Mechanisms and Consequences of Intermittent Hypoxia-Induced Lipolysis

间歇性缺氧诱导脂肪分解的机制和后果

• 批准号: 8299819
• 负责人: Jonathan C. Jun
• 金额: $ 13.68万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8299819
• 关键词: A Mouse; Acute; Adipose tissue; Adrenergic Agents; Affect; Atherosclerosis; Cardiovascular Diseases; Cardiovascular system; Carotid Body; Catecholamines; Cause of Death; Chemoreceptors; Chronic; Critical Care; Disease; Dyslipidemias; Environment; Exhibits; Fatty Liver; Fellowship; Functional disorder; Genetic; Glycerol; Grant; Heart failure; Hyperlipidemia; Hypoxia; Infusion procedures; Insulin Resistance; Laboratories; Lead; Link; Lipids; Lipolysis; Lung; Maryland; Mediating; Medicine; Metabolic; Metabolism; Mus; Nonesterified Fatty Acids; Obesity; Obstructive Sleep Apnea; Operative Surgical Procedures; Organ; Outcome; Oxygen; Pathway interactions; Patients; Physiology; Plasma; Play; Reporting; Research; Research Personnel; Risk Factors; Role; Scientist; Simulate; Sleep; Sleep Apnea Syndromes; Sleep Fragmentations; Sympathetic Nervous System; Testing; Tissues; Training Support; United States; Universities; Western World; Woman; Work; adrenergic; airway obstruction; base; career; disability; experience; instructor; men; metabolic abnormality assessment; mouse model; novel; prevent; public health relevance; response; theories

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.

描述（由申请人提供）：间歇性缺氧引起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为期 5 年的肺科、重症监护和睡眠医学奖学金。他一直在 Vsevolod Polotsky 博士的实验室工作，该博士是利用小鼠间歇性缺氧 (IH) 来研究阻塞性睡眠呼吸暂停 (OSA) 代谢后果的先驱。在这个提案中，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：Jun 博士于 2011 年 7 月 1 日开始担任肺科/重症监护医学科的讲师，从事临床医生科学家的职业生涯。他将通过波洛茨基博士以及约翰·霍普金斯大学和马里兰大学的生理学和新陈代谢专家小组接受持续的培训和支持。研究：OSA 是一种常见疾病，其特征是反复上呼吸道塌陷，导致间歇性休克和睡眠碎片化。 OSA 可能导致代谢功能障碍和动脉粥样硬化性心血管疾病，从而成为西方世界死亡和残疾的主要原因。一些研究人员已经证明，实验性 IH 会导致胰岛素抵抗和高脂血症。然而，这些 IH 引起的代谢异常的基础尚不清楚。我们假设游离脂肪酸 (FFA) 升高可能会导致 IH 期间代谢功能障碍。 FFA 是脂肪组织在脂解过程中释放的循环脂质，过量会导致胰岛素抵抗、脂肪肝和高脂血症。我们最近报道称，OSA 在睡眠期间迅速增加血浆 FFA，但可通过补充氧气消除。这一观察结果激发了该提议的核心假设，即（1）IH 期间的脂肪分解是通过颈动脉体刺激交感神经系统发生的，并且（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。已经开发了 IH 小鼠模型来模拟 OSA 患者经历的氧饱和度降低，以测试这些假设。小鼠在 IH 期间表现出 FFA 和甘油水平快速增加。在具体目标 1 中，我们将使用缺乏正常颈动脉体功能的小鼠来确定颈动脉体在 IH 期间刺激脂肪分解中的作用。具体目标 2 将确定交感神经系统在 IH 期间使用 β 阻滞剂刺激脂肪分解的作用。具体目标 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脂血症。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。通过识别和预防 IH 诱导的脂肪分解，可以避免 OSA 造成的破坏性心血管后果。 公共健康相关性：阻塞性睡眠呼吸暂停会导致睡眠期间间歇性缺氧，影响美国多达 24% 的男性和 9% 的女性。阻塞性睡眠呼吸暂停与胰岛素抵抗和高脂血症有关，而胰岛素抵抗和高脂血症是动脉粥样硬化的主要危险因素，动脉粥样硬化是美国的主要死亡原因。本次拨款申请中提出的研究将确定睡眠呼吸暂停的间歇性缺氧如何导致胰岛素抵抗和高脂血症。