The mammalian circadian clock, expressed throughout the brain and body, controls daily metabolic homeostasis. Clock function in peripheral tissues is required, but not sufficient, for this task. Because of the lack of specialized animal models, it is unclear how tissue clocks interact with extrinsic signals to drive molecular oscillations. Here, we isolated the interaction between feeding and the liver clock by reconstituting Bmal1 exclusively in hepatocytes (Liver-RE), in otherwise clock-less mice, and controlling timing of food intake. We found that the cooperative action of BMAL1 and the transcription factor CEBPB regulates daily liver metabolic transcriptional programs. Functionally, the liver clock and feeding rhythm are sufficient to drive temporal carbohydrate homeostasis. By contrast, liver rhythms tied to redox and lipid metabolism required communication with the skeletal muscle clock, demonstrating peripheral clock cross-talk. Our results highlight how the inner workings of the clock system rely on communicating signals to maintain daily metabolism.

中文翻译：

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肝脏生物钟对进食行为的整合揭示了代谢节律的网络依赖性


哺乳动物的生物钟在整个大脑和身体中表达，控制日常代谢稳态。对于这项任务来说，外周组织的时钟功能是必要的，但还不够。由于缺乏专门的动物模型，目前尚不清楚组织时钟如何与外在信号相互作用以驱动分子振荡。在这里，我们通过在无时钟小鼠的肝细胞（Liver-RE）中专门重建 Bmal1，并控制食物摄入时间，分离了进食和肝脏时钟之间的相互作用。我们发现BMAL1和转录因子CEBPB的协同作用调节日常肝脏代谢转录程序。从功能上讲，肝脏时钟和进食节律足以驱动暂时的碳水化合物稳态。相比之下，与氧化还原和脂质代谢相关的肝脏节律需要与骨骼肌时钟进行通信，这表明外周时钟存在串扰。我们的结果强调了时钟系统的内部运作如何依赖通信信号来维持日常新陈代谢。