Integration of Circadian Rhythm and Metabolism through Coactivator PGC-1alpha

通过辅激活剂 PGC-1alpha 整合昼夜节律和代谢

• 批准号: 7755516
• 负责人: Jiandie D Lin
• 金额: $ 36.66万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7755516
• 关键词: Automobile Driving; Behavioral; Biochemical; Biological; Biological Clocks; Blood Pressure; Body Temperature; CSNK1A1 gene; Cardiovascular Diseases; Cell Respiration; Circadian Rhythms; Energy Metabolism; Exhibits; Fatty Acids; Gene Expression; Gene Targeting; Glucose; Hepatic; Hepatocyte; Homeostasis; Individual; Insulin Resistance; Knockout Mice; Life; Light; Link; Lipids; Liver; Measures; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Molecular; Motor Activity; Mus; Nature; Neuraxis; Obesity; Organism; Pathogenesis; Pathway interactions; Pattern; Peripheral; Phase; Phosphorylation; Physiological; Post-Translational Protein Processing; RNA Interference; Regulation; Rodent; Role; Sleep; Sleep Disorders; System; Testing; Time; Tissues; Transcription Coactivator; abstracting; base; blood glucose regulation; carbohydrate metabolism; cardiovascular risk factor; casein kinase I; circadian pacemaker; feeding; hepatic gluconeogenesis; in vivo; inhibitor/antagonist; insight; lipid metabolism; novel; oxidation; response; tool; ubiquitin-specific protease; upstream kinase

DESCRIPTION (provided by applicant): Most living organisms exhibit behavioral and physiological rhythms, including sleep, activity, blood pressure as well as lipid and carbohydrate metabolism. This diurnal oscillation is regulated by circadian clock, which responds to light and feeding cycles. Perturbed clock function has been implicated in sleep disorders and it is associated with increased cardiovascular risk. Disruption of clock function in rodents leads to obesity and impaired glucose homeostasis, suggesting that energy homeostasis is linked to biological timing systems. The physiological and molecular mechanisms that integrate clock and energy metabolism, however, remain poorly defined. We have previously demonstrated that PGC-11, a transcriptional coactivator that regulates several major aspects of energy metabolism, including hepatic gluconeogenesis, fatty acid 2-oxidation, and mitochondrial oxidative metabolism, also controls clock gene expression. Mice deficient in PGC-11 have aberrant circadian rhythms of locomotor activity, body temperature, metabolic rate, and diurnal patterns of metabolic gene expression. Based on these findings, we hypothesize that the integration of clock and metabolism is achieved through reciprocal crosstalk between circadian pacemaker and metabolic regulatory networks. We will explore this hypothesis by evaluating the role of PGC-11 in tissue- autonomous integration of clock and metabolism. We will also explore molecular components involved in the crosstalk between the circadian pacemaker and PGC-11. Finally, we will investigate novel mechanisms through which the PGC-11 regulatory network controls circadian metabolic rhythms. How circadian pacemaker and energy metabolism are integrated in individual tissues remains a fundamental question. Our study has the potential to elucidate key molecular components that link the circadian timing system to energy homeostasis, and to gain insights into pathogenic mechanisms of metabolic and cardiovascular diseases. (End of Abstract)

描述（由申请人提供）： 大多数活生物体表现出行为和生理节奏，包括睡眠，活性，血压以及脂质和碳水化合物代谢。这种昼夜振荡受昼夜节律的调节，昼夜节律响应于光周期和进食周期。扰动的时钟功能与睡眠障碍有关，与心血管风险增加有关。啮齿动物中时钟功能的破坏会导致肥胖和葡萄糖稳态受损，这表明能量稳态与生物时机系统有关。然而，整合时钟和能量代谢的生理和分子机制仍然很差。我们先前已经证明，PGC-11是一种调节能量代谢的几个主要方面的转录共激活因子，包括肝糖异生，脂肪酸2-氧化和线粒体氧化代谢，也控制了时钟基因表达。缺乏PGC-11的小鼠具有运动活性，体温，代谢率和代谢基因表达的昼夜模式的异常节奏。基于这些发现，我们假设时钟和代谢的整合是通过昼夜节律起搏器和代谢调节网络之间的相互串扰来实现的。我们将通过评估PGC-11在时钟和代谢的组织自主整合中的作用来探讨这一假设。我们还将探索昼夜节律起搏器和PGC-11之间涉及的分子成分。最后，我们将研究PGC-11调节网络控制昼夜力代谢节奏的新型机制。昼夜节律起搏器和能量代谢如何整合到各个组织中仍然是一个基本问题。我们的研究有可能阐明将昼夜节律定时系统与能量稳态联系起来的关键分子成分，并洞悉代谢和心血管疾病的致病机制。 （抽象的结尾）