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）： 肥胖在美国和全世界都很流行。体重通常由内分泌反馈回路调节，其中胰岛素和瘦素激素分泌到血液中，与体内脂肪储存成正比。然后，这些循环激素与大脑下丘脑弓状核中发现的关键神经元相互作用，调节许多生理过程，包括食物摄入和能量消耗，最终将体重维持在正常范围内。肥胖通常伴有糖尿病，其特征是下丘脑对这些激素的正常作用产生抵抗，即尽管胰岛素和瘦素水平增加，食物摄入量和体重仍然升高。为了充分治疗肥胖，我们首先需要了解导致瘦素抵抗的机制。然而，我们目前对胰岛素和瘦素用来激活弓状核神经元的正常信号传导机制还没有很好的了解。 申请人进行的初步研究表明，弓状核神经元中通过细胞内信号转导酶磷脂酰肌醇3-激酶的信号传导是瘦素降低食物摄入的作用所必需的，并且胰岛素也激活这些神经元中的该信号传导途径。拟议研究的目的是确定需要 PI3K 信号传导的神经元的特定表型，确定 PI3K 信号传导受损是否会导致下丘脑瘦素和胰岛素抵抗，就像糖尿病情况下外周胰岛素抵抗一样，最后确定增加弓状神经元中 PI3K 信号传导的基因治疗方法是否可以减弱或预防饮食诱导的胰岛素抵抗。 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，胰岛素和瘦素通过这些机制调节下丘脑弓状核中关键神经元的功能。然后，这些信息将应用于解决饮食引起的肥胖问题以及对这些激素正常作用的抵抗力。希望这些研究将为药物开发提供有吸引力的分子靶点。这些目标也为独立研究项目的开发提供了必要的背景和培训，并将在丰富的培训环境中进行