Cellular Mechanisms of Hypothalamic Inflammation in High Fat Diet-Induced Obesity

描述（由申请人提供）：该提案描述了一个为期5年的计划，以提供在影响能量平衡的神经免疫相互作用研究中发展独立学术研究事业的培训。这项研究计划的目标是确定高脂饮食诱导的肥胖症中能量平衡失调的大脑机制，以便为治疗提供分子靶点。候选人已经通过完成医学博士和博士学位以及内科和内分泌学的临床培训为这一途径做好了准备。这项研究将在下丘脑调节能量平衡和葡萄糖稳态领域的专家Michael Schwartz博士的实验室进行，并将与华盛顿大学的代谢和炎症生物学专家进行合作。它将由一个专家指导委员会监督，该委员会由内分泌科的几名成员以及三名外部顾问组成。 与饮食过量相关的体重增加的临床问题受到了对中枢神经系统（CNS）机制的有限理解的阻碍，中枢神经系统（CNS）机制解释了这种能量稳态的破坏。我们的初步数据揭示了小胶质细胞（大脑的免疫细胞）和神经元（能量平衡的调节器）之间的潜在相互作用。在高脂喂养开始时，有一段时间的早期摄食过多和伴随的炎症反应，特别是在下丘脑。与此同时，弓状核中的小胶质细胞数量和细胞大小增加，弓状核是下丘脑中含有瘦素反应性黑皮质素（POMC）神经元的区域。阻断小胶质细胞活化导致对高脂饮食诱导的体重增加的易感性增强。这项研究将通过两个特定的目的来描述高脂饮食诱导的下丘脑炎症导致体重过度增加的机制。在目标1中，我们将研究能量平衡、炎症、激素和细胞机制，通过这些机制，小胶质细胞抑制增加了高脂饮食对体重增加的敏感性。目的2关注预防高脂饮食诱导的POMC神经元炎症对瘦素敏感性、能量平衡和葡萄糖稳态的影响。该研究课程将提供独立调查职业所需的培训和专业知识，同时将PI转向不断扩大的神经免疫学领域的转化研究。该提案的总体目标是确定炎症信号改变能量稳态的机制，以产生更好的治疗方案来改善患者护理。 公共卫生相关性：肥胖是全球大多数2型糖尿病病例的根本原因。针对肥胖的治疗可以降低糖尿病的发病率，从而大大改善整体健康状况。这项研究的重点是大脑在高脂肪饮食引起的体重增加中的作用，并努力开发减少体重增加的疗法。

DESCRIPTION (provided by applicant): This proposal delineates a 5-year program to provide the training toward the development of an independent academic research career in the study of neuroimmune interactions that affect energy balance. The goal of this research program will be to determine brain mechanisms that govern dysregulation of energy balance in high-fat diet induced obesity in order to provide molecular targets for therapy. The candidate has been prepared for this pathway by completing MD and PhD degrees and clinical training in Internal Medicine and Endocrinology. This research will be conducted in the laboratory of Dr. Michael Schwartz, an expert in the field of hypothalamic regulation of energy balance and glucose homeostasis, and will involve collaboration with a large group of experts in metabolism and inflammatory biology at the University of Washington. It will be overseen by an expert mentoring committee with several members of the Endocrinology Division as well as three external advisors. The clinical problem of weight gain associated with dietary excess has been hampered by a limited understanding of the central nervous system (CNS) mechanisms that account for this disruption in energy homeostasis. Our preliminary data has uncovered a potential interaction between microglia, the immune cells of the brain, and neurons, the regulators of energy balance. At the onset of high-fat feeding, there is a period of early hyperphagia and a concomitant inflammatory response specifically in the hypothalamus. At the same time, an increase in microglial number and cell size occurs in the arcuate nucleus, a region of the hypothalamus containing leptin-responsive melanocortin (POMC) neurons. Blocking microglial activation results in enhanced susceptibility to high-fat diet-induced weight gain. This research will characterize the mechanisms by which high-fat diet-induced inflammation in the hypothalamus contributes to excess weight gain through two specific aims. In Aim 1, we will examine the energy balance, inflammatory, hormonal, and cellular mechanisms by which microglial inhibition confers increased susceptibility to weight gain on high-fat diets. Aim 2 focuses on the effect of preventing high-fat diet-induced inflammation in the POMC neuron on leptin sensitivity, energy balance, and glucose homeostasis. This research course will provide the training and expertise necessary for an independent investigative career while transitioning the PI toward translational research in the expanding field of neuroimmunology. The overarching goal of this proposal is to determine the mechanisms by which inflammatory signals alter energy homeostasis in order to generate better therapeutic options to improve patient care. PUBLIC HEALTH RELEVANCE: Obesity is the underlying cause of most cases of type 2 diabetes worldwide. Therapies that target obesity could reduce the incidence of diabetes, thereby greatly improving general health. This research focuses on the brain's role in high-fat diet-induced weight gain with an effort to develop therapies to reduce weight gain.