Role of the Lateral Hypothalamic Area in Leptin Action

描述(申请人提供)：肥胖症在美国的持续流行代表着一种公共卫生紧急情况，仍然没有得到控制，也没有具体的治疗方法。为了设计特定的治疗方法来预防和治疗肥胖，我们必须首先了解调节摄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)新的瘦素调节神经通路，这些通路可能有助于身体能量动态平衡。我们定义了一种新的LRB表达的、瘦素反应的LHA神经元的存在，这些神经元在局部投射，并密集地支配腹侧被盖区(VTA)。我们推测LRB在LHA中介导的信号对调节VTA和中脑边缘多巴胺系统的活性至关重要，从而对摄食和能量平衡的调节至关重要。因此，我们将研究LHA、LRB神经元的调节以及它们在瘦素对生理调节中的作用。我们提出了以下具体目标：1.了解LHA、LRB神经元的调控。分析LHA、LRB神经元基因表达和活性的调节，明确瘦素和其他因素介导这种调节的机制。2.明确LHA、LRB神经元对下游神经元的作用。明确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Leptin生理作用中的作用。在针对LHA、LRB神经元的各种遗传和药物操作之后，通过检测动物的能量平衡和行为来检查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神经元与中枢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了解LHA驱动的喂养可能受到调控的机制奠定基础，这在我们寻求确定肥胖流行的发病机制和潜在的治疗目标时至关重要。与公共卫生相关：肥胖在美国的持续流行代表着一种公共卫生紧急情况，它仍然没有得到控制，也没有具体的治疗方法。为了设计特定的治疗方法来预防和治疗肥胖，我们必须首先了解调节摄食和能量消耗的机制，以便确定潜在的治疗靶点。在这项提案中，我们将分析大脑中可能有助于身体能量动态平衡的新的神经通路，以确定这些机制和它们所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.