Regulation of adipose tissue metabolism by central insulin and leptin

中枢胰岛素和瘦素对脂肪组织代谢的调节

基本信息

批准号：
7922519
负责人：
CHRISTOPH BUETTNER
金额：
$ 40.27万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-28 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7922519
关键词：
Acute Adipocytes Adipose tissue Adult Aging Area Autonomic nervous system Biological Preservation Brain Brown Fat Caloric Restriction Cardiovascular Diseases Cells Comorbidity Conscious Development Diabetes Mellitus Diet Doctor of Philosophy Dyslipidemias Eating Endocannabinoids Endocrine Glands Failure Fasting Fatty Acids Fatty acid glycerol esters Genetic Glucose Goals Homeostasis Hormones Human Hyperinsulinism Hypothalamic structure In Vitro Inflammatory Infusion procedures Insulin Insulin Receptor Insulin Resistance Isotopes Lead Leptin Leptin resistance Lipids Lipodystrophy Lipolysis Mediating Metabolic syndrome Metabolism Molecular Molecular Genetics Mus Neurons Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Organ PIK3CG gene Pathway interactions Peripheral Physiological Play Rattus Regulation Regulatory Pathway Risk Factors Rodent Model Role Signal Pathway Signal Transduction Techniques Testing Third ventricle structure Tissues Tracer Ventricular Visceral Work adipokines adiponectin base blood glucose regulation cytokine in vivo insulin signaling leptin receptor lipid biosynthesis lipid metabolism mind control mouse model nerve supply novel nutrient metabolism prevent protein expression public health relevance transdifferentiation uptake

项目摘要

DESCRIPTION (provided by applicant): Visceral adiposity is a major risk factor for the development of insulin resistance, type 2. diabetes and its co-morbidities of dyslipidemia and cardiovascular disease. Adipose tissue has been recognized to be an important endocrine organ that regulates energy homeostasis, glucose and lipid metabolism via adipokines like leptin and adiponectin, fatty acid release and possibly neuronal afferens. Insulin and leptin are two of the major adiposity hormones that have been shown to regulate food intake and glucose fluxes to a large extend via central, i.e. brain signaling. While leptin decreases adiposity, insulin increases lipid storage in adipose tissue chiefly by suppressing lipolysis. The inhibition of lipolysis by insulin is believed to be mediated exclusively by insulin signaling in adipocytes. The brain control of adipose tissue metabolism via the autonomic nervous system is poorly understood. Previous work from our lab has demonstrated that leptin suppresses lipogenesis and induces lipolysis in adipose tissue via the medio-basal hypothalamus (MBH) and requires intact sympathetic innervation of adipose tissue. Since insulin exerts the opposite physiological effects on adipose metabolism then insulin, we speculated that part of insulins prolipogenic and antilipolytic effects are mediated by brain insulin signaling. Indeed, we have made the novel observation that insulin infused into the third ventricle or the MBH potently suppresses whole body and adipose tissue lipolysis and induces adipose tissue lipogenic protein expression independent of changes in circulating insulin and glucose levels or food intake. Thus, the central hypothesis of our proposal is that leptin and insulin exert opposing effects on visceral adipose tissue metabolism. We wish to characterize the central and peripheral pathways that participate in the brain control of adipose tissue metabolism and lipid fluxes in physiological and pathophysiological (dietary, inflammatory and genetic insulin resistance) contexts to understand if impaired brain control of adipose tissue metabolism contributes to the unrestrained lipolysis in the insulin resistant state. These studies should advance our understanding of how the brain controls WAT metabolism and adiposity independent of food intake by regulating nutrient partitioning. PUBLIC HEALTH RELEVANCE: Visceral adiposity is a major risk factor for the development of insulin resistance, type 2 diabetes and its co-morbidities of dyslipidemia and cardiovascular disease. Here we provide evidence that the two major adiposity hormones leptin and insulin regulate visceral adiposity and lipolysis via the brain. The goal of the proposed studies is to mechanistically explore the central signaling pathways involved and the relay mechanism that exert this brain control of adipose tissue metabolism and whether impaired brain control of lipolysis contributes to insulin resistance and type 2 diabetes.

描述（由申请人提供）：内脏肥胖是胰岛素抵抗，2型糖尿病及其血脂异常和心血管疾病的合并症的主要危险因素。脂肪组织已被认为是重要的内分泌器官，可通过脂肪素和脂联素，脂肪酸释放以及可能是神经元传入来调节能量稳态，葡萄糖和脂质代谢。胰岛素和瘦素是两种主要的脂肪激素，这些激素已被证明可以调节食物摄入量和葡萄糖通量，从而通过中心（即脑信号传导）进行大延伸。尽管瘦素降低肥胖，但胰岛素主要通过抑制脂解会增加脂肪组织中的脂质储存。据信，胰岛素对脂解的抑制是由脂肪细胞中的胰岛素信号传导仅介导的。通过自主神经系统对脂肪组织代谢的大脑控制知之甚少。我们实验室的先前工作表明，瘦素抑制脂肪生成并通过中质下丘脑（MBH）在脂肪组织中诱导脂肪，并且需要完整的脂肪组织交感神经支配。由于胰岛素对脂肪代谢，然后对胰岛素产生相反的生理作用，因此我们推测，胰岛素衍生物和抗溶液作用的一部分是由脑胰岛素信号传导介导的。确实，我们已经做出了新的观察结果，即胰岛素注入了第三个心室或MBH，有效抑制了整个身体和脂肪组织脂解，并诱导脂肪组织脂肪生成蛋白的表达，与循环胰岛素和葡萄糖水平或食物摄入的变化无关。因此，我们建议的中心假设是瘦素和胰岛素对内脏脂肪组织代谢的影响相反。我们希望表征参与脂肪组织代谢的大脑控制和脂质通量在生理和病理生理学（饮食，炎症和遗传胰岛素抵抗）中的中心和脂质通量，以了解受影响的脂肪组织代谢无效的脑部控制胰岛素抵抗状态的脂解。这些研究应提高我们对大脑如何通过调节营养分配来独立于食物摄入的脑部代谢和肥胖的理解。公共卫生相关性：内脏肥胖是胰岛素抵抗，2型糖尿病及其血脂异常血症和心血管疾病的合并症的主要危险因素。在这里，我们提供的证据表明，两种主要的肥大激素瘦素和胰岛素通过大脑调节内脏肥胖和脂解。拟议的研究的目的是机械地探索所涉及的中心信号通路以及对脑控制脂肪组织代谢的控制的继电器机制，以及对脂肪分解的脑控制受损是否有助于胰岛素抵抗和2型糖尿病。