PERIPHERAL AND CENTRAL INTERACTIONS IN ENERGY BALANCE

能量平衡的调节涉及影响行为和新陈代谢的外周信号和神经回路之间的复杂相互作用。这种能量平衡调节系统的功能失调是肥胖症的基础，肥胖症是一种非常普遍的疾病，在发病率和死亡率方面具有巨大的代价。这一领域的最新发现，例如身份识别。在参与能量平衡的脂肪衍生激素中，Ha创造了一个很好的机会来促进对能量平衡和肥胖的理解，但主要问题仍然没有得到回答。特别是，目前还没有确定瘦素影响能量平衡的复杂神经回路是如何相互联系的，以及瘦素等关键因素是如何通过中枢和/或外周机制影响新陈代谢的。在这项建议中，我们的意图是使用遗传学、生理学、神经解剖学和生化技术来更好地了解调节能量平衡的外周和中央回路。因此，对正常和异常体重调节的综合生理学将出现更完整的理解。我们的提案包括四个项目和三个核心单元，每个项目涉及能量平衡神经控制的一个不同但相互关联的生理学方面。项目1将使用多种功能神经解剖学技术来识别弓状核中受饥饿和瘦素调节的不同化学特征的神经元，并将绘制它们影响下丘脑外侧中心以及自主神经传出路径的路径。项目2将使用基因打靶和腺相关(AAV)病毒载体技术来识别黑素皮质素4受体和瘦素受体调节新陈代谢的下丘脑核团。项目3将研究黑色素浓缩激素和相关神经肽在调节食物摄入、产热和新陈代谢中的作用，采用将在一系列生理环境中研究的单基因和组合基因靶向模型。项目4将使用生化和遗传方法来确定瘦素通过中枢效应途径或直接作用于肌肉或脂肪等外围组织来调节新陈代谢的能力。核心A将是一个行政核心，将监测科学进展和财政状况，并组织与该计划项目相关的学术活动。核心B将是一个神经解剖学核心，它将使用各种技术来支持项目1-4。核心C将是一个生理学和分析核心，将支持项目1-4。综上所述，这些项目将促进我们对能量平衡和新陈代谢通过外周和大脑之间的相互作用进行调节的基本机制的理解。

The regulation of energy balance involves complex interactions between peripheral signals and neural circuits that influence behavior and metabolism. Dysfunction of this energy balance regulatory system underlies obesity, a highly prevalent disorder that has an enormous toll in morbidity and mortality. Recent discoveries in this area, such as identification. of the fat-derived hormone involved in energy balance, ha created a great opportunity to advance understanding of energy balance and obesity but major questions remain unanswered. In particular, it has not been determined how the complex neural circuits involved in energy balance that are influenced by leptin interrelate with each other, and how key factors such as leptin affect metabolism through central and/or peripheral mechanisms. It is our intent, in this proposal, to use genetic, physiologic, neuroanatomic and biochemical techniques to better understand the peripheral and central circuits through which energy balance is regulated. Thereby, a more complete understanding of the integrated physiology of normal and abnormal weight regulation will emerge. Our proposal consists of four projects and three core units each project addressing a distinct, but interrelated aspect of the physiology of neural control of energy balance. Project #1 will use multiple techniques of functional neuroanatomy to identify chemically distinct neurons regulated by starvation and leptin in the arcuate nucleus, and will map the pathways by which they influence centers in the lateral hypothalamus as well as autonomic efferent pathways. Project #2 will use gene targeting and adeno associated (AAV) viral vector technology to identify the hypothalamic nuclei in which melanocortin 4 receptors and leptin receptors act to regulate metabolism. Project #3 will examine the role of melanin concentrating hormone and related neuropeptides to regulated food intake, thermogenesis and metabolism, employing single and combinatorial gene targeting models that will be studied in a range of physiological contexts. Project #4 will employ biochemical and genetic approaches to determine the ability of leptin to regulate metabolism through either central effector pathways or direct actions on peripheral tissues such as muscle or fat. Core A will be an administrative core that will monitor scientific progress and fiscal status and organize academic activities related to the Program project. Core B will be a Neuroanatomic Core that will use a variety of techniques in support of projects 1-4. Core C will be a Physiology and Assay Core that will support projects 1-4. Taken together, these projects will advanced our understanding of the basic mechanisms by which energy balance and metabolism are regulated through interactions between the periphery and the brain.