Leptin and insulin action in the brain; role in obesity

描述(由申请人提供)： 肥胖症在美国和全世界都很流行。体重通常由内分泌反馈环路调节，在内分泌反馈环路中，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，这些循环荷尔蒙与大脑下丘脑弓状核中发现的一个关键神经元亚群相互作用，调节一些生理过程，包括食物摄入量和能量消耗，最终将体重保持在正常范围内。肥胖通常伴随着糖尿病，其特征是下丘脑对这些激素的正常影响产生抵抗，即尽管胰岛素和瘦素水平上升，但食物摄入量和体重仍然增加。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激活弓状核神经元的正常信号机制还没有很好的了解。 申请人进行的初步研究表明，在弓状核神经元中，通过细胞内信号转导酶磷脂酰肌醇3-激酶的信号转导是瘦素降低摄食量所必需的，并且胰岛素也激活了这些神经元中的这一信号通路。这些研究的目的是确定需要PI3K信号的神经元的特定表型，确定通过PI3K信号受损是否像糖尿病环境下的外周胰岛素抵抗一样导致下丘脑瘦素和胰岛素抵抗，最后确定增加弓状神经元PI3K信号的基因治疗方法是否可以减轻或防止饮食诱导的肥胖。 该提案的首要目标是提高我们对基本机制的理解，包括细胞和神经解剖学，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。这些信息将被应用于饮食导致的肥胖和抵抗这些荷尔蒙的正常影响的问题。希望这些研究将为药物开发提供有吸引力的分子靶点。这些目标还提供了制定独立研究方案所需的背景和培训，并将在丰富的培训环境中进行

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