Mechanisms and Consequences of Intermittent Hypoxia-Induced Lipolysis

描述（由申请人提供）：间歇性缺氧诱导的脂肪分解的机制和后果候选人：Jonathan Jun博士最近在约翰霍普金斯大学完成了肺、重症监护和睡眠医学的五年研究。他一直在Vsevolod Polotsky博士的实验室工作，Vsevolod Polotsky博士是在小鼠中使用间歇性缺氧（IH）研究阻塞性睡眠呼吸暂停（OSA）代谢后果的先驱。在这项提议中，Jun博士测试了一种新的理论来解释IH引起的代谢功能障碍。环境：君博士于2011年7月1日开始担任肺/重症医学部讲师，追求临床医生-科学家的职业生涯。他将接受波洛茨基博士以及约翰霍普金斯大学和马里兰大学生理学和代谢专家小组的持续培训和支持。研究：OSA是一种以反复上呼吸道塌陷为特征的常见病，可引起IH和睡眠破碎。阻塞性睡眠呼吸暂停可能导致代谢功能障碍和动脉粥样硬化性心血管疾病，因此在西方世界是导致死亡和残疾的主要原因。一些研究者已经证明实验性IH会导致胰岛素抵抗和高脂血症。然而，这些ih诱导的代谢异常的基础尚不清楚。我们假设游离脂肪酸（FFA）的升高可能导致IH期间的代谢功能障碍。FFA是脂肪组织在脂肪分解过程中释放的循环脂质，过量时可引起胰岛素抵抗、脂肪肝和高脂血症。我们最近报道了OSA在睡眠期间迅速增加血浆FFA，而补充氧气会使其消失。这一观察启发了这一提议的核心假设，即(1)IH期间的脂肪分解是通过颈动脉体对交感神经系统的刺激发生的，(2)慢性IH诱导的脂肪分解促进组织脂质积累，导致胰岛素抵抗和血脂异常。为了验证这些假设，研究人员开发了一种模拟OSA患者氧饱和度的小鼠IH模型。小鼠在IH期间表现出FFA和甘油水平的快速增加。在Specific Aim 1中，我们将利用缺乏正常颈动脉体功能的小鼠，建立颈动脉体在IH期间刺激脂肪分解的作用。特异性目的2将建立交感神经系统在IH期间刺激脂肪分解的作用，使用β阻断。特异性目的3将确定是否可以通过抑制脂肪分解来预防慢性IH后的胰岛素抵抗和高血脂。公共卫生相关性：成功完成这些目标将确立脂肪分解在IH和OSA代谢后果中的核心作用。潜在地，通过识别和预防ih诱导的脂肪分解，可以避免OSA的破坏性心血管后果。

DESCRIPTION (provided by applicant): Mechanisms and Consequences of Intermittent Hypoxia-Induced Lipolysis Candidate: Dr. Jonathan Jun recently completed a 5-year fellowship at Johns Hopkins in Pulmonary, Critical Care, and Sleep Medicine. He has been working in the laboratory of Dr. Vsevolod Polotsky, a pioneer in the use of intermittent hypoxia (IH) in mice to study metabolic consequences of obstructive sleep apnea (OSA). In this proposal, Dr. Jun tests a novel theory to explain the metabolic dysfunction induced by IH. Environment: Dr. Jun is an Instructor in the Division of Pulmonary/Critical Care Medicine beginning on July 1, 2011 to pursue a clinician-scientist career. He will receive ongoing training and support through Dr. Polotsky and a panel of experts in physiology and metabolism at Johns Hopkins and the University of Maryland. Research: OSA is a common condition characterized by repetitive upper airway collapse, causing IH and sleep fragmentation. OSA may predispose to metabolic dysfunction and atherosclerotic cardiovascular disease, thereby contributing to the leading causes of death and disability in the Western world. Several investigators have demonstrated that experimental IH causes insulin resistance and hyperlipidemia. However the basis for these IH-induced metabolic abnormalities is not understood. We hypothesize that elevations of free fatty acids (FFA) may cause metabolic dysfunction during IH. FFA are circulating lipids released by adipose tissue during lipolysis, which in excess induce insulin resistance, fatty liver, and hyperlipidemia. We recently reported that OSA rapidly increases plasma FFA during sleep, which is abolished by supplemental oxygen. This observation inspired the hypotheses central to this proposal, that (1) lipolysis during IH occurs through carotid body stimulation of the sympathetic nervous system, and that (2) chronic IH-induced lipolysis promotes tissue lipid accumulations leading to insulin resistance and dyslipidemia. A mouse model of IH, simulating oxygen desaturations experienced by patients with OSA, has been developed to test these hypotheses. Mice exhibit rapid increases in FFA and glycerol levels during IH. In Specific Aim 1, we will establish the role of the carotid body in stimulating lipolysis during IH, using mice lackig normal carotid body function. Specific Aim 2 will establish the role of the sympathetic nervous system in stimulating lipolysis during IH, using beta blockade. Specific Aim 3 will establish whether insulin resistance and hyperlipidemia following chronic IH can be prevented with the suppression of lipolysis. Public Health Relevance: Successful completion of these aims will establish the central role of lipolysis in the metabolic consequences of IH and OSA. Potentially, devastating cardiovascular consequences of OSA may be averted by recognizing and preventing IH-induced lipolysis. PUBLIC HEALTH RELEVANCE: Obstructive sleep apnea causes intermittent hypoxia during sleep, and affects as many as 24% of men 9% of women in the United States. Obstructive sleep apnea is associated with insulin resistance and hyperlipidemia which are major risk factors for atherosclerosis, the nation's leading cause of death. Research proposed in this grant submission will determine how the intermittent hypoxia of sleep apnea causes insulin resistance and hyperlipidemia.