Molecular Clock Control of Oxidative Metabolism in Metabolic Disease

描述(申请人提供)：过去十年的研究揭示了生物钟和代谢动态平衡之间的联系。缺乏分子时钟组件的小鼠会出现戏剧性的代谢异常，包括肥胖、糖调节中断、游离脂肪酸升高和代谢性肌病。尽管这些表型背后的分子机制仍不清楚，但这些缺陷中的许多都指向线粒体氧化代谢途径的中断，包括脂肪酸氧化和呼吸作用。关于昼夜节律突变中线粒体功能障碍的一个主要线索源于最近的发现，即时钟转录因子环调节细胞内NAD+的水平，进而控制依赖NAD+的Sirtuin家族脱乙酰酶的活性，这是氧化代谢的关键因素。在令人振奋的新结果中，我们现在还表明，昼夜节律突变的小鼠表现出几种线粒体酶的超乙酰化，这些酶在尿素循环、酮产生、脂肪酸氧化和ATP合成中起限速作用。因此，我的研究计划将建立在我之前对代谢转录因子途径的氧依赖控制的研究基础上，并具体检验这样的假设，即昼夜节律基因的破坏会由于NAD+合成和线粒体定位的sirtuin酶的活性失调而导致氧化代谢受损。拟议中的实验将利用实验遗传学、生物化学和细胞生理学方法，并将成为我作为新陈代谢研究的独立研究员发展的宝贵工具。 公共卫生相关性：包括糖尿病和肥胖症在内的代谢性疾病患病率的增加，突显了对人类新陈代谢有更深入了解的必要性。很明显，除了饮食和运动之外，昼夜节律在维持代谢动态平衡方面也起着重要作用。这项建议的目的是阐明昼夜节律和代谢途径之间的联系，以促进我们对代谢性疾病的了解。

DESCRIPTION (provided by applicant): Research over the past decade has uncovered a connection between circadian clocks and metabolic homeostasis. Mice lacking components of the molecular clock develop dramatic metabolic abnormalities, including obesity, disrupted glucoregulation, elevated free fatty acids and metabolic myopathy. Although the molecular mechanisms underlying these phenotypes remain poorly understood, many of these defects point to disruptions in mitochondrial oxidative metabolic pathways, including fatty acid oxidation and respiration. A major clue concerning the cause of mitochondrial dysfunction in circadian mutants stems from the recent discovery that the clock transcription factor loop regulates cellular levels of NAD+, and in turn, controls activity of the sirtuin family of NAD+-dependent deacetylases, key factors in oxidative metabolism. In exciting new results, we also now show that circadian mutant mice exhibit hyperacetylation of several mitochondrial enzymes that are rate-limiting in the urea cycle, ketone production, fatty acid oxidation and ATP synthesis. My research proposal will thus build upon my previous studies of oxygen-dependent control of metabolic transcription factor pathways and specifically test the hypothesis that circadian gene disruption leads to impaired oxidative metabolism due to dysregulation of NAD+ synthesis and activity of mitochondrial-localized sirtuin enzymes. The proposed experiments will exploit experimental genetic, biochemical and cell physiological approaches and will serve as an invaluable vehicle in my development as an independent investigator in metabolism research. PUBLIC HEALTH RELEVANCE: The increased prevalence of metabolic diseases, including diabetes and obesity, underscore the need for a deeper understanding of human metabolism. It is clear that in addition to diet and exercise, circadian rhythms play an important role in maintaining metabolic homeostasis. The goal of this proposal is to elucidate the connection between circadian regulation and metabolic pathways to advance our knowledge of metabolic disease.