Leptin and insulin action in the brain; role in obesity

瘦素和胰岛素在大脑中的作用；

• 批准号: 7238616
• 负责人: KEVIN D NISWENDER
• 金额: $ 12.4万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7238616
• 关键词: 1-Phosphatidylinositol 3-Kinase; Accounting; Attenuated; Blood Circulation; Body Weight; Body fat; Brain; Development; Diabetes Mellitus; Diet; Eating; Endocrine; Energy Metabolism; Environment; Enzymes; Epidemic; Feedback; Goals; Hormones; Hypothalamic structure; Insulin; Insulin Resistance; Leptin; Leptin resistance; Molecular Target; Neurons; Normal Range; Numbers; Obesity; Peripheral; Phenotype; Physiological Processes; Research; Resistance; Role; Signal Pathway; Signal Transduction; Structure of nucleus infundibularis hypothalami; Training; drug development; gene therapy; improved; prevent; programs

DESCRIPTION (provided by applicant): Obesity is epidemic in the US and worldwide. Body weight is normally regulated by an endocrine feedback loop, where the hormones insulin and leptin are secreted into the bloodstream in direct proportion to body fat stores. These circulating hormones then interact with a key subset of neurons found in the hypothalamic arcuate nucleus of the brain to regulate a number of physiological processes, including food intake and energy expenditure, that ultimately function to maintain body weight within a normal range. Obesity, which is commonly accompanied by diabetes, is characterized by hypothalamic resistance to the normal effects of these hormones, i.e. food intake and body weight remain elevated despite increased levels of insulin and leptin. In order to adequately treat obesity, we first need to understand the mechanisms causing leptin resistance. Yet we currently do not have a good understanding of the normal signaling mechanisms that insulin and leptin use to activate arcuate nucleus neurons. Initial studies carried out by the applicant demonstrated that signaling through the intracellular signal transduction enzyme, phosphatidylinositol 3-kinase, in arcuate nucleus neurons is required for the food intake lowering effects of leptin and that insulin also activates this signaling pathway in these neurons. The aims of the proposed studies are to identify the specific phenotype of neurons in which PI3K signaling is required, to determine if impaired signaling through PI3K accounts for hypothalamic leptin and insulin resistance as it does peripheral insulin resistance in the setting of diabetes, and finally to determine if a gene therapy approach to increase PI3K signaling in arcuate neurons can attenuate or prevent diet-induced obesity. The overarching goals of the proposal are to improve our understanding of the basic mechanisms, both cellular and neuroanatomical, by which insulin and leptin regulate the function of key neurons found in the hypothalamic arcuate nucleus. This information will then be applied to the problem of diet-indcued obesity and resistance to the normal effects of these hormones. It is hoped that these studies will provide attractive molecular targets for drug development. These aims also provide the background and training necessary for the development of an independent research program and will be conducted in the context of rich training environment

描述（由申请人提供）： 肥胖在美国和全球都是流行病。体重通常由内分泌反馈环调节，在该环路中，激素胰岛素和瘦素被直接与体内脂肪储存成比例地分泌到血液中。然后，这些循环激素与大脑下丘脑弓形核中发现的关键神经元的关键子集相互作用，以调节许多生理过程，包括食物摄入和能量消耗，最终功能可维持正常范围内的体重。肥胖通常伴有糖尿病，其特征是对这些激素的正常作用的下丘脑抗性，即，尽管胰岛素和瘦素水平升高，但食物摄入和体重仍然升高。为了充分治疗肥胖症，我们首先需要了解引起瘦素耐药性的机制。然而，我们目前对胰岛素和瘦素用来激活弧形神经元的正常信号传导机制有很好的了解。 申请人进行的初步研究表明，通过细胞内信号转导酶（磷脂酰肌醇3-激酶）在弧形核元中的磷脂酰肌醇3-激酶，对于瘦素的食物摄入降低效应是必需的，并且胰岛素也激活了这些神经元中的这种信号途径。 The aims of the proposed studies are to identify the specific phenotype of neurons in which PI3K signaling is required, to determine if impaired signaling through PI3K accounts for hypothalamic leptin and insulin resistance as it does peripheral insulin resistance in the setting of diabetes, and finally to determine if a gene therapy approach to increase PI3K signaling in arcuate neurons can attenuate or prevent diet-induced肥胖。 该提案的总体目标是提高我们对细胞和神经解剖学基本机制的理解，通过这些机制，胰岛素和瘦素调节了下丘脑弧形核中发现的关键神经元的功能。然后，这些信息将应用于饮食引起的肥胖症和对这些激素正常作用的抗性问题。希望这些研究能为药物开发提供有吸引力的分子靶标。这些目标还提供了制定独立研究计划所必需的背景和培训，并将在丰富的培训环境中进行