Zhang Zhe, Liu Bei-Bei, Ding Shu-Zhe
Key Laboratory of Adolescent Health Assessment and Exercise Intervention, Ministry of Education, East China Normal University, Shanghai, China.
College of Physical Education and Health, East China Normal University, Shanghai, China.
FASEB J. 2025 Sep 15;39(17):e71011. doi: 10.1096/fj.202501289R.
The molecular clock exhibits distinct characteristics across various tissues and can be synchronized by particular stimuli. Furthermore, there is an intricate interplay among the molecular clocks within different tissues. In this context, we present an overview of the tissue-specific molecular clock and discuss pivotal nonphotic regulators that govern the host's circadian rhythms and metabolic processes. Intermittent time-restricted feeding establishes rhythmicity and harmony in hepatic proteasome activity through various pathways and modulates hormone levels and lifespan extension via the synergistic action of molecular clocks and autophagy (AMPK, mTOR, SIRT1). High-fat diet (HFD) alters the molecular clock rhythms in the mediobasal hypothalamus (MBH), adipose tissue, and liver, with particularly pronounced changes observed in adipose tissue. HFD alters rhythm by inhibiting CLOCK:BMAL1 chromatin recruitment and activating the PPARγ pathway in the liver. The absence of liver CLOCK or intestinal BMAL1 mitigates metabolic disturbances, such as obesity, induced by long-term HFD. Meanwhile, intestinal microbiota also directly or indirectly regulates the host's circadian network and metabolism through micromolecules. Correspondingly, deletion of molecular clock genes alters the diurnal variations, composition, and function of the gut microbiome at the genus level in mice. The mechanisms underlying the tissue-specific effects of the gut microbiota on peripheral clocks are currently being unraveled and require further elucidation, with PPAR emerging as a pivotal factor in this process. The effect of exercise on the molecular clock of skeletal muscle varies depending on distinct muscle fiber types and the intensity of exercise. Identifying the optimal combination of chrono-exercise and intermittent fasting represents a substantial research opportunity. Additionally, the interplay between the molecular clocks of various tissues in response to specific rhythmic cues merits thorough investigation.
分子时钟在不同组织中表现出不同的特征，并且可以通过特定刺激进行同步。此外，不同组织内的分子时钟之间存在复杂的相互作用。在此背景下，我们概述了组织特异性分子时钟，并讨论了控制宿主昼夜节律和代谢过程的关键非光调节因子。间歇性限时进食通过各种途径在肝脏蛋白酶体活性中建立节律性与协调性，并通过分子时钟和自噬（AMPK、mTOR、SIRT1）的协同作用调节激素水平和延长寿命。高脂饮食（HFD）会改变中基底下丘脑（MBH）、脂肪组织和肝脏中的分子时钟节律，在脂肪组织中观察到的变化尤为明显。高脂饮食通过抑制肝脏中CLOCK:BMAL1染色质募集并激活PPARγ途径来改变节律。肝脏中缺乏CLOCK或肠道中缺乏BMAL1可减轻长期高脂饮食诱导的代谢紊乱，如肥胖。同时，肠道微生物群也通过小分子直接或间接调节宿主的昼夜节律网络和代谢。相应地，分子时钟基因的缺失会改变小鼠肠道微生物群在属水平上的昼夜变化、组成和功能。肠道微生物群对外周时钟的组织特异性影响的潜在机制目前正在被揭示，需要进一步阐明，PPAR在此过程中成为关键因素。运动对骨骼肌分子时钟的影响因不同的肌纤维类型和运动强度而异。确定计时运动和间歇性禁食的最佳组合是一个重大的研究机会。此外，各种组织的分子时钟在响应特定节律线索时的相互作用值得深入研究。
