Journal - The Journal of clinical endocrinology and metabolism (United States )

Abstract :

Estrogen sulfotransferase (EST) catalyzes the inactivation of estrone and estradiol in numerous tissues. Animal studies suggest that EST modulates glucose and lipid metabolism in adipose tissue, but it is unknown whether EST is expressed in human adipose tissue and, if so, how its expression relates to features of the metabolic syndrome.Cross-sectional data from 16 obese men and women with metabolic dysregulation were collected as part of a larger randomized trial at an academic medical center.Participants underwent assessment of body composition, oral glucose tolerance testing, measurement of serum hormones and inflammatory markers, and sc fat biopsy to assess adipose expression of TNF-a, suppressor of cytokine signaling 3 (SOCS3), leptin, adiponectin, and EST.EST expression was detectable in sc adipose tissue from both men and women. Log(10) EST mRNA was not significantly associated with age, race, sex or menopausal status, or circulating levels of estrogen or testosterone. In univariate analysis, log(10) EST mRNA was significantly associated with visceral adipose tissue area (r = 0.57, P = 0.02) as well as adipose tissue expression of TNF-a (r = 0.94, P < 0.0001) and SOCS3 mRNA (r = 0.93, P < 0.0001). The associations between EST expression and TNF-a and SOCS3 held in multivariate modeling controlling for age, race, sex and menopausal status, and visceral adiposity. EST expression was not significantly associated with the adipose tissue levels of leptin or adiponectin expression.EST is expressed in abdominal sc adipose tissue of both obese males and females in association with expression of TNF-a and SOCS3, suggesting potential roles in inflammation. Further studies are needed to determine the specific metabolic roles of EST expression in human adipose tissue.

Journal - Gastroenterology

Journal - Gastroenterology

Journal - Archives of neurology (United States )

Journal - Nature medicine

Journal - Molecular endocrinology (Baltimore, Md.) (United States )

Abstract :

Adipokines are secreted by adipose tissue and control various physiological systems. Low leptin levels during fasting stimulate feeding, reduce energy expenditure, and modulate neuroendocrine and immune function to conserve energy stores. On the other hand, rising leptin levels in the overfed state prevent weight gain by inhibiting food intake and increasing energy expenditure. These actions are mediated by neuronal circuits in the hypothalamus and brainstem. Leptin also controls glucose and lipid metabolism by targeting enzymes such as AMP-activated protein kinase and stearoyl-coenzyme A desaturase-1 in liver and muscle. Likewise, adiponectin and resistin control energy balance and insulin sensitivity via central and peripheral targets. As highlighted in this review, there are distinct as well as common signaling pathways for adipokines. Understanding adipokine signaling in the brain and other organs will provide insights into the pathogenesis and treatment of obesity, diabetes and various metabolic disorders.

Journal - Frontiers of hormone research (Switzerland )

Abstract :

Adipose tissue is the source of soluble mediators (adipokines), secreted mainly by adipocytes. Leptin acts on the brain and peripheral organs to regulate energy homeostasis and the neuroendocrine axis. Adiponectin regulates glucose and lipid metabolism by targeting the liver and skeletal muscle. Adiposederived proinflammatory cytokines, vasoactive peptides, coagulation and complement factors, visfatin, vaspin and retinol-binding protein signal through paracrine and hormonal mechanisms. Understanding the biology of adipose tissue and the rapidly growing list of adipokines provides new insights into normal physiological regulation, as well as the pathogenesis and treatment of obesity, diabetes and disorders of lipid metabolism and cardiovascular system.

Journal - The Journal of clinical investigation (United States )

Abstract :

Obesity predisposes toward renal disease independently of diabetes and hypertension. In this issue of the JCI, Sharma and colleagues assessed the role of adiponectin, an adipose-derived hormone, in the pathogenesis of albuminuria (see the related article beginning on page 1645). Obese African Americans had reduced adiponectin levels associated with albuminuria. Adiponectin deficiency in mice induced oxidative stress, fusion of podocyte foot processes in the kidney glomerulus, and urinary albumin excretion. Adiponectin treatment reversed these abnormalities, likely through activation of AMPK. The benefits of adiponectin were observed in diabetic and nondiabetic mice. These findings suggest that adiponectin is a biomarker for kidney disease and may be targeted for prevention and treatment.

Journal - The Journal of clinical investigation (United States )

Abstract :

Maintenance of weight loss is often unsuccessful because of metabolic adaptations that conserve energy. Studies in rodents suggest that a reduction in leptin level during weight loss signals to the brain to increase feeding and decrease energy expenditure. In this issue of the JCI, Rosenbaum et al. examined this concept in obese patients who lost weight and were maintained at 10% below their initial weight (see the related article beginning on page 2583). Brain activity responses to visual food stimuli were visualized using functional MRI. Leptin levels fell during weight loss and increased brain activity in areas involved in emotional, cognitive, and sensory control of food intake. Restoration of leptin levels maintained weight loss and reversed the changes in brain activity. Thus, leptin is a critical factor linking reduced energy stores to eating behavior. Potentially, leptin therapy could sustain weight loss by overriding the tendency toward energy conservation.

Journal - Endocrinology and metabolism clinics of North America (United States )

Abstract :

Interest in the control of feeding has increased as a result of the obesity epidemic and rising incidence of metabolic diseases. The brain detects alterations in energy stores and triggers metabolic and behavioral responses designed to maintain energy balance. Energy homeostasis is controlled mainly by neuronal circuits in the hypothalamus and brainstem, whereas reward and motivation aspects of eating behavior are controlled by neurons in limbic regions and the cerebral cortex. This article provides an integrated perspective on how metabolic signals emanating from the gastrointestinal tract, adipose tissue, and other peripheral organs target the brain to regulate feeding, energy expenditure, and hormones. The pathogenesis and treatment of obesity and abnormalities of glucose and lipid metabolism are discussed.

Journal - Gastroenterology (United States )

Journal - Endocrinology (United States )

Journal - Obesity (Silver Spring, Md.) (United States )

Abstract :

The obesity epidemic has focused attention on the endocrine function of adipose tissue. Adipose tissue secretes leptin, cytokines, complement factors, and components of the coagulation cascade, most of which are increased in obesity. In contrast, a strong negative correlation exists between adiponectin and adiposity, insulin sensitivity, diabetes, vascular inflammation, and atherosclerosis. Adiponectin treatment in rodents increases insulin sensitivity and reduces lipids and atherogenesis. Chronic and central adiponectin treatment reduces weight, glucose, and lipids. The insulin-sensitizing action of thiazolidinediones is mediated, in part, through adiponectin. A causal role of adiponectin in diabetes, dyslipidemia, and atherosclerosis has been established in knockout mice. Therefore, adiponectin seems to be a marker of obesity-related diseases and a potential therapeutic target.

Journal - Cell metabolism (United States )

Abstract :

The hormone ghrelin regulates secretion of growth hormone and energy homeostasis. Sun et al (2006), in this issue of Cell Metabolism, demonstrate that ghrelin inhibits insulin secretion. Deletion of ghrelin increased basal insulin level, enhanced glucose-stimulated insulin secretion, and improved peripheral insulin sensitivity. These effects were not related to changes in food intake or weight, suggesting ghrelin has unique actions on key components of glucose homeostasis.

Journal - Progress in brain research (Netherlands )

Abstract :

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

Journal - Obesity (Silver Spring, Md.) (United States )

Abstract :

Adipose tissue plays a critical role in energy homeostasis, not only in storing triglycerides, but also responding to nutrient, neural, and hormonal signals and secreting adipokines that control feeding, thermogenesis, immunity, and neuroendocrine function. A rise in leptin signals satiety to the brain through receptors in hypothalamic and brainstem neurons. Leptin activates tyrosine kinase, Janus kinase 2, and signal transducer and activator of transcription 3, leading to increased levels of anorexigenic peptides, e.g., alpha-melanocyte stimulating hormone and cocaine- and amphetamine-regulated transcript, and inhibition of orexigenic peptides, e.g., neuropeptide Y and agouti-related peptide. Obesity is characterized by hyperleptinemia and hypothalamic leptin resistance, partly caused by induction of suppressor of cytokine signaling-3. Leptin falls rapidly during fasting and potently stimulates appetite, reduces thermogenesis, and mediates the inhibition of thyroid and reproductive hormones and activation of the hypothalamic-pituitary-adrenal axis. These actions are integrated by the paraventicular hypothalamic nucleus. Leptin also decreases glucose and stimulates lipolysis through central and peripheral pathways involving AMP-activated protein kinase (AMPK). Adiponectin is secreted exclusively by adipocytes and has been linked to glucose, lipid, and cardiovascular regulation. Obesity, diabetes, and atherosclerosis have been associated with reduced adiponectin levels, whereas adiponectin treatment reverses these abnormalities partly through activation of AMPK in liver and muscle. Administration of adiponectin in the brain recapitulates the peripheral actions to increase fatty acid oxidation and insulin sensitivity and reduce glucose. Although putative adiponectin receptors are widespread in peripheral organs and brain, it is uncertain whether adiponectin acts exclusively through these targets. As with leptin, adiponectin requires the central melanocortin pathway. Furthermore, adiponectin stimulates fatty acid oxidation and reduces glucose and lipids, at least in part, by activating AMPK in muscle and liver.

Journal - Diabetes (United States )

Abstract :

Adipose tissue secretes factors that control various physiological systems. The fall in leptin during fasting mediates hyperphagia and suppresses thermogenesis, thyroid and reproductive hormones, and immune system. On the other hand, rising leptin levels in the fed state stimulate fatty acid oxidation, decrease appetite, and limit weight gain. These divergent effects of leptin occur through neuronal circuits in the hypothalamus and other brain areas. Leptin also regulates the activities of enzymes involved in lipid metabolism, e.g., AMP-activated protein kinase and stearoyl-CoA desaturase-1, and also interacts with insulin signaling in the brain. Adiponectin enhances fatty acid oxidation and insulin sensitivity, in part by stimulating AMP-activated protein kinase phosphorylation and activity in liver and muscle. Moreover, adiponectin decreases body fat by increasing energy expenditure and lipid catabolism. These effects involve peripheral and possibly central mechanisms. Adipose tissue mediates interconversion of steroid hormones and secretes proinflammatory cytokines, vasoactive peptides, and coagulation and complement proteins. Understanding the actions of these "adipocytokines" will provide insight into the pathogenesis and treatment of obesity and related diseases.

Journal - Trends in endocrinology and metabolism: TEM (United States )

Abstract :

Adipose tissue secretes a variety of proteins with important roles in metabolism, reproduction, immunity and cardiovascular function. The endocrine function of adipose tissue, especially that of leptin, is linked to energy storage and thus might provide insights into obesity and other diseases associated with energy imbalance. This review highlights the current understanding of the actions of leptin in the brain, with particular emphasis on transport across the blood-brain barrier, signal transduction, neuropeptide targets and roles during fasting and obesity. Moreover, data pertaining to the potential central effects of adiponectin, cytokines and resistin on energy homeostasis, glucose and lipid metabolism are discussed.

Journal - Physiology & behavior (United States )

Abstract :

The discovery of leptin was a major breakthrough in our understanding of the role of adipose tissue as a storage and secretory organ. Leptin was initially thought to act mainly to prevent obesity; however, studies have demonstrated profound effects of leptin in the response to fasting, regulation of neuroendocrine and immune systems, hematopoiesis, bone and brain development. This review will focus on the signaling pathways which mediate these diverse effects of leptin in the brain and other physiologic systems.Copyright 2004 Elsevier Inc.

Journal - The New England journal of medicine (United States )

Journal - Diabetes (United States )

Abstract :

The rise in obesity and its complications has generated enormous interest in the regulation of feeding and body weight. We show that a spermine metabolite of cholesterol (MSI-1436) decreases body weight, specifically fat, by suppressing feeding and preventing the reduction in energy expenditure, hormonal changes, and patterns of neuropeptide expression normally associated with weight loss. MSI-1436 enters the brain after peripheral injection and is more potent when injected into the cerebral ventricle (intracerebroventricular [ICV]). Systemic or ICV MSI-1436 administration induced similar patterns of Fos immunoreactivity in the brain, especially the paraventricular hypothalamic nucleus (PVN). This brain region integrates neural signals from hypothalamic and brain stem nuclei and regulates feeding behavior, autonomic function, and neuroendocrine function. Microinjection of MSI-1436 into the PVN potently suppressed feeding and reduced body weight for several days. Unlike caloric restriction, MSI-1436 decreased mRNA levels of agouti-related peptide and neuropeptide Y in the hypothalamus. These findings indicate that MSI-1436 acts in the brain to regulate food intake and energy expenditure, likely through suppression of orexigenic hypothalamic pathways.

Journal - Trends in endocrinology and metabolism: TEM (United States )

Abstract :

The discovery of leptin in the mid-1990s has focused attention on the role of proteins secreted by adipose tissue. Leptin has profound effects on appetite and energy balance, and is also involved in the regulation of neuroendocrine and immune function. Sex steroid and glucocorticoid metabolism in adipose tissue has been implicated as a determinant of body fat distribution and cardiovascular risk. Other adipose products, for example, proinflammatory cytokines, complement factors and components of the coagulation/fibrinolytic cascade, may mediate the metabolic and cardiovascular complications associated with obesity.

Journal - Trends in molecular medicine (England )

Abstract :

Obesity is highly prevalent in industralized countries and is increasing worldwide. It is also a major risk factor for type 2 diabetes, hypertension, coronary artery disease and certain cancers. An understanding of the regulation of eating behavior is pertinent to obesity, as the latter results from an imbalance between food consumption and energy expenditure. Leptin and other hormones regulate feeding and energy balance by modulating the expression of neuropeptides in the brain. Major efforts are underway to determine whether the peripheral and central pathways involved in the regulation of feeding behavior and energy balance could be targeted for the treatment of obesity.

Journal - Frontiers in neuroendocrinology (UNITED STATES )

Abstract :

The discovery of leptin has enhanced understanding of the interrelationship between adipose energy stores and neuronal circuits in the brain involved in energy balance and regulation of the neuroendocrine axis. Leptin levels are dependent on the status of fat stores as well as changes in energy balance as a result of fasting and overfeeding. Although leptin was initially thought to serve mainly as an anti-satiety hormone, recent studies have shown that it mediates the adaptation to fasting. Furthermore, leptin has been implicated in the regulation of the reproductive, thyroid, growth hormone, and adrenal axes, independent of its role in energy balance. Although it is widely known that leptin acts on hypothalamic neuronal targets to regulate energy balance and neuroendocrine function, the specific neuronal populations mediating leptin action on feeding behavior and autonomic and neuroendocrine function are not well understood. In this review, we have discussed how leptin engages arcuate hypothalamic neurons expressing putative orexigenic peptides, e.g., neuropeptide Y and agouti-regulated peptide, and anorexigenic peptides, e.g., pro-opiomelanocortin (precursor of alpha-melanocyte-stimulating hormone) and cocaine- and amphetamine-regulated transcript. We show that leptin's effects on energy balance and the neuroendocrine axis are mediated by projections to other hypothalamic nuclei, e.g., paraventricular, lateral, and perifornical areas, as well as other sites in the brainstem, spinal cord, and cortical and subcortical regions.Copyright 2000 Academic Press.

Journal - Regulatory peptides (NETHERLANDS )

Abstract :

Leptin is produced mainly by adipose tissue and has been shown to regulate feeding, energy balance and neuroendocrine function. Regulation of energy homeostasis by leptin is thought to be mediated by hypothalamic neuropeptides, at least in adult rodents. The neonatal period is a critical stage of development during which mammals have to optimize caloric intake to support growth and development, as well as maintain body temperature. It is likely that leptin is involved in the transition from preweaning to adult metabolism. To test this hypothesis, we compared the effect of leptin treatment on body weight and adiposity between neonatal and adult mice. We also determined whether well known hypothalamic neuropeptide targets, e.g. neuropeptide Y (NPY), proopiomelanocortin (POMC), agouti-related peptide (AGRP) and cocaine and amphetamine-regulated transcript (CART) were regulated in a pattern consistent with their presumed roles as mediators of leptin action. Once daily intraperitoneal leptin injection for 7 days did not alter body weight, fat content or expression of hypothalamic neuropeptide mRNAs in 10-day-old mice. In contrast, leptin decreased body weight and adiposity, increased CART and suppressed NPY and AGRP mRNA expression in adult mice. These results are consistent with previous studies showing that the timing of leptin's anorectic action develops after weaning. Furthermore, the association between leptin's ability to influence body weight in adult mice but not in neonates, and the regulation of hypothalamic neuropeptide mRNA expression, is consistent with the view that these peptides mediate leptin's effects on energy balance.

Journal - American Journal of Physiology - Endocrinology and Metabolism

Abstract :

The excess accumulation of lipids in islets is thought to contribute to the development of diabetes in obesity by impairing ß-cell function. However, lipids also serve a nutrient function in islets, and fatty acids acutely increase insulin secretion. A better understanding of lipid metabolism in islets will shed light on complex effects of lipids on ß-cells. Adipose differentiation-related protein (ADFP) is localized on the surface of lipid droplets in a wide range of cells and plays an important role in intracellular lipid metabolism. We found that ADFP was highly expressed in murine ß-cells. Moreover, islet ADFP was increased in mice on a high-fat diet (3.5-fold of control) and after fasting (2.5-fold of control), revealing dynamic changes in ADFP in response to metabolic cues. ADFP expression was also increased by addition of fatty acids in human islets. The downregulation of ADFP in MIN6 cells by antisense oligonucleotide (ASO) suppressed the accumulation of triglycerides upon fatty acid loading (56% of control) along with a reduction in the mRNA levels of lipogenic genes such as diacylglycerol O-acyltransferase-2 and fatty acid synthase. Fatty acid uptake, oxidation, and lipolysis were also reduced by downregulation of ADFP. Moreover, the reduction of ADFP impaired the ability of palmitate to increase insulin secretion. These findings demonstrate that ADFP is important in regulation of lipid metabolism and insulin secretion in ß-cells.

Journal - The Journal of Clinical Investigation

Abstract :

Obesity predisposes toward renal disease independently of diabetes and hypertension. In this issue of the JCI, Sharma and colleagues assessed the role of adiponectin, an adipose-derived hormone, in the pathogenesis of albuminuria (see the related article beginning on page 1645). Obese African Americans had reduced adiponectin levels associated with albuminuria. Adiponectin deficiency in mice induced oxidative stress, fusion of podocyte foot processes in the kidney glomerulus, and urinary albumin excretion. Adiponectin treatment reversed these abnormalities, likely through activation of AMPK. The benefits of adiponectin were observed in diabetic and nondiabetic mice. These findings suggest that adiponectin is a biomarker for kidney disease and may be targeted for prevention and treatment.

Journal - The Journal of Clinical Investigation

Abstract :

Maintenance of weight loss is often unsuccessful because of metabolic adaptations that conserve energy. Studies in rodents suggest that a reduction in leptin level during weight loss signals to the brain to increase feeding and decrease energy expenditure. In this issue of the JCI, Rosenbaum et al. examined this concept in obese patients who lost weight and were maintained at 10% below their initial weight (see the related article beginning on page 2583). Brain activity responses to visual food stimuli were visualized using functional MRI. Leptin levels fell during weight loss and increased brain activity in areas involved in emotional, cognitive, and sensory control of food intake. Restoration of leptin levels maintained weight loss and reversed the changes in brain activity. Thus, leptin is a critical factor linking reduced energy stores to eating behavior. Potentially, leptin therapy could sustain weight loss by overriding the tendency toward energy conservation.

Journal - American Journal of Physiology - Endocrinology and Metabolism

Abstract :

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

Journal - Journal of Neuroscience

Abstract :

Adiponectin is an adipocyte-derived peptide hormone involvedin energy homeostasis and the pathogenesis of obesity, includinghypertension. Area postrema (AP) lacks a blood–brain barrierand is a critical homeostatic integration center for humoraland neural signals. Here we investigate the role of AP in adiponectinsignaling. We show that rat AP expresses AdipoR1 and AdipoR2adiponectin receptor mRNA. We used current-clamp electrophysiologyto investigate whether adiponectin influenced membrane propertiesof AP neurons and found that 60% of rat AP neurons tested weresensitive to adiponectin. Additional electrophysiology experimentscoupled with single-cell reverse transcription-PCR indicatedthat all neurons that expressed both subtypes of receptor weresensitive to adiponectin, whereas neurons expressing only onesubtype were predominantly insensitive. Last, microinjectionof adiponectin into AP caused significant increases in arterialblood pressure, with no change in heart rate, suggesting thatadiponectin acts at AP to provide a possible link between controlof energy homeostasis and cardiovascular function.

Journal - Journal of Biological Chemistry

Abstract :

The adipocytokine resistin impairs glucose tolerance and insulinsensitivity in rodents. Here, we examined the effect of resistinon glucose uptake in isolated adult mouse cardiomyocytes. Murineresistin reduced insulin-stimulated glucose uptake, establishingthe heart as a resistin target tissue. Notably, human resistinalso impaired insulin action in mouse cardiomyocytes, providingthe first evidence that human and mouse resistin homologs havesimilar functions. Resistin is a cysteinerich molecule thatcirculates as a multimer of a dimeric form dependent upon asingle intermolecular disulfide bond, which, in the mouse, involvesCys26; mutation of this residue to alanine (C26A) produces amonomeric molecule that appears to be bioactive in the liver.Remarkably, unlike native resistin, monomeric C26A resistinhad no effect on basal or insulin-stimulated glucose uptakein mouse cardiomyocytes. Resistin impairs glucose uptake incardiomyocytes by mechanisms that involve altered vesicle trafficking.Thus, in cardiomyocytes, both mouse and human resistins directlyimpair glucose transport; and in contrast to effects on theliver, these actions of resistin require oligomerization.* This work was supported in part by National Institutes of HealthGrant DK58073 (to E. D. A.), Grants DK49210 and DK49780 (toM. A. L.), Medical Scientist Training Grant T32-GM07288 (toM. W. R.), and Grant DK55758 (to P. E. S.) and by research grantsfrom the American Diabetes Association and the Ben and IrisMargolis Foundation (to E. D. A.). The costs of publicationof this article were defrayed in part by the payment of pagecharges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicatethis fact. Both authors contributed equally to this work.¶ Supported by the Bioscience Undergraduate Research Program ofthe University of Utah.** Present address: Pfizer Global Research and Development, Groton,CT 06340.

Abstract :

Obesity has reached epidemic proportions and poses serious public health challenges, in particular type 2 diabetes, cardiovascular disease, sleep apnea, osteoarthritis and cancer. Adipocyte hormones may provide key insights into the pathogenesis of obesity-related diseases. Leptin and adiponectin stimulate fatty acid oxidation, decrease lipid levels and increase insulin sensitivity. In contrast, resistin decreases insulin sensitivity, and increases glucose and lipids. Leptin acts in the CMS to suppress appetite and increase energy expenditure, but also has direct effects on peripheral tissues. Adiponectin and resistin have direct actions on liver and muscle, but recent observations suggest that these adipokines also have central effects. We hypothesize that the divergent effects of these adipocytes on metabolism are mediated, at least in part, through distinct neuronal targets and signaling pathways in the hypothalamus. Specific Aim 1 will compare the effects of CMS administration of leptin, adiponectin and resistin on energy and glucose metabolism. We will examine the regulation of peripheral glucose fluxes using insulin clamp and radioactive tracer kinetics. Based on our preliminary studies showing an attenuation of the CMS effects of leptin and adiponectin in agouti mice, we will determine whether the opposite effects of leptin/adiponectin versus resistin on glucose levels is mediated through melanocortin (MC)4 receptor signaling. Specific Aim 2 will determine the sites of action of these adipocyte hormones in the hypothalamus, using Fos immunohistochemistry and in situ hybridization. Finally, Specific Aim 3 will determine whether the opposing metabolic effects of leptin, adiponectin and resistin occur through AMP-kinase and SOCS-3 in the hypothalamus. We will test the hypothesis that central administration of resistin antagonizes the central effects of leptin and adiponectin on metabolism, through reciprocal regulation of AMPK, SOC-3, or both signaling pathways. Understanding the hypothalamic and signaling pathways that mediate the effects of leptin, adiponctin and resistin will provide novel insights into the pathophysiology of obesity and diabetes that will facilitate novel diagnostic and treatment strategies.

Abstract :

ABSTRACT NOT PROVIDED

Abstract :

During the past four years, we have shown that an aminosterol, MSI-1436, decreases body weight in rodents by inhibiting food intake and increasing thermogenesis. MSI-1436 is effective in diet-induced obese as well as leptin-deficient mice, and rapidly decreases plasma glucose and stimulates fatty acid oxidation in these models. Since MSI-1436 is more potent when injected in the cerebral ventricle and into the hypothalamic paraventricular nucleus, it is likely that the pharmacologic effects of this compound occur directly in the brain. Indeed, we have shown increased binding of MSI-1436 within the arcuate nucleus, and suppression of AGRP and NPY mRNA expression in mice, implicating neural pathways expressing these neuropeptides as MSI-1436 targets. Independent of weight loss, MSI-1436 alters the expression of enzymes involved in lipid and glucose metabolism, such as hypothalamic AMP kinase (AMPK) and hepatic fatty acid synthase (FAS). Furthermore, agouti (Ay/a) mice are less sensitive than wild-type animals to MSI-1436 and the response to MSI-1436 is inhibited by SHU9119, consistent with the hypothesis that the melanocortin system is a critical pathway in the central mode of action of MSI-1436. We have recently identified a mouse hypothalamic cell line (GT1-7) in which MSI-1436, at submicromolar concentrations, enhanced the agonist activity of a-MSH, suggesting a possible mechanism by which MSI-1436 might influence the melanocortin pathway. This proposal will further explore the hypothesis that MSI-1436 acts via central mechanisms. Aim 1 will evaluate the effects of pharmacologic blockade or genetic deletion of melanocortin 4 receptor (MC4R) on the ability of MSI-1436 to inhibit feeding and stimulate thermogenesis via the hypothalamic paraventricular nucleus. We will explore whether corticotropin-releasing hormone (CRH) acts downstream of MC4R to mediate the effects of MSI-1436 on feeding and thermogenesis. Aim 2 will attempt to resolve the mechanism by which MSI-1436 enhances the in vitro binding and signaling via MC4R in GT1-7 hypothalamic neurons. Finally, Aim 3 will determine whether the rapid actions on glucose and lipid metabolism are mediated through MC4R and AMPK in the hypothalamus. Understanding of the central neuronal actions MSI-1436 will provide novel insights on the anti-obesity and insulin sensitizing actions of this aminosterol.

Abstract :

DESCRIPTION (provided by applicant): The obesity epidemic has been linked to increasing incidence of diabetes, cardiovascular disease and other complications. Diet and exercise are essential to weight management; however, it is obvious that many patients would require drug treatment to achieve and maintain weight reduction. The goal of this grant is to understand the actions of a novel aminosterol, which we have found to potently decrease body weight. During the past 3 years, we have shown that the anti-obesity effect of MSI-1436 is mediated through inhibition of food intake as well as increased metabolic rate. Unlike other anorectics, a single intraperitoneal or intracerebroventricular (i.c.v.) injection of MSI-1436 decreases body weight for several days. Moreover, MSI-1436 stimulates insulin response and prevents steatosis. An intact leptin signaling is not critical to the action of MSI-1436, since this compound is effective in ob/ob and db/db mice, fa/fa rats, and diet-induced obese mice. In contrast, agouti (Ay/a) mice are less responsive to MSI-1436, suggesting that melanocortin (MC)3/4 receptors are crucial its action in the brain. MSI-1436 binds to hypothalamic and other brain areas which mediate energy balance, and strongly induces Fos-immunoreactivity in the paraventricular hypothalamic nucleus and to a lesser extent in the arcuate, ventromedial nuclei, central amygdala and nucleus solitarius. A CNS action of MSI-1436 is further evident by the suppression of agouti-related peptide (AGRP) and neuropeptide Y (NPY) in hypothalamus. Hence, we hypothesize that MSI-1436 regulates energy balance and glucose through similar hypothalamic circuits. Specific Aim 1 will investigate whether treatment with NPY or AGRP can reverse the effect of MSI-1436. Moreover, we will determine whether deletion of NPY, AGRP and MC4 receptor genes block the action of MSI-1436. Specific Aim 2 will investigate the roles of NPY, AGRP and MC4 receptor in mediating the effect of MSI-1436 on glucose. Specific Aim 3 will evaluate the effects of MSI-1436 on hypothalamic enzymes, i.e. AMP kinase and fatty acid synthase, implicated in energy homeostasis. Finally, specific Aim 4 will determine whether activation of hypothalamic AMP kinase is able to prevent the effect of MSI-1436, as has been shown for various anorectics. Understanding of the central neuronal actions MSI-1436 may elucidate novel targets for the treatment of obesity and related diseases.

Abstract :

DESCRIPTION (provided by applicant): The obesity epidemic has been linked to increasing incidence of diabetes, cardiovascular disease and other complications. Diet and exercise are essential to weight management; however, it is obvious that many patients would require drug treatment to achieve and maintain weight reduction. The goal of this grant is to understand the actions of a novel aminosterol, which we have found to potently decrease body weight. During the past 3 years, we have shown that the anti-obesity effect of MSI-1436 is mediated through inhibition of food intake as well as increased metabolic rate. Unlike other anorectics, a single intraperitoneal or intracerebroventricular (i.c.v.) injection of MSI-1436 decreases body weight for several days. Moreover, MSI-1436 stimulates insulin response and prevents steatosis. An intact leptin signaling is not critical to the action of MSI-1436, since this compound is effective in ob/ob and db/db mice, fa/fa rats, and diet-induced obese mice. In contrast, agouti (Ay/a) mice are less responsive to MSI-1436, suggesting that melanocortin (MC)3/4 receptors are crucial its action in the brain. MSI-1436 binds to hypothalamic and other brain areas which mediate energy balance, and strongly induces Fos-immunoreactivity in the paraventricular hypothalamic nucleus and to a lesser extent in the arcuate, ventromedial nuclei, central amygdala and nucleus solitarius. A CNS action of MSI-1436 is further evident by the suppression of agouti-related peptide (AGRP) and neuropeptide Y (NPY) in hypothalamus. Hence, we hypothesize that MSI-1436 regulates energy balance and glucose through similar hypothalamic circuits. Specific Aim 1 will investigate whether treatment with NPY or AGRP can reverse the effect of MSI-1436. Moreover, we will determine whether deletion of NPY, AGRP and MC4 receptor genes block the action of MSI-1436. Specific Aim 2 will investigate the roles of NPY, AGRP and MC4 receptor in mediating the effect of MSI-1436 on glucose. Specific Aim 3 will evaluate the effects of MSI-1436 on hypothalamic enzymes, i.e. AMP kinase and fatty acid synthase, implicated in energy homeostasis. Finally, specific Aim 4 will determine whether activation of hypothalamic AMP kinase is able to prevent the effect of MSI-1436, as has been shown for various anorectics. Understanding of the central neuronal actions MSI-1436 may elucidate novel targets for the treatment of obesity and related diseases.

Abstract :

DESCRIPTION (provided by applicant): The obesity epidemic has been linked to increasing incidence of diabetes, cardiovascular disease and other complications. Diet and exercise are essential to weight management; however, it is obvious that many patients would require drug treatment to achieve and maintain weight reduction. The goal of this grant is to understand the actions of a novel aminosterol, which we have found to potently decrease body weight. During the past 3 years, we have shown that the anti-obesity effect of MSI-1436 is mediated through inhibition of food intake as well as increased metabolic rate. Unlike other anorectics, a single intraperitoneal or intracerebroventricular (i.c.v.) injection of MSI-1436 decreases body weight for several days. Moreover, MSI-1436 stimulates insulin response and prevents steatosis. An intact leptin signaling is not critical to the action of MSI-1436, since this compound is effective in ob/ob and db/db mice, fa/fa rats, and diet-induced obese mice. In contrast, agouti (Ay/a) mice are less responsive to MSI-1436, suggesting that melanocortin (MC)3/4 receptors are crucial its action in the brain. MSI-1436 binds to hypothalamic and other brain areas which mediate energy balance, and strongly induces Fos-immunoreactivity in the paraventricular hypothalamic nucleus and to a lesser extent in the arcuate, ventromedial nuclei, central amygdala and nucleus solitarius. A CNS action of MSI-1436 is further evident by the suppression of agouti-related peptide (AGRP) and neuropeptide Y (NPY) in hypothalamus. Hence, we hypothesize that MSI-1436 regulates energy balance and glucose through similar hypothalamic circuits. Specific Aim 1 will investigate whether treatment with NPY or AGRP can reverse the effect of MSI-1436. Moreover, we will determine whether deletion of NPY, AGRP and MC4 receptor genes block the action of MSI-1436. Specific Aim 2 will investigate the roles of NPY, AGRP and MC4 receptor in mediating the effect of MSI-1436 on glucose. Specific Aim 3 will evaluate the effects of MSI-1436 on hypothalamic enzymes, i.e. AMP kinase and fatty acid synthase, implicated in energy homeostasis. Finally, specific Aim 4 will determine whether activation of hypothalamic AMP kinase is able to prevent the effect of MSI-1436, as has been shown for various anorectics. Understanding of the central neuronal actions MSI-1436 may elucidate novel targets for the treatment of obesity and related diseases.

Abstract :

DESCRIPTION (provided by applicant): The obesity epidemic has been linked to increasing incidence of diabetes, cardiovascular disease and other complications. Diet and exercise are essential to weight management; however, it is obvious that many patients would require drug treatment to achieve and maintain weight reduction. The goal of this grant is to understand the actions of a novel aminosterol, which we have found to potently decrease body weight. During the past 3 years, we have shown that the anti-obesity effect of MSI-1436 is mediated through inhibition of food intake as well as increased metabolic rate. Unlike other anorectics, a single intraperitoneal or intracerebroventricular (i.c.v.) injection of MSI-1436 decreases body weight for several days. Moreover, MSI-1436 stimulates insulin response and prevents steatosis. An intact leptin signaling is not critical to the action of MSI-1436, since this compound is effective in ob/ob and db/db mice, fa/fa rats, and diet-induced obese mice. In contrast, agouti (Ay/a) mice are less responsive to MSI-1436, suggesting that melanocortin (MC)3/4 receptors are crucial its action in the brain. MSI-1436 binds to hypothalamic and other brain areas which mediate energy balance, and strongly induces Fos-immunoreactivity in the paraventricular hypothalamic nucleus and to a lesser extent in the arcuate, ventromedial nuclei, central amygdala and nucleus solitarius. A CNS action of MSI-1436 is further evident by the suppression of agouti-related peptide (AGRP) and neuropeptide Y (NPY) in hypothalamus. Hence, we hypothesize that MSI-1436 regulates energy balance and glucose through similar hypothalamic circuits. Specific Aim 1 will investigate whether treatment with NPY or AGRP can reverse the effect of MSI-1436. Moreover, we will determine whether deletion of NPY, AGRP and MC4 receptor genes block the action of MSI-1436. Specific Aim 2 will investigate the roles of NPY, AGRP and MC4 receptor in mediating the effect of MSI-1436 on glucose. Specific Aim 3 will evaluate the effects of MSI-1436 on hypothalamic enzymes, i.e. AMP kinase and fatty acid synthase, implicated in energy homeostasis. Finally, specific Aim 4 will determine whether activation of hypothalamic AMP kinase is able to prevent the effect of MSI-1436, as has been shown for various anorectics. Understanding of the central neuronal actions MSI-1436 may elucidate novel targets for the treatment of obesity and related diseases.

Abstract :

MOUSE PHENOTYPING, PHYSIOLOGY, AND METABOLISM CORE: Director - R. Ahima Our understanding of the pathogenesis of diabetes has benefited from the use of gene targeting methodology in mice to elucidate molecular mechanisms. However, such efforts are often hampered by an absence of a clear metabolic phenotype. Failure to identify a phenotype may be due to lack of expertise and/or facilities for evaluating metabolic changes in mice. The Mouse Phenotyping, Physiology and Metabolism Core provides investigators of the Penn Diabetes and Endocrinology Research Center (DERC) with state-of-the-art, timely and cost-effective diagnostic studies in mice. The core offers consultation and experimental design, monitoring of feeding, energy expenditure and locomotor activity using the Comprehensive Laboratory Animal Monitoring System (CLAMS), treadmill exercise using the Oxymax system, and measurement of body composition using dual emission x-ray absorptiometry (DEXA) and carcass chemistry. Glucose homeostasis is assessed by oral or intraperitoneal (i.p.) glucose administration, and whole body insulin sensitivity by i.p. insulin injection. Insulin clamp and radioactive tracers are used to assess glucose fluxes and tissue specific glucose uptake. Studies in the core are performed by two research specialists under the direction of Rex Ahima. Future plans for the core include the use magnetic resonance (MRI) for measurement of water, lean and fat content, assessment of in vivo lipid kinetics, and employment of an additional technician to expedite services. The Mouse Phenotyping, Physiology and Metabolism Core will maintain a databank of metabolic and hormonal parameters in mouse models of diabetes and obesity, and coordinate its activities with other core laboratories, i.e. Islet Cell Biology (Franz Matschinsky), Radioimmunoassay/Biomarkers (Bryan Wolf; Muredach Reilly), Transgenic and Chimeric Mouse (Nancy Cooke), and Genomics and Gene Targeting Cores (Klaus Kaestner). These efforts will result in optimum data acquisition and metabolic phenotyping of mice, and facilitate the translation of ideas from the bench to mice, and ultimately to humans.

Abstract :

Obesity has reached epidemic proportions and poses serious public health challenges, in particular type 2 diabetes, cardiovascular disease, sleep apnea, osteoarthritis and cancer. Adipocyte hormones may provide key insights into the pathogenesis of obesity-related diseases. Leptin and adiponectin stimulate fatty acid oxidation, decrease lipid levels and increase insulin sensitivity. In contrast, resistin decreases insulin sensitivity, and increases glucose and lipids. Leptin acts in the CMS to suppress appetite and increase energy expenditure, but also has direct effects on peripheral tissues. Adiponectin and resistin have direct actions on liver and muscle, but recent observations suggest that these adipokines also have central effects. We hypothesize that the divergent effects of these adipocytes on metabolism are mediated, at least in part, through distinct neuronal targets and signaling pathways in the hypothalamus. Specific Aim 1 will compare the effects of CMS administration of leptin, adiponectin and resistin on energy and glucose metabolism. We will examine the regulation of peripheral glucose fluxes using insulin clamp and radioactive tracer kinetics. Based on our preliminary studies showing an attenuation of the CMS effects of leptin and adiponectin in agouti mice, we will determine whether the opposite effects of leptin/adiponectin versus resistin on glucose levels is mediated through melanocortin (MC)4 receptor signaling. Specific Aim 2 will determine the sites of action of these adipocyte hormones in the hypothalamus, using Fos immunohistochemistry and in situ hybridization. Finally, Specific Aim 3 will determine whether the opposing metabolic effects of leptin, adiponectin and resistin occur through AMP-kinase and SOCS-3 in the hypothalamus. We will test the hypothesis that central administration of resistin antagonizes the central effects of leptin and adiponectin on metabolism, through reciprocal regulation of AMPK, SOC-3, or both signaling pathways. Understanding the hypothalamic and signaling pathways that mediate the effects of leptin, adiponctin and resistin will provide novel insights into the pathophysiology of obesity and diabetes that will facilitate novel diagnostic and treatment strategies.

Abstract :

ABSTRACT NOT PROVIDED

Abstract :

DESCRIPTION (provided by applicant): Diabetes is highly prevalent in the United States and is associated with increased morbidity from cardiovascular, renal, neurological and other complications. Our understanding of the pathogenesis of diabetes has benefited immensely from pharmacological, dietary and genetic manipulations in mice and other rodents. Despite the rapid increase in the use of gene targeting methodology to elucidate the molecular mechanisms mediating diabetes in mice, such efforts are often hampered by the absence of a clear phenotype. Failure to demonstrate a phenotype is attributable in part to the lack of expertise and/or facilities for evaluating physiologic and metabolic features in mice. We propose to establish a Mouse Phenotyping, Physiology and Metabolism Core, with the objective of providing investigators of the Penn Diabetes Center with state-of-the-art, timely and cost-effective diagnostic studies in mice. The core will offer services for analyzing glucose homeostasis, feeding behavior and energy balance, body composition, blood chemistry and hemodynamics. Activities of the core will be carried out by 2 technicians under the direction of Dr. Rex Ahima. The Phenotyping Core will maintain a databank of physiological, hormonal and metabolic measurements in mouse models of diabetes and obesity, and offer advice and training on various aspects of mouse physiology. Activities of the core will be coordinated with other core laboratories, Le Islet Cell Biology (Franz Matschinsky), Radioimmunoassay (Bryan Wolf), Transgenic and Chimeric (Nancy Cooke and Functional Genomics (Klaus Kaestner). These efforts will result in optimum data acquisition in diabetic mouse models, and facilitate the translation of ideas from the bench to mice and ultimately to humans.

Abstract :

DESCRIPTION (provided by applicant): The obesity epidemic has been linked to increasing incidence of diabetes, cardiovascular disease and other complications. Diet and exercise are essential to weight management; however, it is obvious that many patients would require drug treatment to achieve and maintain weight reduction. The goal of this grant is to understand the actions of a novel aminosterol, which we have found to potently decrease body weight. During the past 3 years, we have shown that the anti-obesity effect of MSI-1436 is mediated through inhibition of food intake as well as increased metabolic rate. Unlike other anorectics, a single intraperitoneal or intracerebroventricular (i.c.v.) injection of MSI-1436 decreases body weight for several days. Moreover, MSI-1436 stimulates insulin response and prevents steatosis. An intact leptin signaling is not critical to the action of MSI-1436, since this compound is effective in ob/ob and db/db mice, fa/fa rats, and diet-induced obese mice. In contrast, agouti (Ay/a) mice are less responsive to MSI-1436, suggesting that melanocortin (MC)3/4 receptors are crucial its action in the brain. MSI-1436 binds to hypothalamic and other brain areas which mediate energy balance, and strongly induces Fos-immunoreactivity in the paraventricular hypothalamic nucleus and to a lesser extent in the arcuate, ventromedial nuclei, central amygdala and nucleus solitarius. A CNS action of MSI-1436 is further evident by the suppression of agouti-related peptide (AGRP) and neuropeptide Y (NPY) in hypothalamus. Hence, we hypothesize that MSI-1436 regulates energy balance and glucose through similar hypothalamic circuits. Specific Aim 1 will investigate whether treatment with NPY or AGRP can reverse the effect of MSI-1436. Moreover, we will determine whether deletion of NPY, AGRP and MC4 receptor genes block the action of MSI-1436. Specific Aim 2 will investigate the roles of NPY, AGRP and MC4 receptor in mediating the effect of MSI-1436 on glucose. Specific Aim 3 will evaluate the effects of MSI-1436 on hypothalamic enzymes, i.e. AMP kinase and fatty acid synthase, implicated in energy homeostasis. Finally, specific Aim 4 will determine whether activation of hypothalamic AMP kinase is able to prevent the effect of MSI-1436, as has been shown for various anorectics. Understanding of the central neuronal actions MSI-1436 may elucidate novel targets for the treatment of obesity and related diseases.

Abstract :

DESCRIPTION (provided by applicant): The prevalence of obesity in the United States has reached epidemic proportions and poses enormous public health challenges, as obesity is a major risk factor for type 2 diabetes, hypertension, cardiovascular disease and cancer, as well as an independent risk factor for mortality. Although diet and exercise are essential to weight management, it has become increasingly clear that a large proportion of patients would require drug treatment to decrease and maintain body weight. The goal of this grant is to understand the action of a novel cholesterol derivative with potent anti-obesity and anti-diabetic properties. MSI- 1436 is an aminosterol which we have found to cause reversible suppression of food intake, increased energy expenditure and normalization of glucose levels when administered by peripheral and more potently intracerebroventricular injection to rodents. Unlike other anorectics, a single injection of MSI-1436 produces a prolonged effect lasting several days. MSI- 1436 is effective in ob/ob and db/db mice, fa/fa rats, and diet-induced obese mice, suggesting that leptin signaling is not critical to its action. By contrast, MSI-1436 effect is blunted in agouti (Ay/a) mice, suggesting that its central action may involve the melanocortin pathway. Although acute MSI1436 administration strongly induces Fos-immunoreactivity in the paraventricular nucleus and to a lesser extent in the arcuate, ventromedial and pre-mammillary nuclei, the neuronal circuitry mediating the anti-obesity vs anti-diabetic effects of MSI-1436 is not known. We hypothesize that MSI-1436 enters the braii via a specific transport mechanism and engages hypothalamic neuronal targets to regulate energy balance and glucose homeostasis. Specific Aim 1 involves the injection of MSI-1436 into specific hypothalamic nuclei to determine which sites mediate the effects on feeding, body weight and glucose levels. Specific Aim 2 will analyze the distribution of MSI-1436 binding sites and determine the chemical phenotypes 01 MSI-1436 responsive neurons. Specific Aim 3 will determine the contribution of the central melanocortin system by analyzing MSI-1436 response in melanocortin receptor (MCR)-3 and 4 knockout mice. Finally, Specific Aim 4 will utilize GeneChip microarray to determine whether MSI-1436 regulates novel hypothalamic genes. Putative MS-1436 targets will be validated in multiple mouse models. Together these studies will provide insights into the mechanisms underlying MSI-1436 action in the brain. Understanding the basis for the novel effects of MSI-1436 on feeding behavior, body weight and glucose will greatly enhance the field of obesity and metabolism. New pathways affected by MSI-1436 may elucidate novel cellular targets for the treatment of obesity.

Abstract :

DESCRIPTION (provided by applicant): The prevalence of obesity in the United States has reached epidemic proportions and poses enormous public health challenges, as obesity is a major risk factor for type 2 diabetes, hypertension, cardiovascular disease and cancer, as well as an independent risk factor for mortality. Although diet and exercise are essential to weight management, it has become increasingly clear that a large proportion of patients would require drug treatment to decrease and maintain body weight. The goal of this grant is to understand the action of a novel cholesterol derivative with potent anti-obesity and anti-diabetic properties. MSI- 1436 is an aminosterol which we have found to cause reversible suppression of food intake, increased energy expenditure and normalization of glucose levels when administered by peripheral and more potently intracerebroventricular injection to rodents. Unlike other anorectics, a single injection of MSI-1436 produces a prolonged effect lasting several days. MSI- 1436 is effective in ob/ob and db/db mice, fa/fa rats, and diet-induced obese mice, suggesting that leptin signaling is not critical to its action. By contrast, MSI-1436 effect is blunted in agouti (Ay/a) mice, suggesting that its central action may involve the melanocortin pathway. Although acute MSI1436 administration strongly induces Fos-immunoreactivity in the paraventricular nucleus and to a lesser extent in the arcuate, ventromedial and pre-mammillary nuclei, the neuronal circuitry mediating the anti-obesity vs anti-diabetic effects of MSI-1436 is not known. We hypothesize that MSI-1436 enters the braii via a specific transport mechanism and engages hypothalamic neuronal targets to regulate energy balance and glucose homeostasis. Specific Aim 1 involves the injection of MSI-1436 into specific hypothalamic nuclei to determine which sites mediate the effects on feeding, body weight and glucose levels. Specific Aim 2 will analyze the distribution of MSI-1436 binding sites and determine the chemical phenotypes 01 MSI-1436 responsive neurons. Specific Aim 3 will determine the contribution of the central melanocortin system by analyzing MSI-1436 response in melanocortin receptor (MCR)-3 and 4 knockout mice. Finally, Specific Aim 4 will utilize GeneChip microarray to determine whether MSI-1436 regulates novel hypothalamic genes. Putative MS-1436 targets will be validated in multiple mouse models. Together these studies will provide insights into the mechanisms underlying MSI-1436 action in the brain. Understanding the basis for the novel effects of MSI-1436 on feeding behavior, body weight and glucose will greatly enhance the field of obesity and metabolism. New pathways affected by MSI-1436 may elucidate novel cellular targets for the treatment of obesity.

Abstract :

DESCRIPTION (provided by applicant): The prevalence of obesity in the United States has reached epidemic proportions and poses enormous public health challenges, as obesity is a major risk factor for type 2 diabetes, hypertension, cardiovascular disease and cancer, as well as an independent risk factor for mortality. Although diet and exercise are essential to weight management, it has become increasingly clear that a large proportion of patients would require drug treatment to decrease and maintain body weight. The goal of this grant is to understand the action of a novel cholesterol derivative with potent anti-obesity and anti-diabetic properties. MSI- 1436 is an aminosterol which we have found to cause reversible suppression of food intake, increased energy expenditure and normalization of glucose levels when administered by peripheral and more potently intracerebroventricular injection to rodents. Unlike other anorectics, a single injection of MSI-1436 produces a prolonged effect lasting several days. MSI- 1436 is effective in ob/ob and db/db mice, fa/fa rats, and diet-induced obese mice, suggesting that leptin signaling is not critical to its action. By contrast, MSI-1436 effect is blunted in agouti (Ay/a) mice, suggesting that its central action may involve the melanocortin pathway. Although acute MSI1436 administration strongly induces Fos-immunoreactivity in the paraventricular nucleus and to a lesser extent in the arcuate, ventromedial and pre-mammillary nuclei, the neuronal circuitry mediating the anti-obesity vs anti-diabetic effects of MSI-1436 is not known. We hypothesize that MSI-1436 enters the braii via a specific transport mechanism and engages hypothalamic neuronal targets to regulate energy balance and glucose homeostasis. Specific Aim 1 involves the injection of MSI-1436 into specific hypothalamic nuclei to determine which sites mediate the effects on feeding, body weight and glucose levels. Specific Aim 2 will analyze the distribution of MSI-1436 binding sites and determine the chemical phenotypes 01 MSI-1436 responsive neurons. Specific Aim 3 will determine the contribution of the central melanocortin system by analyzing MSI-1436 response in melanocortin receptor (MCR)-3 and 4 knockout mice. Finally, Specific Aim 4 will utilize GeneChip microarray to determine whether MSI-1436 regulates novel hypothalamic genes. Putative MS-1436 targets will be validated in multiple mouse models. Together these studies will provide insights into the mechanisms underlying MSI-1436 action in the brain. Understanding the basis for the novel effects of MSI-1436 on feeding behavior, body weight and glucose will greatly enhance the field of obesity and metabolism. New pathways affected by MSI-1436 may elucidate novel cellular targets for the treatment of obesity.