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

高脂饮食引起的肥胖中下丘脑炎症的细胞机制

• 批准号: 8100510
• 负责人: JOSHUA P THALER
• 金额: $ 14.92万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8100510
• 关键词: Accounting; Adipose tissue; Affect; Animals; Area; Behavioral; Biochemical; Biological Assay; Biology; Brain; Cell Size; Cells; Clinical; Collaborations; Data; Development; Diabetes Mellitus; Diet; Disease; Doctor of Philosophy; Eating; Endocrinology; Energy Metabolism; Ensure; Fatty acid glycerol esters; Flow Cytometry; Functional disorder; Future; Gene Expression; Genetic; Goals; Health; Homeostasis; Hormonal; Hormones; Human; Hyperphagia; Hypothalamic structure; Immune; Immunohistochemistry; Immunomagnetic Separation; Incidence; Indirect Calorimetry; Inflammation; Inflammatory; Inflammatory Response; Infusion procedures; Insulin; Insulin Resistance; Interleukin-4; Internal Medicine; Intervention; Investigation; Knockout Mice; Knowledge; Laboratories; Leptin; Leptin resistance; Link; Mentored Clinical Scientist Development Award (K08); Mentors; Metabolic; Metabolism; Methods; Microglia; Minocycline; Molecular Target; Monitor; Neuraxis; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Obesity; Outcome; Pathogenesis; Pathway interactions; Patient Care; Peripheral; Play; Predisposition; Pro-Opiomelanocortin; Publishing; Rattus; Recruitment Activity; Regulation; Research; Research Personnel; Resistance; Resources; Rewards; Risk; Rodent; Role; Seminal; Senior Scientist; Series; Signal Transduction; Structure of nucleus infundibularis hypothalami; Techniques; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Training; Translational Research; Universities; Washington; Weight; Weight Gain; base; blood glucose regulation; brain cell; career; diabetes risk; dietary excess; effective therapy; energy balance; experience; feeding; improved; inhibitor/antagonist; interest; macrophage; member; neuroimmunology; novel; prevent; programs; public health relevance; research study; response; skills training; therapy development

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.

描述（由申请人提供）：该提案描述了一项为期5年的计划，以在研究影响能量平衡的神经免疫互动研究中为开发独立的学术研究生涯的培训。该研究计划的目的是确定控制高脂饮食诱导肥胖症能量平衡失调的大脑机制，以提供治疗的分子靶标。该候选人是通过完成医学博士学位和博士学位以及内科和内分泌学方面的临床培训来为这一途径准备的。这项研究将在迈克尔·施瓦茨（Michael Schwartz）博士的实验室进行，该领域是对能量平衡和葡萄糖稳态调节领域的专家，并将与华盛顿大学的代谢和炎症生物学专家合作。它将由一个专家指导委员会监督，内分泌部门的几个成员以及三名外部顾问。 对中枢神经系统（CNS）机制的理解有限，体重增加相关的临床增加与饮食过剩相关的问题受到了阻碍，这些机制解释了能量稳态的破坏。我们的初步数据发现了小胶质细胞，大脑的免疫细胞和能量平衡调节剂神经元之间的潜在相互作用。在高脂喂养开始时，有一段时间的早期晶状体和下丘脑中的炎症反应。同时，小胶质细胞数和细胞大小的增加发生在弧形核，这是含有瘦素反应性黑色素质素（POMC）神经元的下丘脑的一个区域。封闭小胶质细胞激活会增强对高脂饮食诱导的体重增加的敏感性。这项研究将表征高脂饮食引起的下丘脑炎症的机制，从而通过两个特定的目标导致体重增加过多。在AIM 1中，我们将检查小胶质抑制赋予高脂饮食中体重增加的易感性的能量平衡，炎症，激素和细胞机制。 AIM 2的重点是防止POMC神经元中高脂饮食诱导的炎症对瘦素敏感性，能量平衡和葡萄糖稳态的影响。本研究课程将为独立调查职业提供所需的培训和专业知识，同时将PI转变为神经免疫学领域扩展领域的转化研究。该提案的总体目标是确定炎症信号改变能量稳态的机制，以产生更好的治疗选择以改善患者护理。 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。靶向肥胖症的疗法可以降低糖尿病的发病率，从而大大改善一般健康状况。这项研究的重点是大脑在高脂饮食引起的体重增加中的作用，以开发疗法以减轻体重增加。