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

摘要 大多数生物体都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。这种昼夜振荡由以下因素调节 生物钟，它对光线和进食周期做出反应。扰动时钟函数 与睡眠障碍有关，并与心血管风险增加有关。破坏 啮齿类动物的生物钟功能导致肥胖和葡萄糖稳态受损，这表明能量 体内平衡与生物计时系统有关。生理和分子机制， 然而，整合生物钟和能量代谢仍然定义不清。我们先前已经 证明PGC-1是一种转录辅激活因子，它调控着细胞的几个主要方面， 能量代谢，包括肝再生、脂肪酸氧化和线粒体 氧化代谢，也控制时钟基因的表达。缺乏PGC-1的小鼠具有异常的 运动活动的昼夜节律、体温、代谢率和 代谢基因表达基于这些发现，我们假设时钟和 代谢是通过昼夜节律起搏点和代谢之间的相互干扰来实现的 监管网络。我们将通过评估PGC-1在组织中的作用来探索这一假设， 生物钟和新陈代谢的自主整合。我们还将探索分子组成 参与昼夜节律起搏器和PGC-1之间的串扰。最后，我们将调查 PGC-1调节网络控制昼夜代谢的新机制 节奏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关键的分子组分 将昼夜节律计时系统与能量稳态联系起来， 代谢和心血管疾病的机制。

Abstract 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-1¿, a transcriptional coactivator that regulates several major aspects of energy metabolism, including hepatic gluconeogenesis, fatty acid ¿-oxidation, and mitochondrial oxidative metabolism, also controls clock gene expression. Mice deficient in PGC-1¿ 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-1¿ in tissue- autonomous integration of clock and metabolism. We will also explore molecular components involved in the crosstalk between the circadian pacemaker and PGC-1¿. Finally, we will investigate novel mechanisms through which the PGC-1¿ 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.