Role of the Lateral Hypothalamic Area in Leptin Action

描述（由申请人提供）：美国持续流行的肥胖症代表了一种公共卫生紧急情况，这种情况仍未得到控制，也没有具体的治疗方法。为了设计预防和治疗肥胖的具体疗法，我们必须首先了解调节进食和能量消耗的机制，以便确定潜在的治疗靶点。在这项题为“下丘脑外侧区在瘦素作用中的作用”的提案中，我们将分析下丘脑外侧区（LHA）中可能有助于身体能量稳态的新型瘦素调节神经通路。我们已经定义了表达 LRb、瘦素响应的 LHA 神经元的新群体的存在，这些神经元在局部投射并密集地支配腹侧被盖区 (VTA)。我们假设 LHA 中 LRb 介导的信号对于 VTA 的调节和中边缘多巴胺系统的活动至关重要，从而调节摄食和能量平衡。因此，我们将研究 LHA LRb 神经元的调节及其在瘦素调节生理学中的作用。我们提出以下具体目标： 1.了解LHA LRb神经元的调节。分析 LHA LRb 神经元基因表达和活性的调节，并确定瘦素和其他因子介导这种调节的机制。 2. 定义LHA LRb 神经元对下游神经元的作用。定义LHA LRb神经元的下游靶神经元以及LHA LRb神经元在调节这些下游神经元（包括中脑边缘多巴胺系统）中的作用。 3. 确定 LHA LRb 神经元在瘦素生理作用中的功能。通过对这些神经元进行各种遗传和药理学操作后检查动物的能量平衡和行为，检查 LHA LRb 神经元的生理功能。这些研究将使我们能够了解瘦素调节 LHA 功能的机制，以及 LHA LRb 神经元与 CNS 其他区域相互作用的机制，从而有助于调节摄食和能量平衡。这些信息反过来将为理解 LHA 驱动的喂养的调节机制奠定基础，这对于我们寻求确定持续流行的肥胖症的发病机制和潜在治疗目标至关重要。公共卫生相关性：美国持续流行的肥胖症代表了一种公共卫生紧急情况，这种情况仍未得到控制，也没有具体的治疗方法。为了设计预防和治疗肥胖的具体疗法，我们必须首先了解调节进食和能量消耗的机制，以便确定潜在的治疗靶点。在本提案中，我们将分析大脑中可能有助于身体能量稳态的新神经通路，以便定义这些机制及其代表的潜在治疗靶点。

DESCRIPTION (provided by applicant): The ongoing epidemic of obesity in the United States represents a public health emergency that remains unchecked and without specific therapy. To design specific treatments to prevent and treat obesity, we must first understand the mechanisms that regulate feeding and energy expenditure in order to identify potential therapeutic targets. In this proposal, entitled, Role of the lateral hypothalamic area in leptin action, we will analyze novel leptin-regulated neural pathways in the lateral hypothalamic area (LHA) that likely contribute to body energy homeostasis. We have defined the existence of a novel population of LRb-expressing, leptin-responsive LHA neurons that project locally as well as densely innervating the ventral tegmental area (VTA). We hypothesize that LRb-mediated signaling in the LHA is crucial to the regulation of the VTA and activity of the mesolimbic dopamine system, and thereby for the regulation of feeding and energy balance. We will thus study the regulation of LHA LRb neurons and their role in the regulation of physiology by leptin. We propose the following specific aims: 1. Understand the regulation of LHA LRb neurons. Analyze the regulation of gene expression and activity of LHA LRb neurons, and define the mechanisms by which leptin and other factors mediate this regulation. 2. Define the action of LHA LRb neurons on downstream neurons. Define the downstream target neurons of LHA LRb neurons and the role of LHA LRb neurons in the regulation of these downstream neurons, including the mesolimbic dopamine system. 3. Determine the function of LHA LRb neurons in physiologic leptin action. Examine the physiologic function of LHA LRb neurons by examining energy balance and behavior in animals following a variety of genetic and pharmacologic manipulations directed at these neurons. These studies will enable us to understand the mechanisms by which leptin regulates LHA function, and the mechanisms by which LHA LRb neurons interact with other areas of the CNS in order to contribute to the regulation of feeding and energy balance. This information will in turn lay the groundwork for understanding mechanisms by which LHA-driven feeding may be regulated, which is crucial as we seek to determine the pathogenesis of, and potential therapeutic targets for the ongoing epidemic of obesity. PUBLIC HEALTH RELEVANCE: The ongoing epidemic of obesity in the United States represents a public health emergency that remains unchecked and without specific therapy. To design specific treatments to prevent and treat obesity, we must first understand the mechanisms that regulate feeding and energy expenditure in order to identify potential therapeutic targets. In this proposal, we will analyze novel neural pathways in the brain that likely contribute to body energy homeostasis in order to define these mechanisms and the potential therapeutic targets that they represent.