Stratmann Markus, Schibler Ueli
Department of Molecular Biology, National Center of Competence in Research Frontiers in Genetics, Sciences III, University of Geneva, Geneva, Switzerland.
J Biol Rhythms. 2006 Dec;21(6):494-506. doi: 10.1177/0748730406293889.
In mammals, the circadian timing system is composed of multiple oscillators that are organized in a hierarchical manner. The central pacemaker, located in the suprachiasmatic nucleus of the hypothalamus, is believed to orchestrate countless subsidiary clocks in the periphery. These peripheral oscillators are cell-autonomous, self-sustained, resilient to cell division, and virtually insensitive to large fluctuations in general transcription rates. However, they are probably not coupled within an organ, and daily zeitgeber signals emanating from the SCN appear to be required to ensure phase coherence within and between tissues. Peripheral clocks are implicated in a variety of biochemical pathways, and recent results tightly link circadian rhythms to several aspects of metabolism. Thus, the expression of many key enzymes conducting rate-limiting steps in various metabolic pathways is regulated in a circadian fashion by core clock components or clock-controlled transcription factors. Genetic loss-of-function studies have now established a role for mammalian circadian clock components in energy homeostasis and xenobiotic detoxification, and the latter manifests itself in the daytime-dependent modulation of drug efficacy and toxicity.
在哺乳动物中，昼夜节律计时系统由多个以层级方式组织的振荡器组成。位于下丘脑视交叉上核的中央起搏器被认为协调着外周无数的子时钟。这些外周振荡器是细胞自主的、自我维持的、对细胞分裂有弹性的，并且实际上对一般转录速率的大幅波动不敏感。然而，它们可能不在一个器官内耦合，并且似乎需要来自视交叉上核的每日授时信号来确保组织内和组织间的相位一致性。外周时钟参与多种生化途径，最近的结果将昼夜节律与代谢的几个方面紧密联系起来。因此，在各种代谢途径中进行限速步骤的许多关键酶的表达受到核心时钟组件或时钟控制转录因子的昼夜节律调节。基因功能丧失研究现已确定哺乳动物昼夜节律时钟组件在能量稳态和外源性物质解毒中的作用，后者表现为药物疗效和毒性的日间依赖性调节。
