External Cues as Transducers of Peripheral Tissue‐Specific Molecular Clocks to Regulate Systemic Circadian Rhythms and Metabolism

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.