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回路调节，其中激素胰岛素和瘦素被分泌到血液中，与身体脂肪储存成正比。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，最终起到将体重维持在正常范围内的作用。肥胖症通常伴随糖尿病，其特征在于下丘脑对这些激素的正常作用的抵抗，即尽管胰岛素和瘦素水平增加，但食物摄入和体重仍然升高。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，我们目前没有一个很好的了解正常的信号机制，胰岛素和瘦素使用激活弓状核神经元。 申请人进行的初步研究表明，通过弓状核神经元中的细胞内信号转导酶磷脂酰肌醇3-激酶的信号传导是瘦素的食物摄取降低作用所需的，并且胰岛素也激活这些神经元中的该信号传导途径。提出的研究的目的是确定需要PI 3 K信号传导的神经元的特定表型，以确定通过PI 3 K的信号传导受损是否导致下丘脑瘦素和胰岛素抵抗，因为它在糖尿病背景下导致外周胰岛素抵抗，最后确定增加弓形神经元中PI 3 K信号传导的基因治疗方法是否可以减轻或预防饮食诱导的肥胖。 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，这些信息将被应用于饮食引起的肥胖和对这些激素的正常作用的抵抗问题。希望这些研究将为药物开发提供有吸引力的分子靶点。这些目标也提供了背景和培训所需的发展一个独立的研究计划，并将在丰富的培训环境的背景下进行

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