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

描述（由申请人提供）： 大多数生物体表现出行为和生理节律，包括睡眠、活动、血压以及脂质和碳水化合物代谢。这种昼夜振荡是由生物钟调节的，生物钟对光照和摄食周期做出反应。生物钟功能紊乱与睡眠障碍有关，并与心血管风险增加有关。啮齿类动物生物钟功能的破坏导致肥胖和葡萄糖稳态受损，这表明能量稳态与生物计时系统有关。然而，整合生物钟和能量代谢的生理和分子机制仍然不清楚。我们以前已经证明，PGC-11，一个转录辅激活因子，调节能量代谢的几个主要方面，包括肝再生，脂肪酸2-氧化，线粒体氧化代谢，也控制时钟基因的表达。缺乏PGC-11的小鼠具有运动活动、体温、代谢率和代谢基因表达的昼夜模式的异常昼夜节律。基于这些发现，我们假设生物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实现的。我们将通过评估PGC-11在生物钟和代谢的组织自主整合中的作用来探索这一假设。我们还将探索参与昼夜节律起搏器和PGC-11之间串扰的分子组分。最后，我们将研究PGC-11调控网络控制昼夜代谢节律的新机制。生理节律起搏器和能量代谢如何在个体组织中整合仍然是一个基本问题。我们的研究有可能阐明将昼夜节律计时系统与能量稳态联系起来的关键分子组分，并深入了解代谢和心血管疾病的致病机制。(End摘要）

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)