Molecular Clock Control of Oxidative Metabolism in Metabolic Disease

描述（由申请人提供）：过去十年的研究揭示了生物钟和代谢稳态之间的联系。缺乏分子钟组成部分的小鼠会出现显著的代谢异常，包括肥胖、糖调节紊乱、游离脂肪酸升高和代谢性肌病。虽然这些表型的分子机制仍然知之甚少，许多这些缺陷指向线粒体氧化代谢途径，包括脂肪酸氧化和呼吸的中断。关于昼夜节律突变体中线粒体功能障碍的原因的一个主要线索源于最近的发现，即时钟转录因子环调节NAD+的细胞水平，进而控制NAD+依赖性脱乙酰酶的sirtuin家族的活性，这是氧化代谢中的关键因素。在令人兴奋的新结果中，我们现在还表明，昼夜节律突变小鼠表现出几种线粒体酶的超乙酰化，这些酶在尿素循环，酮的产生，脂肪酸氧化和ATP合成中具有限速作用。因此，我的研究计划将建立在我以前的研究代谢转录因子途径的氧依赖性控制，并专门测试的假设，昼夜节律基因破坏导致受损的氧化代谢，由于NAD+的合成和活性失调的大脑定位sirtuin酶。拟议的实验将利用实验遗传学，生物化学和细胞生理学的方法，并将作为一个宝贵的车辆在我的发展作为一个独立的研究人员在代谢研究。 公共卫生相关性：包括糖尿病和肥胖症在内的代谢性疾病的发病率增加，突出表明需要更深入地了解人类代谢。很明显，除了饮食和运动，昼夜节律在维持代谢稳态中起着重要作用。该提案的目标是阐明昼夜节律调节和代谢途径之间的联系，以促进我们对代谢疾病的认识。

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.