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)中瘦素调节的神经通路，这些通路有助于身体能量的动态平衡、激励和活动。在之前的资助期间，我们开发和利用了遗传小鼠模型来证明LHA LepRb神经元直接支配OX神经元和VTA，并需要调节增食欲素作用、中脑边缘DA系统和能量平衡(除了分析一些相关的瘦素调节的神经回路)。在这次续订申请中，我们将采用现有的和新的基因 系统了解此电路对于各种参数的充分性。我们还将了解LHA LepRb神经元亚群在控制食欲素、中脑DA系统和摄食方面的不同和重叠的作用，以及定义这些重要过程调节的电路和神经机制。这些研究将使我们能够了解LHA瘦素作用对总体瘦素作用、能量平衡和神经功能方面的作用机制，这些方面对享乐性暴食至关重要。这些信息将反过来为理解可能调节喂养的机制奠定基础，这在我们寻求确定肥胖症持续流行的发病机制和潜在的治疗目标时至关重要。

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 leptin-regulated neural pathways in the lateral hypothalamic area (LHA) that contribute to body energy homeostasis, incentive, and activity. During the previous funding period, we developed and utilized genetic mouse models to demonstrate that LHA LepRb neurons directly innervate OX neurons and the VTA, and are required to modulate orexin action, the mesolimbic DA system and energy balance (in addition to analyzing some related leptin-regulated neural circuitry). In this renewal application, we will employ existing and novel genetic systems to understand the sufficiency of this circuit for a variety of parameters. We will also understand distinct and overlapping roles for subpopulations of LHA LepRb neurons for the control of orexin, the midbrain DA system, and feeding, as well as defining the circuits and neural mechanisms underlying the regulation of these important processes. These studies will enable us to understand the mechanisms by which the LHA leptin action contributes to overall leptin action, energy balance, and aspects of neural function that are crucial for hedonically-driven overeating. This information will in turn lay the groundwork for understanding mechanisms by which 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.