Central Mechanisms Regulating Energy Homeostasis, Project 2 of 10

不断增加的肥胖率是美国面临的一个主要健康问题。幸运的是，在过去 十年来，控制体重和血糖稳态的几种关键激素和CMS途径 已被确认身份。事实上，我们现在有了一个粗略的CMS路线图，通过它，关键的代谢信号 当瘦素发挥作用时。防治肥胖和饮食失调的有效策略 将被开发，增加对潜在的协调的分子机制的理解 能量动态平衡是必需的。最近，我们组建了一个调查小组，他们的目标是 描述协调控制食物摄入量、体重和血糖的神经基础 动态平衡。在目前的应用中，我们提供了一系列旨在增加我们的 了解下丘脑对肝脏代谢的调控。我们还将通过以下方式调查机制 下丘脑调节复杂的摄食行为，特别是高脂肪的奖赏性质 节食。首先，我们将研究瘦素和5-羟色胺对下丘脑POMC的作用机制 神经元调节肝脏的葡萄糖和脂肪代谢。第二，我们将调查两国之间的相互作用 控制体重的下丘脑通路与调节复杂食欲的大脑通路 行为和奖励。我们假设，这些相互联系对于调节 对包括高脂肪饮食在内的自然奖励的反应。最后，与我们在AIMS 1-2中进行的小鼠研究平行， 我们将在死后的人脑组织中，定量评估其表达的基因的变化 我们的假设在肥胖者和药物诱导的代谢综合征患者中发生了改变。适时的 将基于动物模型的假说翻译到人类是该研究的主要目标之一 达拉斯德克萨斯大学西南医学中心的肥胖特别工作组，我们正准备做出独特的 肥胖症的翻译研究取得重大进展。

The increasing incidence of obesity is a major health issue facing the USA. Fortunately, in the past decade several key hormones and CMS pathways controlling body weight and glucose homeostasis have been identified. Indeed, we now have a rough CMS roadmap through which key metabolic signals such as leptin exert its effects. If effective strategies to combat the incidence of obesity and eating disorders are to be developed, an increased understanding of the molecular mechanisms underlying coordinate energy homeostasis is required. Recently, we have assembled a team of investigators whose goal is to delineate the neural substrates underlying coordinated control of food intake, body weight and glucose homeostasis. In the current application, we provide a series of studies designed to increase our understanding of the hypothalamic control of liver metabolism. We will also investigate mechanisms by which the hypothalamus regulates complex feeding behavior, especially the rewarding nature of high fat diets. First, we will investigate mechanisms by which leptin and serotonin acting on hypothalamic POMC neurons regulate hepatic glucose and lipid metabolism. Second, we will investigate the interaction of hypothalamic pathways controlling body weight with the brain pathways regulating complex appetitive behavior and reward. We hypothesize that these reciprocal connections are crucial for regulating responses to natural rewards including high fat diet. Finally, in parallel to our mouse studies in Aims 1-2, we will, in postmortem human brain tissue, quantitatively assess alterations in genes whose expression we hypothesize is altered in obese humans and those with drug-induced metabolic syndrome. The timely translation of hypotheses based on animal models to the human is one of the primary goals of the Taskforce on Obesity at UT Southwestern Medical Center at Dallas, and we are uniquely poised to make major strides in translational research of obesity.