat (P <.001), greater increase in fat-free mass to body fat ratio (P <.005), and greater attenuation of area under the curve (AUC) insulin response to an oral glucose tolerance test (P <.001). This was associated with enhanced insulin sensitivity, as determined by the fasting plasma glucose:insulin, 2-hour glucose:insulin, and AUC glucose:AUC insulin ratios, in the metformin group compared to controls (P <.01). This corresponded to a significant reduction in plasma leptin (P <.005), cholesterol, triglycerides, and free fatty acid (FFA) levels (P <.05) only in the metformin-treated subjects. Combined metformin treatment and low-calorie diet had a significant antiobesity effect in hyperinsulinemic obese adolescents compared to a low-calorie diet alone.

Topics: Adipose Tissue; Adolescent; Blood Glucose; Body Composition; Body Mass Index; Cholesterol; Diet, Reducing; Double-Blind Method; Energy Intake; Fasting; Fatty Acids, Nonesterified; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Hypoglycemic Agents; Kinetics; Leptin; Male; Metformin; Obesity, Morbid; Placebos; Triglycerides; Weight Loss

This study aimed to identify the acute effect of a physiologic dose of insulin, enough to produce hyperinsulinaemia similar to that obtained in the postprandial state, on serum leptin concentrations in healthy young people. A randomised, single blind controlled clinical trial was performed in 45 healthy, non-obese, young volunteers. Serum leptin concentration, uric acid, creatinine levels and lipid profile were determined for all subjects. Insulin suppression test modified with octreotide, used to produce physiologic hyperinsulinaemia, or saline infusion as control, were performed. Steady state insulin (SSI) concentrations were calculated and they represented the hyperinsulinaemia state. Clinical characteristics and laboratory profiles were similar between groups. There was no significant difference between the effect of insulin or saline infusions on the serum leptin concentration. The acute effect of physiologic hyperinsulinaemia did not modify the serum leptin concentration in healthy young people.

Topics: Acute Disease; Adult; Blood Glucose; Creatinine; Female; Glucose; Hormones; Humans; Hyperinsulinism; Hypoglycemic Agents; Insulin; Leptin; Lipids; Male; Octreotide; Osmolar Concentration; Reference Values; Single-Blind Method; Uric Acid

The polycystic ovary syndrome (PCOS) is characterized by menstrual disturbances, chronic anovulation and hyperandrogenism and is associated with insulin resistance and hyperinsulinemia. Leptin, the product of the ob gene, is an adipocyte-secreted molecule that signals the magnitude of energy stores to the brain and has been recently shown to have important effects on the reproductive axis of rodents. To assess the potential contribution of leptin to the pathogenesis of PCOS, we measured leptin levels in 24 obese women with PCOS and 12 weight- and age-matched controls and determined whether alterations in hyperinsulinemia produced by administration of the insulin-sensitizing agent troglitazone had an effect on serum leptin levels. Leptin concentrations at baseline were not different in women with PCOS (38.1 +/- 2.15 ng/mL) and controls (33.12 +/- 2.39 ng/mL). Moreover, leptin concentrations remained unchanged after treatment with troglitazone (38.1 +/- 2.15 vs. 39.21 +/- 2.65 ng/mL). Baseline leptin correlated strongly with body mass index in both controls (r = 0.59; P < 0.05) and women with PCOS (r = 0.70; P = 0.0004). Leptin levels were not associated with baseline insulin, testosterone, non-sex hormone-binding globulin (SHBG)-bound testosterone, dehydroepiandrosterone sulfate, estradiol, or SHBG. Finally, despite significantly reduced insulin, non-SHBG-bound testosterone, and estradiol levels after troglitazone treatment of women with PCOS, their leptin levels remained unchanged. We conclude that circulating leptin levels in patients with PCOS do not differ from those in age- and weight-matched controls. Furthermore, increased circulating insulin due to insulin resistance does not appear to alter circulating leptin levels in women with PCOS.

Topics: Adult; Body Mass Index; Chromans; Double-Blind Method; Female; Humans; Hyperinsulinism; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Obesity; Osmolar Concentration; Polycystic Ovary Syndrome; Proteins; Thiazoles; Thiazolidinediones; Troglitazone

Congenital generalized lipodystrophy (CGL) is a rare, autosomal recessive disorder characterized by an almost complete absence of body fat. In CGL, patients may have hyperphagia due to leptin deficiency. Recombinant human leptin (metreleptin) has been suggested as an effective treatment option. We present successful treatment with metreleptin in a boy with CGL and results from the first year of follow-up. An eight-month-old boy presented with excessive hair growth and a muscular appearance. On examination he had hypertrichosis, decreased subcutaneous adipose tissue over the whole body and hepatomegaly. Laboratory investigations revealed hypertriglyceridemia, hyperinsulinemia, elevated liver transaminases and low leptin levels. Molecular genetic analysis detected a homozygous, c.465_468delGACT (p.T156Rfs*8) mutation in the

Topics: Child; GTP-Binding Protein gamma Subunits; Humans; Hyperinsulinism; Hyperphagia; Hypertriglyceridemia; Infant; Leptin; Lipodystrophy, Congenital Generalized; Male; Mutation; Quality of Life

Although several studies have investigated factors associated with the onset and occurrence of hyperinsulinaemia-associated laminitis (HAL), few have examined the factors associated with the rate of improvement during recovery from an acute bout of the disease. This observational study sought to discover if a range of demographic, morphologic, hormonal and metabolic variables are associated with the improvement rate from HAL in 37 naturally-occurring cases identified by 16 clinics across Germany. Each case was evaluated for laminitis severity on the day of inclusion in the trial (d 0), then after 4, 9, 14, 25 and 42 d. The horses were managed according to best clinical practice including restricting exercise and prescribing a diet of hay-only, for a minimum of 9 d. Blood samples were also collected during each evaluation, except on d 9, and analysed for glucose, insulin, ACTH and leptin.. Based on individual clinical laminitis scores plotted against time, most horses improved markedly within 2 weeks, with a 'fast group' (n = 27) having a median (interquartile range) score on a 12-point scale of 0 (0-2) by d 14. However, there was a clear disparity within the total cohort, as ~ 1 in 4 horses demonstrated much slower improvement, with a median score of 5 (4-7) by d 14, or a marked relapse thereafter ('slow group', n = 10). Horses in the slow improvement group were younger (12.5 (8.8-16.3) vs 17 (14-24) yr; P = 0.008), but were not more likely to be heavier, male, very fat, to have presented with a previous history of laminitis or elevated ACTH concentrations, or to be receiving pergolide treatment. Of the hormonal and metabolic parameters measured, glucose and insulin concentrations were within the normal range following transition to the hay-only diet, but were higher in the group that failed to improve quickly, with a small but significant difference being evident on d 4, 14 and 25 for glucose (11 to 16%; P < 0.05), and a larger difference for insulin on d 14 and 25 (51 to 55%; P < 0.05). There was no difference between the groups in ACTH or leptin concentrations throughout the study. The main limitations of this study were the small number of slow-improvement horses and an inability to control or measure certain variables, such as feed quality.. Young age and a modest increase in blood glucose and insulin concentrations are associated with delayed laminitis improvement.

Topics: Adrenocorticotropic Hormone; Animals; Dermatitis; Foot Diseases; Germany; Glucose; Hoof and Claw; Horse Diseases; Horses; Hyperinsulinism; Insulin; Leptin; Male; Physical Conditioning, Animal

Circadian misalignment between behaviors such as feeding and endogenous circadian rhythms, particularly in the context of shiftwork, is associated with poorer cardiometabolic health. We examined whether insulin and leptin levels differ between dayshift versus nightshift nurses, as well as explored whether the timing of food intake modulates these effects in nightshift workers.. Female nurses (N=18; 8 dayshift and 10 nightshift) completed daily diet records for 8 consecutive days. The nurses then completed a 24-h inpatient stay, during which blood specimens were collected every 3 h (beginning at 09:00) and meals were consumed at regular 3-h intervals (09:00, 12:00, 15:00, and 18:00). Specimens were analyzed for insulin and leptin levels, and generalized additive models were used to examine differences in mean insulin and leptin levels.. Mean insulin and leptin levels were higher in nightshift nurses by 11.6 ± 3.8 mU/L (p=0.003) and 7.4 ± 3.4 ng/ml (p=0.03), respectively, compared to dayshift nurses. In an exploratory subgroup analysis of nightshift nurses, predominately eating at night (21:00 - 06:00) was associated with significantly higher insulin and leptin levels than consuming most calories during the daytime (06:00 - 21:00).. In our study of hospital nurses, working the nightshift was associated with higher insulin and leptin levels, and these effects were driven by eating predominately at night. We conclude that although nightshift work may raise insulin and leptin levels, eating during the daytime may attenuate some of the negative effects of nightshift work on metabolic health.

Topics: Circadian Rhythm; Feeding Behavior; Female; Hospitals; Humans; Hyperinsulinism; Insulin; Leptin; Nurses; Shift Work Schedule

Activation of innate immunity and low-grade inflammation contributes to hyperglycemia and an onset of Type 2 Diabetes Mellitus (T2DM). Interleukin-2 (IL-2), leptin, High Mobility Group Box-1 (HMGB-1), and increased glucose concentrations are mediators of these processes also by modulating peripheral blood mononuclear cells (PBMCs) response. The aim of this study was to investigate if HMGB-1 and IL-2 turn on PBMCs and their leptin secretion. In isolated human PBMCs and their subpopulations from healthy individuals and naïve T2DM patients, leptin release, pro-inflammatory response and Toll-like Receptors (TLRs) activation was measured. After treatment with IL-2 and HMGB1, NK (Natural Killer) have the highest amount of leptin secretion, whilst NK-T have the maximal release in basal conditions. TLR4 (TAK242) and/or TLR2 (TLR2-IgA) inhibitors decreased leptin secretion after IL-2 and HMGB1 treatment. A further non-significant increase in leptin secretion was reported in PBMCs of naive T2DM patients in response to IL-2 and HMGB-1 stimulation. Finally, hyperglycemia or hyperinsulinemia might stimulate leptin secretion from PBMCs. The amount of leptin released from PBMCs after the different treatments was enough to stimulate the secretion of IL-1β from monocytes. Targeting leptin sera levels and secretion from PBMCs could represent a new therapeutic strategy to counteract metabolic diseases such as T2DM.

Topics: Diabetes Mellitus, Type 2; HMGB1 Protein; Humans; Hyperglycemia; Hyperinsulinism; Interleukin-2; Leptin; Leukocytes, Mononuclear

Topics: Adult; Animals; Anti-Mullerian Hormone; Female; Humans; Hyperinsulinism; Insulin Resistance; Insulin Secretion; Leptin; Polycystic Ovary Syndrome; Rats; Young Adult

Low-grade inflammation is associated with the development of insulin resistance in obese individuals. The present study aims to provide additional evidence strengthening the role of interleukin (IL)-32 in this key process. Using an IL-32 transgenic (IL-32tg) mouse model, we observed that IL-32tg fed a normal diet had greater body weight, due to greater accumulation of white adipose tissue (WAT) along with larger sized adipocytes. This led to metabolic consequences, with significant higher leptin levels and a trend towards hyperinsulinemia, indicating a phenotype resembling the metabolic syndrome. Adipocytes of IL-32tg mice were more prone to induce a pro-inflammatory response locally, which would be expected when predisposed to insulin resistance and type2 diabetes mellitus (T2D). In conclusion, our study provides novel evidence of a direct contribution of IL-32 to pathophysiological perturbations within the adipose tissue, possibly contributing to the metabolic syndrome that precedes frank insulin resistance and T2D. Future research should focus on the role of IL-32 in the obesity epidemic.

Topics: Adipocytes; Adipokines; Adipose Tissue, White; Animals; Body Weight; Cytokines; Hyperinsulinism; Inflammation; Interleukins; Leptin; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Transgenic; Obesity

It was reported that either orexigenic neuropeptide galanin or anorexigenic hormone leptin caught benefit insulin sensitivity through increasing the translocation of glucose transporter 4 (GLUT4) in patients with diabetes. To date, it is unknown whether galanin can potentiate the effect of leptin on alleviation of insulin resistance. Therefore, in the current study we sought to assess the combined effect of central leptin and galanin on insulin resistance in the adipose tissues of type 2 diabetic rats. Galanin and leptin were injected into the intracerebroventricle of the diabetic rats, respectively, or cooperatively once a day for 2 weeks. Then, several indexes of insulin resistance were examined. The results showed that glucose infusion rates in the hyperinsulinaemic-euglycaemic clamp test, plasma adiponectin content and GLUT4 translocation, as well as Akt phosphorylation in fat cells, were higher, not GLUT4 protein and GLUT4 mRNA expression, but HOMA index was lower in the galanin + leptin group than either one of them. Furthermore, treatment with MK-2206, an Akt inhibitor, blocked the combined effects of galanin + leptin on alleviation of insulin resistance. These results suggest that galanin can improve the leptin-induced mitigative effects on insulin resistance in the fat cells, and those provided new insights into the potential tactics for prevention and remedy of insulin resistance.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Animals; Body Weight; Deoxyglucose; Diabetes Mellitus, Experimental; Feeding Behavior; Galanin; Glucose Clamp Technique; Glucose Transporter Type 4; Hyperinsulinism; Insulin Resistance; Leptin; Male; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats, Wistar; RNA, Messenger

Perturbations in postnatal leptin signaling have been associated with altered susceptibility to diet-induced obesity (DIO) under high-fat-diet (HFD), albeit with contradicting evidence. Previous studies have shown that alpha murine urokinase-type plasminogen activator (αMUPA) mice have a higher and longer postnatal leptin surge compared with their wild types (WTs) as well as lower body weight and food intake under regular diet (RD). Here we explored αMUPA's propensity for DIO and the effect of attenuating postnatal leptin signaling with leptin antagonist (LA) on energy homeostasis under both RD and HFD. Four-day-old αMUPA pups were treated on alternate days until postnatal day 18 with either vehicle or LA (10 or 20 mg·day

Topics: Animals; Animals, Newborn; Body Weight; Diet, High-Fat; Disease Susceptibility; Eating; Energy Metabolism; Female; Hyperinsulinism; Leptin; Mice; Obesity; Pregnancy; Receptors, Urokinase Plasminogen Activator; Signal Transduction; Species Specificity; Weight Gain

Six-week-old male KK-A

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

This study aimed to examine changes in the insulin secretory response in early pregnancy, while accounting for changes in insulin sensitivity.. This is a secondary analysis of a previously conducted longitudinal physiological study. In 34 women, insulin secretory response (by IVGTT) and insulin sensitivity (by euglycaemic clamp) were assessed prior to pregnancy, in early pregnancy (12-14 weeks gestation) and in late pregnancy (34-36 weeks gestation). Using mixed-effects models, we compared insulin secretory response and sensitivity in early pregnancy to the same variables prior to pregnancy and in late pregnancy, with adjustment for age, obesity status and gestational diabetes mellitus (GDM). We examined changes in insulin secretory response after adjustment for insulin sensitivity using both multivariate modelling and the disposition index (DI). We explored the relationship between insulin secretory response and circulating hormones.. The insulin secretory response increased from prior to pregnancy to early pregnancy (unadjusted mean [SD] first-phase insulin response 465.1 [268.5] to 720 [358.2], p < 0.0001) and from early pregnancy to late pregnancy (to 924 [494.6], p = 0.01). Insulin sensitivity increased from prior to pregnancy to early pregnancy (insulin sensitivity index 0.10 [0.04] to 0.12 [0.05], p = 0.001) and decreased in late pregnancy (to 0.06 [0.03], p < 0.0001). Accounting for changes in insulin sensitivity, using either multivariate modelling or the DI, did not attenuate the early-pregnancy augmentation of insulin secretory response. Leptin was positively associated with insulin secretory response, independent of insulin sensitivity and adiposity (p = 0.004). Adjustment for leptin attenuated the observed augmentation of insulin secretory response in early pregnancy (adjusted mean change 121.5, p = 0.13).. The insulin secretory response increases markedly in early pregnancy, prior to and independent of changes in insulin sensitivity. Circulating hormones may mediate this metabolic adaptation. Identifying mediators of this physiological effect could have therapeutic implications for treating hyperglycaemia during and outside of pregnancy.

Topics: Adult; Age Factors; Blood Glucose; Body Mass Index; Cytokines; Diabetes, Gestational; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Leptin; Longitudinal Studies; Multivariate Analysis; Obesity; Pregnancy; Pregnancy Complications; Pregnancy Trimester, First; Pregnancy Trimester, Third; Prospective Studies; Tumor Necrosis Factor-alpha

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

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

Non-digestible carbohydrates present in cereals such as fructans and arabinoxylans represent promising prebiotic nutrients to prevent the development of obesity and related metabolic disorders.. The aim of this study was to determine the corrective effects of wheat bran-derived arabinoxylan oligosaccharides in obese mice fed a western diet (WD). WD was given for 4 weeks before wheat bran extract (WBE) supplementation (5%) for an additional 4 weeks, whereas a control group received the standard diet.. Bifidogenic effect of WBE was evidenced by an induction of both Bifidobacterium animalis and Bifidobacterium pseudolongum in the caecal content. WBE supplementation normalised WD-induced fat-mass expansion, steatosis, hypercholesterolemia, hyperleptinemia, hyperglycemia and hyperinsulinemia reaching the values of control mice. The reduced glucose-dependent insulinotropic polypeptide (GIP) release observed in WD + WBE mice may be a protective mechanism in terms of reducing adipose tissue storage, hepatic steatosis and glucose homoeostasis.. We found that WBE completely abolished WD-induced metabolic disorders. Those results might be useful to take into account nutritional advices to treat obesity and related metabolic disorders such as type 2 diabetes, hypercholesterolaemia and fatty liver diseases when obesity was already established.

Topics: Adipose Tissue; Animals; Bifidobacterium; Blood Glucose; Cecum; Diabetes Mellitus, Type 2; Diet, Western; Dietary Fiber; Fatty Liver; Gastric Inhibitory Polypeptide; Hypercholesterolemia; Hyperglycemia; Hyperinsulinism; Leptin; Liver; Male; Metabolic Diseases; Mice, Inbred C57BL; Mice, Obese; Obesity; Oligosaccharides; Prebiotics; Triticum; Xylans

ErbB4, a member of the EGF receptor family, plays a variety of roles in physiological and pathological states. Genetic studies have indicated a link between ErbB4 and type 2 diabetes and obesity, but its role in metabolic syndrome (MetS) has not been reported. In the current study we found that mice with ErbB4 deletion developed MetS after 24 wk on a medium-fat diet (MFD), as indicated by development of obesity, dyslipidemia, hepatic steatosis, hyperglycemia, hyperinsulinemia, and insulin resistance, compared with wild-type mice. ErbB4 deletion mice also exhibited increased amounts of subcutaneous and visceral fat, with increased serum leptin levels, compared with wild-type mice, whereas levels of adiponectin were not significantly different. Histologically, severe inflammation, indicated by F4/80 immunostaining and M1 macrophage polarization, was detected in inguinal and epididymal white adipose tissue in ErbB4 deletion mice. ErbB4 expression decreased during 3T3-L1 preadipocyte differentiation. Administration of neuroregulin 4, a specific ligand for ErbB4, to 3T3-L1 adipocytes had no effect on adipogenesis and lipolysis but significantly inhibited lipogenesis, promoted browning, induced GLUT4 redistribution to the cell membrane, and increased glucose uptake. Neuroregulin 4 also significantly increased glucose uptake in adipocytes isolated from wild-type mice, while these effects were significantly decreased in adipocytes isolated from ErbB4 deletion mice. In conclusion, our results indicate that ErbB4 may play an important role in glucose homeostasis and lipogenesis. ErbB4 deficiency-related obesity and adipose tissue inflammation may contribute to the development of MetS.

Topics: 3T3-L1 Cells; Adipogenesis; Adiponectin; Adipose Tissue, White; Animals; Dietary Fats; Dyslipidemias; Fatty Liver; Gene Deletion; Genetic Predisposition to Disease; Glucose Transporter Type 4; Hyperglycemia; Hyperinsulinism; Inflammation; Insulin Resistance; Intra-Abdominal Fat; Leptin; Lipogenesis; Macrophages; Male; Metabolic Syndrome; Mice; Neuregulins; Obesity; Receptor, ErbB-4; Subcutaneous Fat

To evaluate the association between cord blood amino acid and acylcarnitine profiles and measures of adiposity and hyperinsulinemia in healthy newborns.. A cross-sectional study of 118 full-term infants born to mothers without gestational diabetes was performed. Cord blood leptin, C-peptide, acylcarnitine, and amino acid levels were measured. Body composition was measured by air displacement plethysmography. Multivariate linear regression and principal component analysis were used to analyze associations of cord blood metabolites with newborn anthropometrics, leptin, and C-peptide.. Acylcarnitines AC C2, AC C4-DC/Ci4-DC, and AC C8:1-OH/C6:1-DC were positively associated with leptin, and AC C14, AC C14:2, AC C16, AC C18, and AC C18:2 were negatively associated with C-peptide (P ≤ .0016). Principal component analysis revealed a positive association between factor 1(AC C2, AC C3, AC C5, AC C4/Ci4, AC C4-OH, AC C4-DC/Ci4-DC, glutamate/glutamine, and glycine) and adiposity measures.. The positive association of AC C2 and AC C4-DC/Ci4-DC levels with leptin may reflect excess fat stores, higher fatty acid oxidation rate, and mitochondrial dysfunction leading to accumulation of acylcarnitine intermediates. Principal component analysis revealed a positive association between branched chain amino acid and ketone body metabolites and adiposity, confirming prior findings in adults. Cord blood acylcarnitine profiles may identify at-risk children before obesity or insulin resistance develops.

Topics: Adiposity; Adult; Amino Acids; C-Peptide; Carnitine; Cross-Sectional Studies; Female; Fetal Blood; Humans; Hyperinsulinism; Infant, Newborn; Leptin; Male; Multivariate Analysis; Principal Component Analysis

Berardinelli-Seip Congenital Lipodystrophy (BSCL) is a rare autosomal recessive syndrome characterized by a difficulty in storing lipids in adipocytes, low body fat mass, hypoleptinemia, and hyperinsulinemia. Sclerostin is a product of SOST gene that blocks the Wnt/β-catenin pathway, decreasing bone formation and enhancing adipogenesis. There are no data about sclerostin in people with BSCL.. We aimed to evaluate serum sclerostin, bone mineral density (BMD), and L1-L4 Trabecular Bone Score (TBS) in BSCL patients, generating new knowledge about potential mechanisms involved in the bone alterations of these patients.. In this cross-sectional study, we included 11 diabetic patients with BSCL (age 24.7±8.1years; 6 females). Sclerostin, leptin, L1-L4 TBS, BMD were measured. Potential pathophysiological mechanisms have been suggested.. Mean serum sclerostin was elevated (44.7±13.4pmol/L) and was higher in men than women (55.3±9.0 vs. 35.1±8.4pmol/L, p=0.004). Median of serum leptin was low [0.9ng/mL (0.5-1.9)]. Seven out of 11 patients had normal BMD, while four patients had high bone mass (defined as Z-score>+2.5SD). Patients on insulin had lower sclerostin (37.3±9.2 vs. 52.6±13.4pmol/L, p=0.05). The mean TBS was 1.402±0.106, and it was higher than 1.300 in nine patients.. Patients with lipoatrophic diabetes (BSCL) have high serum concentrations of sclerostin, normal or high BMD, and reasonable trabecular bone mass measured by TBS. This is the first report of high sclerostin and good bone microarchitecture (TBS) in BSCL patients.

Topics: Adaptor Proteins, Signal Transducing; Adolescent; Adult; Bone Density; Bone Morphogenetic Proteins; Cancellous Bone; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Genetic Markers; Humans; Hyperinsulinism; Hypertrophy; Insulin; Leptin; Lipodystrophy, Congenital Generalized; Male; Muscular Diseases; Young Adult

The adipose-derived hormone leptin plays an important role in regulating body weight and glucose homeostasis. Leptin receptors are expressed in the central nervous system as well as peripheral tissues involved in regulating glucose homeostasis, including insulin-producing β cells of the pancreas. Previous studies assessing the role of leptin receptors in β cells used Cre-. We used a mouse model in which endogenous expression of. Male and female. Collectively, these data suggest that direct action of leptin on β cells is insufficient to restore normal insulin secretion and glucose tolerance in mice without leptin receptor signaling elsewhere.

Topics: Animals; Cells, Cultured; Female; Hyperglycemia; Hyperinsulinism; Insulin-Secreting Cells; Leptin; Male; Mice; Mice, Inbred C57BL; Receptors, Leptin

Insulin resistance (IR) is the cornerstone of the obesity-associated metabolic derangements observed in obese children. Targeted metabolomics was employed to explore the pathophysiological relevance of hyperinsulinemia in childhood obesity in order to identify biomarkers of IR with potential clinical application.. One hundred prepubertal obese children (50 girls/50 boys, 50% IR and 50% non-IR in each group), underwent an oral glucose tolerance test for usual carbohydrate and lipid metabolism determinations. Fasting serum leptin, total and high molecular weight-adiponectin and high-sensitivity C-reactive protein (CRP) levels were measured and the metabolites showing significant differences between IR and non-IR groups in a previous metabolomics study were quantified. Enrichment of metabolic pathways (quantitative enrichment analysis) and the correlations between lipid and carbohydrate metabolism parameters, adipokines and serum metabolites were investigated, with their discriminatory capacity being evaluated by receiver operating characteristic (ROC) analysis.. Combined sets of metabolic, adipokine and metabolomic parameters can identify pathophysiological relevant IR in a single fasting sample, suggesting a potential application of metabolomic analysis in clinical practice to better identify children at risk without using invasive protocols.

Topics: Adiponectin; Area Under Curve; Biomarkers; Blood Glucose; Body Mass Index; Child; Fasting; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin Resistance; Leptin; Longitudinal Studies; Male; Metabolomics; Pediatric Obesity; Predictive Value of Tests; Reference Values; ROC Curve; Spain

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

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

Thyroid hormones are important regulators of growth and maturation before birth, although the extent to which their actions are mediated by insulin and the development of pancreatic beta cell mass is unknown. Hypothyroidism in fetal sheep induced by removal of the thyroid gland caused asymmetric organ growth, increased pancreatic beta cell mass and proliferation, and was associated with increased circulating concentrations of insulin and leptin. In isolated fetal sheep islets studied in vitro, thyroid hormones inhibited beta cell proliferation in a dose-dependent manner, while high concentrations of insulin and leptin stimulated proliferation. The developing pancreatic beta cell is therefore sensitive to thyroid hormone, insulin and leptin before birth, with possible consequences for pancreatic function in fetal and later life. The findings of this study highlight the importance of thyroid hormones during pregnancy for normal development of the fetal pancreas.. Development of pancreatic beta cell mass before birth is essential for normal growth of the fetus and for long-term control of carbohydrate metabolism in postnatal life. Thyroid hormones are also important regulators of fetal growth, and the present study tested the hypotheses that thyroid hormones promote beta cell proliferation in the fetal ovine pancreatic islets, and that growth retardation in hypothyroid fetal sheep is associated with reductions in pancreatic beta cell mass and circulating insulin concentration in utero. Organ growth and pancreatic islet cell proliferation and mass were examined in sheep fetuses following removal of the thyroid gland in utero. The effects of triiodothyronine (T

Topics: Animals; Cell Proliferation; Cells, Cultured; Female; Fetal Diseases; Hyperinsulinism; Hypothyroidism; Insulin; Insulin-Secreting Cells; Leptin; Pregnancy; Sheep; Triiodothyronine

The prevalence of obesity during pregnancy continues to increase at alarming rates. This is concerning as in addition to immediate impacts on maternal wellbeing, obesity during pregnancy has detrimental effects on the long-term health of the offspring through non-genetic mechanisms. A major knowledge gap limiting our capacity to develop intervention strategies is the lack of understanding of the factors in the obese mother that mediate these epigenetic effects on the offspring. We used a mouse model of maternal-diet induced obesity to define predictive correlations between maternal factors and offspring insulin resistance. Maternal hyperinsulinemia (independent of maternal body weight and composition) strongly associated with offspring insulin resistance. To test causality, we implemented an exercise intervention that improved maternal insulin sensitivity without changing maternal body weight or composition. This maternal intervention prevented excess placental lipid deposition and hypoxia (independent of sex) and insulin resistance in male offspring. We conclude that hyperinsulinemia is a key programming factor and therefore an important interventional target during obese pregnancy, and propose moderate exercise as a promising strategy to improve metabolic outcome in both the obese mother and her offspring.

Topics: Animals; Blood Glucose; Cholesterol; Diet, High-Fat; Female; Glucose Tolerance Test; Hyperinsulinism; Hypoxia; Insulin; Insulin Resistance; Leptin; Lipid Metabolism; Male; Mice; Obesity; Physical Conditioning, Animal; Placenta; Pregnancy; Triglycerides

Fructose intake from added sugars correlates with the epidemic rise in metabolic syndrome and cardiovascular diseases. However, consumption of beverages containing fructose is allowed during gestation. Recently, we found that an intake of fructose (10 % wt/vol) throughout gestation produces impaired fetal leptin signaling and hepatic steatosis. Therefore, we have investigated whether fructose intake during pregnancy produces subsequent changes in the progeny, when adult.. Fed 261-day-old male and female descendants from fructose-fed, control or glucose-fed mothers were used. Plasma was used to analyze glucose, insulin, leptin, and adiponectin. Hepatic expression of proteins related to insulin signaling was determined.. Fructose intake throughout pregnancy did not produce alterations in the body weight of the progeny. Adult male progeny of fructose-fed mothers had elevated levels of insulin without a parallel increase in phosphorylation of protein kinase B. However, they displayed an augmented serine phosphorylation of insulin receptor substrate-2, indicating reduced insulin signal transduction. In agreement, adiponectin levels, which have been positively related to insulin sensitivity, were lower in male descendants from fructose-fed mothers than in the other two groups. Furthermore, mRNA levels for insulin-responsive genes were not affected (phosphoenolpyruvate carboxykinase, glucose-6-phosphatase) or they were decreased (sterol response element-binding protein-1c) in the livers of male progeny from fructose-supplemented rats. On the contrary, adult female rats from fructose-fed mothers did not exhibit any of these disturbances.. Maternal fructose, but not glucose, intake confined to the prenatal stage provokes impaired insulin signal transduction, hyperinsulinemia, and hypoadiponectinemia in adult male, but not female, progeny.

Topics: Adiponectin; Animals; Animals, Newborn; Blood Glucose; Body Weight; Fatty Liver; Female; Fetus; Fructose; Glucose-6-Phosphatase; Hyperinsulinism; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Leptin; Liver; Male; Maternal Nutritional Physiological Phenomena; Metabolism, Inborn Errors; Phosphoenolpyruvate Carboxykinase (ATP); Phosphorylation; Pregnancy; Prenatal Exposure Delayed Effects; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction; Sterol Regulatory Element Binding Protein 1

The current prevalence of diet-induced overweight and obesity in adolescents and adults is continuously growing. Although the detrimental biochemical and metabolic consequences of obesity are widely studied, its impact on stress-coping behavior and its interaction with specific exercise doses (in terms of intensity, duration and frequency) need further investigation. To this aim, we fed adolescent rats either an obesogenic diet (cafeteria diet, CAF) or standard chow (ST). Each group was subdivided into four subgroups according to the type of treadmill intervention as follows: a sedentary group receiving no manipulation; a control group exposed to a stationary treadmill; a low-intensity treadmill group trained at 12 m/min; and a higher intensity treadmill group trained at 17 m/min. Both the diet and treadmill interventions started at weaning and lasted for 8 weeks. Subjects were tested for anxiety-like behavior in the open field test and for coping strategies in the two-way active avoidance paradigm at week 7 and were sacrificed at week 8 for biometric and metabolic characterization. CAF feeding increased the weight gain, relative retroperitoneal white adipose tissue (RWAT %), and plasma levels of glucose, insulin, triglycerides and leptin and decreased the insulin sensitivity. Treadmill intervention partially reversed the RWAT% and triglyceride alterations; at higher intensity, it decreased the leptin levels of CAF-fed animals. CAF feeding decreased the motor activity and impaired the performance in a two-way active avoidance assessment. Treadmill intervention reduced defecation in the shuttle box, suggesting diminished anxiety. CAF feeding combined with treadmill training at 17 m/min increased the time spent in the center of the open field and more importantly, partially reversed the two-way active avoidance deficit. In conclusion, this study demonstrates that at doses that decreased anxiety-like behavior, treadmill exercise partially improved the coping strategy in terms of active avoidance behavior in the CAF-fed animals. This effect was not observed at lower doses of treadmill training.

Topics: Adipose Tissue, White; Animals; Blood Glucose; Diet; Dietary Fats; Exercise Test; Female; Hyperinsulinism; Insulin; Insulin Resistance; Intra-Abdominal Fat; Leptin; Obesity; Physical Conditioning, Animal; Rats; Rats, Sprague-Dawley; Stress, Physiological; Triglycerides; Weight Gain

This study tested whether the maternal transport of dexamethasone (DEXA) may affect the development of the neuroendocrine system. DEXA (0.2mg/kg b.w., subcutaneous injection) was administered to pregnant rats from gestation day (GD) 1-20. In the DEXA-treated group, a decrease in maternal serum thyroxine (T4), triiodothyronine (T3), and increase in thyrotropin (TSH) levels (hypothyroid status) were observed at GDs 15 & 20 with respect to control group. The reverse pattern (hyperthyroid status) was observed in their fetuses at embryonic days (EDs) 15 & 20. Although the maternal body weight was diminished, the weight of the thyroid gland was increased at studied GDs as compared to the control group. The fetal growth retardation, hyperleptinemia, hyperinsulinism, and cytokines distortions (transforming growth factor-beta; TGF-β, tumor necrosis factor-alpha; TNF-α, and interferon-γ; IFN-γ) were noticed at examined EDs if compared to the control group. Alternatively, the maternofetal thyroid dysfunctions due to the maternal DEXA administration attenuated the levels of fetal cerebral norepinephrine (NE) and epinephrine (E), and elevated the levels of dopamine (DA) and 5-hydroxytryptamine (5-HT) at considered days. These alterations were age-dependent and might damage the nerve transmission. Finally, maternal DEXA might act as neuroendocrine disruptor causing dyshormonogenesis and fetal cerebral dysfunction.

Topics: Animals; Anti-Inflammatory Agents; Cytokines; Dexamethasone; Endocrine Disruptors; Female; Fetal Development; Fetal Growth Retardation; Hyperinsulinism; Hypothyroidism; Injections, Subcutaneous; Leptin; Maternal-Fetal Exchange; Neurosecretory Systems; Organ Size; Pregnancy; Rats, Wistar; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine; Weight Gain

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

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

Topics: Adipose Tissue; Body Mass Index; Bone and Bones; Bone Density; Homeostasis; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Leptin; Lipodystrophy, Congenital Generalized; Mutation; Vitamin D

Several studies have investigated the beneficial effects of dehydroepiandrosterone (DHEA) on lipid and glucose metabolism. However, many of these studies are inconclusive about the effects of DHEA administration on metabolic disorders, and there appear to be sex-related differences in the effects of DHEA treatment. Few animal studies have addressed the effects of DHEA on diet-induced metabolic disorders. The present study sought to ascertain whether sex differences exist in the effects of a high-fat diet (HFD) on weight gain, adiposity, and biochemical and hormonal parameters in DHEA-treated rats. Rats were fed a HFD for 4 weeks and simultaneously received treatment with DHEA (10 mg/kg by subcutaneous injection) once weekly. Body weight, retroperitoneal fat depot weight, serum glucose, insulin, and leptin levels, and hepatic lipids were measured. HFD exposure increased the adiposity index in both sexes, the hepatic triglyceride content in both sexes, and the hepatic total cholesterol level in males. Moreover, the HFD induced an increase in blood glucose levels in both sexes, and hyperinsulinemia in males. In this experimental model, DHEA treatment reduced hepatic triglyceride levels only in females, regardless of HFD exposure. Exposure to a HFD, even if it does not cause obesity, may enhance risk factors for metabolic disorders, and males are more sensitive to this effect. DHEA treatment can help prevent metabolic derangements, but its effect varies with sex.

Topics: Animals; Blood Glucose; Body Weight; Dehydroepiandrosterone; Diet, High-Fat; Female; Hyperinsulinism; Insulin; Leptin; Lipid Metabolism; Lipids; Liver; Male; Obesity; Rats; Rats, Wistar; Risk Factors; Sex Factors

Reduced GH levels have been associated with improved glucose metabolism and increased longevity despite obesity in multiple mouse lines. However, one mouse line, the GH receptor antagonist (GHA) transgenic mouse, defies this trend because it has reduced GH action and increased adiposity, but glucose metabolism and life span are similar to controls. Slight differences in glucose metabolism and adiposity profiles can become exaggerated on a high-fat (HF) diet. Thus, in this study, male and female GHA and wild-type (WT) mice in a C57BL/6 background were placed on HF and low-fat (LF) diets for 11 weeks, starting at 10 weeks of age, to assess how GHA mice respond to additional metabolic stress of HF feeding. On a HF diet, all mice showed significant weight gain, although GHA gained weight more dramatically than WT mice, with males gaining more than females. Most of this weight gain was due to an increase in fat mass with WT mice increasing primarily in the white adipose tissue perigonadal depots, whereas GHA mice gained in both the sc and perigonadal white adipose tissue regions. Notably, GHA mice were somewhat protected from detrimental glucose metabolism changes on a HF diet because they had only modest increases in serum glucose levels, remained glucose tolerant, and did not develop hyperinsulinemia. Sex differences were observed in many measures with males reacting more dramatically to both a reduction in GH action and HF diet. In conclusion, our findings show that GHA mice, which are already obese, are susceptible to further adipose tissue expansion with HF feeding while remaining resilient to alterations in glucose homeostasis.

Topics: Adipocytes; Adiposity; Animals; Body Weight; Cattle; Diet, High-Fat; Disease Models, Animal; Eating; Female; Glucose; Glucose Intolerance; Hyperinsulinism; Insulin; Leptin; Liver; Male; Mice, Inbred C57BL; Mice, Transgenic; Obesity; Receptors, Somatotropin; Triglycerides; Weight Gain

The aim of this study was to evaluate the effects of maternal obesity on pancreas structure and carbohydrate metabolism in early adult life, focusing on the F1 and F2 generations after F0 maternal pregestational, gestation, and lactation high-fat diet (HF).. C57 BL/6 female mice (F0) were fed standard chow (SC) or an HF diet for 8 wk before mating and during the gestation and lactation periods to provide the F1 generation (F1-SC and F1-HF). At 3 mo old, F1 females were mated to produce the F2 generation (F2-SC and F2-HF). The male offspring from all groups were evaluated at 3 mo old.. F0-HF and F1-HF dams were overweight before gestation and had a higher body mass gain and energy intake during gestation, although only F0-HF dams presented pregestational hyperglycemia. The F1-HF offspring had higher body mass, energy intake, fasting glucose levels, and were glucose intolerant compared with F1-SC offspring. These parameters were not significantly altered in F2-HF offspring. Both F1-HF and F2-HF offspring showed hyperinsulinemia, hyperleptinemia, decreased adiponectin levels, increased pancreatic mass, and islet volume density with elevated α- and β-cell mass, hypertrophied islet characterized by an altered distribution of α- and β-cells and weak pancreatic-duodenal homeobox (Pdx)1 immunoreactivity.. Maternal HF diet consumed during the preconception period and throughout the gestation and lactation periods in mice promotes metabolism and pancreatic programming in F1 and F2 male offspring, implying intergenerational effects.

Topics: Adiponectin; Animals; Blood Glucose; Body Mass Index; Diet, High-Fat; Disease Models, Animal; Energy Intake; Female; Hyperglycemia; Hyperinsulinism; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Lactation; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Pregnancy; Prenatal Exposure Delayed Effects

Almost 50% of the women with polycystic ovary syndrome (PCOS) are obese. Obesity in PCOS affects reproduction via various mechanisms. Hyperandrogenism, increased luteinizing hormone (LH) and insulin resistance play a pivotal role. Several substances produced by the adipose tissue including leptin, adiponectin, resistin and visfatin may play a role in the pathophysiology of PCOS. Infertility in PCOS is related to anovulation. For induction of ovulation, clomiphene citrate and human gonadotrophins are first- and second-line treatments, respectively. Other treatment modalities include the use of insulin sensitizers, such as metformin as well as aromatase inhibitors and laparoscopic ovarian drilling, while in vitro fertilization is the last resort. Obesity can adversely affect infertility treatment in PCOS. Diet and lifestyle changes are recommended for the obese women before they attempt conception. The use of anti-obesity drugs and bariatric surgery in PCOS require further evaluation.

Topics: Adipokines; Adiponectin; Female; Humans; Hyperandrogenism; Hyperinsulinism; Hypoglycemic Agents; Infertility, Female; Insulin Resistance; Leptin; Life Style; Luteinizing Hormone; Metformin; Nicotinamide Phosphoribosyltransferase; Obesity; Ovulation Induction; Polycystic Ovary Syndrome; Resistin

Rats fed with high-fat-high-sucrose (HFHS) diet are known to manifest metabolic syndrome including hyperinsulinemia, hyperleptinemia, hyperglycemia, diabetic dyslipidemia, and hepatic steatosis. The aim of the current study is to determine the temporal relationships between the development of hepatic steatosis and the onset of insulin and leptin resistance in hypothalamus and liver in male Wistar rats (six weeks of age) fed chow or HFHS diet for up to 8 weeks. Fasting plasma glucose, lipids/lipoproteins, insulin and leptin levels were quantified, histopathologic score of hepatic steatosis and inflammation were assessed, and the responses of common checkpoints of insulin and leptin signalling responsible for lipogenesis and gluconeogenesis were analyzed. In addition, acute insulin or leptin administration was performed at different stages of HFHS dieting to determine the responsiveness of the respective signalling pathways. Hyperinsulinemia, hyperglycemia, dyslipidemia, and increased homeostasis model assessment of basal insulin resistance occurred 1-week after HFHS dieting, coinciding with upregulation of suppressor of cytokine signalling 3 in both hypothalamus and liver. However, hepatosteatosis, accompanied with increased expression of sterol regulatory element binding protein 1c and phosphoenolpyruvate carboxykinase, did not manifest until 4- to 8-week after HFHS dieting. Lowered insulin sensitivity (shown by decreased insulin receptor substrate 1 and protein kinase B phosphorylation) occurred approximately 2 weeks prior to leptin resistance (shown by impaired signal transducer and activator of transcription 3 activation) in both the liver and hypothalamus. Acute insulin/leptin administration also demonstrated the impaired insulin or leptin signalling transduction. These data suggest that lowered insulin sensitivity and leptin resistance occurred at least 2-3 weeks earlier than the manifestation of hepatosteatosis in rats fed HFHS diet.

Topics: Animals; Blood Glucose; Diet, High-Fat; Dietary Sucrose; Dyslipidemias; Fatty Liver; Hyperglycemia; Hyperinsulinism; Hypothalamus; Inflammation; Insulin; Insulin Resistance; Leptin; Lipid Metabolism; Lipids; Lipoproteins; Liver; Male; Rats, Wistar

Obesity impairs cognition, and the leptin-induced increase of brain-derived neurotrophic factor (BDNF) and neurogenesis. Tea consumption improves cognition and increases brain activation in the prefrontal cortex.. This study examined whether teasaponin, an active ingredient in tea, could improve memory and central leptin effects on neurogenesis in the prefrontal cortex of obese mice, and in vitro in cultured prefrontal cortical neurons. Teasaponin (10 mg/kg, intraperitoneal) for 21 days improved downstream leptin signaling (JAK2 and STAT3), and leptin's effect on BDNF, in the prefrontal cortex of high-fat diet (HFD) fed mice. Prefrontal cortical neurons were cultured with teasaponin and palmitic acid (the most abundant dietary saturated fatty acid) to examine their effects on neurogenesis and BDNF expression in response to leptin. Palmitic acid decreased leptin's effect on neurite outgrowth, postsynaptic density protein 95, and BDNF expression in cultured cortical neurons, which was reversed by teasaponin.. Teasaponin improved the leptin sensitivity of prefrontal cortical neurons in obese mice or when treated by palmitic acid. This in turn increased BDNF expression and neurite growth. Therefore, teasaponin supplementation may be used to prevent obesity-associated neurodegeneration and improve cognitive function.

Topics: Animals; Brain-Derived Neurotrophic Factor; Cells, Cultured; Diet, High-Fat; Hyperinsulinism; Insulin; Leptin; Male; Mice, Inbred C57BL; Mice, Obese; Neurons; Obesity; Palmitic Acid; Prefrontal Cortex; Saponins; STAT3 Transcription Factor; Tea; Weight Gain

Nonnutritive sweeteners (NNSs) have been studied in terms of their potential roles in type 2 diabetes, obesity, and related metabolic disorders. Several studies have suggested that NNSs have several specific effects on metabolism such as reduced postprandial hyperglycemia and insulin resistance. However, the detailed effects of NNSs on body adiposity and energy metabolism have not been fully elucidated. We investigated the effects of an NNS on energy metabolism in mice with diet-induced obesity (DIO).. DIO mice were divided into NNS-administered (4% NNS in drinking water), sucrose-administered (33% sucrose in drinking water), and control (normal water) groups. After supplementation for 4 weeks, metabolic parameters, including uncoupling protein (UCP) levels and energy expenditure, were assessed.. Sucrose supplementation increased hyperglycemia, body adiposity, and body weight compared to the NNS-administered and control groups (P<0.05 for each). In addition, NNS supplementation decreased hyperglycemia compared to the sucrose-administered group (P<0.05). Interestingly, NNS supplementation increased body adiposity, which was accompanied by hyperinsulinemia, compared to controls (P<0.05 for each). NNS also increased leptin levels in white adipose tissue and triglyceride levels in tissues compared to controls (P<0.05 for each). Notably, compared to controls, NNS supplementation decreased the UCP1 level in brown adipose tissue and decreased O2 consumption in the dark phase.. NNSs may be good sugar substitutes for people with hyperglycemia, but appear to influence energy metabolism in DIO mice.

Topics: Adipose Tissue; Adipose Tissue, Brown; Adipose Tissue, White; Adiposity; Animals; Diet; Energy Metabolism; Hyperinsulinism; Ion Channels; Leptin; Mice; Mitochondrial Proteins; Obesity; Sucrose; Sweetening Agents; Triglycerides; Uncoupling Protein 1

In the present study, we investigated whether maternal exposure to a cafeteria diet affects the metabolism and body composition of offspring and whether such an exposure has a cumulative effect during the lifetime of the offspring. Female rats were fed a control (CON) or a cafeteria (CAF) diet from their own weaning to the weaning of their offspring. At 21 d of age, male offspring were divided into four groups by diet during gestation and after weaning (CON-CON, CON-CAF, CAF-CON and CAF-CAF). Blood was collected from dams (after weaning) and pups (at 30 and 120 d of age) by decapitation. CAF dams had significantly greater body weight and adipose tissue weight and higher concentrations of total cholesterol, insulin and leptin than CON dams (Student's t test). The energy intake of CAF rats was higher than that of CON rats regardless of the maternal diet (two-way ANOVA). Litters had similar body weights at weaning and at 30 d of age, but at 120 d, CON-CAF rats were heavier. At both ages, CAF rats had greater adipose tissue weight than CON rats regardless of the maternal diet, and the concentrations of TAG and cholesterol were similar between the two groups, as were blood glucose concentrations at 30 d of age. However, at 120 d of age, CAF rats were hyperglycaemic, hyperinsulinaemic and hyperleptinaemic regardless of the maternal diet. These findings suggest that maternal obesity does not modulate the metabolism of male offspring independently, modifying body weight only when associated with the intake of a cafeteria diet by the offspring.

Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Cholesterol; Diet; Female; Hyperglycemia; Hyperinsulinism; Insulin; Leptin; Male; Metabolic Diseases; Obesity; Pregnancy; Pregnancy Complications; Prenatal Nutritional Physiological Phenomena; Rats; Rats, Wistar; Triglycerides; Weaning

Leptin, an adipocyte-derived hormone, has well-established anorexigenic effects but is also able to regulate glucose homeostasis independent of body weight. Until recently, the ob/ob mouse was the only animal model of global leptin deficiency. Here we report the effects of leptin deficiency on glucose homeostasis in male and female leptin knockout (KO) rats. Leptin KO rats developed obesity by 6 to 7 weeks of age, and lipid mass was increased by more than 2-fold compared with that of wild-type (WT) littermates at 18 weeks of age. Hyperinsulinemia and insulin resistance were evident in both males and females and were sustained with aging. Male KO rats experienced transient mild fasting hyperglycemia between 14 and 25 weeks of age, but thereafter fasting glucose levels were comparable to those of WT littermates up to 36 weeks of age. Fasting glucose levels of female KO rats were similar to those of WT littermates. Male KO rats exhibited a 3-fold increase in the proportion of β-cell area relative to total pancreas at 36 weeks of age. Islets from 12-week-old KO rats secreted more insulin when stimulated than islets from WT littermates. Leptin replacement via miniosmotic pump (100 μg/d) reduced food intake, attenuated weight gain, normalized glucose tolerance, and improved glucose-stimulated insulin secretion and insulin sensitivity. Together, these data demonstrate that the absence of leptin in rats recapitulates some of the phenotype previously observed in ob/ob mice including development of hyperinsulinemia, obesity, and insulin resistance.

Topics: Animals; Blood Glucose; Body Composition; Body Weight; Disease Models, Animal; Female; Glucose Tolerance Test; Homeostasis; Hyperinsulinism; Insulin; Insulin Resistance; Islets of Langerhans; Leptin; Liver; Male; Muscles; Obesity; Phenotype; Rats; Rats, Sprague-Dawley; Rats, Transgenic

Environmental and genetic activation of a brain-adipocyte axis inhibits cancer progression. Leptin is the primary peripheral mediator of this anticancer effect in a mouse model of melanoma. In this study we assessed the effect of a leptin receptor antagonist on melanoma progression. Local administration of a neutralizing nanobody targeting the leptin receptor at low dose adjacent to tumor decreased tumor mass with no effects on body weight or food intake. In contrast, systemic administration of the nanobody failed to suppress tumor growth. Daily intraperitoneal injection of high-dose nanobody led to weight gain, hyperphagia, increased adiposity, hyperleptinemia, and hyperinsulinemia, and central effects mimicking leptin deficiency. The blockade of central actions of leptin by systemic delivery of nanobody may compromise its anticancer effect, underscoring the need to develop peripherally acting leptin antagonists coupled with efficient cancer-targeting delivery.

Topics: Adiposity; Animals; Body Weight; Cell Line, Tumor; Hyperinsulinism; Hyperphagia; Leptin; Male; Melanoma; Mice; Mice, Inbred C57BL; Receptors, Leptin; Single-Domain Antibodies

This study sought to determine the role of white adipose tissue (WAT) metabolism in the prevention of insulin resistance (IR) by physical training (PT).. Male C57BL/6J mice were assigned into groups CHOW-SED (chow diet, sedentary; n=15), CHOW-TR (chow diet, trained; n=18), CAF-SED (cafeteria diet, sedentary; n=15) and CAF-TR (cafeteria diet, trained; n=18). PT consisted of running sessions of 60 min at 60% of maximal speed conducted five days per week for eight weeks.. PT prevented body weight and fat mass accretion in trained groups and prevented hyperglycemia, hyperinsulinemia, glucose intolerance and IR in the CAF-TR. The CAF-SED group presented higher leptin and free fatty acid and lower adiponectin serum levels compared with other groups. Lipolytic activity (in mmol/10(6) adipose cells) stimulated by isoproterenol increased in CHOW-TR (16347±3005), CAF-SED (18110±3788) and CAF-TR (15837±2845) compared with CHOW-SED (8377±2284). The CAF-SED group reduced FAS activity compared with CHOW-SED and CHOW-TR, reduced citrate synthase activity and increased DGAT2 content compared with other groups. Both trained groups reduced G6PDH activity and increased the expression of p-AMPK (Thr172) compared with sedentary groups. CAF-SED group had lower levels of AMPK, p-AMPK (Thr172), ACC and p-ACC (Ser79) compared with other groups.. The prevention of IR by PT is mediated by adaptations in WAT metabolism by improving lipolysis, preventing an increase in enzymes responsible for fatty acid esterification and by activating enzymes that improve fat oxidation instead of fat storage.

Topics: Adipocytes; Adiponectin; Adipose Tissue, White; Adiposity; Animals; Fatty Acids, Nonesterified; Glucose Intolerance; Hyperglycemia; Hyperinsulinism; Insulin Resistance; Isoproterenol; Leptin; Lipolysis; Male; Mice; Mice, Inbred C57BL; Oxidation-Reduction; Physical Conditioning, Animal; Physical Exertion; Weight Gain

To determine the prevalence of hyperinsulinaemia in a population of ponies in Queensland, Australia, and identify associated factors.. Breeders or traders of ponies within a 100 km radius of Gatton, Queensland, were recruited for study using an internet database. Clinical and management details were obtained, including body condition score, fat deposition and history or evidence of laminitis. Blood samples were analysed for serum insulin and triglyceride concentrations and plasma adrenocorticotrophic hormone (ACTH) and leptin concentrations following short-term removal from pasture and withholding of supplementary food for at least 12 h.. Of 23 pony studs identified, 22 were available for visit. The study population consisted of 208 ponies: 70 Australian Ponies; 67 Welsh Mountain Ponies or Cobs; 51 Connemara Ponies; 20 Shetland ponies. We excluded 20 with suspected pituitary pars intermedia dysfunction (>15 years, ACTH >50 pg/mL). In total, 27% of the ponies (51/188) were hyperinsulinaemic (insulin >20 μIU/mL). The final multivariable model revealed increasing age, supplementary feeding and increased leptin and triglyceride concentrations to be associated with hyperinsulinaemia.. Hyperinsulinaemia was prevalent and associated with age and evidence of metabolic disturbance, including elevated leptin and triglyceride concentrations, in this population. A significant number of ponies were at risk of hyperinsulinaemia, which has implications for strategies to reduce the risk of laminitis in this population.

Topics: Adrenocorticotropic Hormone; Animals; Female; Horse Diseases; Horses; Hyperinsulinism; Insulin; Leptin; Logistic Models; Male; Queensland; Triglycerides

We investigated the relation of serum leptin, soluble leptin receptor (sLR) and free leptin index (FLI) with metabolic and anthropometric parameters in obese and healthy children. Height, weight, waist circumference (WC), fasting serum glucose, insulin, lipid profile, leptin and sLR levels of 35 obese children and 36 healthy children were measured and FLI was calculated as the ratio of leptin to sLR. In obese children, serum leptin and FLI were found significantly higher, while sLR level was significantly lower than the healthy children. Comparison of obese children regarding the insulin resistance showed significantly higher serum leptin and FLI in the insulin resistant group; however sLR level was not different between the insulin resistant and non-resistant obese children. In obese children, sLR was not correlated with any of the metabolic parameters except total cholesterol, while FLI was significantly and positively correlated with BMI, WC, TC, fasting insulin, and HOMA-IR. However, regression analysis confirmed that the HOMA-IR was the only independent variable significantly correlated with FLI in obese children. Findings of this study suggest that in obese children and adolescents (i) serum leptin and FLI were found significantly higher, while sLR level was significantly lower than the healthy children, (ii) increased FLI might be a compensatory mechanism for increasing leptin effect in peripheral tissue, (iii) FLI is a more accurate marker to evaluate leptin resistance than leptin or sLR alone, and (iv) increased FLI may contribute toward the development of hyperinsulinemia and insulin resistance.

Topics: Adolescent; Body Mass Index; Child; Female; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Leptin; Male; Obesity; Receptors, Leptin; Waist Circumference

Pantothenate kinase (PANK) is the first enzyme in CoA biosynthesis. Pank1-deficient mice have 40% lower liver CoA and fasting hypoglycaemia, which results from reduced gluconeogenesis. Single-nucleotide polymorphisms in the human PANK1 gene are associated with insulin levels, suggesting a link between CoA and insulin homeostasis. We determined whether Pank1 deficiency (1) modified insulin levels, (2) ameliorated hyperglycaemia and hyperinsulinaemia, and (3) improved acute glucose and insulin tolerance of leptin (Lep)-deficient mice.. Serum insulin and responses to glucose and insulin tolerance tests were determined in Pank1-deficient mice. Levels of CoA and regulating enzymes were measured in liver and skeletal muscle of Lep-deficient mice. Double Pank1/Lep-deficient mice were analysed for the diabetes-related phenotype and global metabolism.. Pank1-deficient mice had lower serum insulin and improved glucose tolerance and insulin sensitivity compared with wild-type mice. Hepatic and muscle CoA was abnormally high in Lep-deficient mice. Pank1 deletion reduced hepatic CoA but not muscle CoA, reduced serum glucose and insulin, but did not normalise body weight or improve acute glucose tolerance or protein kinase B phosphorylation in Lep-deficient animals. Pank1/Lep double-deficient mice exhibited reduced whole-body metabolism of fatty acids and amino acids and had a greater reliance on carbohydrate use for energy production.. The results indicate that Pank1 deficiency drives a whole-body metabolic adaptation that improves aspects of the diabetic phenotype and uncouples hyperglycaemia and hyperinsulinaemia from obesity in leptin-deficient mice.

Topics: Animals; Energy Metabolism; Glucose; Hyperglycemia; Hyperinsulinism; Insulin Resistance; Leptin; Liver; Male; Mice; Obesity; Phosphotransferases (Alcohol Group Acceptor)

Exocrine pancreatic digestive enzymes are essential for the digestion of dietary components and are regulated by them. Chronic excess dietary high fat (HF) consumption is a contributing factor of diet-induced obesity (DIO) and associated chronic diseases and requires adaptation by the pancreas. The aim of the present study was to investigate the effects of chronic HF diet feeding on exocrine pancreatic digestive enzyme transcript levels in DIO C57BL/6J mice. C57BL/6J mice were fed diets containing either 10 or 45% energy (E%) derived from fat for 12 weeks (n 10 mice per diet group). Pancreatic tissue and blood samples were collected at 0, 4 and 12 weeks. The expression of a panel of exocrine pancreatic digestive enzymes was analysed using quantitative RT-PCR and Western blot analysis. The HF (45 E%) diet-fed C57BL/6J mice developed obesity, hyperleptinaemia, hyperglycaemia and hyperinsulinaemia. The transcript levels of pancreatic lipase (PL), pancreatic lipase-related protein 2 (PLRP2) and pancreatic phospholipase A2 (PLA2) were initially elevated; however, they were down-regulated to basal control levels at week 12. The transcript levels of colipase were significantly affected by diet and time. The protein levels of PL and PLRP2 responded to HF diet feeding. The transcript levels of amylase and proteases were not significantly affected by diet and time. The transcript levels of specific lipases in hyperinsulinaemic, hyperleptinaemic and hyperglycaemic DIO C57BL/6J mice are down-regulated. However, these mice compensate for this by the post-transcriptional regulation of the levels of proteins that respond to dietary fat. This suggests a complex regulatory mechanism involved in the modulation of fat digestion.

Topics: Animals; Colipases; Diet, High-Fat; Gene Expression Regulation, Enzymologic; Hyperglycemia; Hyperinsulinism; Insulin Resistance; Leptin; Lipase; Male; Mice; Mice, Inbred C57BL; Obesity; Pancreas, Exocrine; Phospholipases A2, Secretory; Protein Processing, Post-Translational; Random Allocation; RNA Processing, Post-Transcriptional; RNA, Messenger

The mechanisms for the association of the consumption of sugar-sweetened beverages (SSBs) with obesity and type 2 diabetes are only partly understood. The objective of the study was to examine the association of habitual SSB consumption with biomarkers of energy metabolism, including serum glucose, glycated hemoglobin, insulin, insulin resistance [homeostasis model assessment of insulin resistance (HOMA-IR)], and leptin. Data were taken from the Study on Nutrition and Cardiovascular Risk in Spain (ENRICA), a cross-sectional study conducted during 2008-2010 in 7842 individuals representative of the population of Spain aged 18-59 y. Diet was assessed with a validated computerized diet history. Biomarkers were determined in 12-h fasting blood samples. Analyses were performed with linear regression with adjustment for the main confounders, including body mass index (BMI), waist circumference, and morbidity. In men, a 1-serving (200 mL)/d increase in the consumption of SSBs was associated with higher plasma concentrations of insulin (2.14%, P = 0.01), higher HOMA-IR (1.90%, P = 0.04), and higher concentrations of leptin (2.73%, P = 0.01). Among women, these associations were found only in those with a BMI <25 kg/m² (insulin: 2.88%, P = 0.004; HOMA-IR: 3.03%, P = 0.01; and leptin: 4.57%, P = 0.01) or with a waist circumference <80 cm (insulin: 2.79%, P = 0.01; HOMA-IR: 3.00%, P = 0.01; and leptin: 3.63%, P = 0.05). In conclusion, the consumption of SSBs was associated with higher concentrations of insulin and leptin and a higher HOMA-IR in men and in nonoverweight women. Insulin resistance and higher leptin may be early markers of metabolic dysfunction associated with SSBs.

Topics: Adolescent; Adult; Beverages; Body Mass Index; Carbonated Beverages; Cross-Sectional Studies; Dietary Sucrose; Feeding Behavior; Female; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Overweight; Sex Characteristics; Spain; Up-Regulation; Waist Circumference; Young Adult

High fat programming, by exposure to a high saturated fat diet during fetal and/or lactational life induces metabolic derangements and alters islet cell architecture in neonate and weanling rats.. The present study assessed metabolic changes and islet cell dynamics in response to high fat maintenance during specific developmental periods in adolescent rats, with some parameters also studied in neonate and weanling rats.. The experimental groups comprised neonates, weanlings and adolescents maintained on a high fat diet during specific periods of fetal, lactational and/or postnatal life. Control neonates, weanlings and adolescents were maintained on a standard laboratory (control or low fat) diet. Fetal high fat programmed (i.e., maintained on a high fat diet exclusively during fetal life) neonates were insulin resistant.. Weanlings maintained on a high fat diet throughout fetal and lactational life had increased pancreas weights. Fetal high fat programmed adolescents presented a normal phenotype mimicking the control adolescents. Adolescents maintained on a postnatal high fat diet had increased body weights, hyperglycemia, hyperinsulinemia, hyperleptinemia and insulin resistance displaying beta cell hypertrophy and increased islet cell proliferation. Adolescents maintained on a fetal and postnatal high fat diet had increased body weights, hyperleptinemia, hyperinsulinemia and insulin resistance.. High fat programming induces various diabetogenic phenotypes which present at different life stages. The postnatal period from birth to adolescence represents an extension for high fat programming of metabolic disease.

Topics: Acinar Cells; Age Factors; Animals; Animals, Newborn; Animals, Suckling; Blood Glucose; Cell Proliferation; Dietary Fats; Fatty Acids; Female; Hyperglycemia; Hyperinsulinism; Insulin Resistance; Insulin-Secreting Cells; Lactation; Leptin; Organ Size; Prediabetic State; Pregnancy; Rats, Wistar; Weaning

Obesity appears to be associated with male reproductive dysfunction and infertility, although this has been inconsistent and inconclusive. Insulin and leptin are known mediators and modulators of the hypothalamus-pituitary-testes axis, contributing to the regulation of male reproductive potential and overall wellbeing. These hormones are also present in semen influencing sperm functions. Although abdominal obesity is closely associated with insulin resistance (hyperinsulinaemia), hyperleptinaemia and glucose dysfunction, changes in seminal plasma concentrations of insulin, leptin and glucose in obese males has not previously been investigated.. This small case controlled study assessed serum and seminal concentrations of insulin, leptin and glucose in obese (BMI > =30; n = 23) and non-obese (BMI < 30; n = 19) males. Following a detailed medical history and examination, participants meeting the inclusion criteria were entered for data analysis. Body parameters such as BMI, waist and hip circumference and the waist hip ratio were measured. Serum and semen samples were collected and assayed for insulin, leptin and glucose. Semen samples also underwent a standard semen analysis, with sperm mitochondrial membrane potential (MMP) and DNA fragmentation (DF).. Obesity was associated with increased serum and seminal insulin and leptin, with no significant difference in seminal glucose. Serum and seminal concentrations of insulin and leptin were positively correlated. Furthermore, obesity was associated with decreased sperm concentration, sperm vitality and increased MMP and DF, with a non-significant impact on motility and morphology.. Hyperinsulinaemia and hyperleptinaemia are associated with increased seminal insulin and leptin concentrations, which may negatively impact male reproductive function in obesity. Insulin was also found to be highly concentrated in the seminal plasma of both groups. This data will contribute to the contradictive information available in the literature on the impact of obesity and male reproduction.

Topics: Adult; Body Mass Index; Case-Control Studies; Cohort Studies; DNA Fragmentation; Humans; Hyperinsulinism; Infertility, Male; Insulin; Leptin; Male; Membrane Potential, Mitochondrial; Middle Aged; Obesity; Pilot Projects; Semen; Semen Analysis; South Africa; Up-Regulation; Young Adult

Type 2 diabetes, obesity, and metabolic syndrome are pathologies where insulin resistance plays a central role, and that affect a large population worldwide. These pathologies are usually associated with a dysregulation of insulin secretion leading to a chronic exposure of the tissues to high insulin levels (i.e. hyperinsulinemia), which diminishes the concentration of key downstream elements, causing insulin resistance. The complexity of the study of insulin resistance arises from the heterogeneity of the metabolic states where it is observed. To contribute to the understanding of the mechanisms triggering insulin resistance, we have developed a zebrafish model to study insulin metabolism and its associated disorders. Zebrafish larvae appeared to be sensitive to human recombinant insulin, becoming insulin-resistant when exposed to a high dose of the hormone. Moreover RNA-seq-based transcriptomic profiling of these larvae revealed a strong downregulation of a number of immune-relevant genes as a consequence of the exposure to hyperinsulinemia. Interestingly, as an exception, the negative immune modulator protein tyrosine phosphatase nonreceptor type 6 (ptpn6) appeared to be upregulated in insulin-resistant larvae. Knockdown of ptpn6 was found to counteract the observed downregulation of the immune system and insulin signaling pathway caused by hyperinsulinemia. These results indicate that ptpn6 is a mediator of the metabolic switch between insulin-sensitive and insulin-resistant states. Our zebrafish model for hyperinsulinemia has therefore demonstrated its suitability for discovery of novel regulators of insulin resistance. In addition, our data will be very useful in further studies of the function of immunological determinants in a non-obese model system.

Topics: Animals; Disease Models, Animal; Gene Knockdown Techniques; Humans; Hyperinsulinism; Immunity; Insulin; Insulin Resistance; Larva; Leptin; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Signal Transduction; Transcriptome; Up-Regulation; Zebrafish

Increased leptin levels have been suggested to contribute to cardiac hypertrophy and attenuate cardiac lipid accumulation in obesity, although it has been difficult to separate leptin's direct effects from those caused by changes in body weight and adiposity. To determine whether leptin attenuates cardiac lipid accumulation in obesity or directly causes left ventricular hypertrophy (LVH), we generated a novel mouse model in which the long form of the leptin receptor (LepR) was "rescued" only in cardiomyocytes of obese db/db mice. Reexpression of cardiomyocyte leptin receptors in db/db mice did not cause LVH but reduced cardiac triglycerides and improved cardiac function. Compared with lean wild-type (WT) or db/db-cardiac LepR rescue mice, db/db mice exhibited significantly lower E/A ratio, a measurement of early to late diastolic filling, which averaged 1.5 ± 0.07 in db/db vs. 1.9 ± 0.08 and 1.8 ± 0.11 in WT and db/db-cardiac LepR rescue mice, respectively. No differences in systolic function were observed. Although db/db and db/db-cardiac LepR rescue mice exhibited similar increases in plasma triglycerides, insulin, glucose, and body weight, cardiac triglycerides were significantly higher in db/db compared with WT and db/db cardiac LepR rescue mice, averaging 13.4 ± 4.2 vs. 3.8 ± 1.6 vs. 3.8 ± 0.7 mg/g, respectively. These results demonstrate that despite significant obesity and increases in plasma glucose and triglycerides, db/db cardiac LepR rescue mice are protected against myocardial lipid accumulation. However, we found no evidence that leptin directly causes LVH.

Topics: Animals; Crosses, Genetic; Heart Ventricles; Heterozygote; Hyperglycemia; Hyperinsulinism; Hypertriglyceridemia; Hypertrophy, Left Ventricular; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mice, Transgenic; Myocardium; Obesity; Receptors, Leptin; Recombinant Proteins; Signal Transduction; Triglycerides

Studies in both humans and rodents suggest that maternal diabetes leads to a higher risk of the fetus developing impaired glucose tolerance and obesity during adulthood. However, the impact of hyperinsulinemia in the mother on glucose homeostasis in the offspring has not been fully explored. We aimed to determine the consequences of maternal insulin resistance on offspring metabolism and endocrine pancreas development using the LIRKO mouse model, which exhibits sustained hyperinsulinemia and transient increase in blood glucose concentrations during pregnancy. We examined control offspring born to either LIRKO or control mothers on embryonic days 13.5, 15.5, and 17.5 and postpartum days 0, 4, and 10. Control offspring born to LIRKO mothers displayed low birth weights and subsequently rapidly gained weight, and their blood glucose and plasma insulin concentrations were higher than offspring born to control mothers in early postnatal life. In addition, concentrations of plasma leptin, glucagon, and active GLP-1 were higher in control pups from LIRKO mothers. Analyses of the endocrine pancreas revealed significantly reduced β-cell area in control offspring of LIRKO mothers shortly after birth. β-Cell proliferation and total islet number were also lower in control offspring of LIRKO mothers during early postnatal days. Together, these data indicate that maternal hyperinsulinemia and the transient hyperglycemia impair endocrine pancreas development in the control offspring and induce multiple metabolic alterations in early postnatal life. The relatively smaller β-cell mass/area and β-cell proliferation in these control offspring suggest cell-autonomous epigenetic mechanisms in the regulation of islet growth and development.

Topics: Animals; Animals, Newborn; Blood Glucose; Cell Proliferation; Diabetes, Gestational; Disease Models, Animal; Female; Glucagon; Glucagon-Like Peptide 1; Hyperglycemia; Hyperinsulinism; Insulin; Insulin Resistance; Insulin-Secreting Cells; Islets of Langerhans; Leptin; Mice; Organ Size; Phenotype; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Weight Gain

Although pregnancies associated with hyperinsulinemia and altered placental angiogenic and inflammatory factors are at increased risk for developing preeclampsia, the effects of euglycemic hyperinsulinemia on placental factors and blood pressure regulation during pregnancy are unclear. We hypothesized that chronic hyperinsulinemia results in increased placental soluble fms-like tyrosine kinase 1(sFlt-1) and tumor necrosis factor α (TNF- α) levels and hypertension in pregnant rats.. On gestational day (GD) 14, Sprague-Dawley rats were assigned as normal pregnant or pregnant + insulin. Insulin was infused subcutaneously by osmotic minipump for 5 days at a dose of 1.5 mU/kg/min. Those rats receiving insulin were supplemented with 20% glucose in drinking water to maintain euglycemia. On GD 19, mean arterial pressure (MAP) and heart rate (HR) were assessed in conscious rats by indwelling carotid catheters, followed by collections of blood, placentas, and fetuses. In addition to placental sFlt-1 and TNF-α levels, circulating insulin, glucose, leptin, cholesterol, triglyceride, and free fatty acid concentrations were measured.. MAP was higher in pregnant + insulin vs. normal pregnant rats; however, HR was similar between groups. Although litter size and placental weight were comparable, fetuses from pregnant + insulin rats were heavier. Importantly, circulating insulin concentration was elevated in the pregnant + insulin group, with no change in glucose level. Moreover, circulating leptin, cholesterol, triglyceride, and free fatty acid concentrations were increased in the pregnant + insulin group. There were no differences in placental sFlt-1 and TNF-α concentrations between groups.. In summary, sustained euglycemic hyperinsulinemia, comparable with insulin levels in preeclamptic women, can raise blood pressure in pregnancy independent of recognized placental factors associated with preeclampsia.

Topics: Animals; Biomarkers; Blood Pressure; Cholesterol; Disease Models, Animal; Female; Glucose; Heart Rate; Hyperinsulinism; Hypertension; Insulin; Leptin; Placenta; Pre-Eclampsia; Pregnancy; Random Allocation; Rats; Rats, Sprague-Dawley; Triglycerides; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor Receptor-1

Female rat neonates reared on a high carbohydrate (HC) milk formula developed chronic hyperinsulinemia and adult-onset obesity (HC phenotype). Furthermore, we have shown that fetal development in the HC intrauterine environment (maternal obesity complicated with hyperinsulinemia, hyperleptinemia, and increased levels of proinflammatory markers) resulted in increased levels of serum insulin and leptin in term HC fetuses and the spontaneous transfer of the HC phenotype to the adult offspring. The objectives of this study are to identify changes in global gene expression pattern and cellular development in term HC fetal brains in response to growth in the adverse intrauterine environment of the obese HC female rat.. GeneChip analysis was performed on total RNA obtained from fetal brains for global gene expression studies and immunohistochemical analysis was performed on fetal brain slices for investigation of cellular development in term HC fetal brains.. Gene expression profiling identified changes in several clusters of genes that could contribute to the transfer of the maternal phenotype (chronic hyperinsulinemia and adult-onset obesity) to the HC offspring. Immunohistochemical analysis indicated diminished proliferation and neuronal maturation of stem-like cells lining the third ventricle, hypothalamic region, and the cerebral cortex in HC fetal brains.. These results suggest that maternal obesity during pregnancy could alter the developmental program of specific fetal brain cell-networks. These defects could underlie pathologies such as metabolic syndrome and possibly some neurological disorders in the offspring at a later age.

Topics: Animals; Cell Proliferation; Dietary Carbohydrates; Female; Fetal Development; Gene Expression; Gene Expression Profiling; Hyperinsulinism; Hypothalamus; Insulin; Leptin; Male; Obesity; Phenotype; Pregnancy; Rats

Preterm infants are exposed to numerous stressors during hospitalization and by term corrected gestational age they have lower body weight but a greater proportion of total body as well as abdominal visceral adipose tissue (VAT) accumulation. Greater abdominal VAT stores have a known association with metabolic syndrome. Mechanical-tactile stimulation (MTS) improves modulation of stress response in both humans and rodents. We hypothesize that MTS, administered during an established model of neonatal stress, would decrease stress-driven adiposity and prevent associated metabolic imbalances in adult rats. Neonatal stress, administered to rat pups from postnatal days 5 to P9, consisted of needle puncture and hypoxic/hyperoxic challenge during 60 min of maternal separation (STRESS; n=20). Mechanical-tactile stimulation (MTS; n=20) was administered to rat pups for 10 min during maternal separation in the stress protocol. Control animals received standard care (CTL; n=20). MRI measured adult (P120) abdominal total fat mass, subcutaneous (SAT) and visceral adipose tissue (VAT). Body weight and fasting serum adiponectin, leptin, glucose, insulin, and corticosterone were also measured. STRESS results in elevated VAT/SAT ratio compared to CTL but lower abdominal total fat mass and abdominal SAT. STRESS males experience hyperinsulinemia. Both STRESS and MTS had elevated leptin with lower adiponectin and corticosterone compared to CTL. In summary, neonatal stress promotes greater abdominal VAT accumulation and, in males, caused hyperinsulinemia and hypoadiponectinemia. Importantly, MTS normalized the VAT/SAT ratio and prevented hyperinsulinemia. We speculate that MTS ameliorates some of the negative metabolic consequences of early life perturbations due to neonatal stress exposure.

Topics: Adiponectin; Adipose Tissue; Adiposity; Animals; Animals, Newborn; Blood Glucose; Corticosterone; Female; Hyperinsulinism; Hyperoxia; Hypoxia; Insulin; Leptin; Male; Physical Stimulation; Rats; Rats, Sprague-Dawley; Sex Factors; Stress, Physiological; Stress, Psychological; Touch

The adipocyte-derived cytokine leptin acts as a metabolic switch, connecting the body's metabolism to high-energy consuming processes such as reproduction and immune responses. Accumulating evidence suggests that leptin plays a role in human pathologies, such as autoimmune diseases and cancer, thus providing a rationale for the development of leptin antagonists. In the present study, we generated and evaluated a panel of neutralizing nanobodies targeting the LR (leptin receptor). A nanobody comprises the variable domain of the naturally occurring single-chain antibodies found in members of the Camelidae family. We identified three classes of neutralizing nanobodies targeting different LR subdomains: i.e. the CRH2 (cytokine receptor homology 2), Ig-like and FNIII (fibronectin type III) domains. Only nanobodies directed against the CRH2 domain inhibited leptin binding. We could show that a nanobody that targets the Ig-like domain potently interfered with leptin-dependent regulation of hypothalamic NPY (neuropeptide Y) expression. As a consequence, daily intraperitoneal injection increased body weight, body fat content, food intake, liver size and serum insulin levels. All of these characteristics resemble the phenotype of leptin and LR-deficient animals. The results of the present study support proposed models of the activated LR complex, and demonstrate that it is possible to block LR signalling without affecting ligand binding. These nanobodies form new tools to study the mechanisms of BBB (blood-brain barrier) leptin transport and the effect of LR inhibition in disease models.

Topics: Adipose Tissue; Animals; Antibodies; Camelids, New World; Gene Expression Regulation; HEK293 Cells; Humans; Hyperinsulinism; Leptin; Liver; Mice; Mice, Inbred C57BL; Nanostructures; Neuropeptide Y; Organ Size; Protein Binding; Protein Structure, Tertiary; Receptors, Leptin; Signal Transduction; Weight Gain

Environmental factors such as a high-fat diet contribute to type 2 diabetes and obesity. This study examined glycemia, insulin sensitivity, and β-cell function after switching from a high-fat diet to a low-fat diet in mice.. C57BL/6J mice were fed a high-fat diet or low-fat diet for 18 months, after which mice on the high-fat diet either maintained this diet or switched to a low-fat diet for 4 weeks. Body weight and glucose and insulin responses to intraperitoneal glucose were determined. Insulin secretion (insulinogenic index: the 10-minute insulin response divided by the 10-minute glucose level) and insulin sensitivity (1 divided by basal insulin) were determined.. After 18 months on a high-fat diet, mice had glucose intolerance, marked hyperinsulinemia, and increased body weight compared to mice on a low-fat diet (P < 0.001). Switching from a high-fat diet to low-fat diet normalized glucose tolerance, reduced but not normalized body weight (P < 0.001), increased insulin secretion (248 ± 39 vs 141 ± 46 pmol/mmol; P = 0.028) and improved but not normalized insulin sensitivity (3.2 ± 0.1 vs 1.0 ± 0.1 [pmol/L]; P = 0.012).. Switching from a high-fat diet to low-fat diet normalizes glucose tolerance and improves but not normalizes insulin secretion and insulin sensitivity. These effects are more pronounced than the reduced body weight.

Topics: Animals; Blood Glucose; Body Weight; Diet, Fat-Restricted; Diet, High-Fat; Fatty Acids, Nonesterified; Female; Glucose Intolerance; Glucose Tolerance Test; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Leptin; Mice; Mice, Inbred C57BL; Recovery of Function; Time Factors

Glucocorticoids (GCs) are potent pharmacological agents used to treat a number of immune conditions. GCs are also naturally occurring steroid hormones (e.g. cortisol, corticosterone) produced in response to stressful conditions that are thought to increase the preference for calorie dense 'comfort' foods. If chronically elevated, GCs can contribute to the development of type 2 diabetes mellitus (T2DM), although the mechanisms for the diabetogenic effects are not entirely clear. The present study proposes a new rodent model to investigate the combined metabolic effects of elevated GCs and high-fat feeding on ectopic fat deposition and diabetes development. Male Sprague-Dawley rats (aged 7-8 weeks) received exogenous corticosterone or wax (placebo) pellets, implanted subcutaneously, and were fed either a standard chow diet (SD) or a 60% high-fat diet (HFD) for 16 days. Animals given corticosterone and a HFD (cort-HFD) had lower body weight and smaller relative glycolytic muscle mass, but increased relative epididymal mass, compared with controls (placebo-SD). Cort-HFD rats exhibited severe hepatic steatosis and increased muscle lipid deposition compared with placebo-SD animals. Moreover, cort-HFD animals were found to exhibit severe fasting hyperglycemia (60% increase), hyperinsulinemia (80% increase), insulin resistance (60% increase) and impaired β-cell response to oral glucose load (20% decrease) compared with placebo-SD animals. Thus, a metabolic syndrome or T2DM phenotype can be rapidly induced in young Sprague-Dawley rats by using exogenous GCs if a HFD is consumed. This finding might be valuable in examining the physiological and molecular mechanisms of GC-induced metabolic disease.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Adipose Tissue; Adiposity; Animals; Body Composition; Circadian Rhythm; Corticosterone; Diabetes Mellitus, Experimental; Diet, High-Fat; Disease Models, Animal; Energy Intake; Fasting; Feeding Behavior; Glucocorticoids; Hyperglycemia; Hyperinsulinism; Hyperphagia; Insulin; Insulin Resistance; Leptin; Male; Muscular Atrophy; Rats; Receptors, Glucocorticoid; Triglycerides; Weight Gain

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

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

An experiment was conducted to study the protective effect of feeding extruded and unextruded blueberry pomace (BBP) on selected metabolic parameters associated with metabolic syndrome in a model of high fructose (HF)-fed growing Sprague-Dawley rats. Treatments were as follows: (1) control (modified AIN-based diet); (2) HF diet (AIN diet with 58% fructose); (3) HF diet with 1.5% unextruded BBP; (4) HF diet with 1.5% extruded BBP; (5) HF diet with 3% unextruded BBP; and (6) HF diet with 3% extruded BBP. Compared with the control, HF feeding increased fasting plasma insulin and fasting and postprandial plasma triglycerides as well as homeostatic scores of insulin resistance and β-cell function, but not weight gain, diet intake and efficiency, abdominal fat, oral glucose tolerance, and fasting and postprandial plasma glucose, cholesterol, and leptin levels. Inclusion of unextruded or extruded BBP was effective in minimizing or ameliorating the fructose-induced metabolic anomalies, except postprandial plasma triglycerides, especially at 3% of the diet. In addition, unextruded or extruded BBP at 3% of the diet was also able to reduce plasma cholesterol and abdominal fat relative to the HF control, which may impart additional health benefits. Compared with the control, inclusion of unextruded or extruded BBP at both 1.5% and 3% resulted in lower total fat weight, and animals fed a diet supplemented with 3% unextruded BBP in fasting state or 3% unextruded BBP in fed state had lower leptin levels than the control. This is the first study demonstrating the beneficial effects of feeding blueberry pomace on health.

Topics: Abdominal Fat; Adiposity; Animals; Antioxidants; Blueberry Plants; Dietary Supplements; Food-Processing Industry; Fructose; Fruit; Hypercholesterolemia; Hyperinsulinism; Industrial Waste; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Polyphenols; Random Allocation; Rats; Rats, Sprague-Dawley

Selenium (Se) is an essential trace element used for biosynthesis of selenoproteins and is acquired either through diet or cellular recycling mechanisms. Selenocysteine lyase (Scly) is the enzyme that supplies Se for selenoprotein biosynthesis via decomposition of the amino acid selenocysteine (Sec). Knockout (KO) of Scly in a mouse affected hepatic glucose and lipid homeostasis. Mice lacking Scly and raised on an Se-adequate diet exhibit hyperinsulinemia, hyperleptinemia, glucose intolerance, and hepatic steatosis, with increased hepatic oxidative stress, but maintain selenoprotein levels and circulating Se status. Insulin challenge of Scly KO mice results in attenuated Akt phosphorylation but does not decrease phosphorylation levels of AMP kinase alpha (AMPKα). Upon dietary Se restriction, Scly KO animals develop several characteristics of metabolic syndrome, such as obesity, fatty liver, and hypercholesterolemia, with aggravated hyperleptinemia, hyperinsulinemia, and glucose intolerance. Hepatic glutathione peroxidase 1 (GPx1) and selenoprotein S (SelS) production and circulating selenoprotein P (Sepp1) levels are significantly diminished. Scly disruption increases the levels of insulin-signaling inhibitor PTP1B. Our results suggest a dependence of glucose and lipid homeostasis on Scly activity. These findings connect Se and energy metabolism and demonstrate for the first time a unique physiological role of Scly in an animal model.

Topics: AMP-Activated Protein Kinases; Animals; Fatty Liver; Glucose Intolerance; Glutathione Peroxidase; Glutathione Peroxidase GPX1; Hypercholesterolemia; Hyperinsulinism; Leptin; Lyases; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Oxidative Stress; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Proto-Oncogene Proteins c-akt; Selenium; Selenoproteins

The TALLYHO/Jng (TH) mouse is an inbred polygenic model for type 2 diabetes (T2D) with moderate obesity. Both male and female TH mice are characterized by increased body and fat pad weights, hyperleptinemia, hyperinsulinemia, and hyperlipidemia. Glucose intolerance and hyperglycemia are exhibited only in males. Reduced 2-deoxy-glucose uptake occurs in adipose tissue and skeletal muscle of male TH mice. While both sexes of TH mice exhibit enlarged pancreatic islets, only males have degranulation and abnormal architecture in islets. Endothelial dysfunction and considerably decreased bone density are also observed in male TH mice. The blood pressure of male TH mice is normal. Genetic outcross experiments with non-diabetic strains revealed multiple susceptibility loci (quantitative trait loci) for obesity, hypertriglyceridemia, hypercholesterolemia, and hyperglycemia. In conclusion, TH mice encompass many aspects of polygenic human diabetes and are a very useful model for T2D.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Female; Humans; Hyperglycemia; Hyperinsulinism; Hyperlipidemias; Insulin Resistance; Leptin; Male; Mice; Obesity; Phenotype; Quantitative Trait Loci

Obesity and diabetes contribute to cardiovascular disease and alter cytokine profile. The cytokine, tumour necrosis factor alpha (TNFα), activates a protective signalling cascade during ischaemic postconditioning (IPostC). However, most successful clinical studies with IPostC have not included obese and/or diabetic patients. We aimed to investigate the influence of TNFα on the outcome of IPostC in obese or diabetic mice. TNF knockout or wildtype mice were fed for 11 weeks with a high carbohydrate diet (HCD) to induce modest obesity. Diabetes was induced in a separate group by administration of a single intraperitoneal injection of streptozotocin. Hearts were then isolated and subjected to ischaemia (35 min of global ischaemia) followed by 45 min of reperfusion. HCD increased body weight, plasma insulin and leptin levels while the glucose level was unchanged. In streptozotocin-treated mice, blood glucose, plasma leptin and insulin were altered. Control, obese or diabetic mice were protected with IPostC in wiltype animals. In TNF knockout mice, IPostC failed to protect control and diabetic hearts while a slight protection was observed in obese hearts. Our data confirm a bidirectional role for TNFα associated with the severity of concomitant comorbidities and suggest that diabetic and/or modestly obese patients may still benefit from IPostC.

Topics: Animals; Cardiomegaly; Diabetes Mellitus, Type 1; Dietary Carbohydrates; Disease Susceptibility; Heart; Hyperglycemia; Hyperinsulinism; In Vitro Techniques; Ischemic Postconditioning; Leptin; Mice; Mice, Knockout; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Obesity; Organ Size; Severity of Illness Index; Streptozocin; Tumor Necrosis Factor-alpha

Organotin compounds such as tributyltin (TBT) have been used worldwide in agriculture and industry as biocides, heat stabilizers, and chemical catalysts. However, few studies addressing the effects of TBT on growth and metabolism have been reported. This study was conducted to investigate the effects of TBT at low doses (0.5, 5, and 50 μg/kg) on body weight gain in male mice exposed as from puberty and to determine the alterations in related hormones. The results showed that exposure to TBT for 45 days resulted in an increase in body weight gain and hepatic steatosis accompanied with hyperinsulinemia and hyperleptinemia. Reduction of hepatic adiponectin levels in a dose-dependent manner was related to the lipid increase in the liver. These results suggest that chronic and repeat exposure to low doses of TBT can result in obesity and hepatic steatosis and induce the occurrence of insulin and leptin resistance.

Topics: Adipose Tissue; Animals; Dose-Response Relationship, Drug; Environmental Pollutants; Fatty Liver; Growth and Development; Hormones; Hyperinsulinism; Leptin; Liver; Male; Mice; Obesity; Trialkyltin Compounds; Weight Gain

The "portal hypothesis" proposes that the liver is directly exposed to free fatty acids and cytokines increasingly released from visceral fat tissue into the portal vein of obese subjects, thus rendering visceral fat accumulation particularly hazardous for the development of hepatic insulin resistance and type 2 diabetes. In the present study, we used a fat transplantation paradigm to (artificially) increase intra-abdominal fat mass to test the hypothesis that venous drainage of fat tissue determines its impact on glucose homeostasis.. Epididymal fat pads of C57Bl6/J donor mice were transplanted into littermates, either to the parietal peritoneum (caval/systemic venous drainage) or, by using a novel approach, to the mesenterium, which confers portal venous drainage.. Only mice receiving the portal drained fat transplant developed impaired glucose tolerance and hepatic insulin resistance. mRNA expression of proinflammatory cytokines was increased in both portally and systemically transplanted fat pads. However, portal vein (but not systemic) plasma levels of interleukin (IL)-6 were elevated only in mice receiving a portal fat transplant. Intriguingly, mice receiving portal drained transplants from IL-6 knockout mice showed normal glucose tolerance.. These results demonstrate that the metabolic fate of intra-abdominal fat tissue transplantation is determined by the delivery of inflammatory cytokines to the liver specifically via the portal system, providing direct evidence in support of the portal hypothesis.

Topics: Adiponectin; Adipose Tissue; Animals; Blood Glucose; Cytokines; DNA Primers; Epididymis; Fatty Acids, Nonesterified; Glucose Clamp Technique; Glucose Intolerance; Hyperinsulinism; Inflammation; Insulin; Insulin Resistance; Interleukin-6; Intra-Abdominal Fat; Leptin; Male; Mesentery; Mice; Mice, Inbred C57BL; Mice, Knockout; Peritoneum; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Messenger

Stress in early life negatively influences growth quality through perturbations in body composition including increased fat mass. At term (40 weeks) preterm infants have greater fat mass and abdominal visceral adipose tissue than term-born infants. Mechanical-tactile stimulation (MTS) attenuates the stress response in preterm infants and rodents. We tested the hypothesis that MTS, administered during an established model of neonatal stress, would decrease stress-driven adiposity and prevent associated metabolic imbalances in rat pups. Pups received one of three treatments from postnatal days 5 to P9: Neonatal Stress (Stress; n=20) = painful stimulus and hypoxic/hyperoxic challenge during 60 min of maternal separation; MTS (n=20) = neonatal stress+10 min of MTS; or Control (n=20). Body weight, DXA whole body fat mass (g), MRI subcutaneous and visceral adipose tissue, and fasting adiponectin, leptin, glucose, insulin, and corticosterone were measured at weaning (P21). Stress and MTS weight gain (g/d) were accelerated following neonatal stress with greater fat mass, abdominal subcutaneous adipose tissue, serum adiponectin, leptin, and fasting glucose at weaning (P21). Male Stress and MTS pups had greater visceral adipose tissue depot. Male and female Stress pups were hyperinsulinemic. In summary, neonatal stress compromised body composition by increasing fat mass and abdominal subcutaneous adipose tissue depot, and in males, visceral adipose tissue depot. Importantly, MTS prevented hyperinsulinemia despite of stress-induced adiposity. We conclude that MTS during neonatal stress has the potential to minimize metabolic consequences associated with stress-driven perturbations in fat mass and abdominal adipose depots.

Topics: Absorptiometry, Photon; Adiponectin; Animals; Animals, Newborn; Blood Glucose; Body Composition; Body Weight; Corticosterone; Female; Hyperinsulinism; Intra-Abdominal Fat; Leptin; Magnetic Resonance Imaging; Male; Rats; Rats, Sprague-Dawley; Stress, Physiological; Touch

Mechanisms underlying obesity-related vascular dysfunction are unclear. This study examined the effect of diet-induced obesity on expression and function of large conductance Ca(2+)-activated potassium channel (BK(Ca)) in rat pressurized small resistance vessels with myogenic tone. Male Sprague-Dawley rats fed a cafeteria-style high fat diet (HFD; ∼30% energy from fat) for 16-20 wk were ∼30% heavier than controls fed standard chow (∼13% fat). Obesity did not alter BK(Ca) α-subunit function or α-subunit protein or mRNA expression in vessels isolated from the cremaster muscle or middle-cerebral circulations. In contrast, BK(Ca) β(1)-subunit protein expression and function were significantly reduced in cremaster muscle arterioles but increased in middle-cerebral arteries from obese animals. Immunohistochemistry showed α- and β(1)-subunits were present exclusively in the smooth muscle of both vessels. Cremaster muscle arterioles from obese animals showed significantly increased medial thickness, and media-to-lumen ratio and pressurized arterioles showed increased myogenic tone at 30 mmHg, but not at 50-120 mmHg. Myogenic tone was not affected by obesity in middle-cerebral arteries. The BK(Ca) antagonist iberiotoxin constricted both cremaster muscle and middle-cerebral arterioles from control rats; this effect of iberiotoxin was abolished in cremaster muscle arteries only from obese rats. Diet-induced obesity has contrasting effects on BK(Ca) function in different vascular beds, through differential effects on β(1)-subunit expression. However, these alterations in BK(Ca) function had little effect on overall myogenic tone, suggesting that the mechanisms controlling myogenic tone can be altered and compensate for altered BK(Ca) expression and function.

Topics: Animals; Arterioles; Blotting, Western; Cerebral Arteries; Diet; Dietary Fats; Energy Intake; Heart Rate; Hyperinsulinism; Hypertension; Immunohistochemistry; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; Leptin; Male; Microscopy, Electron; Muscle Tonus; Muscle, Skeletal; Obesity; Potassium Channels; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Reverse Transcriptase Polymerase Chain Reaction; Weight Gain

The role of the gaseous messengers NO and CO for β-cell function and survival is controversial. We examined this issue in the hyperglycemic-hyperinsulinemic ob/ob mouse, an animal model of type 2 obese diabetes, by studying islets from obese vs lean mice regarding glucose-stimulated insulin release in relation to islet NO and CO production and the influence of modulating peptide hormones. Glucose-stimulated increase in ncNOS-activity in incubated lean islets was converted to a decrease in ob/ob islets associated with markedly increased insulin release. Both types of islets displayed iNOS activity appearing after ~60 min in high-glucose. In ob/ob islets the insulinotropic peptides glucagon, GLP-1 and GIP suppressed NOS activities and amplified glucose-stimulated insulin release. The insulinostatic peptide leptin induced the opposite effects. Suppression of islet CO production inhibited, while stimulation amplified glucose-stimulated insulin release. Nonincubated isolated islets from young and adult obese mice displayed very low ncNOS and negligible iNOS activity. In contrast, production of CO, a NOS inhibitor, was impressively raised. Glucose injections induced strong activities of islet NOS isoforms in lean but not in obese mice and confocal microscopy revealed iNOS expression only in lean islets. Islets from ob/ob mice existing in a hyperglycemic in vivo milieu maintain elevated insulin secretion and protection from glucotoxicity through a general suppression of islet NOS activities achieved by leptin deficiency, high CO production and insulinotropic cyclic-AMP-generating hormones. Such a beneficial effect on islet function and survival might have its clinical counterpart in human leptin-resistant type 2 obese diabetes with hyperinsulinemia.

Topics: Animals; Blood Glucose; Carbon Monoxide; Diabetes Mellitus, Type 2; Enzyme Assays; Female; Glucagon; Glucose; Humans; Hyperinsulinism; In Vitro Techniques; Insulin; Insulin Secretion; Islets of Langerhans; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Nitric Oxide; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II

It remains elusive what factors induce growth without growth hormone (GWGH) in children after neurosurgery of brain tumors. Growth velocity and endocrinological data were compared between the patients with and without GWGH. We experienced three patients with GWGH (median, 12 years; 2 germinoma and 1 craniopharyngioma; three females; group 1) and 11 patients without (12 years; 8 craniopharyngioma, 2 germinoma and 1 medulloblastoma; 7 males; group 2) after neurosurgery. All patients in group 2 received GH replacement therapy. Growth velocity and endocrinological data were compared. Median height velocity was normal in group 1 (5.5 cm/year), but low in group 2 (2.2 cm/year), which improved after GH replacement therapy (7.0 cm/year). Median serum insulin level was increased in group 1 (87.0 μU/ml, P < 0.05) compared with normal level in group 2 (10.0 μU/ml). Despite hyperinsulinemia, serum glucose level was normal in group 1. Three of 5 with hyperinsulinemia and 2 of 9 without were obese or overweight, but the difference was not significant. Current body mass index and serum levels of IGF-1, IGFBP-3, leptin, and prolactin were similar between groups. Serum estradiol was prepuberty level in group 1. Hyperinsulinemia may induce GWGH in children with brain tumors after neurosurgery.

Topics: Adolescent; Brain Neoplasms; Child; Child, Preschool; Craniopharyngioma; Female; Germinoma; Growth; Growth Hormone; Humans; Hyperinsulinism; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Male; Medulloblastoma; Neurosurgical Procedures; Prolactin; Retrospective Studies; Young Adult

Hypothalamic obesity (HO) is a major and unsolved problem in patients with medial hypothalamic lesions and is associated with hyperinsulinemia and hyperleptinemia. The purpose of this study was to create a rodent model that mimics metabolic changes in HO for use in therapeutic testing. Female Sprague-Dawley rats were used to test the individual and combined effects of two types of medial hypothalamic lesions: arcuate nucleus (ARC) lesions by injection of monosodium glutamate at neonatal age, and ventromedial nucleus (VMN) lesions by passing an anodal current through an electrode placed in the VMN at age 80 days. Adiposity in ARC-lesioned animals was associated with decreased food intake and stunted growth, while VMN lesions were associated with hyperphagia but not reduced growth. The greatest weight gain (weight at age 200 days 712 +/- 65 vs. 451 +/- 19 g in controls), hyperphagia (food intake 10 days following surgery 33 +/- 0.8 vs. 18.5 +/- 0.7 g/day in sham-treated rats), hyperinsulinemia and hyperleptinemia occurred in rats that received both ARC and VMN lesions. Thus, the combined medial hypothalamic lesions result in an obesity phenotype similar to that of patients that suffer from HO and are consequently more suitable for testing potential therapeutics for this disorder than lesions of single hypothalamic nuclei.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Brain; Disease Models, Animal; Female; Hyperinsulinism; Hyperphagia; Hypothalamic Diseases; Insulin; Leptin; Obesity; Rats; Rats, Sprague-Dawley; Sodium Glutamate; Ventromedial Hypothalamic Nucleus; Weight Gain

An acute injection of brain-derived neurotrophic factor (BDNF) in the hypothalamic ventromedial nucleus (VMN) decreases body weight by reducing feeding and increasing energy expenditure (EE) in animals on standard laboratory chow. Animals have divergent responses to high-fat diet (HFD) exposure, with some developing obesity and others remaining lean. In the current study, we tested the hypothesis that BDNF in the VMN reduces HFD-induced obesity. Seventy-two 10-week old rats were allowed HFD ad libitum for 8 weeks and then prepared with bilateral VMN cannulae. Animals were then divided into tertiles based on their fat mass rank: high, intermediate, and low (H, I, and L). Each group was further divided into two subgroups: BDNF (1 μg) or control (artificial cerebrospinal fluid, aCSF); they were then injected every other day for 20 days according to subgroup. Energy intake, body weight, and body composition were measured. Other metabolic indexes were measured before and after treatment. In parallel, another 12 rats were fed control diet (CD), VMN-cannulated, and injected with aCSF. HFD exposure induced obesity in the H group, with a significant increase in energy intake, body weight, fat mass, liver size, and serum glucose, insulin, and leptin. BDNF significantly reduced body weight and fat mass in all phenotypes, while it reduced energy intake only in the I group. However, BDNF increased EE, spontaneous physical activity, and fat oxidation in the H group, suggesting that BDNF-induced EE elevation contributed to reduction of body weight and fat mass. Chronic VMN BDNF reduced insulin elevation and/or reversed hyperleptinemia. These data suggest that the VMN is an important site of action for BDNF reduction of HFD-induced obesity.

Topics: Adipose Tissue; Animals; Brain-Derived Neurotrophic Factor; Contraindications; Diet, High-Fat; Disease Models, Animal; Energy Intake; Hyperinsulinism; Leptin; Male; Obesity; Rats; Rats, Sprague-Dawley; Ventromedial Hypothalamic Nucleus

This study tests the hypothesis that a high-fat postnatal diet increases fat mass and reduces improved insulin sensitivity (IS) found in the low-protein model of maternal undernutrition. Offspring from Wistar dams fed either a 20% (control (CON)) or 8% (low protein (LP)) protein diet during gestation and lactation were randomly assigned to a control (con) or cafeteria (caf) diet at weaning (21 days) until 3 months of age at which point IS was measured (hyperinsulinemic-euglycemic clamp). Fat mass, growth, energy intake (EI) and expenditure (EE), fuel utilization, insulin secretion, and leptin and adiponectin levels were measured to identify a possible role in any changes in IS. IS was increased in LP-con in comparison to CON-con animals. Cafeteria feeding prevented this increase in LP animals but had no effect in CON animals (insulin-stimulated glucose infusion rates (GIRs; mg/min/kg); CON-con: 13.9 +/- 1.0, CON caf: 12.1 +/- 2.1, LP-con: 25.4 +/- 2.0, LP-caf: 13.7 +/- 3.7, P < 0.05). CON-caf animals had similar percent epididymal white adipose tissue (%EWAT; CON-con: 1.71 +/- 0.09 vs. CON-caf: 1.66 +/- 0.08) and adiponectin (microg/ml: CON-con: 4.61 +/- 0.34 vs. CON-caf: 3.67 +/- 0.18) except hyperinsulinemia and relative hyperleptinemia in comparison to CON-con. Differently, LP-caf animals had increased %EWAT (LP-con: 1.11 +/- 0.06 vs. LP-caf: 1.44 +/- 0.08, P < 0.05) and adiponectin (microg/ml: LP-con: 5.38 +/- 0.39 vs. LP-caf: 3.75 +/- 0.35, P < 0.05) but did not show cafeteria-induced hyperinsulinemia or relative hyperleptinemia. An increased propensity to store visceral fat in LP animals may prevent the elevated IS in LP offspring.

Topics: Adiponectin; Animals; Animals, Newborn; Blood Glucose; Diet, Protein-Restricted; Dietary Fats; Female; Hyperinsulinism; Insulin; Insulin Resistance; Intra-Abdominal Fat; Leptin; Male; Obesity, Abdominal; Pregnancy; Random Allocation; Rats; Rats, Wistar

We tested whether leptin can ameliorate diabetes independent of weight loss by defining the lowest dose at which leptin treatment of ob/ob mice reduces plasma glucose and insulin concentration. We found that a leptin dose of 12.5 ng/hr significantly lowers blood glucose and that 25 ng/hr of leptin normalizes plasma glucose and insulin without significantly reducing body weight, establishing that leptin exerts its most potent effects on glucose metabolism. To find possible mediators of this effect, we profiled liver mRNA using microarrays and identified IGF Binding Protein 2 (IGFBP2) as being regulated by leptin with a similarly high potency. Overexpression of IGFBP2 by an adenovirus reversed diabetes in insulin-resistant ob/ob, Ay/a, and diet-induced obese mice, as well as insulin-deficient streptozotocin-treated mice. Hyperinsulinemic clamp studies showed a 3-fold improvement in hepatic insulin sensitivity following IGFBP2 treatment of ob/ob mice. These results show that IGFBP2 can regulate glucose metabolism, a finding with potential implications for the pathogenesis and treatment of diabetes.

Topics: Adenoviridae; Animals; Blood Glucose; Gene Transfer Techniques; Humans; Hyperglycemia; Hyperinsulinism; Hypoglycemic Agents; Insulin; Insulin-Like Growth Factor Binding Protein 2; Leptin; Liver; Mice; Mice, Knockout; Oligonucleotide Array Sequence Analysis; RNA, Messenger

Age-associated insulin resistance may be caused by increased visceral adiposity and older animals appear to be more susceptible to obesity-related resistance than young animals. However, it is unclear to what extent the portally drained mesenteric fat depot influences this susceptibility.. Young high-fat-fed and old obese rats were subjected to 0, 2, 4, or 6 weeks of caloric restriction. Insulin sensitivity (S(I)) was assessed by hyperinsulinemic clamp and lean body mass (LBM) and total body fat were assessed by (18)O-water administration.. Six weeks of caloric restriction caused a similar reduction in body weight in young and old animals (P = 0.748) that was not due to reduced subcutaneous fat or LBM, but rather preferential loss of abdominal fat (P < 0.05). Most notably, mesenteric fat was reduced equivalently in young and old rats after 6 weeks of caloric restriction ( approximately decrease 53%; P = 0.537). Despite similar visceral fat loss, S(I) improved less in old ( increase 32.76 +/- 9.80%) than in young ( increase 82.91 +/- 12.66%) rats versus week 0. In addition, there was significantly more reversal of fat accumulation in the liver in young (% reduction: 89 +/- 2) versus old (64 +/- 5) rats (P < 0.0001). Furthermore, in young rats, S(I) changed much more rapidly for a given change in mesenteric fat versus other abdominal depots (slope = 0.53 vs. < or =0.27 kg/min/mg per % fat). CONCLUSIONS Improved S(I) during caloric restriction correlated with a preferential abdominal fat loss. This improvement was refractory in older animals, likely because of slower liberation of hepatic lipid. Furthermore, mesenteric fat was a better predictor of S(I) than other abdominal depots in young but not old rats. These results suggest a singular role for mesenteric fat to determine insulin resistance. This role may be related to delivery of lipid to liver, and associated accumulation of liver fat.

Topics: Abdomen; Abdominal Fat; Adiponectin; Adipose Tissue; Adiposity; Aging; Animals; Blood Glucose; Body Composition; Crosses, Genetic; Diet, Reducing; Dietary Fats; Glucose Clamp Technique; Hyperinsulinism; Insulin; Insulin Resistance; Intra-Abdominal Fat; Leptin; Rats; Rats, Inbred BN; Rats, Inbred F344; Resistin

In an acute treatment experiment, metformin (150, 300 mg/kg, per os (p.o.)) markedly reduced the consumption of a high-fat diet (HFD) (45 kcal% fat-containing diet) for 2 h after the HFD was given to the fasted male C57BL/6J (B6) mice. In addition, metformin at a higher dose increased plasma active glucagon-like peptide-1 (GLP-1) levels at 1 h after the HFD was given. On the other hand, pioglitazone (12 mg/kg, p.o.) slightly increased the food intake but did not affect active GLP-1 levels when given at 6 and 12 mg/kg, p.o. In a long-team experiment for 9 weeks, metformin treatment (0.25, 0.5% in the HFD) resulted in reduction of body weight gain and HFD intake. When wet weights of various body fat pads of each mouse were measured at 9 weeks after treatment, metformin markedly decreased these weights. However, pioglitazone treatment (0.01, 0.02% in the HFD) did not have obvious effects on these parameters. Oral glucose tolerance test was carried out after 20-h fasting at 4 weeks post-treatment. Whereas metformin treatment (0.25, 0.5%) markedly improved glucose intolerance, pioglitazone treatment (0.02%) slightly improved this parameter. At 9 weeks, both metformin and pioglitazone markedly improved hyperglycemia and hyperinsulinemia. Metformin treatment also improved hyperleptinemia, whereas pioglitazone was ineffective. These results indicate that metformin reduces body weight gain and improves glucose intolerance in HFD-induced obese diabetic B6 mice.

Topics: Animals; Blood Glucose; Body Weight; Dietary Fats; Energy Intake; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Hyperglycemia; Hyperinsulinism; Hypoglycemic Agents; Insulin; Leptin; Male; Metformin; Mice; Mice, Inbred C57BL; Obesity; Pioglitazone; Thiazolidinediones; Weight Gain

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

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

Obesity and metabolic syndrome result from excess calorie intake and genetic predisposition and are mechanistically linked to type II diabetes and accelerated body aging; abnormal nutrient and insulin signaling participate in this pathologic process, yet the underlying molecular mechanisms are incompletely understood. Mice lacking the p66 kDa isoform of the Shc adaptor molecule live longer and are leaner than wild-type animals, suggesting that this molecule may have a role in metabolic derangement and premature senescence by overnutrition. We found that p66 deficiency exerts a modest but significant protective effect on fat accumulation and premature death in lepOb/Ob mice, an established genetic model of obesity and insulin resistance; strikingly, however, p66 inactivation improved glucose tolerance in these animals, without affecting (hyper)insulinaemia and independent of body weight. Protection from insulin resistance was cell autonomous, because isolated p66KO preadipocytes were relatively resistant to insulin desensitization by free fatty acids in vitro. Biochemical studies revealed that p66shc promotes the signal-inhibitory phosphorylation of the major insulin transducer IRS-1, by bridging IRS-1 and the mTOR effector p70S6 kinase, a molecule previously linked to obesity-induced insulin resistance. Importantly, IRS-1 was strongly up-regulated in the adipose tissue of p66KO lepOb/Ob mice, confirming that effects of p66 on tissue responsiveness to insulin are largely mediated by this molecule. Taken together, these findings identify p66shc as a major mediator of insulin resistance by excess nutrients, and by extension, as a potential molecular target against the spreading epidemic of obesity and type II diabetes.

Topics: 3T3-L1 Cells; Adipocytes; Adipose Tissue; Animals; Cells, Cultured; Flow Cytometry; Glucose Intolerance; Hyperinsulinism; Hypoglycemic Agents; Immunoblotting; Insulin; Insulin Resistance; Leptin; Longevity; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Knockout; Mice, Obese; Obesity; Phosphorylation; Ribosomal Protein S6 Kinases, 70-kDa; RNA Interference; Shc Signaling Adaptor Proteins; Src Homology 2 Domain-Containing, Transforming Protein 1

β2-adrenoceptor (β2AR) gene polymorphism glutamine 27 glutamic acid (Gln27Glu) and Arg16Gly were reported to have an association with obesity and obesity related disorders in some population. We evaluated Gln27Glu polymorphism in the β2AR gene in obese Saudi populations to investigate the association of β2AR gene with obesity and other related metabolic parameters.. We studied possible association of Gln27Glu in β2AR gene with body mass index (BMI), anthropometric measurements and other metabolic parameters. The β2AR gene polymorphism (Gln27Glu) was identified by sequencing PCR products representing locus of interest. Based on BMI, the subjects were divided into three groups, normal weight, overweight and obese. The genotype and allele frequency were calculated separately for each group.. The allelic frequency of Glu27 did not differ amongst the three groups, though the Glu27 homozygote (Glu/Glu) were more in obese subjects and had higher concentration of triglyceride, leptin and insulin compared to in the Gln27 heterozygotes and Gln/Gln homozygotes.. In this study we were able to provide evidence on the influence of Gln27Glu genetic variant of β2AR gene on lipid phenotypes, insulin and leptin levels in the Saudi populations.

Topics: Adolescent; Adult; Amino Acid Substitution; Anthropometry; Body Mass Index; Female; Gene Frequency; Genetic Association Studies; Humans; Hyperinsulinism; Hypertriglyceridemia; Leptin; Lipids; Male; Obesity; Polymerase Chain Reaction; Polymorphism, Genetic; Saudi Arabia; Young Adult

Impaired insulin metabolism has been implicated in migraine. However, to date only some putative effects, especially regarding the involvement of adipocytokines and glucagon-like peptides (GLPs), have been described. The aim of the present study was to investigate adipocytokines and GLPs in non-obese female migraineurs.. Various parameters of the insulin metabolism and body measurements were determined in 84 non-obese female subjects.. We found highly significantly increased insulin levels with an odds ratio of 10.62 for migraine. Leptin and GLP-2 levels were also increased and correlated with insulin. Logistic regression analysis of leptin and GLP-2 revealed odds ratios of 3.79 and 4.26 for migraine, respectively, when comparing the lowest with the highest quartile of the test variable in the complete study cohort.. We show that non-obese female migraineurs suffer from hyperinsulinemia, which is associated with elevated leptin and GLP-2 levels. Increased leptin and GLP-2 are risk factors for migraine. Our data suggest that migraine is associated with a higher risk for insulin resistance and its clinical consequences.

Topics: Adult; Body Mass Index; Enzyme-Linked Immunosorbent Assay; Female; Glucagon-Like Peptide 2; Humans; Hyperinsulinism; Leptin; Migraine Disorders; Risk Factors

Obesity is a multifactorial disease that arises from complex interactions between genetic predisposition and environmental factors. Leptin is central to the regulation of energy metabolism and control of body weight in mammals.. To better recapitulate the complexity of human obesity syndrome, we applied N-ethyl-N-nitrosourea (ENU) mutagenesis in combination with a set of metabolic assays in screening mice for obesity. Mapping revealed linkage to the chromosome 6 within a region containing mouse Leptin gene. Sequencing on the candidate genes identified a novel T-to-A mutation in the third exon of Leptin gene, which translates to a V145E amino acid exchange in the leptin propeptide. Homozygous Leptin(145E/145E) mutant mice exhibited morbid obesity, accompanied by adipose hypertrophy, energy imbalance, and liver steatosis. This was further associated with severe insulin resistance, hyperinsulinemia, dyslipidemia, and hyperleptinemia, characteristics of human obesity syndrome. Hypothalamic leptin actions in inhibition of orexigenic peptides NPY and AgRP and induction of SOCS1 and SOCS3 were attenuated in Leptin(145E/145E) mice. Administration of exogenous wild-type leptin attenuated hyperphagia and body weight increase in Leptin(145E/145E) mice. However, mutant V145E leptin coimmunoprecipitated with leptin receptor, suggesting that the V145E mutation does not affect the binding of leptin to its receptor. Molecular modeling predicted that the mutated residue would form hydrogen bond with the adjacent residues, potentially affecting the structure and formation of an active complex with leptin receptor within that region.. Thus, our evolutionary, structural, and in vivo metabolic information suggests the residue 145 as of special function significance. The mouse model harboring leptin V145E mutation will provide new information on the current understanding of leptin biology and novel mouse model for the study of human obesity syndrome.

Topics: Animals; Body Weight; Ethylnitrosourea; Evolution, Molecular; Exons; Genetic Predisposition to Disease; Homozygote; Humans; Hyperinsulinism; Leptin; Mice; Mutagenesis; Mutation; Obesity, Morbid; Receptors, Leptin

Weight gain is an adverse metabolic effect in some children with epilepsy. The studies done to detect the effect of antiepileptic drugs and weight homeostatic hormones, insulin and leptin, were limited and controversial.. We evaluated the serum leptin and insulin as predictors of weight gain in children receiving long-term treatment with valproate (VPA), carbamazepine (CBZ), lamotrigine (LTG). This study included 90 patients (treated: 70; untreated: 20). Serum lipid profile, insulin and leptin were measured.. BMI, serum leptin and insulin were significantly elevated in VPA compared with controls, untreated patients and those treated with CBZ, LTG and combined therapy with LTG. Girls on VPA had higher BMI and leptin levels than boys. With VPA, serum insulin was correlated with BMI (r=0.625, p<0.01), leptin (r=0.823, p<0.001), treatment duration (r=0.775, p<0.01) and VPA dose (r=0.975, p<0.0001). Serum leptin was correlated with age (r=0.980, p<0.0001), BMI (r=0.704, p<0.01), serum insulin (r=0.823, p<0.001), LDL-c (r=0.630, p<0.01), HDL-c (r=-0.880, p<0.001), treatment duration (r=0.770, p<0.01) and VPA dose (r=0.970, p<0.001). BMI is correlated with serum insulin, leptin, LDL-c (r=0.835, p<0.001) and HDL-c (r=-0.955, p<0.0001).. Hyperinsulinemia and hyperleptinemia are common with VPA and marked among epileptic children who gained weight suggesting states of insulin and leptin resistances. These alterations were not demonstrated with CBZ or LTG. The relationship between VPA, leptin and weight seems to be gender specific. Serum leptin may serve as a sensitive parameter for weight gain and reduction with intervention programs during follow-up of girls with epilepsy.

Topics: Adolescent; Age Factors; Anticonvulsants; Body Mass Index; Carbamazepine; Case-Control Studies; Child; Epilepsy; Female; Humans; Hyperinsulinism; Insulin; Lamotrigine; Leptin; Lipids; Male; Predictive Value of Tests; Risk Assessment; Sex Factors; Triazines; Valproic Acid; Weight Gain

Adipokines are fat-derived hormones and cytokines with immune-modulating and metabolic properties. Most of them are associated with insulin resistance. The aim of the present investigation was to evaluate circulating levels of adipokines and glucose homeostasis in patients with inflammatory bowel disease (IBD) and to evaluate possible associations with the course and characteristics of the disease.. Serum leptin, resistin, visfatin, retinol-binding protein-4, adiponectin, glucose, insulin, and inflammatory parameters were analyzed in 93 patients with inactive IBD (49 with Crohn's disease [CD], 44 with ulcerative colitis [UC]), 35 patients with active IBD (18 with CD, 17 with UC), and 37 age- and body mass index-matched healthy controls. Ninety-two patients were followed for 6 mo.. Leptin was similar in patients with IBD and controls, whereas resistin and visfatin were increased in patients with active disease but not in those in remission. In active and inactive disease, adiponectin was decreased (P < 0.001) and retinol-binding protein-4 was increased (P < 0.001) compared with controls. About 60% of patients with IBD showed increased levels of insulin, whereas serum glucose remained normal, resulting in increased homeostasis model assessment values in most patients. Hyperinsulinemia was associated with the decrease in adiponectin (r = -0.572, P < 0.001) and proved to be an independent protective factor for 6-mo maintenance of remission (P = 0.016).. IBD led to largely similar alterations in circulating adipokines and hyperinsulinemia in patients with CD and those with UC. The unexpected protective effect of hyperinsulinemia on relapse rate denotes the role of the metabolic-inflammatory response as a modulator in IBD.

Topics: Adiponectin; Adolescent; Adult; Aged; Case-Control Studies; Colitis, Ulcerative; Crohn Disease; Female; Humans; Hyperinsulinism; Inflammation Mediators; Leptin; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Resistin; Retinol-Binding Proteins; Young Adult

Hypoxia and insulin are known key players in the activation leptin transcription and translation in vivo and in vitro. These insulin- and hypoxia-dependent effects are leptin transcription are mediated via independent elements on the leptin-promotor, even more coincubation of the two stimuli in vitro results in a supraadditive effect on leptin transcription. The aim of this study was to examine whether hyperinsulinemia is able to interfere with the hypoxia-driven expression of leptin in adipose and extra-adipose tissue in vivo.. We used the KK/HlJ mouse strain as a model for hyperinsulinemia and C57BL/6J mice as control. These two groups were exposed to hypoxia for 12 h. Serum levels of insulin and leptin were analyzed by ELISA, mRNA expression of leptin was measured via real-time PCR.. In the hyperinsulinemic KK/HlJ mice, hypoxia was not able to further increase the amount of leptin in serum. Instead, a significant decrease of insulin levels was detected, while serum leptin and insulin levels increased in C57BL/6J. Analysis of leptin mRNA expression in subcutaneous fat, mesenteric fat and kidney revealed that hypoxia induces leptin transcription in kidneys of C57/BL6 but not in hyperinsulinemic animals. In contrast, leptin expression in adipose tissue was not increased during hypoxia.. We conclude that leptin regulation during hypoxia in vivo depends at least in part on the modulating role of insulin. The hypoxia driven induction of insulin expression in C57/BL6 animals may be responsible for the stimulation of leptin transcription. In contrast, already hyperinsulinemic animals showed no induction - neither of insulin nor leptin after short-term hypoxia.

Topics: Animals; Blood Glucose; Body Weight; Hyperinsulinism; Hypoxia; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Transcription, Genetic

It is well established that leptin increases the sensitivity of carbohydrate metabolism to the effects of insulin. Leptin and insulin also have potent effects on lipid metabolism. However, the effects of leptin on the regulation of liver lipid metabolism by insulin have not been investigated. The current study addressed the effects of leptin on insulin-regulated hepatic very low-density lipoprotein (VLDL) metabolism in vivo in rats. A 90-min hyperinsulinemic/euglycemic clamp (4 mU/kg x min(-1)) reduced plasma VLDL triglyceride (TG) by about 50% (P < 0.001 vs. saline control). Importantly, a leptin infusion (0.2 microg/kg x min(-1)) in combination with insulin reduced plasma VLDL-TG by about 80% (P < 0.001 vs. insulin alone). These effects did not require altered skeletal muscle lipoprotein lipase activity but did include differential effects of insulin and leptin on liver apolipoprotein (apo) B and TG metabolism. Thus, insulin decreased liver and plasma apoB100/B48 levels (approximately 50%, P < 0.01), increased liver TGs (approximately 20%, P < 0.05), and had no effect on fatty acid oxidation. Conversely, leptin decreased liver TGs (approximately 50%, P < 0.01) and increased fatty acid oxidation (approximately 50%, P < 0.01) but had no effects on liver or plasma apoB levels. Importantly, the TG-depleting and prooxidative effects of leptin were maintained in the presence of insulin. We conclude that leptin additively increases the suppressive effects of insulin on hepatic and systemic VLDL metabolism by stimulating depletion of liver TGs and increasing oxidative metabolism. The net effect of the combined actions of insulin and leptin is to decrease the production and TG content of VLDL particles.

Topics: Animals; Apolipoprotein B-100; Apolipoprotein B-48; Down-Regulation; Drug Synergism; Glucose Clamp Technique; Hyperinsulinism; Insulin; Leptin; Lipid Metabolism; Lipoproteins, VLDL; Liver; Male; Oxidation-Reduction; Rats; Rats, Wistar; Triglycerides

The ability to predict ponies at increased risk of laminitic episodes, when exposed to nutrient dense pasture, would facilitate management to avoid disease.. To identify variables and clinically useful cut-off values with reproducible diagnostic accuracy for the prediction of ponies that subsequently developed laminitis when exposed to nutrient dense pasture.. A cohort of predominantly Welsh and Dartmoor ponies from a closed herd was evaluated in March 2006 (n = 74) and March 2007 (n = 57). Ponies were categorised as never laminitic or previously laminitic according to reported laminitic history and as clinically laminitic (CL) if laminitis was observed within 3 months following evaluation. Body condition score (BCS), cresty neck score (CNS), girth and neck circumferences (NC), withers height, blood pressure and hoof surface temperature, and plasma insulin, glucose, triglyceride, leptin, cortisol, ACTH, uric acid and TNF-alpha concentrations were measured. Analysis of sensitivity, specificity and receiver operating characteristic curves was used to evaluate the diagnostic accuracy for a variable to predict CL ponies.. Variables with diagnostic accuracy for the prediction of CL ponies included insulin, leptin, BCS, CNS, and NC:height ratio. Specific cut-off values of insulin (>32 mu/l), leptin (>73 ng/ml), BCS (> or = 7), CNS (> or = 4) and NC:height ratio (>0.71) had reproducible diagnostic accuracy for the prediction of laminitis. Combining tests did not result in higher diagnostic accuracy than individual tests of insulin or leptin during either evaluation.. Tests of insulin and leptin concentrations and measures of generalised (BCS) and localised (CNS or NC:height ratio) obesity were beneficial in the prediction of laminitic episodes.. These results highlight the importance of monitoring and reducing insulin concentration, and generalised and regional obesity in ponies to reduce risk of laminitis.

Topics: Animal Husbandry; Animals; Cohort Studies; Comorbidity; Diagnosis, Differential; Female; Foot Diseases; Horse Diseases; Horses; Hyperinsulinism; Leptin; Obesity; Poaceae; Predictive Value of Tests; Risk Factors

The purpose of this study was to determine the long-term impact of obesity and related metabolic abnormalities in the absence and presence of hypertension on renal injury and salt-sensitivity of blood pressure. Markers of renal injury and blood pressure salt sensitivity were assessed in 52- to 55-wk-old normotensive melanocortin-4 receptor-deficient (MC4R-/-) mice and lean C57BL/6J wild-type (WT) mice and in 22-wk-old MC4R-/- and WT mice made hypertensive by N(G)-nitro-L-arginine methyl ester (L-NAME) in the drinking water for 8 wk. Old MC4R-/- mice were 60% heavier, hyperinsulinemic, and hyperleptinemic but had similar mean arterial pressure (MAP) as WT mice (115 +/- 2 and 117 +/- 2 mmHg) on normal salt diet (0.4% NaCl). A high-salt diet (4.0% NaCl) for 12 days did not raise MAP in obese or lean mice [DeltaMAP: MC4R (-/-) 4 +/- 2 mmHg; WT, 2 +/- 1 mmHg]. Obese MC4R-/- mice had 23% greater glomerular tuft area and moderately increased GFR compared with WT mice. Bowman's space, total glomerular area, mesangial matrix, urinary albumin excretion (UAE), renal TGF-beta and collagen expression were not significantly different between old MC4R-/- and WT mice. Renal lipid content was greater but renal macrophage count was markedly lower in MC4R-/- than WT mice. Mild increases in MAP during L-NAME treatment (approximately 16 mmHg) caused small, but greater, elevations in UAE, renal TGF-beta content, and macrophage infiltration in MC4R-/- compared with WT mice without significant changes in glomerular structure. Thus despite long-term obesity and multiple metabolic abnormalities, MC4R-/- mice have no evidence of renal injury or salt-sensitivity of blood pressure. These observations suggest that elevations in blood pressure may be necessary for obesity and related metabolic abnormalities to cause major renal injury or that MC4R-/- mice are protected from renal injury by mechanisms that are still unclear.

Topics: Age Factors; Albuminuria; Animals; Biomarkers; Blood Pressure; Body Weight; Disease Models, Animal; Glomerular Filtration Rate; Heart Rate; Hyperinsulinism; Hypertension; Kidney; Kidney Diseases; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Receptor, Melanocortin, Type 4; Sodium Chloride, Dietary

Obesity and obesity-related illnesses are global epidemics impacting the health of adults and children. The purpose of the present work is to evaluate a genetically intact obese mouse model that more accurately reflects the impact of aging on diet-induced obesity and type 2 diabetes in humans. Male C57Bl/6J mice consumed either a control diet or one in which 60% kcal were due to lard beginning at 5-6 weeks of age. Body weight and fat measurements were obtained and necropsy performed at 15, 20, 30, and 40 weeks of age. Serum chemistry, histopathology, gene expression of the liver, and renal and hepatic function were also evaluated. In concert with significant increases in percent body fat and weight, mice fed the high-fat versus control diet had significantly increased levels of serum cholesterol. At ages 20 and 30 weeks, serum glucose was significantly higher in obese versus controls, while serum insulin levels were >/=4-fold higher in obese mice at ages 30 and 40 weeks. The effect of age exacerbated the effects of consuming a high-fat diet. In addition to being hyperinsulinemic and leptin resistant, older obese mice exhibited elevated hepatic PAI-1 and downregulation of GLUT4, G6PC, IGFBP-1, and leptin receptor mRNA in the liver, steatosis with subsequent inflammation, glomerular mesangial proliferation, elevated serum ALT, AST, and BUN, and increased numbers of pancreatic islets.

Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Diet, Atherogenic; Fatty Liver; Glucose Tolerance Test; Hyperinsulinism; Insulin; Kidney Diseases; Leptin; Lipids; Male; Mice; Mice, Inbred C57BL; Obesity

Hormonal and metabolic factors signal the status of energy balance to hypothalamic nuclei. Obesity is characterized by neuronal, metabolic and hormonal alterations. We therefore hypothesized that hypothalamic responses to challenges of energy balance may differ between lean and obese animals. To test this, we compared c-Fos expression in the hypothalamic arcuate (ARC) and paraventricular nuclei (PVN) and the lateral hypothalamic area (LHA) of mice (1-year-old) with late-onset obesity (LOO) and of lean controls under different feeding conditions. Fourteen hours of fasting induced high c-Fos expression in neuropeptide-Y-positive ARC neurons, in the PVN and in the rostral LHA in lean but not in LOO mice. c-Fos expression in melanin-concentrating hormone (MCH) and orexin-containing neurons in the caudal LHA was not affected by fasting. LOO mice showed fasting hyperinsulinemia, hyperleptinemia, elevated fasting blood glucose and an attenuated hyperphagic response during refeeding. Moreover, the anorectic response to leptin and hypoglycemic response to insulin were reduced in LOO mice. We conclude that adiposity blunts the neuronal responses to metabolic challenges in hypothalamic centers which control feeding behavior and energy balance. Elevated blood glucose may be one factor that suppresses hypothalamic responsiveness in obese mice. A similar impact of hyperinsulinemia and hyperleptinemia in LOO mice is also likely although under the current experimental conditions responsiveness to some effects of these hormones appeared to be reduced.

Topics: Age of Onset; Animals; Arcuate Nucleus of Hypothalamus; Blood Glucose; Fasting; Green Fluorescent Proteins; Hyperinsulinism; Hyperphagia; Hypothalamic Area, Lateral; Intracellular Signaling Peptides and Proteins; Leptin; Male; Melanins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons; Neuropeptide Y; Neuropeptides; Obesity; Orexins; Paraventricular Hypothalamic Nucleus; Proto-Oncogene Proteins c-fos

A highly regulated homeostatic system governs body weight; however, it is possible that this system might be impaired by the sustained intake of highly palatable foods. Short-term feeding studies suggest that the appetite-stimulating hormone ghrelin is suppressed less effectively by dietary fat intake, and diets high in sucrose decrease levels of the adipose hormone leptin. We hypothesized that higher habitual intake of dietary fat and carbohydrate (CHO) would be associated with elevated concentrations of circulating plasma ghrelin and lower circulating leptin in humans, a hormonal profile that could promote weight gain. To test our hypothesis, we examined the cross-sectional associations of ghrelin and leptin with the habitual macronutrient intake of 165 healthy overweight and obese sedentary women and tested the modifying role of insulin in these associations. We observed a significant inverse association between leptin concentrations and percentage energy from CHO independent of body mass index, percentage body fat, age, and intraabdominal fat (beta = -0.11 P = .04). No significant associations were observed between ghrelin and macronutrients or their subtypes among the total cohort. Among women with insulin concentrations at or greater than the median, we found a statistically significant positive association between intake of saturated fat and ghrelin concentrations, as well as additional statistically significant associations between leptin concentrations and macronutrients not observed among the total cohort. Our results provide some evidence that diets higher in fat and CHO are associated with a hormonal profile (ie, lower leptin and higher ghrelin concentrations), which could enhance weight gain, particularly among individuals with higher circulating insulin concentrations.

Topics: Aged; Cross-Sectional Studies; Dietary Carbohydrates; Dietary Fats; Fatty Acids; Feeding Behavior; Female; Ghrelin; Humans; Hyperinsulinism; Insulin; Leptin; Middle Aged; Obesity; Overweight; Postmenopause

Both type 1 and 2 diabetes are associated with differential regulation of leptin, adiponectin and ASP. Our aim was to examine whether or not acute hyperinsulinaemia and/or hyperglycaemia per se have differential regulation of these hormones in healthy subjects.. We examined changes in leptin, adiponectin and ASP concentrations and subcutaneous white adipose tissue mRNA expression with 3-hour hyperinsulinaemic (HI, n=10), hyperglycaemic (HG, n=7) and hyperinsulinaemic-hyperglycaemic (HGHI, n=8) clamps in healthy lean young men. As somatostatin was used for the HG and HGHI clamps, a control somatostatin clamp was carried out (n=4). Changes in the expression of HKII and p85alpha Pi3K were examined as positive controls for the induction of gene expression by the insulin pathway.. HI, HG and HGHI clamps increased expression of HKII and p85alpha Pi3K while somatostatin did not. The HI clamp decreased serum adiponectin (-15%, P<0.001) and increased serum leptin (+11%, P=0.031), while the HG clamp reduced serum leptin (-20%, P=0.003). The HGHI clamp increased serum ASP (+21%, P=0.047) and expression of C3 (+26%, P=0.018) and leptin (+50%, P=0.024). Interestingly, the control somatostatin clamp suppressed both serum leptin (-17%, P=0.043) and adiponectin (-7%, P=0.020).. HG and/or HI per se regulated the concentrations and expression of leptin, adiponectin and ASP in healthy lean young men, suggesting a contribution to dysregulation of these hormones in diabetes.

Topics: Adiponectin; Adipose Tissue, White; Adult; Blood Glucose; Complement C3; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucose Clamp Technique; Humans; Hyperglycemia; Hyperinsulinism; Insulin; Leptin; Male; Somatostatin

Topics: Adult; Fatty Acids, Nonesterified; Female; Hormone Replacement Therapy; Humans; Hyperinsulinism; Leptin; Linear Models; Lipid Metabolism; Male; Mutation, Missense; Recombinant Proteins; Weight Gain

Obesity following hypothalamic damage is often severe and resistant to lifestyle changes. Disruption of hypothalamic feedback mechanisms that maintain energy homeostasis may be responsible for this intractable obesity. Adipocytokines including insulin and leptin are also known to be important regulators of appetite and weight.. To investigate the role of insulin, leptin, adiponectin and resistin in the aetiology of hypothalamic obesity (HO).. This was a cross-sectional study of three groups of children, those with HO, congenital hypopituitarism (CH) and simple obesity (SO).. A total of 69 children (HO=28, CH=18, SO=23) had leptin, resistin, adiponectin and insulin measured. Although fasting hyperinsulinaemia and insulin resistance were demonstrated, no differences in insulin or insulin resistance were seen between the groups. The HO group, however, had higher levels of leptin, adiponectin and resistin, which persisted even after adjusting for fat mass, compared with the other groups (P<0.05).. No differences in fasting hyperinsulinaemia or insulin resistance were seen between the groups; however, leptin levels are elevated, even after adjusting for fat mass, suggesting that an element of leptin resistance is associated with HO. This is consistent with the inability of leptin to act on the hypothalamus, either due to transport across the blood-brain barrier or dysfunctional receptors. The lack of response to leptin may be more important in the development of obesity in these individuals, and the fasting hyperinsulinaemia is a result of the increased adipose tissue rather than the cause of the weight gain.

Topics: Adolescent; Child; Child, Preschool; Cross-Sectional Studies; Fasting; Female; Humans; Hyperinsulinism; Hypopituitarism; Hypothalamic Diseases; Hypothalamus; Leptin; Male; Obesity

The present study was carried to develop and analyze the consequences of hypercaloric pellet-diet cycle that promotes obesity in rats. Male Wistar rats were randomly distributed into two groups that received either normal diet (ND; n =32; 3,5 Kcal/g) or a hypercaloric diet (HD; n =32; 4,6 Kcal/g). The ND group received commercial Labina rat feeding while the HD animals received a cycle of five hypercaloric diets over a 14-week period. The effects of the diets were analyzed in terms of body weight, body composition, hormone-metabolite levels, systolic arterial pressure and glucose tolerance at the 5% significance level. The hypercaloric pellet diet cycle promoted an increase in body weight and fat, systolic arterial pressure and a high serum level of glucose, triacylglycerol, insulin and leptin. The HD group also presented an impaired glucose tolerance. In conclusion, the results of this study show that the hypercaloric pellet-diet cycle promoted obesity in Wistar rats and displayed several characteristics that are commonly associated with human obesity, such as high arterial pressure, insulin resistance, hyperglycaemia, hyperinsulinaemia, hyperleptinaemia and dyslipidaemia.

Topics: Analysis of Variance; Animals; Blood Pressure; Body Composition; Body Weight; Dietary Fats; Disease Models, Animal; Dyslipidemias; Energy Intake; Humans; Hyperglycemia; Hyperinsulinism; Hypertension; Leptin; Male; Obesity; Random Allocation; Rats; Rats, Wistar

The osteoblast-secreted molecule osteocalcin favors insulin secretion, but how this function is regulated in vivo by extracellular signals is for now unknown. In this study, we show that leptin, which instead inhibits insulin secretion, partly uses the sympathetic nervous system to fulfill this function. Remarkably, for our purpose, an osteoblast-specific ablation of sympathetic signaling results in a leptin-dependent hyperinsulinemia. In osteoblasts, sympathetic tone stimulates expression of Esp, a gene inhibiting the activity of osteocalcin, which is an insulin secretagogue. Accordingly, Esp inactivation doubles hyperinsulinemia and delays glucose intolerance in ob/ob mice, whereas Osteocalcin inactivation halves their hyperinsulinemia. By showing that leptin inhibits insulin secretion by decreasing osteocalcin bioactivity, this study illustrates the importance of the relationship existing between fat and skeleton for the regulation of glucose homeostasis.

Topics: Animals; Humans; Hyperinsulinism; Insulin; Insulin Secretion; Leptin; Mice; Mice, Obese; Obesity; Osteoblasts; Osteocalcin; Sympathetic Nervous System

To determine if tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6). IL-6 gene expression is influenced by amount and source of dietary fat, 30 weanling female rats were randomly assigned to a moderate-fat soybean oil (MFS; 22% of total energy fed as fat), high-fat (HF) soybean oil (HFS; 39% of total energy fed as fat), or HF tallow (HFT; 39% of total energy fed as fat) diet treatments. Oral glucose tolerance tests (OGTT) were conducted serially over 10 weeks of treatment. HFT and HFS rats gained more weight and had greater body fat than the MFS rats fed similar amounts of energy. Both groups of HF-fed rats had greater (P<.05) insulin resistance (homeostasis model assessment) than MFS-fed rats. TNF-alpha mRNA abundance quantified by real-time reverse transcriptase-polymerase chain reaction was greater (P<.05) in liver and lower (P<.05) in adipose tissue in HFT compared to HFS and MFS rats. There were positive correlations (P<.05) between hepatic TNF-alpha mRNA and insulin resistance, and negative correlations between insulin sensitivity and hepatic TNF-alpha mRNA and hepatic IL-6 mRNA. During Week 3 and Week 6 OGTTs, hyperinsulinemic responses were observed in the HFT group, after which, on Week 9, insulin secretion was diminished in response to the OGTT, suggesting impaired pancreatic insulin secretion. HFS rats exhibited insulin resistance on Week 9 OGTT. In summary, an HFT diet fed to growing female rats caused insulin resistance associated with increased hepatic TNF-alpha mRNA leading to pancreatic insufficiency. Early-onset insulin resistance related to the inflammatory process in obesity is influenced by the amount and type of fat in the diet.

Topics: Animals; Cytokines; Dietary Fats; Female; Gene Expression; Glucose Tolerance Test; Hyperinsulinism; Insulin; Insulin Resistance; Interleukin-1; Leptin; Liver; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Necrosis Factor-alpha; Weaning; Weight Gain

Substantial evidence suggests that poor intrauterine milieu elicited by maternal nutritional disturbance may programme susceptibility in the fetus to later development of chronic diseases, such as obesity, hypertension, cardiovascular disease and diabetes. One of the most interesting features of fetal programming is the evidence from several studies that the consequences may not be limited to the first-generation offspring and that it can be passed transgenerationally. In the present study, female rats (F0) were fed either a normal-protein diet [control diet (C); 19 g of protein/100 g of diet] or a low-protein diet [restricted diet (R); 5 g of protein/100 g of diet]. The offspring were termed according to the period and the types of diet the dams were fed, i.e. CC, RC, CR and RR (first letter indicates the diet during gestation and the second the diet during lactation). At 3 months of age, F1 females were bred to proven males, outside the experiment, to produce F2 offspring. At weaning, F2 offspring were divided by gender. RC1 offspring (with the number indicating the filial generation) were born with low birthweight, but afterwards they had catch-up growth, reaching the weight of the CC1 offspring. The increased glycaemia in RC1 offspring was associated with insulin resistance. CR1 and RR1 offspring had impaired growth with no changes in glucose metabolism. RC2 offspring had high BM (body mass) at birth, which was sustained over the whole experiment in male offspring. The F2 generation had more alteration in glucose metabolism than the F1 generation. CR2 and RC2 offspring had hyperglycaemia accompanied by hyperinsulinaemia and insulin resistance in both genders. CR2 offspring had an increase in body adiposity with hyperleptinaemia. In conclusion, low protein during gestation improves BM, fat mass and growth rate in F1 rats, but has adverse effects on glucose and leptin metabolism, resulting in insulin resistance in adult F1 and F2 offspring. Low protein during lactation has adverse effects on glucose, insulin and leptin metabolism, resulting in insulin resistance in adult F2 offspring. These findings suggest that low protein during gestation and/or lactation can be passed transgenerationally to the second generation.

Topics: Animals; Biometry; Blood Glucose; Diet, Protein-Restricted; Female; Fetal Development; Fetal Nutrition Disorders; Growth; Hyperglycemia; Hyperinsulinism; Insulin Resistance; Lactation; Leptin; Male; Pregnancy; Prenatal Exposure Delayed Effects; Prenatal Nutritional Physiological Phenomena; Rats

To determine the long-term effect of central leptin and resistin on energy homeostasis, peripheral insulin resistance, and beta-cell function and mass, intracerebroventricular (ICV) infusion of leptin (3 ng/h), resistin (80 ng/h), leptin plus resistin, and cerebrospinal fluid (control) was conducted by means of an osmotic pump for 4 wk on normal rats and 90% pancreatectomized diabetic rats fed 40% fat-energy diets. Overall, the effects were greater in diabetic rats than normal rats. Leptin infusion, causing a significant reduction in food intake, decreased body weight and epididymal fat. However, resistin and leptin plus resistin reduced epididymal fat with decreased serum leptin levels in comparison with the control. Unlike serum leptin, only resistin infusion lowered serum resistin levels. Central leptin increased glucose infusion rates during euglycemic hyperinsulinemic clamp and suppressed hepatic glucose production in the hyperinsulinemic state in comparison with the control. However, central leptin did not affect glucose-stimulated insulin secretion and beta-cell mass. Central resistin infusion also increased peripheral insulin sensitivity, but not as much as leptin. Unlike leptin, resistin significantly increased first-phase insulin secretion during hyperglycemic clamp and beta-cell mass by augmenting beta-cell proliferation. These metabolic changes were associated with hypothalamic leptin and insulin signaling. ICV infusion of leptin potentiated signal transducer and activator of transcription 3 phosphorylation and attenuated AMP kinase in the hypothalamus, but resistin had less potent effects than leptin. Leptin enhanced insulin signaling by potentiating IRS2-->Akt pathways, whereas resistin activated Akt without augmenting insulin receptor substrate 2 phosphorylation. In conclusion, long-term ICV infusion of leptin and resistin independently improved energy and glucose homeostasis by modulating in different ways hypothalamic leptin and insulin signaling.

Topics: Animals; Apoptosis; Blood Glucose; Body Weight; Cell Division; Eating; Glucose Clamp Technique; Glucose Tolerance Test; Hyperinsulinism; Hypothalamus; Injections, Intraventricular; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Like Growth Factor I; Insulin-Secreting Cells; Leptin; Male; Pancreatectomy; Rats; Rats, Sprague-Dawley; Resistin; Signal Transduction

Mice with a targeted disruption of bombesin receptor subtype-3 (BRS-3 KO) develop hyperphagia, obesity, hypertension, and impaired glucose metabolism. However, the factors contributing to their phenotype have not been clearly established. To determine whether their obesity is a result of increased food intake or a defect in energy regulation, we matched the caloric intake of BRS-3 KO mice to wild-type (WT) ad libitum (ad lib)-fed controls over 21 wk. Although BRS-3 KO ad lib-fed mice were 29% heavier, the body weights of BRS-3 KO pair-fed mice did not differ from WT ad lib-fed mice. Pair-feeding BRS-3 KO mice normalized plasma insulin but failed to completely reverse increased adiposity and leptin levels. Hyperphagia in ad lib-fed KO mice was due to an increase in meal size without a compensatory decrease in meal frequency resulting in an increase in total daily food intake. An examination of neuropeptide Y, proopiomelanocortin, and agouti-related peptide gene expression in the arcuate nucleus revealed that BRS-3 KO mice have some deficits in their response to energy regulatory signals. An evaluation of the satiety effects of cholecystokinin, bombesin, and gastrin-releasing peptide found no differences in feeding suppression by these peptides. We conclude that hyperphagia is a major factor leading to increased body weight and hyperinsulinemia in BRS-3 KO mice. However, our finding that pair-feeding did not completely normalize fat distribution and plasma leptin levels suggests there is also a metabolic dysregulation that may contribute to, or sustain, their obese phenotype.

Topics: Adiposity; Animals; Body Weight; Bombesin; Cholecystokinin; Eating; Energy Metabolism; Gastrin-Releasing Peptide; Glucose; Hyperinsulinism; Hyperphagia; Hypothalamus; Insulin; Leptin; Male; Mice; Mice, Knockout; Obesity; Receptors, Bombesin; Satiation; Weight Gain

Kinins are potent vasoactive and inflammatory peptides generated by kallikreins in blood and tissues that bind to specific receptors named B1 and B2. On the other hand, leptin is an adipocytokine that displays broad effects on energy balance, inflammation and vascular tone. Here we demonstrate that the intravenous administration of the kinin B1 receptor agonist des-Arg9-bradykinin (DBK) in mice leads to significant increase in serum leptin levels. However, incubation of isolated white adipose tissue with DBK was not sufficient to induce leptin release or leptin mRNA overexpression. On the contrary, long-term DBK treatment in isolated fat tissue impaired insulin-mediated actions on leptin secretion and expression. In order to verify whether the in vivo effect of B1 receptor stimulation on leptin release was also dependent on blood insulin levels, DBK was injected in animals in hyperinsulinemic state. In this case, however, DBK was not able to potentiate leptinemia. Therefore, our results show that the B1 receptor stimulation may modulate leptin homeostasis in an insulin-dependent manner. These new findings contribute to a better understanding of the processes involving leptin regulation and highlight the involvement of kinins with metabolic processes.

Topics: Adipose Tissue; Animals; Homeostasis; Hyperinsulinism; Insulin; Leptin; Mice; Mice, Inbred C57BL; Receptor, Bradykinin B1

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

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

Little is known about the association of endothelial nitric oxide synthase (NOS3) gene polymorphisms and the presence of insulin resistance and the early evolution of atherosclerosis in nondiabetic subjects with cardiovascular disease (CAD) and stent implantation. The present study was performed in an attempt to better understand whether metabolic, endothelial, and angiographic findings characteristic of subjects with cardiovascular disease and in-stent restenosis are related to NOS3 variants. This is a case-control study performed from 2002 to 2006. All subjects admitted to the study were recruited in the Nord-Centre of Italy, most from Milan and its surrounding towns. Measures of glucose tolerance, insulin sensitivity, markers of endothelial dysfunction, forearm vasodilation, and adipokine levels were determined and associated to the frequency of two single-nucleotide polymorphisms of NOS3, i.e., Glu298Asp (rs1799983, G/T) and rs753482 (intron 18 A/C). A total of 747 subjects, not known to have diabetes, were evaluated: 333 subjects had asymptomatic CAD, 106 subjects had unstable angina and were evaluated for in-stent restenosis 6 mo after stent placement, and 308 were control subjects. The presence of TT and CC minor alleles was significantly greater in case groups compared with control subjects. At phenotypic level, subjects with the polymorphisms were characterized by hyperinsulinemia and reduced reactive hyperemia, whereas increased leptin and decreased adiponectin levels were present in subjects with restenosis in the presence of reduced minimal lumen diameter and length of stenosis almost doubled. Hyperinsulinemia, endothelial dysfunction, and a more atherogenic profile seem to be peculiar features of subjects with asymptomatic CAD and restenosis carrying NOS3 gene variants.

Topics: Adiponectin; Aged; Atherosclerosis; Blood Glucose; Coronary Angiography; Coronary Artery Disease; Diabetes Complications; DNA; Female; Forearm; Gene Frequency; Genotype; Glucose Tolerance Test; Glycated Hemoglobin; Graft Occlusion, Vascular; Haplotypes; Humans; Hyperinsulinism; Leptin; Lipids; Male; Middle Aged; Nitric Oxide Synthase Type III; Polymorphism, Genetic; Regional Blood Flow

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

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

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

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

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

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

Total plasma adiponectin and high-molecular weight (HMW) polymeric adiponectin are strongly positively correlated with insulin sensitivity. However, we have recently reported paradoxical hyperadiponectinemia in patients with severe insulin resistance due to genetically defective insulin receptors. This implies either that the insulin receptor has a critical physiological role in controlling adiponectin production and/or clearance or that constitutive insulin receptor dysfunction influences adiponectin levels through developmental effects. The aim of the current study was to distinguish between these possibilities using a human model of reversible antibody-mediated insulin receptor dysfunction and to refine the previous observations by determining adiponectin complex distribution. Cross-sectional and longitudinal determination of fasting plasma adiponectin and adiponectin complex distribution was undertaken in patients with extreme insulin resistance due to insulin receptor mutations, anti-insulin receptor antibodies (type B insulin resistance), or an undefined cause. Despite extreme insulin resistance, patients with type B insulin resistance (all women; mean age 42 years [range 12-54]) had dramatically elevated total plasma adiponectin compared with the general population (mean 43.0 mg/l [range 31.3-54.2] vs. 8.9 mg/l [1.5-28.5 for BMI <25 kg/m(2)]), which was accounted for largely by HMW polymers. Hyperadiponectinemia resolved in parallel with reduction of insulin receptor antibodies and clinical resolution of insulin resistance. Although the well-established inverse relationship between plasma insulin and adiponectin levels may, in part, reflect positive effects of adiponectin on insulin sensitivity, these data suggest that the magnitude of the effect of insulin action on adiponectin levels may have been underestimated.

Topics: Adiponectin; Adult; Autoantibodies; Child; Ethnicity; Female; Humans; Hyperinsulinism; Insulin Resistance; Leptin; Longitudinal Studies; Middle Aged; Molecular Weight; Receptor, Insulin; Reference Values

Hyperinsulinaemia, a pre-clinical condition which is considered to predict insulin resistance and metabolic syndrome, has not been sufficiently investigated in bipolar disorder, despite evidence to suggest that bipolar patients are at risk of developing insulin resistance. This study was set out to determine the alteration in fasting insulin levels and evaluate the factors associated with hyperinsulinaemia during manic episodes. Measurements were taken of the fasting plasma insulin and leptin levels, as well as the body mass index (BMI), amongst 42 physically healthy bipolar I manic (DSM-IV) patients aged < or =45 with Young Mania Rating Scale (YMRS) scores of > or =26. These were then compared with their values in subsequent remission (YMRS < or =12). A total of 14 patients (33.3%) in acute mania and 30 patients (71.4%) in subsequent remission met the Taiwanese criteria for hyperinsulinaemia of > or =8.7 microIU/ml for men, and > or =11.3 microIU/ml for women. Multiple analyses were then undertaken, without correction, as the exploratory analyses. The measurement, by logistic regression, of the use of propranolol in remission (odds ratio [OR]=10.04, 95% confidence interval [95% CI]=1.03-97.96) and the increase in BMI (OR=1.35, 95% CI=1.01-1.80) were found to have independent associations with hyperinsulinaemia in subsequent remission. Our results suggest that medicated bipolar manic patients are vulnerable to hyperinsulinaemia in early remission, particularly those gaining bodyweight or those using beta-adrenoceptor antagonist (beta-blockers), irrespective of the types of mood stabilizers or antipsychotics used.

Topics: Acute Disease; Adrenergic beta-Antagonists; Adult; Bipolar Disorder; Body Mass Index; Female; Humans; Hyperinsulinism; Insulin; Leptin; Male; Propranolol; Psychiatric Status Rating Scales

The development of hypothalamic leptin resistance plays a role in the development of obesity, yet whether peripheral leptin resistance occurs in obesity and diabetes is controversial. Here we investigate whether hyperinsulinemia, as observed during the development of Type 2 diabetes, modifies the effects of leptin on long chain fatty acid metabolism in skeletal muscle cells. We used boron dipyrromethene difluoride (BODIPY)-labeled palmitate to show that leptin (60 nM) caused a time-dependent (0-60 min) increase in fatty acid uptake in L6 myoblasts. Quantitative analysis using 3H-palmitate showed that pre-incubation with insulin (100 nM, 24 h) prevented stimulation of fatty acid uptake by leptin. Insulin pre-treatment also attenuated the ability of leptin to phosphorylate acetyl Co-A carboxylase and increase palmitate oxidation. Suppressor of cytokine-3 (SOCS-3) has been proposed as a possible mediator of insulin-induced leptin resistance. Here we show that treatment of L6 cells with insulin elicited a time-dependent increase in both SOCS-3 mRNA and protein content. In summary, hyperinsulinemia can induce leptin resistance in L6 myoblasts and this may be mediated via a SOCS-3-dependent mechanism.

Topics: Animals; Cell Line; Energy Metabolism; Fatty Acids; Hyperinsulinism; Insulin; Leptin; Myoblasts; Rats; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins

Obesity is frequently associated with the consumption of high carbohydrate/fat diets leading to hyperinsulinemia. We have demonstrated that soy protein (SP) reduces hyperinsulinemia, but it is unclear by which mechanism. Thus, the purpose of the present work was to establish whether SP stimulates insulin secretion to a lower extent and/or reduces insulin resistance, and to understand its molecular mechanism of action in pancreatic islets of rats with diet-induced obesity. Long-term consumption of SP in a high fat (HF) diet significantly decreased serum glucose, free fatty acids, leptin, and the insulin:glucagon ratio compared with animals fed a casein HF diet. Hyperglycemic clamps indicated that SP stimulated insulin secretion to a lower extent despite HF consumption. Furthermore, there was lower pancreatic islet area and insulin, SREBP-1, PPARgamma, and GLUT-2 mRNA abundance in comparison with rats fed the casein HF diet. Euglycemic-hyperinsulinemic clamps showed that the SP diet prevented insulin resistance despite consumption of a HF diet. Incubation of pancreatic islets with isoflavones reduced insulin secretion and expression of PPARgamma. Addition of amino acids resembling the plasma concentration of rats fed casein stimulated insulin secretion; a response that was reduced by the presence of isoflavones, whereas the amino acid pattern resembling the plasma concentration of rats fed SP barely stimulated insulin release. Infusion of isoflavones during the hyperglycemic clamps did not stimulate insulin secretion. Therefore, isoflavones as well as the amino acid pattern seen after SP consumption stimulated insulin secretion to a lower extent, decreasing PPARgamma, GLUT-2, and SREBP-1 expression, and ameliorating hyperinsulinemia observed during obesity.

Topics: Amino Acids; Animals; Blood Glucose; Caseins; Cells, Cultured; Dietary Fats; Dietary Proteins; Gene Expression Regulation; Glucagon; Glucose Clamp Technique; Glucose Transporter Type 2; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Isoflavones; Leptin; Obesity; PPAR gamma; Rats; Rats, Sprague-Dawley; Soybean Proteins; Sterol Regulatory Element Binding Protein 1

We sought to determine the prevalence of hyperinsulinemia and insulin resistance in pediatric patients with chronic kidney disease (CKD) stages 2-4. Data were collected on 43 subjects, aged 6-21 years with mean glomerular filtration rate (GFR) = 47 ml/min per 1.73 m(2) body surface area. Patients were grouped by body mass index (BMI) as either non-lean (>85th percentile) or lean (

Topics: Adiponectin; Adolescent; Adult; Body Mass Index; Child; Glomerular Filtration Rate; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Kidney Failure, Chronic; Leptin; Prevalence; Regression Analysis; Tumor Necrosis Factor-alpha

To explore the relationship between serum level of leptin and the components of metabolic syndrome in a group of mid-aged Chinese population.. 345 adults (184 men and 161 women) aged 46 - 53 were enrolled from Fetal Origin of Adult Disease (FOAD) cohort to participate the clinic examination including anthropometry, measurements of blood pressure, fasting and 2 hr plasma levels of glucose and insulin, serum levels of lipid and leptin. HOMA-IR index was calculated to estimate individual insulin resistance. Metabolic syndrome (MS) was diagnosed according to the definition criteria issued by the International Diabetes Federation (IDF) in 2005.. The prevalences of central obesity, higher serum level of triglyceride (TG), lower serum level of high-density lipoprotein (HDL-C), IFG, higher blood pressure and MS were 53.0%, 47.5%, 34.2%, 26.7%, 33.9%, 31.9% in this mid-aged population, respectively. Serum geometric mean level of leptin was higher in females than in males. Serum level of leptin increased with the prevalence of MS and components of abnormal metabolism. The serum level of leptin compared with central obesity, higher blood pressure, higher serum level of triglyceride (TG), lower serum level of high-density lipoprotein cholesterol (HDL-C), IFG and MS was significantly higher respectively (P < 0.05) without HDL-C in males. The serum level of leptin increased with the number of components of abnormal metabolism subjects had (P < 0.001).. The serum level of leptin in this population is significantly associated with MS and components of MS. Hyperleptinemia could be a new component of metabolic syndrome. It might be a target in selection of MS and relative diseases.

Topics: China; Cholesterol, HDL; Cohort Studies; Female; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Middle Aged; Obesity

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

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

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

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

Noninfectious complications of peritoneal dialysis (PD) are increasing in relative importance due to success in decreasing the rate of PD peritonitis. Mechanical catheter complications are emerging as an important cause of technique failure at the same time as experience with PD is declining in North America. There is also increasing interest in metabolic complications of PD and in glucose-sparing strategies to reduce the risk for hyperglycemia, hyperinsulinemia, and hyperleptinemia. This clinical commentary focuses on these noninfectious complications of PD.

Topics: Glucose; Humans; Hyperglycemia; Hyperinsulinism; Leptin; Peritoneal Dialysis; Peritonitis; Renal Dialysis; Renal Insufficiency

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

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

Obesity is typically associated with resistance to leptin, yet the mechanism by which leptin signaling becomes impaired is poorly understood. Here we sought to determine if the development of obesity and leptin resistance correlates with increased expression of protein tyrosine phosphatase 1B (PTP1B) in peripheral tissues and whether over-expression of this phosphatase, specifically in liver, could alter the leptin-mediated effects on feeding and glucose metabolism. Obesity was induced in mice through a high-fat diet that resulted in hyperglycemia, hyperinsulinemia and hyperleptinemia. Resistance to leptin was confirmed as exogenous leptin administration reduced food intake in animals on low-fat, but not high-fat diets. Diet-induced resistance to leptin and insulin was associated with increased hepatic levels of PTP1B. Intriguingly, hepatic adenoviral over-expression of PTP1B in ob/ob mice attenuated the ability of exogenous leptin to reduce both plasma glucose levels and food intake. These findings suggest that leptin reduces both plasma glucose and food intake in part through actions on the liver, and hepatic leptin resistance resulting from over-expression of PTP1B may contribute to the development of both diabetes and obesity.

Topics: Adenoviridae; Animals; Base Sequence; Blood Glucose; CHO Cells; Cricetinae; Dietary Fats; DNA Primers; Feeding Behavior; Genetic Vectors; Hyperglycemia; Hyperinsulinism; Leptin; Liver; Male; Mice; Mice, Inbred BALB C; Polymerase Chain Reaction; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatases

The eight catalytic subunits of the mammalian phosphoinositide-3-OH kinase (PI(3)K) family form the backbone of an evolutionarily conserved signalling pathway; however, the roles of most PI(3)K isoforms in organismal physiology and disease are unknown. To delineate the role of p110alpha, a ubiquitously expressed PI(3)K involved in tyrosine kinase and Ras signalling, here we generated mice carrying a knockin mutation (D933A) that abrogates p110alpha kinase activity. Homozygosity for this kinase-dead p110alpha led to embryonic lethality. Mice heterozygous for this mutation were viable and fertile, but displayed severely blunted signalling via insulin-receptor substrate (IRS) proteins, key mediators of insulin, insulin-like growth factor-1 and leptin action. Defective responsiveness to these hormones led to reduced somatic growth, hyperinsulinaemia, glucose intolerance, hyperphagia and increased adiposity in mice heterozygous for the D933A mutation. This signalling function of p110alpha derives from its highly selective recruitment and activation to IRS signalling complexes compared to p110beta, the other broadly expressed PI(3)K isoform, which did not contribute to IRS-associated PI(3)K activity. p110alpha was the principal IRS-associated PI(3)K in cancer cell lines. These findings demonstrate a critical role for p110alpha in growth factor and metabolic signalling and also suggest an explanation for selective mutation or overexpression of p110alpha in a variety of cancers.

Topics: Adiposity; Animals; Body Weight; Catalytic Domain; Cell Line, Tumor; Class I Phosphatidylinositol 3-Kinases; Eating; Embryo Loss; Enzyme Activation; Glucose; Growth; Heterozygote; Homozygote; Hyperinsulinism; Insulin; Insulin Receptor Substrate Proteins; Leptin; Mice; Mutation; Neoplasms; Phosphatidylinositol 3-Kinases; Phosphoproteins; Receptor, Insulin; Signal Transduction

Obesity and type 2 diabetes are world wide health issues and their incidence is rapidly increasing. Currently the biological factors responsible for the development of obesity are only partially understood. Recent research has shown that maternal nutrition during pregnancy may have long-term metabolic consequences in offspring. In the present study we investigated interactions between prenatal and postnatal nutrition on leptin sensitivity and obesity development. Wistar rats were time-mated and randomly assigned to either ad-libitum (AD) or to 30% of ad-libitum (UN) food intake throughout pregnancy. After weaning, female offspring were fed standard chow, a high-fat diet or a calorie restricted diet. Female offspring of UN dams were growth retarded at birth and showed increased susceptibility to diet-induced obesity on a high-fat diet. At 142 +/- 5 days of age, leptin sensitivity was measured as a response to 14 days of leptin treatment (2.5 microg/g/day, s.c.). In UN offspring fed chow, leptin treatment failed to reduce food intake and weight loss was diminished. This leptin resistance observed in UN offspring was independent of diet-induced obesity and was associated with fasting hyperinsulinemia and hypertriglyceridemia. Our study suggests that prenatal nutrition can shape future susceptibility to obesity through alterations in leptin sensitivity and changes in energy metabolism during adult life.

Topics: Animals; Animals, Newborn; Diet; Dietary Fats; Disease Susceptibility; Eating; Energy Intake; Female; Fetal Growth Retardation; Hyperinsulinism; Hypertriglyceridemia; Injections; Leptin; Nutrition Disorders; Obesity; Pregnancy; Prenatal Nutritional Physiological Phenomena; Rats; Rats, Wistar; Weight Loss

The transcription factor carbohydrate response element-binding protein (ChREBP) mediates insulin-independent, glucose-stimulated gene expression of multiple liver enzymes responsible for converting excess carbohydrate to fatty acids for long-term storage. To investigate ChREBP's role in the development of obesity and obesity-associated metabolic dysregulation, ChREBP-deficient mice were intercrossed with ob/ob mice. As a result of deficient leptin expression, ob/ob mice overeat, become obese and resistant to insulin, and display marked elevations in hepatic lipogenesis, gluconeogenesis, and plasma glucose and triglycerides. mRNA expression of all hepatic lipogenic enzymes was significantly lower in ob/ob-ChREBP-/- than in ob/ob mice, resulting in decreased hepatic fatty acid synthesis and normalization of plasma free fatty acid and triglyceride levels. Overall weight gain in addition to adiposity was reduced in the doubly deficient mice. The former was largely attributable to decreased food intake and may result from decreased hypothalamic expression of the appetite-stimulating neuropeptide agouti-related protein. mRNA expression and activity of gluconeogenic enzymes also was lower in the doubly deficient mice, contributing to significantly lower blood glucose levels. The results of this study suggest that inactivation of ChREBP expression not only reduces fat synthesis and obesity in ob/ob mice but also results in improved glucose tolerance and appetite control.

Topics: Adipose Tissue; Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Blood Glucose; Feedback; Feeding Behavior; Hyperinsulinism; Leptin; Liver; Mice; Mice, Knockout; Nuclear Proteins; Obesity; Transcription Factors

Conjugated linoleic acids (CLAs) are conjugated dienoic isomers of linoleic acid. Many people supplement their diets with CLAs to attempt weight loss, and the trans-10,cis-12 isomer (t10,c12-CLA) of CLA reduces adiposity in animal models and humans. However, CLA treatment in mice causes insulin resistance that has been attributed to the lipoatrophic state, which is associated with hyperinsulinemia and hepatic steatosis. Here, we investigated the effect of t10,c12-CLA on adipose tissue inflammation, another factor promoting insulin resistance. We confirmed that t10,c12-CLA daily gavage performed in mice reduces white adipose tissue (WAT) mass and adiponectin and leptin serum levels and provokes hyperinsulinemia. In parallel, we demonstrated that this CLA isomer led to a rapid induction of inflammatory factors such as tumor necrosis factor-alpha and interleukin-6 gene expression in WAT without affecting their serum levels. In vitro, t10,c12-CLA directly induced IL-6 secretion in 3T3-L1 adipocytes by an nuclear factor-kappaB-dependent mechanism. In vivo, however, the lipoatrophic adipose tissue of CLA-treated mice was notable for a dramatic increase in macrophage infiltration and gene expression. Thus, CLA supplementation directly induces inflammatory gene expression in adipocytes and also promotes macrophage infiltration into adipose tissue to a local inflammatory state that contributes to insulin resistance.

Topics: 3T3-L1 Cells; Adiponectin; Adipose Tissue, White; Animals; Dietary Supplements; Enzyme-Linked Immunosorbent Assay; Female; Hyperinsulinism; Immunohistochemistry; Inflammation; Insulin Resistance; Interleukin-6; Leptin; Linoleic Acids, Conjugated; Macrophages; Mice; Mice, Inbred C57BL; NF-kappa B; PPAR gamma; Resistin; Reverse Transcriptase Polymerase Chain Reaction; Tumor Necrosis Factor-alpha

Diabetes mellitus has reached epidemic proportions in women of Amerindian origin. The risk of developing diabetes has been found to be related to the serum fatty acid composition in whites.. We prospectively investigated the relation between the serum cholesteryl fatty acid composition and changes in fasting plasma glucose concentrations in Peruvian Indian women who are characterized by hyperinsulinemia in comparison to white women.. A 5-y follow-up study of 73 women with normal fasting plasma glucose values was undertaken by performing a survey in 1999 and a follow-up survey in 2004. The studied variables included anthropometric measurements, plasma insulin and leptin, dietary food consumption from 24-h recall, blood pressure, and serum fatty acid composition.. The participants developed significantly higher fasting plasma glucose concentrations in 2004 compared with 1999 (P < 0.0001) with unaltered plasma insulin values. Palmitoleic acid (16:1n-7) in 1999 was the only fatty acid that was significantly correlated to glucose concentration at follow-up. In a multiple regression analysis that included waist circumference, percentage of body fat, systolic blood pressure, and circulating triacylglycerol, insulin, leptin, and 16:1n-7 as independent determinants, 16:1n-7 and systolic blood pressure were the only significant determinants of plasma glucose concentration 5 y later.. A high proportion of 16:1n-7 in serum is an independent predictor of high plasma glucose concentrations in Amerindian women. The reason for this association remains to be elucidated.

Topics: Adipose Tissue; Adult; Blood Glucose; Diabetes Mellitus, Type 2; Fatty Acids, Monounsaturated; Female; Follow-Up Studies; Humans; Hyperinsulinism; Indians, South American; Insulin; Leptin; Middle Aged; Peru; Predictive Value of Tests; Prospective Studies

To identify the effect of IGF-1 and leptin on the hyperinsulinemia (HI) of patients with polycystic ovarian syndrome (PCOS).. The case-control compared method was applied to the study. Ninety-two PCOS and 92 control subjects were involved in the study. The group of PCOS was further divided into two subgroups of 46 PCOS-HI and 46 PCOS-NHI. The leptin, IGF-1 and other hormones such as serum testosterone, DHT, DHEA, DHEA-S were measured by RIA method.. Leptin and IGF-1 were higher in PCOS group (16.8 +/- 9.8 ng/mL, 214.8 +/- 131.6 ng/mL) than those in control group (11.6 +/- 6.8 ng/ mL, 118.0 +/- 82.9 ng/mL respectively, P < 0.05). Serum leptin level was higher in hyperinsulinemia group (9.2 +/- 10.2 ng/mL) than that in normal insulin group (12.5 +/- 7.6 ng/mL, P < 0.05). IGF-1 (208.7 +/- 109.7 ng/mL vs. 151.7 +/- 120.0 ng/mL, P = 0.66) and fasting glucose (5.1 +/- 0.5 mmol/L vs. 4.9 +/- 0.4 mmol/L, P = 0.15) had no significant difference between two groups. Multiple logistic regression showed that after the body mass index (BMI) adjusted, the testosterone, LH/FSH, DHT, DHEA, and DHEA-S, leptin and IGF-1 showed to be the independent risk factor for PCOS, but not to be for hyperinsulinemia in patients with PCOS.. The leptin and IGF-1 may contribute to the pathogenesis of PCOS, but the relationship between leptin, IGF-1 and hyperinsulinemia needs more researches to confirm.

Topics: Adult; Case-Control Studies; Female; Glucose; Humans; Hyperinsulinism; Insulin-Like Growth Factor I; Leptin; Logistic Models; Polycystic Ovary Syndrome; Risk Factors

The protein p27(Kip1) regulates cell cycle progression in mammals by inhibiting the activity of cyclin-dependent kinases (CDKs). Here we show that p27(Kip1) progressively accumulates in the nucleus of pancreatic beta cells in mice that lack either insulin receptor substrate 2 (Irs2(-/-)) or the long form of the leptin receptor (Lepr(-/-) or db/db). Deletion of the gene encoding p27(Kip1) (Cdkn1b) ameliorated hyperglycemia in these animal models of type 2 diabetes mellitus by increasing islet mass and maintaining compensatory hyperinsulinemia, effects that were attributable predominantly to stimulation of pancreatic beta-cell proliferation. Thus, p27(Kip1) contributes to beta-cell failure during the development of type 2 diabetes in Irs2(-/-) and Lepr(-/-) mice and represents a potential new target for the treatment of this condition.

Topics: Animals; Cell Cycle Proteins; Cell Nucleus; Cyclin-Dependent Kinase Inhibitor p27; Diabetes Mellitus, Type 2; Disease Models, Animal; Enzyme Inhibitors; Hyperglycemia; Hyperinsulinism; Insulin Receptor Substrate Proteins; Insulin-Like Growth Factor I; Intracellular Signaling Peptides and Proteins; Islets of Langerhans; Leptin; Mice; Mice, Knockout; Phosphoproteins; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Receptors, Cell Surface; Receptors, Leptin; Signal Transduction; Tumor Suppressor Proteins

Most patients at risk for developing type 2 diabetes are hyperinsulinemic. Hyperinsulinemia may be a response to insulin resistance, but another possible abnormality is insulin hypersecretion. BTBR mice are insulin resistant and hyperinsulinemic. When the leptin(ob) mutation is introgressed into BTBR mice, they develop severe diabetes. We compared the responsiveness of lean B6 and BTBR mouse islets to various insulin secretagogues. The transamination product of leucine, alpha-ketoisocaproate (KIC), elicited a dramatic insulin secretory response in BTBR islets. The KIC response was blocked by methyl-leucine or aminooxyacetate, inhibitors of branched-chain amino transferase. When dimethylglutamate was combined with KIC, the fractional insulin secretion was identical in islets from both mouse strains, predicting that the amine donor is rate-limiting for KIC-induced insulin secretion. Consistent with this prediction, glutamate levels were higher in BTBR than in B6 islets. The transamination product of glutamate, alpha-ketoglutarate, elicited insulin secretion equally from B6 and BTBR islets. Thus formation of alpha-ketoglutarate is a requisite step in the response of mouse islets to KIC. alpha-Ketoglutarate can be oxidized to succinate. However, succinate does not stimulate insulin secretion in mouse islets. Our data suggest that alpha-ketoglutarate may directly stimulate insulin secretion and that increased formation of alpha-ketoglutarate leads to hyperinsulinemia.

Topics: Animals; Cells, Cultured; Diabetes Mellitus, Type 2; Disease Models, Animal; Glutamate Dehydrogenase; Glutamic Acid; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Keto Acids; Ketoglutaric Acids; Leptin; Mice; Mice, Inbred C57BL; Mice, Transgenic; Species Specificity; Transaminases

Elevated plasma leptin levels have been demonstrated in obesity and hypertension. These conditions are documented as insulin-resistant states with sympathetic overactivity. However, the relation between plasma insulin, leptin levels, and sympathetic nerve activity, especially after meals, has not been established.. To evaluate the impact of insulin sensitivity and obesity on the response of plasma leptin to acute physiologic insulin elevation, we studied 31 nonobese (body mass index [BMI] < 25 kg/m(2)) and 38 overweight or obese (obese; BMI >/= 25 kg/m(2)) normotensive men. Using the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), the subjects were subdivided into insulin-sensitive (HOMA-IR <2.5) and insulin-resistant (HOMA-IR >/=2.5) groups. There were 11 nonobese and 28 obese men who were insulin-resistant. Blood pressure (BP), plasma glucose, insulin, leptin, and norepinephrine (NE) levels were measured before and after 75-g oral glucose loading every 30 min for 120 min.. In nonobese subjects, fasting plasma insulin and leptin levels and areas-under-the-curves (AUC) for insulin and leptin were significantly lower in the insulin-sensitive group than in the insulin-resistant group. In the insulin-sensitive group regardless of BMI, plasma leptin levels decreased after glucose loading. Plasma glucose, insulin, NE, and BP levels increased in nonobese insulin-sensitive subjects after glucose loading, whereas in obese insulin-sensitive subjects, plasma NE and BP did not change in response to glucose. In insulin-resistant subjects regardless of BMI, marked elevations in plasma insulin did not cause any change in plasma leptin, NE, and BP levels.. These results demonstrate that insulin sensitivity and adiposity affect the response of leptin and sympathetic nerve activity to acute postprandial hyperinsulinemia.

Topics: Acute Disease; Adult; Area Under Curve; Asian People; Blood Pressure; Body Mass Index; Case-Control Studies; Fasting; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Leptin; Male; Norepinephrine; Obesity

Some novel antipsychotics, including olanzapine, induce weight gain and metabolic abnormalities, which represent the major adverse effects of these drugs. However, the mechanism(s) involved in such effects are unclear.. The aim of this study was to develop, in female rats, a parametric model of olanzapine-induced weight gain and metabolic abnormalities and evaluate it against clinical findings.. Female rats were administered olanzapine b.i.d. at doses of 0, 1, 2 and 4 mg/kg over 20 days, and a wide range of variables were recorded during and after drug administration.. Olanzapine increased both 24 h and total food intake. This was associated with rapid onset weight gain and increased adiposity (assessed by visceral fat pad masses). Insulin, but not glucose, concentrations were elevated, with a significant increase in the HOMA-IR index, indicative of insulin resistance. A nonsignificant trend towards higher levels of leptin was observed. Paradoxically, there was a significant increase in adiponectin. All of these variables showed maximal increases at either 1 or 2 mg/kg and attenuated effects at 4 mg/kg. Prolactin levels were also increased by olanzapine. However, for this variable, there was a clear dose-response curve, with the maximal effect at the highest dose (4 mg/kg).. These data suggest that aspects of olanzapine-induced weight gain and metabolic abnormalities can possibly be modelled in female rats. It is suggested that olanzapine-induced hyperphagia acts as an initial stimulus which leads to weight gain, enhanced visceral adiposity and subsequent insulin resistance, although the latter may be ameliorated by compensatory responses in adiponectin levels. Prolactin elevation appears likely not to be involved in the weight gain, adiposity and metabolic changes seen in this model.

Topics: Adipose Tissue; Animals; Antipsychotic Agents; Benzodiazepines; Dose-Response Relationship, Drug; Drinking; Eating; Estradiol; Female; Homeostasis; Hyperinsulinism; Insulin Resistance; Leptin; Metabolic Diseases; Olanzapine; Prolactin; Rats; Rats, Wistar; Statistics as Topic; Weight Gain

To gain further insight into the regulatory role of insulin and leptin on plasma ghrelin, 56 normal weight, 128 normoinsulinemic obese, 121 hyperinsulinemic obese, and 30 type 2 diabetic normoinsulinemic and 75 type 2 diabetic hyperinsulinemic obese patients were examined. In the obese subjects, basal hyperinsulinemia was associated with significantly lower ghrelin independent of BMI, age, and leptin. In normoinsulinemic (normal weight and normoinsulinemic obese) subjects, ghrelin was inversely related to stepwise increasing leptin. Multiple regression analysis and matching for insulin revealed a significant negative interaction of ghrelin with leptin but not insulin. In type 2 diabetic normoinsulinemic subjects, ghrelin was significantly lower compared with that in normoinsulinemic obese subjects. In type 2 diabetic hyperinsulinemic subjects, ghrelin was significantly lower than in normoinsulinemic subjects, whereas no further reduction was observed compared with hyperinsulinemic obese subjects. The postprandial decrease was significantly attenuated in normoinsulinemic obese and hyperinsulinemic obese subjects (-214.8 +/- 247 pg/ml [normal weight], -137.6 +/- 107 pg/ml [normoinsulinemic obese], -85.5 +/- 69 pg/ml [hyperinsulinemic obese], P < 0.001; mean +/- SD), whereas type 2 diabetes had no independent postprandial effect. In conclusion, the present data support the concept that leptin could be of importance for suppression of basal ghrelin during moderate weight gain in normoinsulinemic subjects, whereas hyperinsulinemia but not leptin is responsible in more severe obesity. Postprandial suppression of ghrelin is attenuated by as yet unknown mechanisms that are related to body weight but not to insulin or type 2 diabetes.

Topics: Body Mass Index; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Female; Humans; Hyperinsulinism; Insulin; Leptin; Male; Obesity; Postprandial Period; Reference Values; Sex Characteristics

The authors recently reported that gastrin gene knockout (GAS-KO) mice had an increased risk for colon carcinogenesis in response to azoxymethane (AOM) compared with their wild type (WT) littermates. In the current report, the authors discuss the predisposition of GAS-KO mice to develop obesity and metabolic hormonal changes that may contribute to their increased risk of colon carcinogenesis.. The weight and deposition of fat was monitored in the mice over a 14 month period, using magnetic resonance imaging and nuclear magnetic resonance techniques. Changes in plasma concentrations of ghrelin, leptin, insulin, and glucose were assessed using radioimmunoassay analysis and enzyme-linked immunosorbent assays. Preneoplastic markers of colon carcinogenesis (aberrant crypt foci [ACFs]), in response to AOM, were measured in a subset of obese versus lean GAS-KO mice and were compared with the markers in WT mice.. Increases in visceral adiposity were evident by age 2 months in GAS-KO mice, resulting in macroscopic obesity by age 7 months. Hyperinsulinemia and insulin:glucose ratios were increased significantly in GAS-KO mice as young as 1 month and preceded alterations in nonfasting leptin and ghrelin levels. The number of ACFs per mouse colon were increased significantly in the following order: obese GAS-KO mice > lean GAS-KO mice > WT mice. Fasting plasma insulin levels were 0.88 +/- 0.1 ng/mL, 1.45 +/- 0.3, and 2.76 +/- 0.9 ng/mL in the WT, GAS-KO lean, and GAS-KO obese mice, respectively.. The current results suggest the novel possibility that loss of amidated gastrins may increase adipogenesis, hyperinsulinemia, and colon carcinogenesis in GAS-KO mice. The increase in colon carcinogenesis may be due in part to hyperinsulinemia, increased obesity, and other associated hormone changes that were measured in GAS-KO mice.

Topics: Animals; Azoxymethane; Body Weight; Carcinogens; Colonic Neoplasms; Gastrins; Gene Expression; Ghrelin; Glucose; Hyperinsulinism; Insulin; Insulin Resistance; Leptin; Magnetic Resonance Imaging; Male; Mice; Mice, Knockout; Obesity; Peptide Hormones; Precancerous Conditions; Radioimmunoassay; Thinness

Dietary supplementation with conjugated linoleic acids (CLA) has a fat-reducing effect in various species, but induces severe hyperinsulinaemia and hepatic steatosis in the mouse. This study aimed to determine the causes of the deleterious effects of CLA on insulin homeostasis.. The chronology of adipose and liver weight, hepatic triglyceride accumulation and selected blood parameters, including lipids, insulin, leptin and adiponectin, was determined in C57BL/6J female mice fed a 1% isomeric mixture of CLA for various periods of time ranging from 2 to 28 days. Insulin secretion was measured in 1-h static incubations of pancreatic islets, and pancreas morphometric parameters were determined in mice fed CLA for 28 days.. Plasma levels of leptin and adiponectin sharply decreased after 2 days of CLA feeding, although adipose tissue mass only decreased after day 6. Hyperinsulinaemia developed at day 6 and consistently worsened up to day 28, in parallel with increases in hepatic lipid content. Islets from CLA-fed mice displayed three- to four-fold increased rates of glucose-stimulated insulin secretion, both in the absence and presence of isobutyl methylxanthine or carbachol. The increased insulin-releasing capacity of islets from CLA-fed mice was explained by an increase in beta cell mass and number.. The data suggest that CLA supplementation induces a profound reduction of leptinaemia and adiponectinaemia, followed by hyperinsulinaemia due to the increased secretory capacity of pancreatic islets, leading, in turn, to liver steatosis. These observations cast doubt on the safety of dietary supplements containing CLA.

Topics: Adiponectin; Adipose Tissue; Animals; Body Weight; Disease Models, Animal; Female; Hyperinsulinism; Hyperplasia; Insulin; Insulin Secretion; Intercellular Signaling Peptides and Proteins; Islets of Langerhans; Leptin; Linoleic Acids, Conjugated; Liver; Mice; Mice, Inbred C57BL; Organ Size; Triglycerides

The TallyHo (TH) mouse strain is a polygenic model for Type 2 diabetes with obesity. Genetic analysis in backcross progeny from a cross between F1 [C57BL/6J (B6) x TH] and TH mice mapped a quantitative trait locus (QTL) named TH-associated body weight 2 (tabw2) to chromosome 6. The TH-derived allele is associated with increased body weight. As a first step to identify the molecular basis of this obesity QTL, we constructed a congenic line of mice on the B6 genetic background that carries a genomic region from TH mice containing tabw2. Congenic mice homozygous for tabw2 (B6.TH-tabw2/tabw2) fed a chow diet exhibited slightly, but significantly, higher body weight and body fat and plasma leptin levels compared with controls (B6.TH-+/+). This difference was exacerbated when the animals were maintained on a high-fat and high-sucrose (HFS) diet. The diet-induced obesity in tabw2 congenic mice is accompanied by hyperleptinemia, mild hyperinsulinemia, impaired glucose tolerance, and reduced glucose uptake in adipose tissue in response to insulin administration. Using F2 progeny fed a HFS diet from an intercross of B6.TH-tabw2/+ mice, we were able to refine the map position of the tabw2 obesity susceptibility locus to a 15-cM region (95% confidence interval) extending distally from the marker D6Mit102. In summary, tabw2 congenic mice are a new animal model for diet-induced obesity that will be valuable for the study of gene-diet interactions.

Topics: Alleles; Animals; Body Weight; Chromosomes, Mammalian; Crosses, Genetic; Diabetes Mellitus, Type 2; Diet; Disease Models, Animal; Female; Genetic Predisposition to Disease; Genotype; Glucose; Glucose Tolerance Test; Hyperinsulinism; Leptin; Lod Score; Male; Mice; Mice, Congenic; Obesity; Physical Chromosome Mapping

Leptin has metabolic effects on peripheral tissues including muscle, liver, and pancreas, and it has been successfully used to treat lipodystrophic diabetes, a leptin-deficient state. To study whether leptin therapy can be used for treatment of more common cases of type 2 diabetes, we used a mouse model of type 2 diabetes (MKR mice) that show normal leptin levels and are diabetic due to a primary defect in both IGF-I and insulin receptors signaling in skeletal muscle. Here we show that leptin administration to the MKR mice resulted in improvement of diabetes, an effect that was independent of the reduced food intake. The main effect of leptin therapy was enhanced hepatic insulin responsiveness possibly through decreasing gluconeogenesis. In addition, the reduction of lipid stores in liver and muscle induced by enhancing fatty acid oxidation and inhibiting lipogenesis led to an improvement of the lipotoxic condition. Our data suggest that leptin could be a potent antidiabetic drug in cases of type 2 diabetes that are not leptin resistant.

Topics: Adipose Tissue; AMP-Activated Protein Kinases; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Disease Models, Animal; Eating; Energy Metabolism; Hyperglycemia; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Leptin; Liver; Male; Mice; Mice, Inbred Strains; Mice, Mutant Strains; Multienzyme Complexes; Muscle, Skeletal; Protein Serine-Threonine Kinases; Triglycerides

Nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency (NC-CAH) is associated with hyperandrogenemia, chronic anovulation, hirsutism, acne and adrenal hyperplasia. A few studies have shown hyperinsulinemia and insulin insensitivity in NC-CAH. Hyperinsulinemia can stimulate leptin secretion, and androgens can inhibit leptin secretion. Thus, we designed a study to investigate the insulin levels and insulin sensitivity and the effect of chronic endogenous hyperinsulinemia and androgens on leptin in patients with NC-CAH.. Eighteen women with untreated NC-CAH and 26 normally cycling control women with a similar body mass index (BMI) were studied. Basal hormones, fasted and fed insulin levels, leptin and stimulated 17-hydroxyprogesterone (17-OHP) concentrations were studied. Homeostasis model assessment was used to assess insulin sensitivity.. The basal 17-OHP, the free testosterone (fT) and dehydroepiandrosterone sulfate (DHEA-S) were significantly different in the 2 groups (p < 0.05). Fasting and fed insulin levels of the NC-CAH group were higher than those of the control group (p < 0.05) and insulin sensitivity was lower in NC-CAH than in controls (p < 0.05). Insulin levels were correlated with fT and 17-OHP (p < 0.05). Serum leptin levels for NC-CAH (25.9 +/- 12.5 microg/l) did not differ from the controls (25.4 +/- 12.06 microg/l) and were positively correlated with BMI (r = 0.725) and percent body fat (r = 0.710) for both groups (both p < 0.001). Leptin levels were not correlated with estrogen or androgens, gonadotropins or insulin levels.. Hyperinsulinemia and insulin insensitivity associated with hyperandrogenism were detected in untreated NC-CAH patients as in previous reports, whereas serum leptin levels did not differ from those of controls.

Topics: Adrenal Hyperplasia, Congenital; Adrenocorticotropic Hormone; Adult; Blood Glucose; Dehydroepiandrosterone Sulfate; Estradiol; Female; Follicle Stimulating Hormone; Humans; Hydrocortisone; Hyperinsulinism; Insulin Resistance; Leptin; Luteinizing Hormone; Prolactin; Statistics, Nonparametric; Steroid 21-Hydroxylase; Testosterone

Ovarian enlargement is a constant feature of syndromes of extreme insulin resistance. The objective of this study is to show the role of insulin on ovarian growth in the presence of low gonadotropin levels.. Seven young patients with syndromes of extreme insulin resistance (five with lipodystrophy, one with Type B syndrome and one with Rabson-Mendenhall syndrome) were studied.. Baseline LH concentrations and luteinizing hormone releasing hormone (LHRH) tests were performed. Total testosterone, insulin and C-peptide values were measured. Pelvic ultrasounds were performed.. Four patients were prepubertal (age range 7-10 years old) and had prepubertal gonadotropin levels, and 2 of the 4 who were tested did not respond to LHRH (NIH 10 and RM-PAL). Three patients were Tanner stage 4 (age range 13-17 years old) and had low gonadotropins that did not respond to LHRH stimulation test. All seven patients had marked hyperinsulinaemia and 6 of 7 had at least one enlarged ovary. Testosterone values were increased in 4 of 7 patients.. This represents the first example of the pathologic role of insulin to stimulate ovarian growth with low circulating gonadotropins. Thus, while ovarian growth and steroidogenesis are normally stimulated by gonadotropins at puberty, hyperinsulinaemia stimulates pathologic growth of the ovary and an androgenic steroid profile that is active at all ages. We suggest that these patients constitute a model to separate the effect of insulin from gonadotropin in stimulating ovarian growth and/or steroidogenesis.

Topics: Adolescent; C-Peptide; Child; Female; Gonadotropin-Releasing Hormone; Gonadotropins; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Leptin; Lipodystrophy; Luteinizing Hormone; Ovary; Puberty; Testosterone; Ultrasonography

The present study sought to assess the combined effects of body composition and diet (level of feeding) on the postfertilization developmental potential of oocytes recovered from heifers using ultrasound-guided transvaginal follicular aspiration and to relate oocyte quality to the metabolic status of these animals. By collecting oocytes on repeated occasions spanning several weeks, it was possible to assess the cumulative effects of changes in nutritional status on oocyte quality over this period. Twenty-four heifers of low and moderate body condition were placed on one of two levels of feeding (equivalent to once or twice the maintenance requirements of these animals). Oocytes were recovered at two defined time points within each of three successive estrous cycles and were matured, fertilized, and cultured to the blastocyst stage in vitro. The results show that the effect of feeding level on oocyte quality is dependent on the body condition of the animal, with the high level of feeding being beneficial to oocytes from animals of low body condition but detrimental to oocytes from animals of moderately high body condition. Furthermore, the effects of high levels of feeding on oocyte quality were cumulative, with blastocyst yields for relatively fat heifers on twice the maintenance requirement deteriorating with time relative to yields for relatively thin heifers on the same level of feeding. Finally, a significant proportion of the moderately fat animals on the high level of feeding were hyperinsulinemic, and we show, to our knowledge for the first time in ruminants, that this condition is associated with impaired oocyte quality.

Topics: Animal Nutritional Physiological Phenomena; Animals; Blastocyst; Body Composition; Body Weight; Cattle; Cattle Diseases; Diet; Female; Fertilization in Vitro; Glucose Tolerance Test; Hyperinsulinism; Insulin; Insulin-Like Growth Factor I; Leptin; Oocytes; Ovarian Follicle

The purpose of this study was to test whether the melanocortin-4 receptor (MC4R) is critical in the development of hypertension associated with obesity and its metabolic disorders. MC4R-deficient homozygous (-/-) and heterozygous (+/-) and wild-type (WT) C57BL/6J mice 17 to 19 weeks old (n=5 to 7 per group) were implanted with telemetry devices for monitoring 24-hour mean arterial pressure (MAP) and heart rate (HR). After 3-day stable control measurements on normal-salt diet (NSD; 0.4% NaCl), mice received a high-salt diet (HSD; 4% NaCl) for 7 days, followed by 3-day recovery on NSD. MC4R (-/-) mice were severely obese compared with MC4R (+/-) and WT mice (body weight 48+/-1.5 versus 31+/-0.6 and 30+/-0.5 g respectively). On NSD, MAP was similar in all groups of mice (MC4R (-/-) 110+/-3 mm Hg; MC4R (+/-) 109+/-2 mm Hg; WT 114+/-2 mm Hg), and HR in MC4R (-/-) was lower than in WT (604+/-5 versus 645+/-9 bpm; P<0.05) but not different from MC4R (+/-) (625+/-13 bpm) mice. HSD did not significantly alter MAP or HR in any of the groups. Epididymal and retroperitoneal fat weights and plasma leptin levels were several-fold greater in MC4R (-/-) compared with MC4R (+/-) and WT mice. Plasma insulin and glucose levels were also significantly greater in MC4R (-/-) than in MC4R (+/-) and WT mice. These data suggest that despite obesity, visceral adiposity, hyperleptinemia, and hyperinsulinemia, MC4R (-/-) mice are neither hypertensive nor salt sensitive, indicating that a functional MC4R may be necessary for the development of hypertension associated with obesity and its metabolic abnormalities.

Topics: Adipose Tissue; Animals; Blood Pressure; Body Size; Dose-Response Relationship, Drug; Drinking; Eating; Heart Rate; Hormones; Hyperinsulinism; Hypertension; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Receptor, Melanocortin, Type 4; Sodium Chloride; Sodium Chloride, Dietary; Viscera; Weight Gain

To correlate serum leptin and insulin levels, and the glucosic profile of 21 patients shared in diabetics and non diabetics with Congenital Generalized Lipodystrophy (CGL).. In a prospective study, were dosed serum leptin level with radioimmunoassay technique, fasting plasma glucose through of the glucoseoxidase-peroxidase reaction, the hemoglobin glycate using the technique microchromatography for ionic exchange resin and insulin through immunoassay system. The fructosamine concentration serum was determinated for reduction nitroblue tetrazolium method. The Student's test was used to compare results between the groups and the correlation "r" coefficient to analise the relation among the several variants studied, with significant level of 5% (p < 0.05). All the statistical procedures were performed using the Excel by Microsoft and the Statistic program for Windows by StatSoft, Inc. version 5.1 edition 97.. Leptin decreased on the most patients, showing no statistically significant difference between the groups. Also there wasn't difference statistically significant (p = 0.9542) of the insulin's value between diabetics and non diabetics.. The hyperinsulinism and the hypoleptinemia occurred independently of diabetes in the CGL's patients and this can be due to the natural history of disease, in which the raise insulin levels precede the initial diabetes mellitus and the low leptin levels were related to the lipoatrophy.

Topics: Adipose Tissue; Adolescent; Adult; Blood Glucose; Body Mass Index; Child; Child, Preschool; Consanguinity; Diabetes Mellitus, Lipoatrophic; Female; Fructosamine; Glycated Hemoglobin; Humans; Hyperinsulinism; Insulin Resistance; Leptin; Lipodystrophy, Congenital Generalized; Male; Prospective Studies

Mutations in the melanocortin-4 receptor (MC4R) are associated with obesity. The obesity syndrome observed in humans with MC4R haploinsufficiency is similar to that observed in MC4R knockout mice, including increased longitudinal growth, hyperphagia, and fasting hyperinsulinemia. For comparison with other commonly investigated models of obesity and insulin resistance, we have backcrossed Mc4r-/- mice into the C57BL/6J (B6) background. Female obese Mc4r-/- mice exhibit reduced energy expenditure and an attenuated increase in fatty acid (FA) oxidation after exposure to high-fat diets compared with obese Lepob/Lepob mice. The reduced energy expenditure and FA oxidation correlates with changes in hepatic gene expression. The expression of genes involved in FA oxidation increased in obese Lepob/Lepob mice compared with wild-type and obese Mc4r-/- mice. In contrast, a key lipogenic enzyme, FA synthase (FAS), is increased in obese Mc4r-/- mice compared with obese Lepob/Lepob mice. Hyperinsulinemia, increased FAS mRNA expression and hepatic steatosis appear to be secondary to obesity in B6 Mc4r-/- mice. However, Mc4r-/- mice in a mixed genetic background develop severe hepatic steatosis at an early age. This might suggest an important role of the MC4R in regulating liver FA metabolism that is masked on the B6 background. Interestingly, the 10- to 20-fold increase in liver triglyceride in the outbred strain of Mc4r-/- mice is not always associated with fasting hyperinsulinemia or increased FAS mRNA expression. This observation suggests that changes in liver secondary to triglyceride accumulation lead to hyperinsulinemia and increased hepatic FAS expression in Mc4r-/- mice.

Topics: Animals; Body Weight; Dietary Fats; Eating; Fatty Acid Synthases; Fatty Acids; Fatty Liver; Female; Gene Expression; Hyperinsulinism; Insulin; Insulin Receptor Substrate Proteins; Intracellular Signaling Peptides and Proteins; Leptin; Lipids; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Oxidation-Reduction; Phosphoproteins; Receptor, Melanocortin, Type 4; Triglycerides

To assess the role of the alpha1b-adrenergic receptor (AR) in glucose homeostasis, we investigated glucose metabolism in knockout mice deficient of this receptor subtype (alpha1b-AR-/-). Mutant mice had normal blood glucose and insulin levels, but elevated leptin concentrations in the fed state. During the transition to fasting, glucose and insulin blood concentrations remained markedly elevated for at least 6 h and returned to control levels after 24 h whereas leptin levels remained high at all times. Hyperinsulinemia in the post-absorptive phase was normalized by atropine or methylatropine indicating an elevated parasympathetic activity on the pancreatic beta cells, which was associated with increased levels of hypothalamic NPY mRNA. Euglycemic clamps at both low and high insulin infusion rates revealed whole body insulin resistance with reduced muscle glycogen synthesis and impaired suppression of endogenous glucose production at the low insulin infusion rate. The liver glycogen stores were 2-fold higher in the fed state in the alpha1b-AR-/- compared with control mice, but were mobilized at the same rate during the fed to fast transition or following glucagon injections. Finally, high fat feeding for one month increased glucose intolerance and body weight in the alpha1b-AR-/-, but not in control mice. Altogether, our results indicate that in the absence of the alpha1b-AR the expression of hypotalamic NPY and the parasympathetic nervous activity are both increased resulting in hyperinsulinemia and insulin resistance as well as favoring obesity and glucose intolerance development during high fat feeding.

Topics: Animals; Blood Glucose; Body Weight; Glucagon; Glucose; Glycogen; Homeostasis; Hyperinsulinism; Insulin Resistance; Leptin; Liver; Male; Mice; Mice, Mutant Strains; Mice, Obese; Receptors, Adrenergic; Receptors, Adrenergic, alpha-1; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors

The effects of diet and adiposity have been implicated in disturbances of female reproductive function. In an effort to better elucidate the relationship between obesity and female fertility, we analyzed the effect of increasing dietary fat content on body composition, insulin sensitivity, and pregnancy rates in two common inbred mouse strains, DBA/2J and C57BL/6J. After 16 wk, females of both strains on the high fat diet developed glucose intolerance and insulin resistance, but only the female DBA/2J mice developed dietary-induced obesity and hyperleptinemia. The high fat diet was associated with more than a 60% decrease in natural pregnancy rates of female DBA/2J mice, whereas the fertility of female C57BL/6J mice was unaffected. Despite developing a similar degree of obesity, insulin resistance, and hyperleptinemia, male DBA/2J mice did not manifest diminished fertility. Obese female DBA/2J mice achieved normal ovulatory responses and pregnancy rates after exogenous gonadotropin stimulation, suggesting their fertility defect to be central in origin. Real-time PCR quantification of hypothalamic cDNA revealed a 100% up-regulation of neuropeptide Y and a 50% suppression of GnRH expression accompanied by a 95% attenuation of leptin receptor type B expression in obese female DBA/2J mice. These findings suggest that obesity-associated hyperleptinemia, and not insulin resistance or increased dietary fat per se, gradually induces central leptin resistance, increases hypothalamic neuropeptide Y-ergic tone, and ultimately causes hypothalamic hypogonadism. The data establish high fat-fed female DBA/2J mice as a wild-type murine model of obesity-related infertility.

Topics: Animals; Body Composition; Dietary Fats; Female; Gene Expression; Hyperinsulinism; Hypothalamus; Infertility, Female; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Neuropeptide Y; Obesity; Pregnancy; Receptors, Cell Surface; Receptors, Leptin; Repressor Proteins; Species Specificity; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Transcription Factors

Epidemiological studies have shown that obesity and diabetes mellitus may be risk factors for colon cancer. However, the underlying mechanisms of how these chronic diseases promote colon carcinogenesis remain unknown. C57BL/KsJ-db/db mice have obese and diabetic phenotypes because of disruption of the leptin receptor. The present study was designed to investigate whether development of azoxymethane (AOM)-induced dysplastic and early neoplastic (premalignant) lesions of the colon is modulated in db/db mice. Homozygous db/db mice, heterozygous db/+ mice and littermate controls (+/+) were injected with AOM under food restriction ( approximately 10.8 kcal/mouse/day) and killed 5 weeks after the carcinogen treatment. Their colons were assessed for premalignant lesions induced by AOM. We found a significant increase in the multiplicity of the total premalignant lesions in db/db mice when compared with db/+ or +/+ mice. Phenotypically, serum leptin and insulin levels in db/db mice were significantly higher than those in db/+ or +/+ mice, whereas the body weights and glucose levels in blood of db/db, db/+ and +/+ mice were comparable. In addition, immunostaining of the leptin receptor and insulin-like growth factor-I receptor showed up-regulation of these protein levels specifically in the lesions. Our data indicate that development of AOM-induced premalignant lesions is enhanced in db/db mice with hyperleptinemia and hyperinsulinemia. The results have important implications for further exploration of the possible underlying events that affect the positive association between colon cancer and chronic diseases (obesity and diabetes).

Topics: Animals; Azoxymethane; Blood Glucose; Body Weight; Carcinogens; Colonic Neoplasms; Diabetes Mellitus, Experimental; Heterozygote; Homozygote; Hyperinsulinism; Immunoblotting; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Precancerous Conditions; Receptor, IGF Type 1; Receptors, Cell Surface; Receptors, Leptin

Sterol regulatory element binding protein-1c (SREBP-1c), a transcription factor that is important for mediating insulin effects on metabolic gene expression in liver during the fasted-to-fed transition, is also expressed in skeletal muscle. However, the regulation and role of SREBP-1c in skeletal muscle are poorly understood. The present study compared the effects of nutritional status, physiological hyperinsulinemic clamps, and adenovirus-mediated hyperleptinemia (HLEP) in rats on expression of SREBP-1c and other metabolic genes in skeletal muscle. Three- and 6-h refeeding of 18-h-fasted animals increased levels of SREBP-1c mRNA and the SREBP-1 protein (full length and mature) in gastrocnemius muscle (P < 0.05). Fatty acid synthase (FAS) and hexokinase II (HKII) mRNA levels were also increased by refeeding, and uncoupling protein 3 (UCP3) mRNA level was decreased (all P < 0.05). Surprisingly, 3-h hyperinsulinemic clamps did not increase gastrocnemius muscle SREBP-1c and FAS mRNA levels or SREBP-1 protein levels but did increase HKII mRNA levels and decrease UCP3 mRNA levels (P < 0.05). HLEP reduced refeeding-induced increases of SREBP-1c and FAS mRNA levels but did not reduce the level of SREBP-1 protein. We conclude that 1) skeletal muscle SREBP-1c gene expression is regulated by nutritional status in a fashion similar to that observed in liver and adipose tissue, 2) physiological hyperinsulinemia is not sufficient to imitate the effects of refeeding on SREBP-1c gene expression, and 3) leptin suppresses refeeding effects on SREBP-1c mRNA levels.

Topics: Animals; Blood Glucose; Blotting, Northern; Body Weight; CCAAT-Enhancer-Binding Proteins; DNA Primers; DNA-Binding Proteins; Eating; Gene Expression Regulation; Glucose Clamp Technique; Hyperinsulinism; Insulin; Leptin; Liver; Male; Muscle, Skeletal; Nutritional Status; Rats; Rats, Wistar; RNA, Messenger; Sterol Regulatory Element Binding Protein 1; Transcription Factors

Chronic attenuation of hyperinsulinemia by diazoxide (DZ), a K-adenosine triphosphate (ATP) channel opener and an inhibitor of glucose-mediated insulin secretion, improved glucose tolerance and lipid profile and decreased the rate of weight gain in obese Zucker rats. To determine whether suppression of hyperinsulinemia alters daily food consumption, rate of weight gain, glucose tolerance, and lipid profile, we compared the effects of NN414, a potent and SUR1/Kir6.2 selective K(atp)() channel opener, with DZ in obese and lean Zucker rats. DZ (150 mg/kg/d), low-dose (LDNN414: 10 mg/kg/d), high-dose (HDNN414: 30 mg/kg/d), and vehicle (C) were administered to 7-week-old obese and lean female Zucker rats for a period of 6 weeks. Each animal underwent an intraperitoneal glucose tolerance test (IPGTT) at the end of study period. While NN414 treatment did not affect food intake and rate of weight gain in any of the strains, DZ treatment reduced food intake (P <.001) and rate of weight gain (P <.001) in obese rats. The fasting plasma insulin levels and area under the curve (AUC) insulin response to IPGTT were significantly attenuated in LDNN414 (P <.05), HDNN414 (P <.01), and DZ (P <.01) obese and lean rats compared with their controls. This was accompanied by a significant reduction in AUC glucose only in LDNN414 (P <.05), HDNN414 (P <.01), and DZ (P <.01) obese rats compared with controls. While hemoglobin A(1c) (HbA(1c)) was not affected in LDNN414 obese rats, it was higher in HDNN414 obese animals (P <.001), LD-, HDNN414 (P <.001), and DZ (P <.005) lean rats compared with their respective controls. DZ obese rats showed lower HbA(1c) levels than C obese rats (P <.02). The plasma free fatty acid (FFA) levels were only decreased in HDNN414 (P <.05) and DZ (P <.002) obese rats, whereas plasma triglyceride (TG) levels were decreased in LDNN414 (P <.05), HDNN414 (P <.001), and DZ (P <.001) obese rats compared with controls. Finally, plasma leptin level was only decreased in DZ obese rats compared with controls (P <.001). The new SUR1/Kir6.2 selective K(atp)() channel opener, NN414, reduced hyperinsulinemia in a dose-dependent manner without a significant effect on food consumption and rate of weight gain. NN414-induced beta-cell rest in obese rats was associated with a significant improvement in glucose responsiveness, suggesting an increase in insulin sensitivity after its withdrawal. There was an overall deterioration in glycemic control at the high dose as measur

Topics: Animals; Area Under Curve; Blood Glucose; Bridged Bicyclo Compounds, Heterocyclic; Cyclic S-Oxides; Eating; Fatty Acids, Nonesterified; Female; Glucose Tolerance Test; Glycated Hemoglobin; Hyperinsulinism; Hypoglycemic Agents; Insulin; Islets of Langerhans; Leptin; Potassium Channels, Inwardly Rectifying; Rats; Rats, Zucker; Triglycerides; Weight Gain

Topics: Cell Membrane; Coronary Restenosis; Erythrocytes; Humans; Hyperinsulinism; Leptin; Nitric Oxide; Viscosity

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

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

Both diabetes (db/db) and obese (ob/ob) genotype mutations induce a hyperglycemic-hyperinsulinemic endometabolic state in C57BL mice, manifesting a type II NIDDM diabetes-obesity syndrome (DOS) in these leptin ligand/receptor-deficient models. The severity of the DOS induced by these single gene, homozygous-recessive mutations may be moderated by the background genome on which the mutation is expressed. The current studies define the phenotypic, systemic, cytochemical and cellular metabolic responses to db/db and ob/ob mutation expression when modified by /KsJ (severe DOS expression) or /6 (modified DOS expression) background strain influences as compared to littermate control (+/?) indices. Both db/db and ob/ob mutations induced dramatic increases in body weights, blood glucose and serum insulin concentrations relative to +/? indices when expressed on either the C57BL/KsJ (-/KsJ) or C57BL/6 (-/6) backgrounds. However, the -/KsJ background enhanced the severity of expression of these DOS indices relative to the -/6 strain. Similarly, the -/KsJ genome suppressed cellular glucose uptake rates, pancreatic tissue weights and insulin concentrations in both db/db and ob/ob mutants relative to /6 background strain influences or +/? indices. Concurrent enhancement of tissue and cellular lipogenic metabolism and islet cytolipid depositions were exaggerated when the mutations were expressed on the -/KsJ background relative to the -/6 genome. Pancreatic islet B-cell lipodeposition was markedly enhanced in ob/ob and db/db mutants expressed on either the -/KsJ or -/6 background. In both ob/ob and db/db models, B-cell insulin granulation was prominent in mildly hypertrophic pancreatic islets when the mutations were expressed on the -/6 background. In contrast, the severity of the DOS state expressed on the -/KsJ background resulted in pronounced B-cell atrophy, characterized by insulin degranulation, cellular hypertrophy and hypercytolipidemia associated with tissue involution, in both ob/ob and db/db mutants. Dramatic alterations in tissue norephinephrine (NE) and alpha-1-receptor populations in ob/ob and db/db mutants were exaggerated by the -/KsJ genome as compared to -/6 or control indices. The influences of the -/KsJ genome on the progressive expression of tissue NE counter-regulatory responses to enhanced cytolipidemic indices were inversely related, with cytochemical lipodeposition occurring under conditions of diminished adrenergic responses to the DOS indices.

Topics: Animals; Atrophy; Blood Glucose; Body Weight; Cell Size; Diabetes Mellitus, Type 2; Female; Genotype; Hyperinsulinism; Hypertrophy; Insulin; Islets of Langerhans; Leptin; Lipid Metabolism; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Norepinephrine; Obesity; Organ Size; Oxidative Stress; Phenotype; Receptors, Cell Surface; Receptors, Leptin; Species Specificity

To investigate the pharmacological mechanism of Semen Litchi water extract (SL) on enhancing insulin sensitivity in type 2 diabetic rats (T2DR) with insulin resistance (IR).. The effects of SL were observed on serum contents of fasting glucose (FSG), blood urea nitrogen (BUN), creatine (Cr), total proteins (TP), albumin (A), malondialdehyde (MDA), total cholesterols (TC), triacylglycerol (TG), free fatty acid (FFA), leptin, tumor necrosis factor-alpha (TNF-alpha), fasting insulin (Fins) and index of insulin sensitivity (ISI), and activities of superoxide dismutase (SOD), alanine aminotransferase (ALT), aspartate aminotransferase (AST) in T2DR-IR.. In T2DR-IR, SL could lower concentrations of FSG, TC, TG, FFA, leptin, TNF-alpha and Fins (P < 0.05-0.01), increase ISI (P < 0.01), reform the hyperinsulinemia and insulin sensitivity, decrease the levels of BUN, Cr and the activities of ALT, AST, increase concentration of TP, A (P < 0.05-0.01), recover the hepatic and nephric functions, increase the activity of SOD and decrease content of MDA (P < 0.01).. SL could reduce the levels of TNF-alpha, hyper-leptinemia and hyperinsulinemia, antagonize insulin resistance, fortify insulin sensitivity, readjust lipodystrophy and maladjustment of glycometabolism, enhance antioxidation,and improve functions of liver and kidney in T2DR-IR.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Drugs, Chinese Herbal; Female; Hyperinsulinism; Insulin; Insulin Resistance; Leptin; Litchi; Male; Malondialdehyde; Phytotherapy; Rats; Rats, Sprague-Dawley; Seeds; Tumor Necrosis Factor-alpha

To examine serum leptin concentrations in obese and lean patients with polycystic ovary syndrome (PCOS) to assess whether the changes in leptin levels are due to obesity or hormonal alterations.. Controlled clinical study.. Academic research environment.. Obese and lean women with PCOS.. Blood samples were collected before and after food consumption.. Serum leptin and insulin levels.. Serum leptin concentrations were significantly correlated with body mass index (r = 0.649) and also with HOMA (r = 0.535). However, after controlling for body mass index in a partial correlation analysis, no significant correlation was found between serum leptin levels and HOMA or hyperinsulinemia. While lean patients with PCOS had a significant correlation between leptin concentrations and obesity parameters, they did not show any significant correlation with insulin resistance parameters.. Although leptin concentrations in women with PCOS correlate with insulin resistance/hyperinsulinemia, this is related only to obesity.

Topics: Adult; Body Mass Index; Case-Control Studies; Female; Homeostasis; Humans; Hyperinsulinism; Insulin Resistance; Leptin; Obesity; Polycystic Ovary Syndrome

Topics: Cardiovascular Diseases; Clinical Trials as Topic; Humans; Hyperinsulinism; Leptin; Metabolic Syndrome; Risk Factors

Obesity-related phenotypes have been linked to human chromosomes 1q21 and 20q13, regions where the lamin A/C gene (LMNA) and the melanocortin 3 receptor gene (MC3R) map, respectively. Recently, a common single nucleotide polymorphism (SNP) in LMNA (1908C/T) was associated with plasma leptin and obesity indices in aboriginal Canadians, but these associations have not yet been explored in other populations. In contrast, no significant associations of MC3R variants with obesity have been detected, although a significant association with hyperinsulinemia has been reported in Caucasian populations. We investigated the associations between the LMNA 1908C/T variant and the 241G/A variant of the MC3R gene (Val81Ile missense mutation) and body composition, as well as plasma leptin and insulin levels, in two samples of unrelated healthy Greek subjects. A group of 112 young nonobese subjects, and a group of 116 adult women with a body mass index (BMI) ranging from 23.2 to 47.7 kg/m2 were studied cross-sectionally. We found no significant association of the LMNA 1908C/T and a borderline significant association of MC3R 241G/A SNPs with body composition variables, in the entire study sample. However, unlike the LMNA 1908C/T genetic variation, the MC3R 241G/A genetic variation was significantly associated with hyperleptinemia and huperinsulinemia in obese subjects, and there was evidence of interaction between this polymorphism and fat mass or BMI in predicting hyperinsulinemia. Our results suggest that the LMNA 1908C-->T substitution and the Val81Ile mutation of the MC3R gene are unlikely to be major predictors of body composition in Greek Caucasians, but the latter genetic variation may predispose obese subjects to develop insulin and leptin resistance. Future studies are needed to confirm these data and assess whether individuals carrying this mutation are more resistant to weight-reducing and insulin-sensitizing treatments.

Topics: Adult; Amino Acid Substitution; Body Composition; Body Mass Index; DNA; Female; Gene Frequency; Greece; Humans; Hyperinsulinism; Insulin; Lamin Type A; Leptin; Male; Mutation, Missense; Obesity; Polymorphism, Genetic; Receptor, Melanocortin, Type 3; Regression Analysis; Valine

Hyperinsulinemia and hyperleptinemia occur concurrently in obese subjects, and both have been suggested to mediate increased blood pressure associated with excess weight gain. The goal of this study was to determine whether chronic hyperleptinemia exacerbates the effects of insulin on arterial pressure and renal function. Group I and II rats were infused with insulin (1.5 mU. kg(-1). min(-1)) for 21 days while maintaining euglycemia. After 7 days of insulin infusion, group II rats received leptin (1.0 microg. kg(-1). min(-1)) for 7 days, concomitant with insulin. Insulin plus glucose infusion reduced food intake to 55 +/- 7% of control, while leptin + insulin lowered food intake further to 22 +/- 4% of the initial control. Insulin initially raised mean arterial pressure (MAP) by 12 +/- 1 mmHg; then MAP declined to 5-8 mmHg above control during continued hyperinsulinemia. Leptin + insulin infusion increased MAP by 7 +/- 2 mmHg above the level observed in rats infused with insulin alone. Insulin raised heart rate (HR) by 17 +/- 5 beats/min, whereas leptin + insulin increased HR by 34 +/- 5 beats/min. Thus leptin appears to increase the effects of insulin to suppress appetite and to raise arterial pressure and HR.

Topics: Animals; Appetite; Blood Pressure; Cardiovascular System; Heart Rate; Hyperinsulinism; Insulin; Kidney; Leptin; Male; Obesity; Rats; Rats, Sprague-Dawley; Time Factors

High-fat diet and intrauterine growth retardation may predispose to obesity, insulin resistance, and type 2 diabetes. Because prenatal ethanol (ETOH) exposure causes intrauterine growth retardation, we investigated its interactions with postnatal high-fat diet on glucose tolerance and adipocyte-derived hormones in the rat offspring. High-fat-fed offspring had increased adiposity, serum leptin, and muscle uncoupling protein-3, but decreased adiponectin mRNA, compared with corresponding chow-fed groups. ETOH-exposed offspring had normal adiponectin, but increased resistin mRNA and protein, compared with controls, regardless of postnatal diet. Skeletal muscle glucose transporter-4 content was decreased after both ETOH exposure and high-fat feeding. Glycemic and insulin responses to an ip glucose challenge were equally increased in non-ETOH-exposed high-fat-fed offspring and in ETOH-exposed chow-fed offspring, with additive effects of ETOH and high-fat diet. Pancreatic insulin content was elevated only in non-ETOH-exposed high-fat-fed offspring. The data suggest that high-fat diet worsens glucose intolerance in offspring of rats exposed to ETOH. Prenatal ETOH exposure and postnatal high-fat diet might cause insulin resistance through separate mechanisms, involving resistin and adiponectin, respectively.

Topics: Adiponectin; Adipose Tissue; Animals; Body Weight; Carrier Proteins; Central Nervous System Depressants; Dietary Fats; Eating; Ethanol; Fatty Acids, Nonesterified; Female; Gene Expression; Glucose Intolerance; Glucose Transporter Type 4; Hormones, Ectopic; Hyperinsulinism; Insulin; Intercellular Signaling Peptides and Proteins; Ion Channels; Leptin; Mitochondrial Proteins; Monosaccharide Transport Proteins; Muscle Proteins; Muscle, Skeletal; Nerve Growth Factor; Organ Size; Pancreas; Pregnancy; Prenatal Exposure Delayed Effects; Proteins; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, Leptin; Resistin; Uncoupling Protein 3

Proopiomelanocortin (POMC) neurons in the hypothalamus are direct targets of the adipostatic hormone leptin and contribute to energy homeostasis by integrating peripheral and central information. The melanocortin and beta-endorphin neuropeptides are processed from POMC and putatively coreleased at axon terminals. Melanocortins have been shown by a combination of pharmacological and genetic methods to have inhibitory effects on appetite and body weight. In contrast, pharmacological studies have generally indicated that opioids stimulate food intake. Here we report that male mice engineered to selectively lack beta-endorphin, but that retained normal melanocortin signaling, were hyperphagic and obese. Furthermore, beta-endorphin mutant and wild-type mice had identical orexigenic responses to exogenous opioids and identical anorectic responses to the nonselective opioid antagonist naloxone, implicating an alternative endogenous opioid tone to beta-endorphin that physiologically stimulates feeding. These genetic data indicate that beta-endorphin is required for normal regulation of feeding, but, in contrast to earlier reports suggesting opposing actions of beta-endorphin and melanocortins on appetite, our results suggest a more complementary interaction between the endogenously released POMC-derived peptides in the regulation of energy homeostasis.

Topics: Animals; beta-Endorphin; Eating; Energy Metabolism; Glucose; Homeostasis; Hyperinsulinism; Hyperphagia; Leptin; Male; Mice; Mice, Knockout; Naloxone; Narcotic Antagonists; Neuropeptide Y; Obesity; Reference Values

Dietary restriction (DR) extends life span and improves glucose metabolism in mammals. Recent studies have shown that DR stimulates the production of brain-derived neurotrophic factor (BDNF) in brain cells, which may mediate neuroprotective and neurogenic actions of DR. Other studies have suggested a role for central BDNF signaling in the regulation of glucose metabolism and body weight. BDNF heterozygous knockout (BDNF+/-) mice are obese and exhibit features of insulin resistance. We now report that an intermittent fasting DR regimen reverses several abnormal phenotypes of BDNF(+/-) mice including obesity, hyperphagia, and increased locomotor activity. DR increases BDNF levels in the brains of BDNF(+/-) mice to the level of wild-type mice fed ad libitum. BDNF(+/-) mice exhibit an insulin-resistance syndrome phenotype characterized by elevated levels of circulating glucose, insulin, and leptin; DR reduces levels of each of these three factors. DR normalizes blood glucose responses in glucose tolerance and insulin tolerance tests in the BDNF(+/-) mice. These findings suggest that BDNF is a major regulator of energy metabolism and that beneficial effects of DR on glucose metabolism are mediated, in part, by BDNF signaling. Dietary and pharmacological manipulations of BDNF signaling may prove useful in the prevention and treatment of obesity and insulin resistance syndrome-related diseases.

Topics: Animals; Blood Glucose; Brain Chemistry; Brain-Derived Neurotrophic Factor; Caloric Restriction; Hyperinsulinism; Hyperphagia; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Male; Mice; Mice, Knockout; Motor Activity; Obesity; Phenotype; Signal Transduction

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

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

The gastric peptide ghrelin augments and the adipocyte-derived hormone leptin reduces appetite and food intake. In the central nervous system, insulin directly decreases hunger sensation but could also act indirectly by modulating ghrelin and leptin secretion. This study examines dose-dependent effects of insulin on plasma ghrelin and leptin concentrations during hyperinsulinemic (1, 2, and 4 mU x kg(-1) x min(-1))-euglycemic clamp tests in six nondiabetic (control subjects) and six type 2 diabetic patients. Type 2 diabetic patients were studied before and after prolonged (12-h and 67-h) variable intravenous insulin treatment aiming at near-normoglycemia (115 +/- 4 mg/dl). Nondiabetic subjects were also studied during saline infusion, which did not affect ghrelin but decreased leptin by 19 +/- 6% (P < 0.03). In control subjects, plasma ghrelin decreased at all clamp steps (-17 +/- 1, -27 +/- 6, and -33 +/- 4%, respectively; P < 0.006 vs. baseline), whereas leptin increased by 35 +/- 11% (P < 0.05). In type 2 diabetic patients without insulin treatment, ghrelin decreased by 18 +/- 7% (P < 0.05) only after 4 mU x kg(-1) x min(-1) insulin infusion and leptin increased by 19 +/- 6% (P < 0.05). After prolonged insulin treatment and near-normoglycemia, ghrelin and leptin remained unchanged in type 2 diabetic patients during the clamps. In conclusion, insulin reduces plasma ghrelin in nondiabetic patients and, to a lesser extent, in type 2 diabetic patients before insulin therapy. These findings indicate an indirect effect of insulin via ghrelin on the suppression of hunger sensation and appetite.

Topics: Aged; Blood Glucose; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Ghrelin; Glucose Clamp Technique; Glycated Hemoglobin; Human Growth Hormone; Humans; Hyperinsulinism; Insulin; Kinetics; Leptin; Male; Middle Aged; Peptide Hormones; Reference Values; Regression Analysis

To characterize the meal patterns of free feeding Sprague-Dawley rats that become obese or resist obesity when chronically fed a high-fat diet.. Male Sprague-Dawley rats (N = 120) were weaned onto a high-fat diet, and body weight was monitored for 19 weeks. Rats from the upper [diet-induced obese (DIO)] and lower [diet-resistant (DR)] deciles for body-weight gain were selected for study. A cohort of chow-fed (CF) rats weight-matched to the DR group was also studied. Food intake was continuously monitored for 7 consecutive days using a BioDAQ food intake monitoring system.. DIO rats were obese, hyperphagic, hyperleptinemic, hyperinsulinemic, hyperglycemic, and hypertriglyceridemic relative to the DR and CF rats. The hyperphagia of DIOs was caused by an increase in meal size, not number. CF rats ate more calories than DR rats; however, this was because of an increase in meal number, not size. When expressed as a function of lean mass, CF and DR rats consumed the same amount of calories. The intermeal intervals of DIO and DR rats were similar; both were longer than CF rats. The nocturnal satiety ratio of DIO rats was significantly lower than DR and CF rats. The proportion of calories eaten during the nocturnal period did not differ among groups.. The hyperphagia of a Sprague-Dawley rat model of chronic diet-induced obesity is caused by an increase in meal size, not number. These results are an important step toward understanding the mechanisms underlying differences in feeding behavior of DIO and DR rats.

Topics: Animals; Body Composition; Circadian Rhythm; Diet; Eating; Energy Intake; Food; Genetic Predisposition to Disease; Hyperglycemia; Hyperinsulinism; Hyperphagia; Hypertriglyceridemia; Insulin; Leptin; Male; Obesity; Rats; Rats, Sprague-Dawley; Satiation; Weight Gain

After parturition, dairy cows suffer from an intense energy deficit caused by the onset of copious milk secretion and an inadequate increase in voluntary food intake. We previously showed that this energy deficit contributes to a decline in plasma leptin. This decline mirrors that of plasma insulin but is reciprocal to the profile of plasma growth hormone (GH), suggesting that both hormones may regulate plasma leptin in periparturient dairy cows. To study the role of insulin, hyperinsulinemic-euglycemic clamps were performed on six dairy cows in late pregnancy (LP, 31 days prepartum) and early lactation (EL, 7 days postpartum). Infusion of insulin (1 microg.kg body wt-1.h-1) caused a progressive rise in the plasma concentration of leptin that reached maximum levels at 24 h during both physiological states. At steady states, the absolute increase in plasma leptin was greater in LP than in EL cows (2.4 vs. 0.4 ng/ml). Insulin infusion increased leptin mRNA in adipose tissue during LP but not during EL. During lactation, mammary epithelial cells expressed leptin mRNA but insulin did not increase milk leptin output. In contrast, a 3-day period of GH administration had no effect on plasma leptin during LP or EL. Therefore, insulin increases plasma leptin in LP by stimulating adipose tissue synthesis but has only marginal effects in EL, when cows are in negative energy balance. Other factors, such as increased response of adipose tissue to beta-adrenergic signals, probably contribute to the reduction of plasma leptin in early lactating dairy cows.

Topics: Animals; Blood Glucose; Cattle; Female; Glucose Clamp Technique; Growth Hormone; Hyperinsulinism; Insulin; Lactation; Leptin; Mammary Glands, Animal; Postpartum Period; Pregnancy

In healthy individuals, peripheral insulin resistance evoked by dietary saturated lipid can be accompanied by increased insulin secretion such that glucose tolerance is maintained. Substitution of long-chain omega-3 fatty acids for a small percentage of dietary saturated fat prevents insulin resistance in response to high-saturated fat feeding. We substituted a small amount (7%) of dietary lipid with long-chain omega-3 fatty acids during 4 wk of high-saturated fat feeding to investigate the relationship between amelioration of insulin resistance and glucose-stimulated insulin secretion (GSIS). We demonstrate that, despite dietary delivery of saturated fat throughout, this manipulation prevents high-saturated fat feeding-induced insulin resistance with respect to peripheral glucose disposal and reverses insulin hypersecretion in response to glucose in vivo. Effects of long-chain omega-3 fatty acid enrichment to lower GSIS were also observed in perifused islets suggesting a direct effect on islet function. However, long-chain omega-3 fatty acid enrichment led to hepatic insulin resistance with respect to suppression of glucose output and impaired glucose tolerance in vivo. Our data demonstrate that the insulin response to glucose is suppressed to a greater extent than whole-body insulin sensitivity is enhanced by enrichment of a high-saturated fat diet with long-chain omega-3 fatty acids. Additionally, reduced GSIS despite glucose intolerance suggests that either long-chain omega-3 fatty acids directly impair the beta-cell response to saturated fat such that insulin secretion cannot be augmented to normalize glucose tolerance or beta-cell compensatory hypersecretion represents a response to insulin resistance at the level of peripheral glucose disposal but not endogenous glucose production.

Topics: Animals; Dietary Fats; Fatty Acids, Omega-3; Female; Fish Oils; Glucose; Glucose Clamp Technique; Glucose Intolerance; Glycogen; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Leptin; Liver; Phenotype; Rats; Rats, Wistar; Triglycerides

A tyrosine kinase adaptor protein containing pleckstrin homology and SH2 domains (APS) is rapidly and strongly tyrosine phosphorylated by insulin receptor kinase upon insulin stimulation. The function of APS in insulin signaling has heretofore remained unknown. APS-deficient (APS(-/-)) mice were used to investigate its function in vivo. The blood glucose-lowering effect of insulin, as assessed by the intraperitoneal insulin tolerance test, was increased in APS(-/-) mice. Plasma insulin levels during fasting and in the intraperitoneal glucose tolerance test were lower in APS(-/-) mice. APS(-/-) mice showed an increase in the whole-body glucose infusion rate as assessed by the hyperinsulinemic-euglycemic clamp test. These findings indicated that APS(-/-) mice exhibited increased sensitivity to insulin. However, overexpression of wild-type or dominant-negative APS in 3T3L1 adipocytes did not affect insulin receptor numbers, phosphorylations of insulin receptor, insulin receptor substrate-1, or Akt and mitogen-activated protein kinase. The glucose uptake and GLUT4 translocation were not affected by insulin stimulation in these cells. Nevertheless, the insulin-stimulated glucose transport in isolated adipocytes of APS(-/-) mice was increased over that of APS(+/+) mice. APS(-/-) mice also showed increased serum levels of leptin and adiponectin, which might explain the increased insulin sensitivity of adipocytes.

Topics: 3T3 Cells; Adaptor Proteins, Signal Transducing; Adaptor Proteins, Vesicular Transport; Adipocytes; Adiponectin; Animals; Blood Glucose; Body Weight; Energy Intake; Glucagon; Glucose; Glucose Clamp Technique; Hyperinsulinism; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Mice; Mice, Knockout; Proteins; Receptor, Insulin; Triglycerides

In order to circumvent the multiple peripheral effects of hyperleptinemia and leptin resistance, the efficacy of leptin transgene expression in the hypothalamic paraventricular nucleus (PVN) to reinstate the central energy homeostasis in obesity was examined.. A recombinant adeno-associated viral vector encoding either leptin (rAAV-lep) or green fluorescent protein (rAAV-GFP) was microinjected into the PVN of obesity-prone rats consuming a high-fat diet (HFD).. rAAV-lep, and not rAAV-GFP, microinjection significantly reduced energy intake and enhanced energy expenditure, thereby resulting in normalization of weight and blood levels of leptin, insulin, free fatty acids, and glucose concomitant with enhanced ghrelin secretion during the extended period of observation.. Thus, we show, for the first time, that amelioration of leptin insufficiency with enhanced localized leptin availability in the PVN alone can reverse dietary obesity and the attendant hyperinsulinemia and concurrently block the central stimulatory effects of elevated endogenous ghrelin on food intake and adiposity.

Topics: Adenoviridae; Adipose Tissue, Brown; Animals; Carrier Proteins; Dietary Fats; Eating; Fatty Acids, Nonesterified; Female; Genetic Therapy; Genetic Vectors; Ghrelin; Hyperinsulinism; Ion Channels; Leptin; Membrane Proteins; Microinjections; Mitochondrial Proteins; Obesity; Paraventricular Hypothalamic Nucleus; Peptide Hormones; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Uncoupling Protein 1

Ghrelin, leptin and adiponectin are three hormones which are frequently associated with metabolism, obesity and appetite. Recently, it has been shown that they may possess other physiologic roles, specially in connection with the circulation. Ghrelin infusion increases forearm blood-flow in a dose-dependent manner. Leptin has been shown to be involved not only in thermogenesis but angiogenesis as well. Adiponectin, apart from its insulin-sensitizing action, appears to modulate inflammation by inhibiting monocyte adhesion to endothelial cells. Six monkeys, which had been classified as being in the pre-diabetic state, where administered a triglyceride lowering regimen. Microvascular function was assessed using a laser Doppler flow-meter during a temperature provocation test. Percent change in flow from baseline following temperature elevation, as well as percent change in flow/degree rise in temperature were used to evaluate microvascular reserve and reactivity. Using univariate analysis, it appears that increased perfusion is significantly correlated with adiponectin, followed by leptin. Flow was also positively correlated with ghrelin, but the relationship did not attain significance. As expected, flow was also negatively and significantly correlated with fibrinogen. Trends show that flow was also negatively correlated to circulating triglyceride levels (p=0.08). The data indicate that the three hormones appear to possess microvascular actions that may impact on their other physiologic functions.

Topics: Adiponectin; Animals; Blood Glucose; Fibrinogen; Ghrelin; Hyperglycemia; Hyperinsulinism; Hypertriglyceridemia; Hypolipidemic Agents; Intercellular Signaling Peptides and Proteins; Leptin; Macaca mulatta; Metabolic Syndrome; Microcirculation; Obesity; Peptide Hormones; Prediabetic State; Proteins

Intracerebroventricular administration of recombinant adeno-associated virus (rAAV) encoding the rat leptin gene (rAAV-lep) to 24-d-old female and male rats suppressed postpubertal weight gain for extended periods by decreasing food consumption and adiposity, as reflected by lowered serum leptin, insulin, and FFA. Serum ghrelin levels were increased in young but not older rats. Central rAAV-lep therapy also increased energy expenditure through nonshivering thermogenesis in younger rats as shown by expression of uncoupling protein mRNA in brown adipose tissue. The sustained decrease in appetite seemingly resulted from attenuation of appetite-stimulating neuropeptide Y and enhancement of appetite-inhibiting melanocortin signalings in the hypothalamus. Neither the onset of pubertal sexual maturation nor reproductive cyclicity in adult female rats was affected by the sustained reduction in energy consumption and weight gain. These findings demonstrate that central leptin gene therapy in prepubertal rats is a novel therapy to control postpubertal weight gain, adiposity, and hyperinsulinemia for extended periods.

Topics: Adipose Tissue, Brown; Animals; Appetite; Carrier Proteins; Dependovirus; Energy Intake; Estrous Cycle; Female; Gene Expression; Genetic Therapy; Ghrelin; Growth; Hyperinsulinism; Hypothalamus; Injections, Intraventricular; Insulin; Ion Channels; Leptin; Male; Membrane Proteins; Mitochondrial Proteins; Neuropeptides; Obesity; Peptide Hormones; Rats; Rats, Sprague-Dawley; RNA, Messenger; Uncoupling Protein 1; Vagina; Weight Gain

Administration of tumor necrosis factor-alpha (TNF-alpha) acutely increases leptin gene expression and circulating leptin concentrations in rodents and humans. Since TNF-alpha also induces hyperinsulinemia, and because insulin is a potent stimulator of leptin production, we hypothesized that elevated plasma insulin mediates TNF-alpha-induced increases of circulating leptin. To test this hypothesis, rats were made insulin-deficient with streptozotocin (STZ) and treated with subcutaneous implants that released insulin at a constant rate and thereby "clamped" insulin levels. STZ-diabetic and nondiabetic rats were injected with TNF-alpha or vehicle; plasma leptin, insulin, and glucose concentrations were measured during an initial 12-hour postinjection period of fasting and after a subsequent 12-hour period of refeeding. Food intake during the 12 hours after fasting was assessed as a physiologic correlate of changes in leptin concentrations. In nondiabetic rats, TNF-alpha increased plasma insulin (P =.016) and prevented the fasting-induced decrease of circulating leptin (P =.004) over the initial 12 hours compared with vehicle. Food intake during the refeeding period was 30% lower (P =.008) when the nondiabetic animals were injected with TNF-alpha. In contrast, TNF-alpha did not affect leptin concentrations in STZ-diabetic animals with clamped plasma insulin levels or their food intake during the refeeding period. These results suggest that TNF-alpha-induced hyperinsulinemia likely mediates the stimulatory effect of TNF-alpha on circulating leptin in vivo. Elevated leptin levels may in turn contribute to the effect of TNF-alpha to decrease food intake.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Eating; Fasting; Hyperinsulinism; Insulin; Leptin; Male; Rats; Rats, Sprague-Dawley; Reference Values; Tumor Necrosis Factor-alpha

To evaluate the relationships between leptin, body composition, insulin resistance, androgens, and reproductive indices among women with polycystic ovary syndrome (PCOS).. Matched case-control study.. Academic reproductive endocrine practice; school of public health.. Forty-six Caucasian women with PCOS and 46 population-based controls matched by age and body mass index (BMI).. None.. Leptin, insulin, androgenic hormones, body composition parameters; reproductive parameters.. Overall, leptin levels among women with PCOS did not differ significantly from those of control women (20.4 +/- 14.9 vs. 21.9 +/- 14.3 ng/mL). However, within the lowest BMI tertile, women with PCOS had significantly lower leptin levels (9.6 vs. 18.3 ng/mL), comparable insulin, and higher testosterone concentrations than controls of similar body mass. Within the overweight and obese subgroups, both insulin and testosterone levels were increased among women with PCOS; leptin levels, although higher among obese cases, were not statistically different than those in controls.. Below a certain BMI, hyperandrogenic women with PCOS have lower leptin levels than controls. Conversely, overweight and obese PCOS subjects appear to produce insufficient leptin for a given fat mass, relative to the degree of hyperinsulinemia, potentially because of the competing effects of adipocyte insulin resistance and androgens on leptin.

Topics: Adult; Body Composition; Body Mass Index; Body Weight; Case-Control Studies; Female; Humans; Hyperinsulinism; Insulin Resistance; Leptin; Obesity; Pennsylvania; Polycystic Ovary Syndrome; Reference Values; Reproduction; Thinness; White People

We studied body size and cord blood leptin and insulin concentrations in newborn urban Indian (Pune, India) and white Caucasian (London, UK) babies to test the hypothesis that the adiposity and hyperinsulinemia of Indians are present at birth. Indian babies (n = 157) were lighter in weight compared with white Caucasian babies [n = 67; median weight, 2805 g vs. 3475 g, respectively; P < 0.001, adjusted for gestational age and sex; -1.52 SD score; confidence interval (CI), -1.66, -1.42] and had smaller abdominal (-2.39 SD score; CI, -2.52, -2.09), midarm (-1.47 SD score; CI, -1.58, -1.34), and head (-1.23 SD score; CI, -1.42, -1.13) circumferences. However, their skinfolds were relatively preserved: subscapular (central) skinfold (-0.32 SD score; CI, -0.43, -0.20) was better preserved than triceps (peripheral) skinfold (-0.86 SD score; CI, -0.97, -0.75). Cord plasma leptin (median, 6.2 ng/ml Pune and 6.4 ng/ml London) and insulin (median, 34.7 pmol/liter Pune and 20.8 pmol/liter London) concentrations were comparable in the two populations but were higher in Indians when adjusted for birth weight, confirming relative adiposity and hyperinsulinemia of Indian babies. Indian mothers were smaller in all respects, compared with white Caucasian mothers, except subscapular skinfold, which was similar in the two populations. Our results support the intrauterine origin of adiposity, central adiposity, and hyperinsulinemia in Indians. Further research should concentrate on elucidating genetic and environmental influences on fetal growth and body composition. Prevention of insulin resistance syndrome in Indians will need to address regulation of fetal growth in addition to prevention of obesity in later life.

Topics: Adipose Tissue; Adult; Anthropometry; Birth Weight; Body Constitution; Female; Fetal Blood; Humans; Hyperinsulinism; India; Infant, Newborn; Insulin; Leptin; London; Mothers; Osmolar Concentration; Parturition; White People

Based on the phenotypes of knockout mice and cell lines, as well as pathway-specific analysis, the insulin receptor substrates IRS-1, IRS-2, IRS-3, and IRS-4 have been shown to play unique roles in insulin signal transduction. To investigate possible functional complementarity within the IRS family, we generated mice with double knockout of the genes for IRS-1/IRS-3 and IRS-1/IRS-4. Mice with a combined deficiency of IRS-1 and IRS-4 showed no differences from Irs1(-/-) mice with respect to growth and glucose homeostasis. In contrast, mice with a combined deficiency of IRS-1 and IRS-3 developed early-onset severe lipoatrophy associated with marked hyperglycemia, hyperinsulinemia, and insulin resistance. However, in contrast to other models of lipoatrophic diabetes, there was no accumulation of fat in liver or muscle. Furthermore, plasma leptin levels were markedly decreased, and adenovirus-mediated expression of leptin in liver reversed the hyperglycemia and hyperinsulinemia. The results indicate that IRS-1 and IRS-3 play important complementary roles in adipogenesis and establish the Irs1(-/-)/Irs3(-/-) double knockout mouse as a novel model of lipoatrophic diabetes.

Topics: Adenoviridae; Adipose Tissue; Animals; Diabetes Mellitus, Lipoatrophic; Disease Models, Animal; Fatty Acids, Nonesterified; Glucose; Hyperglycemia; Hyperinsulinism; Immunoenzyme Techniques; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Leptin; Mice; Mice, Knockout; Phosphoproteins; Transfection; Triglycerides

Leptin, an adipocyte-derived factor, has multiple biological roles including mitogenesis. We investigated the effect of normal development, acute and chronic hyperglycemia and hypoglycemia, and selective acute hyperglycemia, or hyperinsulinemia, on fetal ovine white adipose tissue (WAT) leptin mRNA concentrations. Leptin mRNA amounts expressed as a ratio to the internal control ribosomal S2 mRNA decreased threefold with advancing gestational age (P < 0.05). This gestational decrease was opposite to the 10-fold increase in fetal body weight during the same developmental period. Chronic hyperglycemia with hyperinsulinemia led to no change in WAT leptin mRNA concentrations over a 1- to 10-day duration, but it caused a 40% increase over a 14- to 20-day duration (P < 0.05) along with an increase in fetal body weight (P < 0.05). In contrast, hypoglycemia with hypoinsulinemia, while not affecting WAT leptin mRNA from 1 to 34 days, resulted in a 50% decline over a 36- to 76-day duration along with a decline in fetal body weight (P < 0.05). Acute 24-h studies of selective hyperglycemia with euinsulinemia showed no significant change in WAT leptin mRNA, but in response to selective hyperinsulinemia with euglycemia at 24 h, a twofold increase was observed (P < 0.05). We conclude that fetal WAT leptin mRNA amounts are regulated by fetal development and circulating insulin concentrations. We speculate that chronic in utero metabolic perturbations that alter circulating insulin concentrations affect fetal leptin production that may mediate insulin's influence on fetal growth.

Topics: Adipose Tissue; Animals; Female; Gene Expression Regulation, Developmental; Gestational Age; Glucose; Hyperglycemia; Hyperinsulinism; Hypoglycemia; Hypoglycemic Agents; Insulin; Leptin; Obesity; Pregnancy; RNA, Messenger; Sheep

Leptin is a protein hormone produced predominantly by adipocytes that plays a role in food intake regulation and a series of other physiological processes including blood pressure regulation.. The aim of our study was to compare serum leptin levels in patients with primary hyperaldosteronism (PA) with those of healthy subjects and to explore the relationship of serum leptin levels and the parameters of insulin action in these patients before and after surgical or pharmacological treatment.. Serum potassium, leptin, aldosterone, insulin levels and plasma renin activity were measured and hyperinsulinaemic euglycaemic clamp was performed in 11 patients with PA and 11 healthy age-, gender- and body mass index (BMI)-matched subjects. In eight of 11 patients the same measurements were repeated at least 6 months after surgical or pharmacological treatment.. The basal serum leptin levels in PA patients did not significantly differ from those of healthy subjects (mean+/-s.e.m. 8.4+/-1.9 vs 11.2+/-1.8 ng/ml, P=0.30), although their insulin sensitivity was significantly impaired (PA patients vs control subjects: glucose disposal rate in the last 20 min of clamp (M) 18.7+/-1.8 vs 30.6+/-3.3 micromol/kg/min, metabolic clearance rate of glucose (MCR(g)) 3.9+/-0.5 vs 7.2+/-1.1 ml/kg/min, P<0.05). The surgical or pharmacological treatment of PA patients increased significantly their serum leptin levels (10.9+/-3.7 vs 8.4+/-1.9 ng/ml, P<0.05) and simultaneously improved their insulin sensitivity. Basal serum leptin levels in both groups correlated positively with BMI and serum insulin levels. The inverse relationship between serum leptin levels and the insulin sensitivity parameters was found in both PA patients before treatment and healthy subjects. These relationships disappeared after treatment of PA patients except for those between serum leptin levels and MCR(g).. Basal serum leptin levels in untreated patients with PA do not significantly differ from those of healthy subjects, but increase significantly after surgical or pharmacological treatment. The increase in serum leptin levels is paradoxically accompanied by the improvement of insulin sensitivity in these patients.

Topics: Adrenal Glands; Adrenalectomy; Adult; Female; Glucose Clamp Technique; Humans; Hyperaldosteronism; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Leptin; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Spironolactone

To explore the determinants of the tumor necrosis factor alpha (TNFalpha) system and their relationship with plasma leptin levels.. We studied a cohort of 157 diabetic and non-diabetic females with a wide range of adiposity distributed into five groups: control--body mass index (BMI) between 19 and 27 kg/m(2) (n=24); obese--BMI between 27 and 40 kg/m(2) (n=63); obese type 2 diabetes mellitus--BMI between 27 and 40 kg/m(2) with diabetes mellitus (n=19); morbid obese--BMI >40 kg/m(2) (n=29); and morbid obese type 2 diabetes mellitus--BMI >40 kg/m(2) with diabetes (n=22). Fasting glucose levels, plasma total triglycerides and cholesterol, high-, low- and very low-density lipoprotein cholesterol were assayed by enzymatic and colorimetric methods. Plasma TNFalpha levels were measured by ELISA assay and insulin and leptin levels by radioimmunoenzymatic assays. Both soluble TNFalpha (sTNFalpha) receptors were measured by immunoenzymometric assays.. All groups of patients showed significant increases in both sTNFalpha receptors relative to control. sTNFalpha receptor 1 (sTNFR1) was higher in morbid obese diabetic individuals compared with their non-diabetic counterparts (P=0.003), while sTNFR2 was significantly different between obese and morbid obese subjects (P=0.036). Bivariate correlation analysis showed a significant relationship between both plasma sTNFalpha receptors and BMI, percentage of body fat, fasting glucose, insulin and leptin. In multivariate analysis, both sTNF receptor plasma levels were predicted by percentage of body fat and the presence of diabetes (R(2)=0.20 for sTNFR1 and sTNFR2). When plasma leptin levels were added into the model, this protein and the presence of diabetes explained 27% of the variance of the plasma sTNFR1 levels.. The presence of diabetes, adiposity or leptin levels are independent determinants of both sTNFalpha receptors. The independent association between plasma TNFalpha receptors and leptin levels in obese patients is consistent with the hypothesis that these proteins could be involved in the same pathway that regulates body adiposity.

Topics: Adult; Aged; Aging; Body Height; Body Weight; Diabetes Mellitus, Type 2; Female; Humans; Hyperinsulinism; Leptin; Middle Aged; Obesity; Obesity, Morbid; Receptors, Leptin; Receptors, Tumor Necrosis Factor; Tumor Necrosis Factor-alpha

The ability of insulin to suppress gluconeogenesis in type II diabetes mellitus is impaired; however, the cellular mechanisms for this insulin resistance remain poorly understood. To address this question, we generated transgenic (TG) mice overexpressing the phosphoenolpyruvate carboxykinase (PEPCK) gene under control of its own promoter. TG mice had increased basal hepatic glucose production (HGP), but normal levels of plasma free fatty acids (FFAs) and whole-body glucose disposal during a hyperinsulinemic-euglycemic clamp compared with wild-type controls. The steady-state levels of PEPCK and glucose-6-phosphatase mRNAs were elevated in livers of TG mice and were resistant to down-regulation by insulin. Conversely, GLUT2 and glucokinase mRNA levels were appropriately regulated by insulin, suggesting that insulin resistance is selective to gluconeogenic gene expression. Insulin-stimulated phosphorylation of the insulin receptor, insulin receptor substrate (IRS)-1, and associated phosphatidylinositol 3-kinase were normal in TG mice, whereas IRS-2 protein and phosphorylation were down-regulated compared with control mice. These results establish that a modest (2-fold) increase in PEPCK gene expression in vivo is sufficient to increase HGP without affecting FFA concentrations. Furthermore, these results demonstrate that PEPCK overexpression results in a metabolic pattern that increases glucose-6-phosphatase mRNA and results in a selective decrease in IRS-2 protein, decreased phosphatidylinositol 3-kinase activity, and reduced ability of insulin to suppress gluconeogenic gene expression. However, acute suppression of HGP and glycolytic gene expression remained intact, suggesting that FFA and/or IRS-1 signaling, in addition to reduced IRS-2, plays an important role in downstream insulin signal transduction pathways involved in control of gluconeogenesis and progression to type II diabetes mellitus.

Topics: Animals; Fatty Acids, Nonesterified; Hyperinsulinism; Insulin; Insulin Receptor Substrate Proteins; Intracellular Signaling Peptides and Proteins; Leptin; Liver; Mice; Mice, Transgenic; Phosphatidylinositol 3-Kinases; Phosphoenolpyruvate Carboxykinase (ATP); Phosphoproteins; Promoter Regions, Genetic; RNA, Messenger; Signal Transduction

Type 2 diabetes is associated with biochemical evidence of low-grade inflammation, and experimental studies have suggested that both insulin and glucose affect inflammatory responses. To determine the effect of in vivo changes in glucose availability and plasma insulin concentrations in humans, we administered 20 U/kg Escherichia coli lipopolysaccharide (LPS) or saline (control) to 14 subjects during a euglycemic hyperinsulinemic clamp (n = 6) or an infusion of sterile saline (n = 8). Parallel in vitro studies on human whole blood were undertaken to determine whether there was a direct effect of glucose, insulin, and leptin on proinflammatory cytokine production. Infusion of glucose and insulin significantly amplified and/or prolonged the cardiovascular, plasma interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and counterregulatory hormone responses to LPS, whereas the effects on fever, plasma norepinephrine concentrations, and oxygen consumption were unaffected. In vitro studies showed no modulation of LPS-stimulated IL-6 or TNF-alpha production by glucose, insulin, or leptin at physiologically relevant concentrations. Hyperinsulinemia indirectly enhances key components of the systemic inflammatory and stress responses in this human model of infection.

Topics: Adult; Blood Glucose; Blood Pressure; Body Temperature; Cytokines; Diabetes Mellitus, Type 2; Escherichia coli; Female; Glucose Clamp Technique; Humans; Hyperinsulinism; Inflammation; Insulin; Insulin-Like Growth Factor Binding Protein 1; Interleukin-6; Leptin; Lipopolysaccharides; Male; Norepinephrine; Oxygen Consumption; Pulse; Tumor Necrosis Factor-alpha

Recombinant adeno-associated virus (rAAV), encoding either rat leptin (rAAV-lep) or green fluorescent protein (rAAV-GFP, control), was injected intracerebroventricularly in rats consuming a high-fat diet (HFD; 45 kcal%). Caloric consumption and body weight were monitored weekly until the rats were killed at 9 weeks. Untreated control rats consuming regular rat diet (RCD; 11 kcal%) were monitored in parallel. Body weight gain was accelerated in rAAV-GFP + HFD control rats relative to those consuming RCD, despite equivalent kcal consumption. At 9 weeks, serum leptin, free fatty acids, triglycerides, and insulin were elevated in HFD control rats. In contrast, rAAV-lep treatment reduced intake and blocked the HFD-induced increase in weight, adiposity, and metabolic variables. Blood glucose was slightly reduced but within the normal range, and serum ghrelin levels were significantly elevated in rAAV-lep + HFD rats. Uncoupling protein-1 (UCP1) mRNA in brown adipose tissue (BAT), an index of energy expenditure through nonshivering thermogenesis, was decreased in rats consuming HFD. Treatment with rAAV-lep significantly augmented BAT UCP1 mRNA expression, indicating increased thermogenic energy expenditure. These findings demonstrate that central leptin gene therapy efficiently prevents weight gain, increased adiposity, and hyperinsulinemia in rats consuming an HFD by decreasing energy intake and increasing thermogenic energy expenditure.

Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Body Composition; Carrier Proteins; Dependovirus; Dietary Fats; Energy Intake; Energy Metabolism; Fatty Acids, Nonesterified; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Ghrelin; Green Fluorescent Proteins; Hyperinsulinism; Ion Channels; Leptin; Luminescent Proteins; Male; Membrane Proteins; Mitochondrial Proteins; Obesity; Peptide Hormones; Peptides; Rats; Rats, Sprague-Dawley; RNA, Messenger; Thermogenesis; Triglycerides; Uncoupling Protein 1; Weight Gain

Insulin is thought to be an important regulator of leptin secretion. However, increasing evidence suggests that insulin-mediated glucose uptake rather than insulin per se regulates circulating leptin concentration. Here, we hypothesised that a reduction of insulin sensitivity, ie insulin resistance, will diminish the stimulatory effect of insulin on leptin secretion as a consequence of decreased insulin-mediated glucose uptake.. Changes in serum leptin concentration during 30 hyperinsulinaemic-hypoglycaemic clamps were studied after induction of different levels of insulin resistance in normal-weight men. In 15 subjects insulin sensitivity was reduced by exposing them to a 2.5 h antecedent hypoglycaemia (3.1 mmol/l) induced by a high rate of insulin infusion (15.0 mU/min/kg) on the day before the proper experiment ('ante-hypo' condition). In the other 15 subjects no antecedent hypoglycaemia was induced ('control' condition). The proper experiment on both conditions was a 6 h stepwise hypoglycaemic clamp induced by a constant rate of insulin infusion (1.5 mU/min/kg).. Experiments were carried out in 30 lean healthy subjects (age, mean +/- s.e.m., 26 +/- 1 y; body mass index, 23.1 +/- 0.6 kg/m2).. As expected, glucose demand during the clamp was lower in the ante-hypo condition than in the control condition (gram of glucose infused per kilogram body weight, 1.52 +/- 0.16 vs 2.01 +/- 0.17 g/kg; P < 0.05). During the clamp, leptin levels increased by 25.4 +/- 4.3% in the control condition (P < 0.05), but not in the ante-hypo condition (+4.8 +/- 4.5%; P > 0.25). Thus, serum leptin response to the clamp significantly differed between the two conditions (P < 0.01). Across both conditions, the increase of leptin levels during the clamp was correlated with the amount of glucose infused (r = 0.37; P < 0.05).. Considering that insulin concentrations were identical during both clamp conditions, the data indicate that experimentally-induced insulin resistance diminishes the stimulatory effect of insulin on leptin secretion.

Topics: Adult; Blood Glucose; Body Mass Index; Glucose Clamp Technique; Humans; Hydrocortisone; Hyperinsulinism; Hypoglycemia; Insulin Resistance; Kinetics; Leptin; Male

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

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

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

In addition to suppressing appetite, leptin may also modulate insulin secretion and action. Leptin was administered here to insulin-resistant rats to determine its effects on secretagogue-stimulated insulin release, whole body glucose disposal, and insulin-stimulated skeletal muscle glucose uptake and transport. Male Wistar rats were fed either a normal (Con) or a high-fat (HF) diet for 3 or 6 mo. HF rats were then treated with either vehicle (HF), leptin (HF-Lep, 10 mg. kg(-1). day(-1) sc), or food restriction (HF-FR) for 12-15 days. Glucose tolerance and skeletal muscle glucose uptake and transport were significantly impaired in HF compared with Con. Whole body glucose tolerance and rates of insulin-stimulated skeletal muscle glucose uptake and transport in HF-Lep were similar to those of Con and greater than those of HF and HF-FR. The insulin secretory response to either glucose or tolbutamide (a pancreatic beta-cell secretagogue) was not significantly diminished in HF-Lep. Total and plasma membrane skeletal muscle GLUT-4 protein concentrations were similar in Con and HF-Lep and greater than those in HF and HF-FR. The findings suggest that chronic leptin administration reversed a high-fat diet-induced insulin-resistant state, without compromising insulin secretion.

Topics: 3-O-Methylglucose; Animals; Blood Glucose; Body Mass Index; Diet; Dietary Fats; Energy Intake; Glucose Clamp Technique; Glucose Tolerance Test; Glucose Transporter Type 4; Glycogen; Hyperinsulinism; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Male; Monosaccharide Transport Proteins; Muscle Proteins; Muscle, Skeletal; Rats; Rats, Wistar; Tolbutamide

The relationships between abdominal and pelvic fat compartments and glucose and lipid metabolism were investigated in early postmenopausal women. Fifty-five healthy, postmenopausal women aged 52-53 yr participated in the study. Fat distribution (intra-abdominal and sc abdominal fat, and intrapelvic and sc pelvic fat) was estimated by computed tomography. Insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp. In a multiple regression analysis, the size of the intra-abdominal fat compartment was the only significant predictor of insulin sensitivity (r(2) = 24%; P = 0.0002). Plasma triglycerides were closely related to the size of the intra-abdominal fat compartment (r(2) = 26%; P < 0.0001), whereas plasma free fatty acid concentrations only correlated to the size of the sc abdominal fat compartment (r(2) = 18.5%, P = 0.001). In early postmenopausal women the amount of the intra-abdominal fat strongly influences insulin sensitivity and plasma triglyceride levels, whereas plasma free fatty acids are closely related to the amount of the sc abdominal fat. Accordingly, from a metabolic standpoint it seems most essential to reduce intra-abdominal fat in postmenopausal women.

Topics: Abdomen; Adipose Tissue; Blood Glucose; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Exercise Test; Fatty Acids, Nonesterified; Female; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Insulin Secretion; Leptin; Lipids; Middle Aged; Postmenopause; Reference Values; Regression Analysis; Skin; Tomography, X-Ray Computed; Triglycerides

To assess the acute regulation of leptin concentrations by insulin, glucose and free fatty acids (FFAs).. Four protocols: saline control experiment (CON); hyperglycemic clamps (approximately 8.3 mmol/l, 120 min) after an overnight fast (12 FAST); after a 36 h fast (36 FAST); and after a 36 h fast during which Intralipid/heparin was given over the last 24 h (36 FAST+FFA).. Lean, young, healthy volunteers; control group (n=6), experimental group (n=6).. Serum leptin concentrations.. Glucose and insulin concentrations were similar during the three clamp protocols. Average FFAs during the last 60 min of the clamp were 671+/-68 microM (CON),109+/-15 microM (12 FAST), 484+/-97 microM (36 FAST) and 1762+/-213 microM (36 FAST+FFA). Leptin concentrations decreased similarly during 36 FAST and 36 FAST+FFA. Leptin concentrations at 120 min (expressed as percentage of mean basal value) were 0.82+/-0.02 (CON), 0.93+/-0.08 (12 FAST) (P=0.29), 1.19+/-0.06 (36 FAST) (P<0.01) and 1.44+/-0.12 (36 FAST+FFA) (P<0.01).. During a one-day fast leptin concentrations decrease regardless of maintainance of an isocaloric balance. During acute hyperinsulinemic hyperglycemia leptin concentrations increase only after a preceding fast. This increase was most pronounced during simultaneous elevation of FFAs. Overall, our findings are compatible with the hypothesis that leptin secretion may be coupled to triglyceride synthesis rather than to the absolute lipid content of the adipocyte. International Journal of Obesity (2001) 25, 138-142

Topics: Adult; Blood Glucose; Fasting; Fat Emulsions, Intravenous; Fatty Acids, Nonesterified; Female; Glucose Clamp Technique; Heparin; Humans; Hyperglycemia; Hyperinsulinism; Kinetics; Leptin; Male; Triglycerides

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

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

Studies reveals that plasma leptin levels (LEP) in females are higher than those in males, and that LEP in hypertensive subjects are higher than those in BMI-matched normotensive subjects. To investigate the relationships among LEP, blood pressure (BP) and insulin sensitivity, we studied these relationships in 133 Japanese males and 263 females. LEP were positively correlated with BP, body mass index, body fat mass (FM) and homeostasis model assessment (HOMA). Regression analysis in which age and FM were adjusted showed LEP were associated with BP and HOMA. Even with adjustment by age, FM and HOMA, LEP were still positively correlated BP in males. LEP in insulin-resistant hypertensives was significantly higher than those in insulin-sensitive hypertensives, in insulin-sensitive normotensives and in insulin-resistant normotensives in males. However, in females, a significantly higher LEP was observed in insulin-resistant subjects than in insulin-sensitive subjects regardless of hypertension. These data suggest that it would be sexual difference in the relationships among hyperleptinemia, hyperinsulinemia and hypertension.

Topics: Adult; Blood Pressure; Body Mass Index; Female; Humans; Hyperinsulinism; Hypertension; Insulin; Insulin Resistance; Japan; Leptin; Male; Middle Aged; Population Surveillance; Sex Factors

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

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

New Zealand obese (NZO) mouse, a genetic model of obesity, shows hyperphagia, hyperinsulinemia and leptin resistance. We analyzed subcutaneous adipose tissue proteins in NZO mice with a two-dimensional gel electrophoresis technique followed by protein sequence analysis. NZO mice showed hyperinsulinemia and hyperleptinemia. Abdominal subcutaneous adipose tissue was inspected in NZO and C57BL/6J lean mice. Two-dimensional gel electrophoresis detected 4 spots which were obviously reduced in NZO mice. Those spots were p26, p19, p18 and p15. Internal sequences of the p26 and p15 protein were homologous with those of carbonic anhydrase III, p19 was cytochrome b5, p18 was superoxide dismutase. Serum arachidonic acid level in NZO mice was lower by 80% of C57BL/6J mice. The present study demonstrated the reduction of several enzymes related to lipid metabolism in NZO mice. These data raises the hypothesis that the supposed changes of membrane fluidity caused by altered membrane lipid content may involve central leptin resistance of this model of obesity.

Topics: Adipose Tissue; Amino Acid Sequence; Animals; Arachidonic Acid; Blood Glucose; Carbonic Anhydrase III; Cytochromes b5; Drug Resistance; Electrophoresis, Gel, Two-Dimensional; Fatty Acids; Hyperinsulinism; Leptin; Male; Membrane Fluidity; Membrane Lipids; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Proteins; Superoxide Dismutase

We examined whether low-dose dexamethasone administration during late pregnancy modifies hepatic and/or peripheral insulin action or glucose-stimulated insulin secretion. Dexamethasone (100 microg/kg maternal body weight/d) was administered via an osmotic minipump from d 14--19 of gestation. Maternal glucose-insulin homeostasis was assessed on d 19 of pregnancy in the postabsorptive state. Insulin secretion and glucose tolerance was assessed after iv glucose, and insulin action examined during insulin infusion at euglycemia. Dexamethasone treatment during late pregnancy elicited fasting hyperinsulinaemia (by 88%; P < 0.001) and hyperglycaemia (by 20%; P < 0.05), and enhanced endogenous glucose production (by 29%; P < 0.001). Insulin secretion and rates of glucose disappearance after iv glucose were greatly impaired (by 44% and 39% respectively; P < 0.05). Suppression of endogenous glucose production by insulin was enhanced by dexamethasone treatment, but insulin's ability to promote glucose clearance was diminished. We demonstrate that excess maternal glucocorticoids during late pregnancy impairs glucose-stimulated insulin secretion and insulin-simulated glucose clearance but enhances insulin's ability to suppress endogenous glucose production. The data also indicate that elevated maternal glucocorticoids impair adaptations of the endocrine pancreas to pregnancy in vivo in that insulin hypersecretion in response to deteriorating peripheral insulin action is no longer apparent, leading to impaired glucose tolerance.

Topics: Animals; Body Weight; Dexamethasone; Eating; Female; Glucocorticoids; Glucose; Hyperglycemia; Hyperinsulinism; Injections, Intravenous; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Leptin; Liver; Postprandial Period; Pregnancy; Pregnancy Complications; Pregnancy, Animal; Rats; Rats, Wistar

Brain-derived neurotrophic factor has been associated previously with the regulation of food intake. To help elucidate the role of this neurotrophin in weight regulation, we have generated conditional mutants in which brain-derived neurotrophic factor has been eliminated from the brain after birth through the use of the cre-loxP recombination system. Brain-derived neurotrophic factor conditional mutants were hyperactive after exposure to stressors and had higher levels of anxiety when evaluated in the light/dark exploration test. They also had mature onset obesity characterized by a dramatic 80-150% increase in body weight, increased linear growth, and elevated serum levels of leptin, insulin, glucose, and cholesterol. In addition, the mutants had an abnormal starvation response and elevated basal levels of POMC, an anorexigenic factor and the precursor for alpha-MSH. Our results demonstrate that brain derived neurotrophic factor has an essential maintenance function in the regulation of anxiety-related behavior and in food intake through central mediators in both the basal and fasted state.

Topics: Animals; Anxiety; Body Weight; Brain; Brain-Derived Neurotrophic Factor; Fasting; Fluoxetine; Gene Deletion; Gene Expression; Hyperglycemia; Hyperinsulinism; Hyperkinesis; Hypothalamus; Integrases; Leptin; Mice; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; RNA, Messenger; Selective Serotonin Reuptake Inhibitors; Serotonin; Transfection; Viral Proteins

Leptin resistance in obese humans seems to be predominantly caused by signalling abnormalities at the post receptor level. Leptin resistance in obese individuals is frequently associated with insulin resistance and pronounced hyperinsulinaemia indicating a negative crosstalk of the insulin and leptin signalling chain.. This hypothesis was tested using a cell model of peripheral leptin signalling, i. e. insulin-secreting cell lines (RINr1046-38). Mechanisms for a crosstalk between the insulin and leptin signalling pathway were also studied in rat-1 and HEK293 cells overexpressing elements of the insulin and leptin signalling chain.. The effects of leptin on insulin secretion are completely cancelled by a 4-h preincubation with 1 nmol/l insulin, supporting the hypothesis of a negative crosstalk of insulin and leptin signalling. We investigated the potential molecular mechanisms in more detail in HEK293 cells and Rat-1 fibroblasts that overexpressed proteins of the insulin and leptin signalling chain. Leptin (60 ng/ml) stimulated autophosphorylation of JAK-2 in HEK 293 cells. This leptin effect could be inhibited by simultaneous treatment of cells with insulin. Furthermore, overexpression of the insulin receptor in HEK 293 cells clearly reduced JAK-2 phosphorylation and led further downstream to a diminished phosphatidylinositol 3-kinase activity. The inhibitory effect of the insulin signal could be partially prevented by transfection of the cells with an inactive mutant of the tyrosine phosphatase SHP-1.. In summary, our data suggest that the insulin receptor signalling pathway interferes with leptin signalling at the level of JAK-2. Inhibition of JAK-2 phosphorylation might occur through SHP-1-dependent pathways, indicating that hyperinsulinaemia contributes to the pathogenesis of leptin resistance.

Topics: Animals; Carrier Proteins; Cell Line; Drug Resistance; Electrophoresis, Polyacrylamide Gel; Embryo, Mammalian; Gene Expression; Humans; Hyperinsulinism; Insulin; Insulinoma; Intracellular Signaling Peptides and Proteins; Janus Kinase 2; Kidney; Leptin; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Phosphorylation; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Protein Tyrosine Phosphatases; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Rats; Receptor, Insulin; Receptors, Cell Surface; Receptors, Leptin; Signal Transduction; Transfection; Tumor Cells, Cultured

The adverse metabolic consequences of obesity are best predicted by the quantity of visceral fat. Excess glucocorticoids produce visceral obesity and diabetes, but circulating glucocorticoid levels are normal in typical obesity. Glucocorticoids can be produced locally from inactive 11-keto forms through the enzyme 11beta hydroxysteroid dehydrogenase type 1 (11beta HSD-1). We created transgenic mice overexpressing 11beta HSD-1 selectively in adipose tissue to an extent similar to that found in adipose tissue from obese humans. These mice had increased adipose levels of corticosterone and developed visceral obesity that was exaggerated by a high-fat diet. The mice also exhibited pronounced insulin-resistant diabetes, hyperlipidemia, and, surprisingly, hyperphagia despite hyperleptinemia. Increased adipocyte 11beta HSD-1 activity may be a common molecular etiology for visceral obesity and the metabolic syndrome.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Abdomen; Adipocytes; Adipose Tissue; Animals; Body Composition; Cell Size; Corticosterone; Dietary Fats; Disease Models, Animal; Eating; Gene Targeting; Humans; Hydroxysteroid Dehydrogenases; Hyperglycemia; Hyperinsulinism; Insulin Resistance; Leptin; Lipid Metabolism; Lipids; Lipoprotein Lipase; Male; Metabolic Syndrome; Mice; Mice, Transgenic; Obesity; Receptors, Glucocorticoid; Viscera; Weight Gain

Overweight is a considerable clinical problem in patients treated with antipsychotic agents. Recent results suggest that insulin resistance with increased insulin levels is also associated with treatment with the atypical antipsychotic agent clozapine. Leptin is important for the control of body weight and has been proposed to be a link between obesity and the insulin resistance syndrome. This study examined if clozapine-treated subjects and subjects treated with conventional antipsychotics had increased leptin levels compared with the general population and whether there was a gender difference in this respect.. Clozapine-treated patients (N = 41), patients treated with conventional antipsychotic drugs (N = 62), and healthy subjects from the Northern Sweden Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) project (N = 189) were investigated with a cross-sectional study design. Weight, body mass index (BMI), and plasma leptin concentrations were measured, and all study subjects were investigated for the presence of diabetes mellitus. Drug treatment, health status, and smoking habits were registered.. After adjustment for gender, BMI, smoking habits, age, and diabetes, hyperleptinemia was independently (p < .001) associated with clozapine treatment and with treatment with conventional antipsychotics (p < .005) within a multiple regression analysis. In separate multiple regression analyses, leptin levels were significantly associated with clozapine treatment in men (p = .002) and women (p =.023) and with conventional antipsychotic treatment in men (p = .027) but not in women.. Treatment with clozapine as well as with conventional antipsychotics is associated with increased levels of circulating leptin. Hyperleptinemia can be an important link in the development of overweight and the insulin resistance syndrome in subjects receiving antipsychotic drugs, especially atypical agents like clozapine.

Topics: Adult; Aged; Antipsychotic Agents; Body Mass Index; Clozapine; Cross-Sectional Studies; Delayed-Action Preparations; Dose-Response Relationship, Drug; Female; Humans; Hyperinsulinism; Leptin; Male; Middle Aged; Obesity; Psychotic Disorders; Radioimmunoassay

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

Human obesity and high fat feeding in rats are associated with the development of insulin resistance and perturbed carbohydrate and lipid metabolism. It has been proposed that these metabolic abnormalities may be reversible by interventions that increase plasma leptin. Up to now, studies in nongenetic animal models of obesity and in human obesity have concentrated on multiple injection therapy with mixed results. Our study sought to determine whether a sustained, moderate increase in plasma leptin, achieved by administration of a recombinant adenovirus containing the leptin cDNA (AdCMV-leptin) would be effective in reversing the metabolic abnormalities of the obese phenotype. Wistar rats fed a high-fat diet (HF) were heavier (P < 0.05), had increased fat mass and intramuscular triglycerides (mTG), and had elevated plasma glucose, insulin, triglyceride, and free fatty acids compared with standard chow-fed (SC) control animals (all P < 0.01). HF rats also had impaired glucose tolerance and were markedly insulin resistant, as demonstrated by a 40% reduction in insulin-stimulated muscle glucose uptake (P < 0.001). Increasing plasma leptin levels to 29.0 +/- 1.5 ng/ml (from 7.0 +/- 1.4 ng/ml, P < 0.001) for a period of 6 days decreased adipose mass by 40% and normalized plasma glucose and insulin levels. In addition, insulin-stimulated skeletal muscle glucose uptake was normalized in hyperleptinemic rats, an effect that correlated closely with a 60% (P < 0.001) decrease in mTG. Importantly, HF rats that received a control adenovirus containing the beta-galactosidase cDNA and were calorically matched to AdCMV-leptin-treated animals remained hyperglycemic, hyperinsulinemic, insulin resistant, and maintained elevated mTG. We conclude that a gene-therapeutic intervention that elevates plasma leptin moderately for a sustained period reverses diet-induced hyperglycemia, hyperinsulinemia, and skeletal muscle insulin resistance, and that these improvements are tightly linked to leptin-induced reductions in mTG.

Topics: Animals; Blood; Dietary Fats; Fasting; Genetic Therapy; Hyperglycemia; Hyperinsulinism; Insulin Resistance; Leptin; Male; Muscle, Skeletal; Rats; Rats, Wistar; Triglycerides

The co-existence of hyperinsulinemia and hyperleptinemia of obesity is well established. Additionally, both insulin resistance and leptin resistance are also characteristic of these states. Possible central nervous system (CNS) mechanisms could mediate these responses in that leptin receptors are located on hypothalamic neurons that coexpress neuropeptide-Y (NPY) or proopiomelanocortin (POMC) and both peptides that have been implicated as mediators of the CNS action of leptin. Leptin has been demonstrated to decrease or down regulate NPY expression and increase POMC expression. Insulin also has been demonstrated to decrease NPY and insulin insufficiency is associated with an increased POMC. Since both leptin and insulin share and modulate the same effector systems, we investigated the effect of CNS-induced hyperinsulinemia on the subsequent cardiovascular and sympathetic nervous response to leptin. Normal rats were implanted with intracerebroventricular (i.c.v.) cannula and allowed to recover. They were treated with insulin via i.c.v. cannula for 3 days. Following treatment, they were instrumented for the recording of cardiovascular and sympathetic nervous responses. Intracerebroventricular leptin administration in normal animals result in a progressive increase in both lumbar sympathetic nerve activity and mean arterial pressure. However, in animals pretreated with insulin for 3 days the leptin-induced response was completely attenuated. However, insulin treatment did not affect the POMC peptide product, alpha-melanocyte stimulating hormone (alphaMSH), mediated sympathetic nervous and cardiovascular responses. From these studies we conclude that CNS hyperinsulinemia can act to attenuate the leptin-induced increases in sympathetic nervous and cardiovascular system activity. The decreased responsiveness is not due to decreased sensitivity of the melanocortin, alphaMSH, mediated pathway.We suggest that the hyperinsulinemia of obesity may play a role in the obesity-induced leptin resistance.

Topics: alpha-MSH; Animals; Blood Pressure; Body Weight; Cerebral Ventricles; Drug Administration Schedule; Heart Rate; Hyperinsulinism; Injections, Intraventricular; Insulin; Leptin; Male; Rats; Rats, Wistar; Sympathetic Nervous System

To determine if aging is associated with altered serum leptin response to diet-induced changes in endogenous hyperinsulinemia, male Fisher 344 (F344) rats at different age groups were studied while on regular rat chow and following 10 days of experimental diets consisting of 60% of the weight as fructose or glucose. The serum leptin concentration (ng/ml) gradually increased from basal levels of 2.5+/-0.1 at age of 4 months to 3.7+/-0.1, 6.9+/-0.9, 9. 4+/-0.3 and 8.9+/-1.1 at 6, 12, 18 and 24 months of age, respectively (P<0.001). Hyperinsulinemia associated with 60% fructose diet was associated with increased serum leptin levels in 4, 12, and 24 month old rats to 5.1+/-0.8, 6.7+/-1.2, and 8.6+/-1.1, respectively (P<0.001). Feeding 60% glucose diet also was associated with increased serum leptin levels in 4, 12 and 24 month old rats to 7.6+/-0.6, 7.2+/-0.7, and 9.1+/-1.1, respectively (P<0.001). Restricting dietary intake to 60% of the calories consumed by control rats for 10 days resulted in a decrease in serum leptin to 1.0+/-0.02 in 4 month old rats and 2.5+/-0.4 in 24 month old rats (P<0.01). It is concluded that aging in F344 rats is associated with increased serum leptin concentrations. However, diet-related hyperinsulinemic effect on leptin is blunted in aging rats although leptin response to caloric restriction is maintained. The inability of aging rats to mount hyperleptinemic response to dietary changes may contribute to the age-related increase in adiposity.

Topics: Aging; Animals; Dietary Sucrose; Energy Intake; Fructose; Glucose; Hyperinsulinism; Leptin; Male; Osmolar Concentration; Rats; Rats, Inbred F344

Protein-tyrosine phosphatase 1B (PTP-1B) is a major protein-tyrosine phosphatase that has been implicated in the regulation of insulin action, as well as in other signal transduction pathways. To investigate the role of PTP-1B in vivo, we generated homozygotic PTP-1B-null mice by targeted gene disruption. PTP-1B-deficient mice have remarkably low adiposity and are protected from diet-induced obesity. Decreased adiposity is due to a marked reduction in fat cell mass without a decrease in adipocyte number. Leanness in PTP-1B-deficient mice is accompanied by increased basal metabolic rate and total energy expenditure, without marked alteration of uncoupling protein mRNA expression. In addition, insulin-stimulated whole-body glucose disposal is enhanced significantly in PTP-1B-deficient animals, as shown by hyperinsulinemic-euglycemic clamp studies. Remarkably, increased insulin sensitivity in PTP-1B-deficient mice is tissue specific, as insulin-stimulated glucose uptake is elevated in skeletal muscle, whereas adipose tissue is unaffected. Our results identify PTP-1B as a major regulator of energy balance, insulin sensitivity, and body fat stores in vivo.

Topics: Adipose Tissue; Animals; Body Weight; Carrier Proteins; Energy Metabolism; Female; Glucose; Glucose Tolerance Test; Homeostasis; Hyperinsulinism; Insulin Resistance; Ion Channels; Leptin; Male; Membrane Proteins; Membrane Transport Proteins; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mitochondrial Proteins; Muscle, Skeletal; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatases; Proteins; RNA, Messenger; Uncoupling Protein 1; Uncoupling Protein 2; Uncoupling Protein 3

Overaccumulation of lipids in nonadipose tissues of obese rodents may lead to lipotoxic complications such as diabetes. To assess the pathogenic role of the lipogenic transcription factor, sterol regulatory element binding protein 1 (SREBP-1), we measured its mRNA in liver and islets of obese, leptin-unresponsive fa/fa Zucker diabetic fatty rats. Hepatic SREBP-1 mRNA was 2.4 times higher than in lean +/+ controls, primarily because of increased SREBP-1c expression. mRNA of lipogenic enzymes ranged from 2.4- to 4.6-fold higher than lean controls, and triacylglycerol (TG) content was 5.4 times higher. In pancreatic islets of fa/fa rats, SREBP-1c was 3.4 times higher than in lean +/+ Zucker diabetic fatty rats. The increase of SREBP-1 in liver and islets of untreated fa/fa rats was blocked by 6 weeks of troglitazone therapy, and the diabetic phenotype was prevented. Up-regulation of SREBP-1 also occurred in livers of Sprague-Dawley rats with diet-induced obesity. Hyperleptinemia, induced in lean +/+ rats by adenovirus gene transfer, lowered hepatic SREBP-1c by 74% and the lipogenic enzymes from 35 to 59%. In conclusion, overnutrition increases and adenovirus-induced hyperleptinemia decreases SREBP-1c expression in liver and islets. SREBP-1 overexpression, which is prevented by troglitazone, may play a role in the ectopic lipogenesis and lipotoxicity complicating obesity in Zucker diabetic fatty rats.

Topics: Adenoviridae; Animals; CCAAT-Enhancer-Binding Proteins; Chromans; DNA-Binding Proteins; Genetic Vectors; Hyperinsulinism; Hypolipidemic Agents; Islets of Langerhans; Leptin; Liver; Male; Nuclear Proteins; Obesity; Rats; Rats, Sprague-Dawley; Rats, Zucker; Sterol Regulatory Element Binding Protein 1; Sterol Regulatory Element Binding Protein 2; Thiazoles; Thiazolidinediones; Transcription Factors; Troglitazone; Up-Regulation

Plasma leptin has been shown to correlate positively with many indices of obesity, as well as insulin resistance. For a given body weight, the levels are higher in women than in men, but the reasons for this difference are not clear. Insulin has been shown to stimulate leptin production by adipose tissue in vivo and in vitro. Previous studies have reported that leptin levels are similar in diabetic and nondiabetic individuals. However, these studies were not performed in newly diagnosed diabetics, and other variables (such as gender) could have confounded the results. Therefore, the goal of the present cross-sectional study is to examine the effect of metabolic variables (such as glucose and insulin) on plasma leptin concentrations in men and women separately. We measured leptin levels in 48 subjects (17 with newly diagnosed type 2 diabetes mellitus, 13 with impaired glucose tolerance [IGT], and 18 normal individuals). The 3 groups were well matched for gender, age, and body mass index (BMI). When adjusted for the BMI and gender, a statistically significant gender-related difference in mean plasma leptin was observed across the 3 glucose tolerance subgroups (P < .03 by analysis of covariance [ANCOVA]). More specifically, plasma leptin levels were, on average, 44% lower in women with diabetes or IGT versus normal women (P < .02). No such between-group difference was observed in the men. In univariate analysis in the same female subgroup, plasma leptin correlated positively with fasting insulin (rs = +.43, P < .06) and negatively with 2-hour post-75-g glucose load plasma glucose concentration (rs = -.54, P < .02). In a multiple regression model controlling for the BMI in the female subgroup, circulating insulin and glucose concentrations 2 hours after the 75-g glucose load were good predictors of fasting plasma leptin (r = +.38, P = .02 and r = -.70, P < .001, respectively). Leptin levels in women appear to be influenced independently and to an important degree by ambient plasma glucose and plasma insulin concentrations. These findings suggest that the synthesis of leptin by adipose tissue is more susceptible to in vivo regulation by insulin and glucose in women than in men. Plasma leptin concentrations were also lower in women with IGT or type 2 diabetes versus normal women, suggesting that fasting and/or postprandial hyperglycemia interferes with the stimulatory effect of plasma insulin on the synthesis of leptin by adipose tissue in women only.

Topics: Adipose Tissue; Adult; Aged; Blood Glucose; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Fasting; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Leptin; Male; Middle Aged; Multivariate Analysis; Predictive Value of Tests; Regression Analysis; Sex Factors

Genetic and pharmacological studies have defined a role for the melanocortin-4 receptor (Mc4r) in the regulation of energy homeostasis. The physiological function of Mc3r, a melanocortin receptor expressed at high levels in the hypothalamus, has remained unknown. We evaluated the potential role of Mc3r in energy homeostasis by studying Mc3r-deficient (Mc3r(-/-)) mice and compared the functions of Mc3r and Mc4r in mice deficient for both genes. The 4-6-month Mc3r-/- mice have increased fat mass, reduced lean mass and higher feed efficiency than wild-type littermates, despite being hypophagic and maintaining normal metabolic rates. (Feed efficiency is the ratio of weight gain to food intake.) Consistent with increased fat mass, Mc3r(-/-) mice are hyperleptinaemic and male Mc3r(-/-) mice develop mild hyperinsulinaemia. Mc3r(-/-) mice did not have significantly altered corticosterone or total thyroxine (T4) levels. Mice lacking both Mc3r and Mc4r become significantly heavier than Mc4r(-/-) mice. We conclude that Mc3r and Mc4r serve non-redundant roles in the regulation of energy homeostasis.

Topics: Adipose Tissue; Age Factors; alpha-MSH; Animals; Blotting, Southern; Body Temperature; Body Weight; Calorimetry; Corticosterone; Feeding Behavior; Female; Genotype; Glucose; Humans; Hyperinsulinism; In Situ Hybridization; Insulin; Leptin; Male; Mice; Mice, Knockout; Models, Genetic; Motor Activity; Obesity; Oligopeptides; Phenotype; Protein Isoforms; Receptor, Melanocortin, Type 3; Receptor, Melanocortin, Type 4; Receptors, Corticotropin; Receptors, Peptide; Recombination, Genetic; Thyroxine; Time Factors; Tissue Distribution

The present study was conducted in order to analyze the relationship existing between leptin and insulin levels in massive weight loss and weight recovery. Thirteen patients with severe obesity, 14 patients with anorexia nervosa and 13 healthy control subjects were studied. The patients with severe obesity underwent a vertical banded gastroplasty followed by an 800 kcal/day diet for 12 weeks. They were evaluated prior to (body mass index [BMI] 51.2 +/- 8.8 Kg/m2) and after drastic weight loss (BMI 40.6 +/- 6.7 Kg/m2). Patients with anorexia nervosa were treated exclusively with nutritional therapy during 12 weeks, and they were evaluated at their lowest weight status (BMI 16.2 +/- 2.2 Kg/m2) and after weight recovery (BMI 17.9 +/- 2.3 Kg/m2). The BMI of the normal subjects was in the normal range of 20 to 27 Kg/m2 (average 22.8 +/- 2.6 Kg/m2). BMI, percentage of body fat, waist circumference, and serum levels of leptin, insulin, and C-peptide were determined in each patient and normal subject. In severely obese patients, serum leptin and insulin decreased significantly after drastic weight reduction (leptin: from 51.8 +/- 22.3 to 23.7 +/- 10.2 ng/ml; insulin: from 27.1 +/- 13.3 to 17.2 +/- 7.2 mU/ml). In patients with anorexia nervosa, the mean serum leptin levels were significantly higher after weight recovery (5.5 +/- 3.2 vs 7.6 +/- 6 ng/ml). Serum leptin in the severe obesity group correlated positively with BMI, percentage body fat and waist circumference before and after weight loss. In those patients suffering from anorexia nervosa, serum leptin correlated positively with the BMI, percentage of body fat, and waist circumference in the low weight state and after weight recovery. In addition, their serum insulin correlated with BMI and waist circumference after weight recovery. These data reveal that serum leptin concentration correlates significantly with the BMI and body fat content 1) in subjects with a range of weight and caloric intake, 2) in obese patients after drastic weight loss; 3) in anorexic patients after weight gain; and that hyper- or normoinsulinemia do not seem to have any influence on the leptin changes caused by weight loss or gain.

Topics: Adipose Tissue; Adolescent; Adult; Anorexia Nervosa; Anthropometry; Body Mass Index; C-Peptide; Combined Modality Therapy; Female; Gastroplasty; Humans; Hyperinsulinism; Insulin; Leptin; Male; Middle Aged; Obesity, Morbid; Postoperative Period; Weight Gain; Weight Loss

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

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

Hyperinsulinism and hyperandrogenism have the capacity to increase bone mineral density (BMD) and serum leptin, independently of body fat mass. We therefore assessed lumbar BMD and serum leptin in girls with the sequence of a low birthweight and precocious pubarche (PP) in childhood, in whom hyperinsulinism and hyperandrogenism have been described.. Fifty-two non-obese PP girls were studied (age range 6.9-14.9 years). Serum leptin was also measured in 42 control girls, matched for age, body mass index and pubertal stage.. BMD SDS, measured by dual-energy X-ray absorptiometry, was elevated in PP girls compared to the population reference (0.39 +/- 0.18 SDS; p = 0.03) and bone age, assessed from hand radiographs, was significantly advanced compared to chronological age (1.2 +/- 0.1 years; p < 0.0005).. Compared to control girls, PP girls had higher leptin levels for degree of body mass index (PP girls: 9.4 +/- 0.6 ng/ml; controls: 7.8 +/- 0.6 ng/ml; p = 0.01). In PP girls, serum leptin was inversely related to birthweight (r = -0.32, p = 0.01) and positively related to free androgen index (FAI) (r = 0.71, p < 0.0005). BMD SDS was also inversely related to birthweight (r = -0.26, p < 0.05) and positively related to serum leptin (r = 0.42, p < 0.05), FAI (r = 0.45, p < 0.05) and mean serum insulin during oral glucose tolerance testing (MSI) (r = 0.59, p < 0.0005). In multiple regression, MSI was the strongest determinant of BMD SDS (beta = 0.50, p = 0.002). In conclusion, elevated BMD and serum leptin in non-obese PP girls were related to degrees of low birthweight, hyperinsulinism and hyperandrogenism. The characteristic hyperinsulinism of PP girls is proposed to be the key variable in this constellation.

Topics: Adolescent; Age Determination by Skeleton; Androgens; Birth Weight; Body Mass Index; Bone Density; Child; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Leptin; Puberty, Precocious; Reference Values

Leptin controls feeding behavior and insulin secretion from pancreatic beta-cells. Insulin stimulates the production of leptin, thereby establishing an adipoinsular axis. Earlier we identified leptin receptors on pancreatic beta-cells and showed leptin-mediated inhibition of insulin secretion by activation of ATP-sensitive potassium channels. Here we examine transcriptional effects of leptin on the promoter of the rat insulin I gene in rodent beta-cells. A fall in levels of preproinsulin mRNA is detected in vivo in islets of ob/ob mice 24 h after a single injection of leptin, in isolated ob/ob islets treated with leptin in vitro and in the beta-cell line INS-1 on leptin exposure when preproinsulin mRNA expression is stimulated by 25 mM glucose or 10 nM glucagon-like peptide 1. Under these conditions, transcriptional activity of -410 bp of the rat insulin I promoter is inhibited by leptin, whereas transactivation of a 5'-deleted promoter (-307 bp) is not. The -307 sequence contains the known glucose-responsive control elements (E2:A3/4). Constitutive activation of ATP-sensitive potassium channels by diazoxide does not alter leptin inhibition of preproinsulin mRNA levels. Distinct protein-DNA complexes appear on the rat insulin I promoter sequences located between -307 and -410 with nuclear extracts from ob/ob islets in response to leptin, including a signal transducer and activator of transcription (STAT)5b binding site. These results indicate that leptin inhibits transcription of the preproinsulin gene by altering transcription factor binding to sequences upstream from the elements (307 bp) that confer glucose responsivity to the rat insulin I gene promoter. Thus leptin exerts inhibitory effects on both insulin secretion and insulin gene expression in pancreatic beta-cells, but by different cellular mechanisms.

Topics: Animals; Cell Line; DNA-Binding Proteins; Gene Expression Regulation; Glucagon; Glucagon-Like Peptide 1; Glucose; Hyperinsulinism; Insulin; Islets of Langerhans; Leptin; Mice; Mice, Obese; Nuclear Proteins; Peptide Fragments; Proinsulin; Promoter Regions, Genetic; Protein Precursors; Proteins; Rats; Recombinant Proteins; RNA, Messenger; Transcription, Genetic

It has been claimed that factors favoring the development or maintenance of animal or human obesity may include increases in glucocorticoid production or hyperresponsiveness of the hypothalamic-pituitary-adrenal axis. In normal rats, glucocorticoids have been shown to be necessary for chronic intracerebroventricular infusion of neuropeptide Y to produce obesity and related abnormalities. Conversely, glucocorticoids inhibited the body weight-lowering effect of leptin. Such dual action of glucocorticoids may occur within the central nervous system, since both neuropeptide Y and leptin act within the hypothalamus. The aim of this study was to determine the effects of glucocorticoids (dexamethasone) given intracerebroventricularly to normal rats on body weight homeostasis and hypothalamic levels of neuropeptide Y and corticotropin-releasing hormone. Continuous central glucocorticoid infusion for 3 days resulted in marked sustained increases in food intake and body weight relative to saline-infused controls. The infusion abolished endogenous corticosterone output and produced hyperinsulinemia, hypertriglyceridemia, and hyperleptinemia, three salient abnormalities of obesity syndromes. Central glucocorticoid infusion also produced a marked decrease in the expression of uncoupling protein (UCP)-1 and UCP-3 in brown adipose tissue and UCP-3 in muscle. Finally, chronic central glucocorticoid administration increased the hypothalamic levels of neuropeptide Y and decreased those of corticotropin-releasing hormone. When the same dose of glucocorticoids was administered peripherally, it resulted in decreases in food intake and body weight, in keeping with the decrease in hypothalamic neuropeptide Y levels. These results suggest that glucocorticoids induce an obesity syndrome in rodents by acting centrally and not peripherally.

Topics: Animals; Body Weight; Brain; Carrier Proteins; Corticosterone; Corticotropin-Releasing Hormone; Dexamethasone; Eating; Glucocorticoids; Homeostasis; Hyperinsulinism; Hypertriglyceridemia; Hypothalamus; Injections, Intraperitoneal; Ion Channels; Leptin; Membrane Proteins; Mitochondrial Proteins; Neuropeptide Y; Obesity; Proteins; Rats; Rats, Zucker; Uncoupling Protein 1

Plasma leptin is considered to play a role in maintenance of energy balance and body weight by neuroendocrine mechanisms. Thyroid hormones are permissive for adrenergic activation, which in turn has been shown to decrease leptin expression. This study was therefore designed to test the hypothesis that hyperthyroidism results in lower leptin concentrations, whereas hypothyroidism leads to higher plasma leptin concentrations. In addition, the effects of normalization of thyroid function on plasma leptin were investigated.. Fasting plasma leptin concentrations and body fat mass (total body electrical conductivity) were measured in patients with overt hypothyroidism and hyperthyroidism before and after successful treatment. Plasma leptin, glucose, insulin and free fatty acid concentrations were monitored during an oral glucose tolerance test (OGTT 75 g).. Fasting plasma leptin concentrations were similar in lean patients, independently of their thyroid function (hyperthyroid 12.5 +/- 2 ng mL-1, hypothyroid 10.2 +/- ng mL-1, euthyroid 12.7 +/- 3 ng mL-1). In obese hypothyroid patients, plasma leptin was threefold higher (P < 0.0005) than in lean hypothyroid patients, twofold higher (P < 0.005) than in obese hyperthyroid patients matched for fat mass and 30% increased (P < 0.01) compared with obese euthyroid subjects. There were no differences between fasting and post-prandial (OGTT) leptin concentrations in any group. Normalization of thyroid function did not affect plasma leptin, which remained elevated (P < 0.005) in formerly obese hypothyroid patients. Plasma leptin was not associated with serum thyroid hormones but highly correlated with body mass index and body fat mass in all patients (r = 0.85, P < 0.001). Plasma leptin correlated with plasma insulin concentration only in hyperthyroid patients (P < 0.01, r = 0.64), who presented with blunted stimulation of insulin release and higher plasma glucose (P < 0.05) than hypothyroid subjects.. The results indicate that (a) the correlation of leptin with body fat mass is preserved in thyroid dysfunction, (b) plasma leptin is markedly increased in obese hypothyroid hyperinsulinaemic patients and (c) plasma leptin is not affected by oral glucose loading.

Topics: Adult; Blood Glucose; C-Peptide; Fatty Acids, Nonesterified; Female; Glucose Tolerance Test; Humans; Hydrocortisone; Hyperinsulinism; Hyperthyroidism; Hypothyroidism; Insulin; Leptin; Male; Middle Aged; Obesity; Proteins

Whether serum leptin levels are associated with insulin resistance independent of the effects of hyperinsulinemia and adiposity is an important unanswered question. We examined the relationship between the rate of insulin-mediated glucose uptake and serum leptin concentrations among nondiabetic men and women.. A cross-sectional analysis was performed among 49 young to middle-aged men and women who participated in the Miami Community Health Study. All participants had measures of insulin resistance (euglycemic-hyperinsulinemic clamp), postchallenge insulin levels, fasting serum leptin levels, and several measures of adiposity.. The rate of insulin-mediated glucose uptake (M in milligrams per kilogram per minute) was significantly associated with leptin concentrations in both men (r = -0.83; P < 0.001) and women (r = -0.59; P < 0.001). M was also inversely related to percent body fat and to the 2-h insulin area under the curve (AUC). After covariate adjustment for sex, percent body fat, and AUC, leptin remained a significant correlate of M (P = 0.04).. Cross-sectionally, leptin was significantly associated with insulin resistance in this nondiabetic sample of men and women. There may be a different physiological mechanism to explain the leptin/insulin resistance association apart from the insulin/adiposity link. Confirmatory evidence awaits the results of clinical trials.

Topics: Adult; Blood Glucose; Cross-Sectional Studies; Ethnicity; Fasting; Female; Florida; Glucose Clamp Technique; Humans; Hyperinsulinism; Infusions, Intravenous; Insulin; Insulin Resistance; Leptin; Male; Proteins; Regression Analysis; Sex Factors

Centrally administered leptin has been shown to increase insulin-stimulated glucose utilization and to favor the expression of uncoupling proteins (UCPs). To study if leptin also has direct peripherally mediated effects on these processes, this hormone (1 mg/day) or its vehicle was infused i.v. for 4 days to lean rats and insulin-stimulated glucose utilization in skeletal muscle and adipose tissue as well as the expression of UCP messenger RNAs (mRNAs) in brown adipose tissue were measured. I.v. leptin administration resulted in decreases in food intake (31%), body weight gain, and plasma insulin levels (45%), in increases in overall (23%) as well as brown adipose tissue and muscle glucose utilization, and in decreases in white adipose tissue glucose uptake. Most of these changes were mimicked, in control rats, by giving them the same amount of food as that consumed by the leptin-infused group (pair-feeding). I.v. leptin infusion also favored the expression of UCPs in brown adipose tissue, either by increasing their expression or preventing the fall occurring during the pair-feeding regimen. Relative UCP expression levels were 100, 104, and 33 for UCP1, 100, 191, and 125 for UCP2 and 100, 107, and 29 for UCP3 in ad libitum fed control rats, in leptin-treated rats and in pair-fed control rats, respectively. These results suggest that the overall effect of leptin on glucose utilization and on the expression of UCPs may be mediated through central mechanism.

Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Blood Glucose; Body Weight; Carrier Proteins; Energy Intake; Feeding Behavior; Gene Expression Regulation; Glucose; Glucose Clamp Technique; Hyperinsulinism; Infusions, Intravenous; Insulin; Ion Channels; Leptin; Male; Membrane Proteins; Membrane Transport Proteins; Mitochondrial Proteins; Muscle, Skeletal; Proteins; Rats; Rats, Zucker; Recombinant Proteins; RNA, Messenger; Thinness; Transcription, Genetic; Uncoupling Agents; Uncoupling Protein 1; Uncoupling Protein 2; Uncoupling Protein 3; Weight Gain

To study the relationship between hyperinsulinaemia, insulin resistance, leptin and atherosclerosis in subjects with familial hypercholesterolaemia (FH).. Case-control cross-sectional study.. Lipid clinic, Johannesburg Hospital, South Africa.. Fasting serum lipid, glucose, insulin and leptin levels were measured in 24 homozygous FH subjects; 20 FH heterozygotes without coronary artery disease (CAD); 22 heterozygotes with documented CAD; and 20 healthy normocholesterolaemic subjects. Insulin resistance was calculated using the homeostasis model assessment (HOMA) formula.. Mean glucose and insulin levels were similar in all 4 groups. There was no significant difference in calculated insulin resistance between any of the groups. There was also no relationship between the degree of insulin resistance and total or LDL-cholesterol levels. Using Spearman's correlation coefficient (Rs) calculated insulin resistance correlated with triglyceride (Rs = 0.27; P<0.05) and inversely with HDL-cholesterol (Rs = -0.26; P<0.05). Fasting insulin concentrations and calculated insulin resistance were similar in FH subjects with overt CAD compared to those without. Leptin levels were higher in the FH subjects with CAD. However, these subjects were older and had a larger body mass index (BMI), and when adjusted for age and BMI, only BMI correlated with leptin levels (multiple r = 0.65; P<0.001).. In the absence of other causes of insulin resistance, FH subjects have normal fasting insulin levels and, in general, they are not insulin resistant. Insulin resistance appears to play little role in the pathogenesis of accelerated atherosclerosis in FH.

Topics: Adolescent; Adult; Arteriosclerosis; Blood Glucose; Body Mass Index; Coronary Disease; Female; Heterozygote; Homozygote; Humans; Hyperinsulinism; Hyperlipoproteinemia Type II; Insulin; Insulin Resistance; Leptin; Lipids; Male; Proteins

The mechanisms of marked increase in plasma leptin soon after ventromedial hypothalamus (VMH) lesions were investigated. Although rats did not gain body weight or parametrial fat-pad mass 24 h after the operation, the acute VMH-lesioned rats exhibited substantial five- and fourfold increases in plasma leptin levels compared with sham-operated control rats in fed (22.6 +/- 3.2 vs. 5.8 +/- 1.2 ng/ml) and fasted (8.8 +/- 2.0 vs. 2.3 +/- 0.3 ng/ml) states, respectively. Plasma insulin concentration was doubled in VMH-lesioned rats compared with sham-operated controls in both fed and fasting states. Northern blot analysis revealed that mRNA of ob gene was not increased in parametrial fat pad of animals 24 h after the creation of VMH lesions. However, leptin content in the fat pad was significantly increased in VMH-lesioned rats compared with sham-operated controls (32.2 +/- 4.7 vs. 17.4 +/- 2.3 ng/g wet tissue). The leptin content in parametrial fat pad was highly correlated with plasma leptin concentrations (r = 0.898, P < 0.001). To define the effect of hyperinsulinemia on their hyperleptinemia, a small dose of streptozotocin (STZ) (25 mg/kg body wt) was intravenously administered into rats 5 days before the creation of VMH lesions. Plasma insulin levels were not increased after VMH lesions in STZ-pretreated rats. Plasma leptin levels were halved in the absence of hyperinsulinemia, but still remained twofold higher than those in their sham-operated counterparts (9.9 +/- 1.3 vs. 4.8 +/- 0.7 ng/ml). These results indicate that the destruction of VMH rapidly promotes leptin production before obesity develops through an enhanced translational process in which hyperinsulinemia occurring after VMH lesioning plays an important role. The present study also suggests that there are other mechanisms that rapidly upregulate leptin production in adipocytes in VMH-lesioned rats in which the target organ of this hormone has been destroyed.

Topics: Animals; Blotting, Northern; Body Weight; Female; Hyperinsulinism; Hypothalamus, Middle; Insulin; Leptin; Obesity; Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger; Up-Regulation

Insulin-induced leptinemia in humans appears to be blunted by insulin resistance. We therefore examined the relationship between insulin action and plasma leptin by monitoring regional and whole body lipolysis and plasma leptin levels in 15 premenopausal women (body fat range, 14-59%) during a two-stage euglycemic clamp (insulin was infused 90 min each at 6-10 and 12-20 mU/m2 x min). Microdialysis probes were placed in abdominal and femoral sc adipose tissue. Subjects were given a primed, constant infusion of a stable isotope tracer (2H5-glycerol), and plasma glycerol isotope enrichments were analyzed by mass spectrometry to determine glycerol kinetics. Although there was no mean change in plasma leptin during the clamp (baseline, 16.6 +/- 4.5 ng/mL; final, 16.3 +/- 4.3 ng/mL), there was large interindividual variability in the changes in plasma leptin (range, -18% to +19%). Changes in plasma leptin during the clamp stages were correlated with abdominal dialysate glycerol concentrations (r = -0.44; P < 0.05), but not femoral dialysate glycerol concentrations (r = -0.15), the rate of appearance of glycerol in plasma (r = 0.005), or plasma insulin levels (r = 0.16). The results suggest that insulin-induced changes in plasma leptin are more related to the lipolytic state (i.e. low leptin response when lipolysis is high) of abdominal sc adipose tissue than that of other fat depots.

Topics: Abdomen; Adipose Tissue; Adult; Blood Circulation; Female; Glycerol; Humans; Hyperinsulinism; Insulin; Leptin; Lipolysis; Time Factors

Plasma leptin levels and plasma insulin levels have been found to be elevated in patients with essential hypertension (EH) and have been suggested to be components of the metabolic syndrome. Increased heart rate (HR) may predict the development of EH in normal or borderline-hypertensive individuals. The aim of our study was to test the hypothesis that elevated plasma leptin and insulin levels as well as systolic blood pressure (SBP) and diastolic blood pressure (DBP) and increased resting HR preexist in the healthy offspring of patients with EH.. Twenty-six (12 male, 14 female) healthy offspring of hypertensive patients, mean age 16 +/- 2.5 years and body mass index (BMI) of 21.5 +/- 2.8 kg/m(2) (group A), and 30 (14 male, 16 female) healthy offspring of normotensive patients, mean age 17 +/- 2.3 years and BMI of 21.9 +/- 2.4 kg/m(2) (group B), were studied. (The two groups were matched for sex, age, and BMI). Mean SBP, DBP, resting HR, plasma leptin, and plasma insulin levels (radioimmunoassay method) were determined in the whole study population. Mean SBP, DBP, and resting HR were significantly higher in group A than in group B (120 +/- 12 vs 112 +/- 9.5 mm Hg, 77 +/- 9 vs 72 +/- 7 mm Hg, 79 +/- 8 vs 75 +/- 5 beats/min, P <.01, P <.05, and P <.05, respectively). Plasma leptin and insulin levels were significantly higher in group A than in group B (9 +/- 5.06 vs 5.6 +/- 2.5 ng/mL and 20.11 +/- 11.3 vs 14.8 +/- 5.2 microIU/mL, P <.01 and P <.05, respectively).. Our findings support the hypothesis that hyperleptinemia, hyperinsulinemia, and elevated blood pressure and resting HR preexist in the healthy offspring of patients with EH.

Topics: Adolescent; Biomarkers; Blood Pressure; Female; Genetic Predisposition to Disease; Heart Rate; Humans; Hyperinsulinism; Hypertension; Insulin; Leptin; Male; Radioimmunoassay

Leptin, the product of the ob gene, has been shown to increase heart rate and blood pressure through a stimulation of cardiac sympathetic nervous system activity, a phenomenon also involved in the pathogenesis of left ventricular hypertrophy in hypertensives. Thus, we hypothesize that plasma leptin concentration is associated with left ventricular hypertrophy. Forty hypertensive males and 15 healthy male subjects underwent anthropometric and echocardiographic evaluations, assessment of insulin sensitivity through euglycemic glucose clamp combined with indirect calorimetry, and determination of fasting plasma leptin concentration. Fasting plasma leptin levels were higher in hypertensives than in controls (6.48+/-2.9 versus 4. 62+/-1.5 ng/mL, P<0.05); these results were unchanged after adjustment for body mass index (P<0.05). In the whole group of patients (n=55), fasting plasma leptin concentration was correlated with body mass index (r=0.46, P<0.001) and waist/hip ratio (r=0.50, P<0.001); independent of body mass index and waist/hip ratio, fasting plasma leptin concentration was correlated (n=55) with whole-body glucose disposal (r=-0.27, P<0.04), interventricular septum thickness (r=0.34, P<0.001), posterior wall thickness (r=0.38, P<0.003), and the sum of wall thicknesses (r=0.68, P<0.001). In a multivariate analysis (n=55), age, body mass index, fasting plasma leptin concentration, plasma Na(+) concentration, whole-body glucose disposal, and diastolic blood pressure explained 68% of the variability of the sum of wall thicknesses with fasting plasma leptin concentration (P<0.03), whole body glucose disposal (P<0.002), and diastolic blood pressure (P<0.001), which were significantly and independently associated with the sum of wall thicknesses. In conclusion, our study demonstrates that fasting plasma leptin levels are associated with increased myocardial wall thickness independent of body composition and blood pressure levels in hypertensives.

Topics: Adult; Body Mass Index; Echocardiography; Humans; Hyperinsulinism; Hypertension; Hypertrophy, Left Ventricular; Insulin Resistance; Leptin; Male; Middle Aged

C57BL/6 female mice were fed high fat diets containing different types of carbohydrate (sucrose or corn starch) and contents of cholesterol (0.03 % or 1 %) to identify early metabolic changes leading to increases in leptin levels and eventual insulin resistance. Under identical dietary fat conditions, type of carbohydrate and cholesterol content contributed to the timing of leptin increases. Mice fed a high-fat, high-sucrose diet showed early (4 weeks) and robust increases in circulating insulin and leptin levels (2-fold and 5-fold, respectively). In contrast, mice fed this diet with added cholesterol or with sucrose substituted by corn starch led to marked delays (8-10 weeks) in the elevations of insulin and leptin, although body weight gains were nearly identical among test diet groups. Thus, sucrose in combination with saturated fat played a specific role in initiating early metabolic changes associated with elevated leptin and insulin levels. Because leptin levels were most reflective of changes in insulin, our data support a role for insulin in determining plasma leptin levels in mice.

Topics: Animals; Body Weight; Cholesterol; Cholesterol, Dietary; Diet; Dietary Carbohydrates; Dietary Fats; Dietary Sucrose; Female; Hyperinsulinism; Insulin; Insulin Resistance; Leptin; Lipoproteins; Liver; Mice; Mice, Inbred C57BL; Organ Size; Triglycerides

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

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

To study the relationship between serum leptin and circulating insulin under basal and in response to oral glucose administration in hyperinsulinemic patients with or without obesity.. Fifteen female patients of known hyperinsulinemia provided material for the study. Leptin and insulin in sera were estimated by radioimmunoassay methods.. Eight of the 15 hyperinsulinemic patients with high body mass index (BMI) (31 +/- 0.94 kg/m2) had significantly (p < 0.01) elevated serum leptin concentrations (26.1 +/- 2 ng/ml) as compared to the levels in the remaining seven non-obese hyperinsulinemic patients with BMI of 20 +/- 1.0 kg/m2; their mean levels of serum leptin were low 5.7 +/- 1.1 ng/ml. Four of the latter group had face-sparing partial lipodystrophy. The mean circulating leptin concentrations in the control group of seven healthy normoinsulinemic and regularly menstruating women with normal BMI (19 +/- 0.95 kg/m2) were 13.7 +/- 1.8 ng/ml.. The results of the present study in 15 hyperinsulinemic patients show that circulating levels of leptin are not related to serum insulin. However, there was a positive correlation with BMI. An interesting observation of the study is that, notwithstanding the normal BMI, the group of hyperinsulinemic patients with face-sparing partial lipodystrophy had the lowest levels of circulating leptin concentrations. They were closer to the values found in prepubertal girls.

Topics: Adolescent; Adult; Body Mass Index; Case-Control Studies; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Leptin; Lipodystrophy; Obesity; Reference Values

Troglitazone (CS-045) is one of the thiazolidinediones that activate the peroxisome proliferator-activated receptor gamma (PPARgamma), which is expressed primarily in adipose tissues. To elucidate the mechanism by which troglitazone relieves insulin resistance in vivo, we studied its effects on the white adipose tissues of an obese animal model (obese Zucker rat). Administration of troglitazone for 15 d normalized mild hyperglycemia and marked hyperinsulinemia in these rats. Plasma triglyceride level was decreased by troglitazone in both obese and lean rats. Troglitazone did not change the total weight of white adipose tissues but increased the number of small adipocytes (< 2,500 micron2) approximately fourfold in both retroperitoneal and subcutaneous adipose tissues of obese rats. It also decreased the number of large adipocytes (> 5,000 micron2) by approximately 50%. In fact, the percentage of apoptotic nuclei was approximately 2.5-fold higher in the troglitazone-treated retroperitoneal white adipose tissue than control. Concomitantly, troglitazone normalized the expression levels of TNF-alpha which were elevated by 2- and 1.4-fold in the retroperitoneal and mesenteric white adipose tissues of the obese rats, respectively. Troglitazone also caused a dramatic decrease in the expression levels of leptin, which were increased by 4-10-fold in the white adipose tissues of obese rats. These results suggest that the primary action of troglitazone may be to increase the number of small adipocytes in white adipose tissues, presumably via PPARgamma. The increased number of small adipocytes and the decreased number of large adipocytes in white adipose tissues of troglitazone-treated obese rats appear to be an important mechanism by which increased expression levels of TNF-alpha and higher levels of plasma lipids are normalized, leading to alleviation of insulin resistance.

Topics: Adipocytes; Adipose Tissue; Animals; Apoptosis; Blood Glucose; Blotting, Northern; Body Weight; Chromans; DNA; DNA, Complementary; Hyperglycemia; Hyperinsulinism; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Male; Mesentery; Polymerase Chain Reaction; Proteins; Rats; Rats, Zucker; Receptors, Cytoplasmic and Nuclear; Retroperitoneal Space; RNA; RNA, Messenger; Thiazoles; Thiazolidinediones; Transcription Factors; Triglycerides; Troglitazone; Tumor Necrosis Factor-alpha

We investigated the dose- and time-dependent effect of insulin infusion on peripheral and portal plasma leptin concentrations in normal rats. Three groups were studied: group I: euglycemic (6 mmol/l) insulin (6 mU . kg-1 . min-1) clamps for 0, 2, 4, 12, and 24 h; group II: euglycemic insulin (18 mU . kg-1 . min-1) clamp for 2 h; and group III: euglycemic insulin (3 mU . kg-1 . min-1) clamp for 7 days. In group III, food intake was quantified during days 1-7. After an overnight fast, peripheral and portal plasma leptin levels were identical (1.5 +/- 0.2 and 1.6 +/- 0.2 ng/ml). Insulin infusion (6 mU . kg-1 . min-1) for 2 h had no effect on plasma leptin levels (1.5 +/- 0.2 ng/ml). After 4 h (2.0 +/- 0.2 ng/ml), 12 h (2.2 +/- 0. 4 ng/ml), and 24 h (2.7 +/- 0.6 ng/ml; all P < 0.05) of insulin infusion, a progressive time-related increase in plasma leptin concentration was observed; portal vein leptin levels rose in parallel and were similar to peripheral levels. When insulin (18 mU . kg-1 . min-1) was infused for 2 h, plasma leptin levels increased to 3.0 +/- 0.3 ng/ml (P < 0.01). Seven days of constant insulin infusion (3 mU . kg-1 . min-1) resulted in a progressive increase in fasting plasma leptin and a parallel decrease in food intake. A mean increase in plasma leptin concentration of 1 ng/ml during the 7-day insulin infusion period was associated with a mean decrease in food intake of 2.5 g/day (multivariate ANOVA, P < 0.05). We conclude that the insulin-induced rise in peripheral and portal vein leptin levels is similar and both dose and time dependent. The inverse relationship between plasma leptin concentration and food intake during prolonged hyperinsulinemia, but not during short-term hyperinsulinemia, supports the role of leptin in long-term food consumption.

Topics: Animals; Blood Glucose; Eating; Glucose Clamp Technique; Hyperinsulinism; Insulin; Kinetics; Leptin; Male; Portal Vein; Proteins; Rats; Rats, Sprague-Dawley

Topics: Animals; Base Sequence; Carrier Proteins; DNA Primers; Enzyme-Linked Immunosorbent Assay; Female; Hyperinsulinism; Insulin; Leptin; Male; Mutation; Obesity; Proteins; Rats; Rats, Zucker; Receptors, Cell Surface; Receptors, Leptin

Insulin resistance is associated with hyperleptinemia, whilst exposure of hepatoma cells and isolated adipocytes to high concentrations of leptin has been demonstrated to result in attenuated insulin response and a reduced suppression of gluconeogenesis. To determine the acute metabolic effects of hyperleptinemia, we measured whole body glucose uptake (WBU) and hepatic glucose production rate (HGP) in rats using the euglycemic hyperinsulinemic clamping technique. Anesthetised male rats received recombinant murine leptin (1 microg/min) or vehicle into the jugular vein for 90 min. After 30 min of leptin infusion, insulin was infused to a level of 70 microU/ml and a variable-rate glucose infusion was adjusted to maintain blood glucose levels to 4-4.5 mmol/l. Glucose infusion rates during clamping were not different between leptin-infused and control rats, and there were no significant effects on the HPR or WBU measured using [6-(3)H]glucose under basal or clamped conditions. In summary, our data demonstrate that acute hyperleptinemia in normal weight Wistar rats does not appear to reduce insulin sensitivity, in vivo, or to affect HPR under clamp conditions.

Topics: Adipocytes; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Glucose; Hyperinsulinism; Insulin Resistance; Leptin; Lipid Metabolism; Liver; Male; Proteins; Rats; Rats, Wistar; Signal Transduction

Leptin, a hormone secreted by adipocytes, decreases food intake and increases energy expenditure. The role of insulin in the regulation of leptin secretion is poorly understood and is still a topic of debate. Insulin increases leptin mRNA synthesis in rodents, but in humans, the available data are discordant. To investigate the role of chronic hyperinsulinemia in the regulation of plasma leptin concentrations, we studied 13 patients with surgically confirmed insulinoma before and after tumor removal, along with 15 healthy control subjects matched for sex, age, and BMI. Immunoreactive plasma leptin levels were measured by radioimmunoassay; leptin mRNA levels were also determined by reverse transcription-competitive polymerase chain reaction in a subgroup of six patients with insulinoma and six control subjects. All determinations were made with subjects in the fasting state. Plasma leptin concentrations correlated positively with leptin mRNA levels (r = 0.880, P < 0.001). Leptin levels, both plasma protein and mRNA, were significantly higher in the insulinoma patients than in the control subjects (plasma protein: 17.5 +/- 3.6 vs. 2.9 +/- 0.4 ng/ml, respectively, P < 0.001; mRNA: 0.98 +/- 0.33 vs. 0.19 +/- 0.064 amol/microg RNA, respectively, P < 0.05), and they correlated positively with fasting plasma insulin levels in the patients with insulinoma (plasma protein: r = 0.686, P < 0.01; mRNA: 0.796, P < 0.05). Finally, removal of the insulin-secreting tumor was followed by the normalization of plasma leptin levels. In summary, in patients with insulinoma, 1) plasma leptin levels and leptin mRNA are elevated; 2) a direct relationship exists between leptin, both circulating protein and mRNA, and insulin concentrations; and 3) plasma leptin returns to normal levels after tumor removal. These data, therefore, support a role for insulin in the chronic regulation of leptin gene expression.

Topics: Adipose Tissue; Adult; Blood Glucose; Fasting; Female; Gene Expression; Humans; Hyperinsulinism; Insulin; Insulinoma; Leptin; Male; Middle Aged; Obesity; Pancreatic Neoplasms; Polymerase Chain Reaction; Proteins; RNA-Directed DNA Polymerase; RNA, Messenger

This study aimed to elucidate possible age-related changes in islet blood perfusion in lean and obese C57BL/6 mice. Obese mice aged 1 mo were hyperglycemic and hyperinsulinemic and had an increased islet blood flow compared with age-matched lean mice. This augmented blood flow could be abolished by pretreatment with leptin. The islet blood perfusion was, in contrast to this, markedly decreased in obese 6- to 7-mo-old animals compared with age-matched lean mice. Reversal of hyperglycemia, but not hyperinsulinemia, in these obese mice with phlorizin normalized the islet blood flow. Spontaneous reversal of hyperglycemia, but not hyperinsulinemia, was seen in the 12-mo-old obese mice. Islet blood perfusion in obese mice at this age did not differ compared with lean mice. It is suggested that the initial increase in islet blood flow in obese mice is due to the leptin deficiency. The subsequent decrease in islet blood perfusion is probably caused by the chronic hyperglycemia. The described islet blood flow changes may be of importance for impairment of islet function in obese-hyperglycemic mice.

Topics: Aging; Animals; Arginine; Blood Glucose; Body Weight; Hyperglycemia; Hyperinsulinism; Insulin; Insulin Secretion; Islets of Langerhans; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Neuropeptide Y; Obesity; Organ Size; Pancreas; Perfusion; Phlorhizin; Proteins; Receptors, Leptin; Receptors, Neuropeptide Y; Regional Blood Flow

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

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

Leptin, a product of the ob gene, is known to increase energy expenditure. Given that chronic heart failure is a hypercatabolic state, we sought to determine whether congestive heart failure involves elevations in plasma leptin levels. Since leptin secretion is up-regulated by insulin, we also explored whether in congestive heart failure, a hyperinsulinaemic state, plasma leptin levels relate to plasma insulin levels.. Male patients with weight-stable congestive heart failure (n = 25, aged 55.5 +/- 2.0, mean +/- SEM, body mass index = 27.4 +/- 0.8, radionuclide left ventricular ejection fraction = 29.3 +/- 3.0%) and 18 controls, matched for age, sex and body fat (dual energy X-ray absorptiometry), underwent measurement of fasting plasma leptin (radioimmunoassay) and insulin levels.. Compared to controls, patients with congestive heart failure had higher plasma leptin [8.12 (-1.12, +1.31) vs 4.48 (-0.61, +0.70) ng.ml-1, mean +/- asymmetrical SEM, P = 0.003], 41.5% higher plasma leptin per percent body fat mass (P < 0.001), and higher fasting insulin levels [67.8 (-11.1, +13.3) vs 32.9 (-5.7, +6.9) pmol.l-1, P = 0.010]. In the congestive heart failure group, plasma leptin correlated with total body fat (r = 0.66) and fasting insulin (r = 0.68) (both P < 0.001). In multivariate regression analyses of the congestive heart failure group, fasting insulin (standardized coefficient = 0.41, P = 0.011) emerged as a predictor of plasma leptin levels, independent of total body fat (standardized coefficient = 0.73, P = 0.002, R2 = 0.66, P < 0.001).. Plasma leptin levels are raised in patients with congestive heart failure. The observation of a positive relationship between plasma leptin and insulin concentrations suggests that the insulin-leptin axis may be related to the increased energy expenditure observed in patients with congestive heart failure.

Topics: Adipose Tissue; Biomarkers; Body Mass Index; Cardiomyopathy, Dilated; Chronic Disease; Coronary Disease; Heart Failure; Humans; Hyperinsulinism; Insulin; Leptin; Male; Middle Aged; Proteins; Radioimmunoassay

The regulation of leptin secretion is complex and not entirely understood in humans. Insulin has been shown to stimulate leptin secretion in humans, whereas in vitro data suggest that catecholamines inhibit leptin secretion. The present studies were therefore undertaken to examine the leptin response to hyperinsulinemia in the presence and absence of elevated plasma levels of endogenous catecholamines in humans. Leptin concentrations were determined during both a euglycemic and hypoglycemic hyperinsulinemic clamp study in 10 normal and 10 type I diabetic subjects. Serum leptin increased during the hyperinsulinemic euglycemic clamp in normal (from 6.1 +/- 0.9 to 7.2 +/- 1.1 ng/dl, p = 0.003) and diabetic subjects (from 6.2 +/- 1.4 to 7.8 +/- 1.8 ng/dl, p = 0.001). During hyperinsulinemic hypoglycemia leptin concentrations increased significantly in type 1 diabetic patients (from 5.6 +/- 1.1 to 7.6 +/- 1.7 ng/dl, p = 0.003) but remained unaltered in normals (from 5.5 +/- 0.7 to 5.7 +/- 0.9 ng/dl, p = 0.7). During hypoglycemia in all subjects the increase in leptin was negatively correlated with the increase in epinephrine (r = 0.60, p = 0.005) and positively with the decrease in free fatty acids (r = 0.71, p = 0.003). In conclusion our results indicate that catecholamines play a suppressive role in the regulation of leptin secretion.

Topics: Adult; Blood Glucose; Catecholamines; Diabetes Mellitus, Type 1; Epinephrine; Fatty Acids, Nonesterified; Female; Glucose Clamp Technique; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Leptin; Male; Proteins

Acute immunoneutralization of circulating leptin, with an anti-leptin antibody, significantly reduced rectal temperature at 30 min and 75 min post-injection in overnight fasted and at 30 min in overnight fed mice, while no effects in metabolic and ponderal indicators were observed after antibody administration for 22 days. Furthermore, hyperinsulinemia and hypoglycemia were induced by passive immunization against leptin, being both influenced by the post-prandrial status. These experiments confirm through an indirect approach that leptin is involved in energy, but also in glucose homeostasis.

Topics: Animals; Antibodies, Monoclonal; Blood Glucose; Eating; Fasting; Hyperinsulinism; Hypoglycemia; Hypothermia; Immunization, Passive; Insulin; Leptin; Mice; Mice, Inbred BALB C; Proteins; Triglycerides; Weight Gain

Current knowledge of the regulatory mechanisms of leptin synthesis and release is limited. To elucidate the role of short-term hyperinsulinaemia and hypoglycaemia on circulating levels of leptin, 7 healthy lean men underwent a 360-min hyperinsulinaemic (insulin infusion rate: 1.5 mU/kg/min) clamp in two conditions: (i) during 360 min of euglycaemia and (ii) during 120 min of euglycaemia followed by 240 min of graded hypoglycaemia (nadir 2.9 +/- 0.1 mmol/l). During hyperinsulinaemic euglycaemia, serum leptin levels were initially stable and then rose gradually after 180 min to a peak value of 147 +/- 7% of baseline (ANOVA, p < 0.01). During the hypoglycaemic clamp, the leptin profile differed from that of euglycaemic conditions (p < 0.01) since the increase was postponed and reduced. In both clamp studies, leptin dynamics contrasted with the changes in a control study performed in 7 other men whose serum leptin fell significantly (p < 0.05) to 77 +/- 4% of baseline values during a 360-min fast (following overnight fasting). It is concluded that hyperinsulinaemia for more than 3 h increases circulating levels of leptin in lean males, whereas hyperinsulinaemia with concomitant hypoglycaemia leads to transient suppression. The exact nature of the underlying mechanisms, e.g. changes in levels of insulin, glucose, various substrates, glucose turnover and/or counterregulatory hormones, remains to be determined.

Topics: Adult; Analysis of Variance; Blood Glucose; Case-Control Studies; Fatty Acids, Nonesterified; Glucose Clamp Technique; Hormones; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Leptin; Male; Obesity; Proteins; Reference Values

To determine the effects of obesity on fasting plasma leptin levels and assess the effects of feeding on plasma leptin and OB gene expression in subcutaneous adipose tissue in non-diabetic subjects.. Blood and subcutaneous adipose tissue needle biopsy samples were obtained after an overnight fast and 1, 2 and 3 h following a mixed meal (606 kcal).. Eighteen female subjects: eight lean with a mean age of 40.1 yr (range 20-65) and mean body mass index of 22.24 kg/m2 (range 18.6-26.6) and ten obese subjects with a mean age of 48.6 yr (range 29-71) and body mass index of 33.53 kg/m2 (range 28.7-41.7).. Apart from obesity the only significant difference between groups was a 2.6 fold higher fasting plasma leptin concentration in obese subjects compared to leans (26.9 +/- 2.9 vs 10.2 +/- 2.22 (P < 0.05) respectively). Adipose tissue OB mRNA levels were not significantly higher in the obese group. Plasma leptin correlated with BMI and visceral fat weight in lean subjects only. No significant association between plasma leptin and adiposity was evident in obese patients. In addition, there was no association between plasma leptin and the insulin: glucose ratio (an index of insulin sensitivity). Following a mixed meal, post-prandial plasma insulin levels were significantly increased, with a concomitant significant reduction in plasma NEFA levels in both groups. Despite the large increase in plasma insulin, there were no post-prandial changes in either plasma leptin concentrations or subcutaneous adipose tissue OB mRNA levels in either lean or obese subjects.. The data indicate that plasma leptin levels are correlated with the degree of adiposity, especially in lean subjects, and confirm that circulating leptin levels are greater in obese subjects than lean subjects. The present study also failed to show a significant association between plasma leptin and insulin sensitivity in lean and obese women. Furthermore, plasma leptin and subcutaneous adipose tissue OB gene expression are not under short term regulation following feeding in fasted lean or obese female subjects.

Topics: Adipose Tissue; Adult; Aged; Biopsy, Needle; Body Composition; Female; Food; Gene Expression; Humans; Hyperinsulinism; Insulin; Leptin; Middle Aged; Obesity; Proteins

Polycystic ovary syndrome (PCOS) is associated with chronic anovulation, hyperandrogenemia, insulin resistance (IR)/hyperinsulinemia, and a high incidence of obesity. Thus, PCOS serves as a useful model to assess the role of IR and chronic endogenous insulin excess on leptin levels. Thirty-three PCOS and 32 normally cycling (NC) women of similar body mass index (BMI) were studied. Insulin sensitivity (S(I)) was assessed by rapid ivGTT in a subset of 28 PCOS and 29 NC subjects; percent body fat was determined by dual-energy x-ray absorptiometry (DEXA) in 14 PCOS and 17 NC. Fasting (0800 h) and 24-h mean hourly insulin levels were 2-fold higher (P < 0.0001), and S(I) was 50% lower (P = 0.005) in PCOS than in NC, while serum androstenedione (A), testosterone (T), 17-alpha hydroxyprogesterone (17OHP), and estrone (E1) levels were elevated (P < 0.0001), and sex hormone-binding globulin (SHBG) levels were decreased (P < 0.01). Twenty-four hour LH pulse frequency, mean pulse amplitude, and mean LH levels were elevated in PCOS (P < 0.001) as compared with NC. Serum leptin levels for PCOS (24.1 +/- 2.6 ng/mL) did not differ from NC (21.5 +/- 3.5 ng/mL) and were positively correlated with BMI (r = 0.81) and percent body fat (r = 0.91) for the two groups (both P < 0.0001). Leptin levels for PCOS and NC correlated positively with fasting and 24-h mean insulin levels (r = 0.81, P < 0.0001 for both PCOS and NC) and negatively with S(I) and SHBG levels. Leptin concentrations for PCOS, but not NC, correlated positively with 24-h mean glucose levels and inversely with 24-h mean LH levels and 24-h mean LH pulse amplitude. Leptin levels were not correlated with estrogen or androgen levels for either PCOS or NC, although leptin levels were positively related to the ratios of E1/SHBG and E2/SHBG for both PCOS and NC and to the ratio of T/SHBG for PCOS only. In stepwise multivariate regression with forward selection, only 24-h mean insulin levels contributed significantly (P < 0.01) to leptin levels independent of BMI and percent body fat for both PCOS and NC. Given this relationship and the presence of 2-fold higher 24-h mean insulin levels in PCOS, the expected elevation of leptin levels in PCOS was not found. This paradox may be explained by the presence of adipocyte IR specific to PCOS, which may negate the stimulatory impact of hyperinsulinemia on leptin secretion, a proposition requiring further study.

Topics: Adipose Tissue; Adolescent; Adult; Body Composition; Body Mass Index; Endocrine Glands; Female; Humans; Hyperinsulinism; Insulin Resistance; Leptin; Osmolar Concentration; Polycystic Ovary Syndrome; Proteins

To evaluate the plasma leptin concentration in lean and genetically obese fa/fa rats and to assess the response to 2 h hyperinsulinaemia.. The recently discovered peptide leptin is a putative link between the size of the adipose mass and the hypothalamic centres controlling feeding behaviour. Several genetic models of animal obesity have been characterized as carriers of mutations of either the ob gene or leptin receptor.. Lean (+/?) and obese (fa/fa) Zucker rats were studied under pentobarbital anaesthesia and underwent a 2 h euglycaemic hyperinsulinaemic clamp. Plasma leptin was measured in basal condition and at the end of the clamp study. Glucose rate of disappearance was evaluated by means of the isotope dilution technique using 3-3H-glucose as tracer.. fa/fa rats showed a 40 fold higher leptin concentration compared to lean littermates (0.47 +/- 0.10 vs 19.55 +/- 1.50 ng/ml, P < 0.0001). Euglycaemic hyperinsulinaemia increased plasma leptin in lean but not in genetically obese rats.. Our results suggest that insulin may be a regulator of in vivo leptin secretion by adipose tissue of lean rates whereas it is ineffective in increasing plasma leptin in obese Zucker rats.

Topics: Animals; Blood Glucose; Glucose Clamp Technique; Hyperinsulinism; Insulin; Leptin; Male; Obesity; Proteins; Rats; Rats, Zucker

To determine whether leptin has insulin sensitizing effects in normal rodents, we measured plasma glucose and insulin concentrations in male Sprague-Dawley rats treated with leptin or vehicle by continuous s.c. infusion for 48 h. In additional experiments, we examined the acute effect of i.v. leptin upon insulin sensitivity under conditions of clamped glycemia. Subcutaneous leptin was administered at 10.0 and 1.0 microg/h. To avoid confounding effects of differences in food intake, both leptin- and vehicle-treated rats were fasted during the 48-h period of infusion. Infusion of leptin, 10 microg/h, significantly reduced both plasma glucose and insulin. Leptin, 1.0 microg/h, also decreased plasma glucose and insulin, although the effects on insulin did not achieve statistical significance. Leptin at either dose did not alter body weight or epididymal fat mass compared with vehicle treated controls. Leptin, 10 microg/h, decreased circulating insulin-like growth factor-1 levels. No differences in GLUT-4 content in either in brown or epididymal fat were observed as a result of leptin-treatment. Leptin, 10 microg/h, significantly decreased urine osmolality, increased water intake, and reduced renal potassium excretion compared with vehicle-infused rats. In additional rats, we measured the acute effect of i.v. leptin on insulin sensitivity determined as whole body glucose utilization during hyperinsulinemic glucose clamps performed at glucose targets of 60 and 90 mg/100 ml. Glucose utilization was increased by 29% during the last 135 min of glycemia clamped at 60 mg/100 ml (P < 0.05) and by 30% during the last 135 min of glycemia clamped at 90 mg/dl (P < 0.01) in rats infused with leptin compared with vehicle. In summary, leptin increased insulin sensitivity in normal rats both under fasting conditions and in the presence of hyperinsulinemia at clamped glucose. These effects did not appear dependent on altered body weight. Leptin also altered salt and water metabolism under fasting conditions resulting in increased water intake and more dilute urine.

Topics: Adipose Tissue, Brown; Animals; Blood Glucose; Body Weight; Epididymis; Glucose; Glucose Transporter Type 4; Hyperinsulinism; Infusion Pumps, Implantable; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Male; Monosaccharide Transport Proteins; Muscle Proteins; Proteins; Rats; Rats, Sprague-Dawley; Time Factors; Water-Electrolyte Balance

We have studied the effect of prolonged hyperinsulinemia and hyperglycemia on serum leptin levels in young nonobese males during 72-h euglycemic-hyperinsulinemic and hyperglycemic ( approximately 8.5 and 12.6 mM) clamps. Hyperinsulinemia increased serum leptin concentrations (by RIA) dose-dependently. An increase in serum insulin concentration of > 200 pM for > 24 h was needed to significantly increase serum leptin. An increase of approximately 800 pM increased serum leptin by approximately 70% over 72 h. Changes in plasma glucose concentrations (from approximately 5.0 to approximately 12.6 mM) or changes in plasma FFA concentrations (from < 100 to > 1,000 microM) had no effect on serum leptin. Serum leptin concentrations changed with circadian rhythmicity. The cycle length was approximately 24 h, and the cycle amplitude (peak to trough) was approximately 50%. The circadian leptin cycles and the circadian cycles of total body insulin sensitivity (i.e., GIR, the glucose infusion rates needed to maintain euglycemia during hyperinsulinemic clamping) changed in a mirror image fashion. Moreover, GIR decreased between Days 2 and 3 (from 11.4+/-0.2 to 9. 8+/-0.2 mg/kg min, P< 0.05) when mean 24-h leptin levels reached a peak. In summary, we found (a) that 72 h of hyperinsulinemia increased serum leptin levels dose-dependently; (b) that hyperglycemia or high plasma FFA levels did not affect leptin release; (c) that leptin was released with circadian rhythmicity, and (d) that 24-h leptin cycles correlated inversely with 24-h cycles of insulin sensitivity. We speculate that the close positive correlation between body fat and leptin is mediated, at least in part, by insulin.

Topics: Adult; Circadian Rhythm; Fatty Acids, Nonesterified; Humans; Hyperinsulinism; Insulin; Leptin; Male; Proteins

New Zealand Obese (NZO) mice exhibit a polygenic syndrome of hyperphagia, obesity, hyperinsulinemia, and hyperglycemia similar to that observed in young diabetes mutant mice on the C57BLKS/J background (C57BLKS/J-Lepr(db)/Lepr(db)). Here we show that in NZO this syndrome is accompanied by a marked elevation of the leptin protein in adipose tissue and serum. The promoter region and the complementary DNA of the ob gene of NZO mice, including its 5'-untranslated region, are identical with the wild-type sequence (C57BL, BALB/c), except that the transcription start is located 5 bp upstream of the reported site. In contrast to C57BLKS/J+/+ and C57BL/6J-Lep(ob)/Lep(ob) mice, NZO mice failed to respond to recombinant leptin (7.2 microg/g) with a reduction of food intake. Leptin receptor messenger RNA as detected by PCR appears as abundant in hypothalamic tissue of NZO mice as in tissue from lean mice. Ten nucleotide polymorphisms are found in the complementary DNA of the leptin receptor, resulting in two conservative substitutions (V541I and V651I) in the extracellular part of the receptor and one nonconservative substitution (T1044I) in the intracellular domain between the presumed Jak and STAT binding boxes. However, these mutations are also present in the related lean New Zealand Black strain (body fat at 9 weeks: New Zealand Black, 6.2 +/- 1.3%; NZO, 17.0 +/- 1.7%). Thus, the polymorphic leptin receptor seems to play only a minor, if any, role in the obesity and hyperleptinemia of the NZO mouse. It is suggested that the main defect in NZO is located distal from the leptin receptor or at the level of leptin transport into the central nervous system.

Topics: Adipose Tissue; Animals; Base Sequence; Blotting, Northern; Body Weight; Carrier Proteins; Disease Models, Animal; DNA, Complementary; Eating; Hyperglycemia; Hyperinsulinism; Hypothalamus; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Molecular Sequence Data; Obesity; Polymerase Chain Reaction; Polymorphism, Genetic; Precipitin Tests; Promoter Regions, Genetic; Proteins; Receptors, Cell Surface; Receptors, Leptin; Recombinant Proteins; RNA, Messenger

To examine the relationship between leptin levels and visceral obesity or plasma insulin levels, we studied serum leptin levels, fat distribution assessed by CT scan, and plasma insulin levels during 75 g oral glucose load in 100 Japanese men. Regression analysis adjusted by age and body mass index (BMI) showed leptin levels to be associated with visceral fat area(V)(p = 0.003), subcutaneous fat area(S)(p < 0.0001), and V + S(p < 0.0001), but not with V/S ratio(p = 0.897). By regression analysis adjusted by age, BMI, and V + S, serum leptin levels were still highly and positively correlated with plasma insulin levels during 75 g oral glucose load (p < 0.001), insulin resistance index(p < 0.001), and beta cell function index(p = 0.009) in homeostasis model assessment. These data suggest that hyperinsulinemia, but not visceral obesity, may be regulators of serum leptin levels independent of BMI.

Topics: Adult; Blood Pressure; Body Mass Index; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Islets of Langerhans; Leptin; Male; Obesity; Proteins

Long term administration of leptin decreases caloric intake and fat mass and improves glucose tolerance. Here we examine whether leptin acutely regulates peripheral and hepatic insulin action. Recombinant mouse leptin (0.3 mg/kg.h, Leptin +) or vehicle (Leptin -) were administered for 6 h to 4-month-old rats (n = 20), and insulin (3 milliunits/kg.min) clamp studies were performed. During physiologic hyperinsulinemia (plasma insulin approximately 65 microunits/ml), the rates of whole body glucose uptake, glycolysis, and glycogen synthesis and the rates of 2-deoxyglucose uptake in individual tissues were similar in Leptin - and Leptin +. Post-absorptive hepatic glucose production (HGP) was similar in the two groups. However, leptin enhanced insulin's inhibition of HGP (4.1 +/- 0.7 and 6.2 +/- 0.7 mg/kg.min; p < 0.05). The decreased HGP in the Leptin + group was due to a marked suppression of hepatic glycogenolysis (0.7 +/- 0.1 versus 4.1 +/- 0.6 mg/kg.min, in Leptin + versus Leptin -, respectively; p < 0.001), whereas the % contribution of gluconeogenesis to HGP was markedly increased (82 +/- 3% versus 36 +/- 4% in Leptin + and Leptin -, respectively; p < 0.001). At the end of the 6-h leptin infusion, the hepatic abundance of glucokinase mRNA was decreased, whereas that of phosphoenolpyruvate carboxykinase mRNA was increased compared with Leptin -. We conclude that an acute increase in plasma leptin 1) enhances insulin's ability to inhibit HGP, 2) does not affect peripheral insulin action, and 3) induces a redistribution of intrahepatic glucose fluxes and changes in the gene expression of hepatic enzymes that closely resemble those of fasting.

Topics: Animals; Deoxyglucose; Glucokinase; Gluconeogenesis; Hyperinsulinism; Insulin; Leptin; Liver Glycogen; Male; Patch-Clamp Techniques; Phosphoenolpyruvate Carboxykinase (ATP); Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger

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

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

This study was undertaken to investigate temporal association between dexamethasone administration, OB gene expression, and leptin response in humans in the presence and absence of exogenous hyperinsulinemia. Six healthy males (age 24.5 +/- 1.0 yr, body mass index 26.4 +/- 1.0, body fat 16.2 +/- 1.8%) received 10 mg oral dexamethasone in five divided doses twice (protocols A and B) 1-2 weeks apart beginning at 0800 h on day 1 and ending at 0700 h on day 2. The dexamethasone administration was combined with two subcutaneous abdominal fat biopsies performed at 0800 h before and after dexamethasone administration (protocol A), or 4-h isoglycemic hyperinsulinemic (300 mU/m2 BSA/min, protocol B) clamp carried out between 0900 and 1300 h on day 2. OB gene expression (protocol A) did not change. In both protocols on day 2, the 0800 h leptin levels nearly doubled (P < 0.001), whereas 1300 h levels nearly quadrupled (P < 0.001). The elevation in leptin persisted until 0800 h of day 3 (24 h after last dexamethasone dose) with its subsequent rapid normalization. The short-term isoglycemic hyperinsulinemia (protocol B) had no additional effect on the postdexamethasone leptin response. We summarize that: 1) 24-h administration of dexamethasone has a marked stimulatory effect on circulating leptin levels but not on OB gene expression in the subcutaneous abdominal fat. 2) The effect is sustained for the next 24 h. 3) Short-term hyperinsulinemia has no additional effect. We conclude that dexamethasone is a powerful stimulator of leptin production in vivo through a mechanism that appears to be independent of OB gene transcription in the human subcutaneous abdominal fat.

Topics: Adipose Tissue; Adult; Body Mass Index; Dexamethasone; Gene Expression; Glucocorticoids; Glucose Clamp Technique; Humans; Hyperinsulinism; Kinetics; Leptin; Male; Obesity; Proteins

The aim of this work was to determine the possible inter-relationship between neuropeptide Y (NPY, a hypothalamic stimulator of feeding) and adipose tissue expression of the ob protein (a novel potent inhibitor of feeding). Such a relationship could be of importance in the maintenance of normal body weight. To this end, normal rats were intracerebroventricularly (i.c.v.) infused for 6 days with NPY. NPY infusion resulted in hyperphagia and a marked increase in adipose tissue ob mRNA levels. The effect of NPY on ob expression persisted when hyperphagia was prevented by pair-feeding, and was reversed following cessation of NPY infusion. Basal and glucose-stimulated insulinaemia were increased by i.c.v. NPY infusion compared to control values, regardless of whether animals were ad libitum-fed or pair-fed. Cessation of NPY infusion was accompanied by normalisation of insulinaemia. These changes in insulinaemia produced by i.c.v. NPY infusion paralleled the observed changes in ob expression. When normal rats were made hyperinsulinaemic-euglycaemic for 24 h, such hyperinsulinaemia also resulted in increased ob mRNA levels in white adipose tissue. This suggested that NPY-induced hyperinsulinaemia could be responsible for the upregulation of ob mRNA levels of NPY-infused rats. It is concluded that central (i.c.v.) NPY infusion increases adipose tissue ob expression, a functional relationship that is linked, at least in part, via NPY-induced hyperinsulinaemia.

Topics: Adipose Tissue; Animals; Blood Glucose; Cerebral Ventricles; Female; Gene Expression; Glucose Clamp Technique; Hyperinsulinism; Hyperphagia; Infusions, Parenteral; Insulin; Leptin; Neuropeptide Y; Protein Biosynthesis; Rats; Rats, Zucker; Reference Values

Leptin, the product of the ob gene, is a hormone secreted by adipocytes. Animals with mutations in the ob gene are obese and lose weight when given leptin, but little is known about the physiological role of leptin in humans. Obese subjects have higher concentrations of leptin than lean subjects, the strongest correlation being with percentage body fat. Thus, it appears that obese subjects are resistant to the effects of endogenously secreted leptin. We have also shown that insulin stimulates leptin production, chronically but not acutely, presumably through its trophic effect on adipocytes. Troglitazone is an insulin-sensitizing thiazolidinedione, which improves hepatic and skeletal muscle insulin resistance in NIDDM and obesity. This study was undertaken to investigate the effects of troglitazone on leptin production in vitro and in vivo. In the presence and absence of 100 nmol/l insulin and 10 umol/l troglitazone, 72-h primary cultures of isolated abdominal adipocytes were studied. Insulin led to an almost twofold increase in leptin in vitro, and this increase was completely abolished by coincubation with troglitazone. Incubation with troglitazone alone led to a 40% decrease in leptin production. In obese patients administered troglitazone 200 mg twice daily for 12 weeks, there was no significant change in fasting plasma leptin concentrations, despite a 40-50% reduction in fasting and postmeal plasma insulin concentrations. Troglitazone treatment led to a significant increase in insulin sensitivity, and there was a positive correlation between the change in insulin sensitivity and the change in plasma leptin concentration in these subjects. In conclusion, troglitazone treatment had no net effect on plasma leptin concentrations, possibly because of improvement in insulin sensitivity and reduction in plasma insulin concentrations.

Topics: Adipocytes; Adult; Animals; Blood Glucose; Cells, Cultured; Chromans; Fasting; Female; Glucose; Humans; Hyperinsulinism; Hypoglycemic Agents; Infusions, Intravenous; Insulin; Leptin; Male; Middle Aged; Obesity; Protein Biosynthesis; Proteins; Thiazoles; Thiazolidinediones; Troglitazone

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

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

In rodents, food intake and insulin increase ob gene expression and circulating leptin concentrations, but it is unknown whether insulin regulates plasma leptin concentrations in humans. We measured plasma leptin concentrations in 27 normal subjects (16 men, 11 women; age, 24 +/- 1 years; BMI, 22.6 +/- 0.5 kg/m2; body fat, 18 +/- 1%) during a 6-h euglycemic hyperinsulinemic clamp (sequential insulin infusions of 1, 2, and 5 mU.kg-1.min-1 for 2 h each). During these insulin infusions, plasma leptin increased from a basal concentration of 7.4 +/- 1.6 ng/ml by -2 +/- 2, 17 +/- 4, and 50 +/- 6% to 7.2 +/- 1.5 (NS vs. basal), 8.5 +/- 1.7 (P < 0.001), and 10.4 +/- 2.0 ng/ml (P < 0.001), respectively. Of the subjects, eight also participated in a control study where saline was infused for 6 h. In these subjects, plasma leptin increased by 5 +/- 4, 26 +/- 10, and 62 +/- 10% during the insulin infusions, and decreased by 9 +/- 4 (P = 0.07 for change during saline vs. insulin), 13 +/- 4 (P < 0.01), and 17 +/- 4% (P < 0.001) after 2, 4, and 6 h of the saline infusion, respectively. Women had higher plasma leptin concentrations basally and during hyperinsulinemia (P < 0.001) than men, but this difference was entirely accounted for by greater adiposity in women (22 +/- 2 vs. 14 +/- 1%, P < 0.001). These data provide evidence for the insulin regulation of plasma leptin concentrations in humans. This effect requires hours of high insulin concentrations, implying that postprandial satiety is not regulated via changes in plasma leptin concentrations. Insulin may, however, be of importance in the long-term or diurnal regulation of plasma leptin concentrations.

Topics: Adipose Tissue; Adult; Blood Glucose; Female; Humans; Hyperinsulinism; Infusions, Intravenous; Insulin; Kinetics; Leptin; Male; Obesity; Proteins; Reference Values; Sex Characteristics; Time Factors

Leptin, a recently discovered protein produced in adipocytes, may be important in the regulation of body energy stores. In humans, leptin is present in the circulation in direct proportion to the amount of body fat. In rodents, insulin seems to regulate the production of leptin, but there is only limited evidence that this occurs in humans. We, therefore, measured plasma leptin concentrations in 13 insulin-sensitive and 13 insulin-resistant Pima Indians at baseline, at the end of 100 min of physiologic hyperinsulinemia (mean plasma insulin = 563 pmol/L) and after a further 100 min of supraphysiologic hyperinsulinemia (mean plasma insulin = 11,910 pmol/L), during a 2-step hyperinsulinemic-euglycemic glucose clamp. At baseline, plasma leptin concentrations were directly related to percent body fat, determined by hydrodensitometry (r = 0.85, P < 0.0001). After adjusting for percent body fat, there were no differences in fasting plasma leptin concentrations between insulin-sensitive and insulin-resistant subjects. Plasma leptin concentrations did not change in response to insulin in either the insulin-sensitive or insulin-resistant subjects. These results suggest that insulin does not acutely regulate plasma leptin concentrations in humans.

Topics: Acute Disease; Adipocytes; Adult; Female; Humans; Hyperinsulinism; Indians, North American; Insulin Resistance; Leptin; Male; Proteins; RNA, Messenger

The acute effects of hyperglycemia and hyperinsulinemia on plasma leptin levels were determined in 42 highly trained women athletes (18-69 yr) and 14 sedentary control women (18-50 yr, body mass index < 25 kg/m2), using the glucose clamp technique. The relationships of body composition, physical fitness, age, and plasma leptin levels were examined in all participants. In addition, the effect of weight loss and aerobic exercise and plasma leptin levels were examined in 4 Newly diagnosed untreated noninsulin-dependent diabetes mellitus patients. The time course of plasma leptin levels changed little from basal during hyperglycemic (approximately 10 mmol/L) or hyperinsulinemic-euglycemic (400-3000 pmol/L) clamp studies in either athletes, controls, or noninsulin-dependent diabetes mellitus patients. A strong correlation between plasma leptin levels and fasting insulin was present (r = 0.60, P < 0.001). Plasma leptin and percent fat were higher in controls than athletes (12.6 vs. 4.0 ng/mL and 33.2 vs. 20.8%; both P < 0.001). The relationships between percent fat (dual-energy x-ray absorptiometry) or intraabdominal adipose tissue (computed tomography) and leptin for the entire group were highly significant (r = 0.70, r = 0.52; P < 0.001). When percent fat was controlled, the relationship between fasting insulin and leptin remained (P < 0.002). There was not a significant association between age and plasma leptin levels in a univariate analysis in this population. However, after adjustment for percent fat, a significant inverse relationship between age and leptin appeared (P < 0.05). The weight loss and aerobic exercise program resulted in an average 6 +/- 0.8 kg wt loss. Leptin levels decreased > 28% in each patient (P < 0.01). In conclusion, neither acute hyperglycemia or hyperinsulinemia affects plasma leptin levels. Percent fat is the strongest predictor of leptin levels, even in lean, highly trained women athletes.

Topics: Adipose Tissue; Adolescent; Adult; Age Factors; Aged; Diabetes Mellitus, Type 2; Exercise; Female; Glucagon; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hyperinsulinism; Leptin; Middle Aged; Peptide Fragments; Protein Precursors; Proteins; Weight Loss