Trends in Cell Biology
Volume 31, Issue 11, November 2021, Pages 869-872
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Time to eat reveals the hierarchy of peripheral clocks

https://doi.org/10.1016/j.tcb.2021.08.003Get rights and content

Meal timing resets trillions of cellular circadian clocks in the body. Recent advances in multiomics demonstrate that clocks in peripheral tissues are differentially reset by feeding rhythm, and modulated by the central clock and the liver clock. This highlights the essential roles of tissue-specific regulation and intercellular signaling in clock synchronization.

Section snippets

Hepatocyte

Feeding rhythm resets the phase of the liver clock through nutrient-sensing pathways. Daily cycles of glucose and insulin lead to periodic activation of cellular redox sensors such as NAD+-dependent poly(ADP-ribose) polymerase 1 (PARP1) and Sirtuin 1 (SIRT1), and metabolic sensors such as AMP-activated protein kinase (AMPK), O-GlcNAc transferase (OGT), and mechanistic target of rapamycin complex 1 (mTORC1; Box 1). PARP1 modifies CLOCK by poly-ADP-ribosylation and facilitates phase entrainment

Adipocyte

The adipocyte clock is a major component of energy balance and metabolic health [2]. However, it is prone to losing rhythmicity upon inverted feeding in both sexes [5,6]. Only a few core clock genes maintain rhythmicity in female adipocytes under inverted feeding; the phase of Per2 and Bmal1 transcripts seems to be shifted by 2 and 6 h, respectively [5]. In males, inverted feeding shifts the phase of Bmal1 transcript by 8–9 h [6] within 7 days [5]. Mechanistically, regulatory cues from the

Cardiomyocyte

The cardiomyocyte clock modulates heart metabolism and electrophysiology, leading to daily cycles of the heart rhythm [2]. How does feeding rhythm regulate the cardiomyocyte clock and function? Surprisingly, the cardiomyocyte clock and transcriptome are both resistant to food entrainment. None of the major clock genes shift in phase for more than 2 h, and only 21.68% of circadian transcripts are reversed by inverted feeding [5]. Constant light facilitates food entrainment of the cardiomyocyte

Concluding remarks

In summary, peripheral clocks are organized hierarchically with respect to food entrainment under the SCN clock (Figure 1B). Peripheral clocks at high levels can buffer or facilitate the entrainment of circadian rhythms in tissues with lower-level peripheral clocks under inverted feeding. Nevertheless, inverted feeding is a means to study food entrainment, but may not reflect the endogenous function of feeding rhythm. Future research should focus on revealing the peripheral clock hierarchy

Acknowledgments

This work was supported by National Natural Science Foundation of China [Grant Numbers 92057109 (M.-D.L.) and 92057202 (G.S.)]. We thank the anonymous reviewers, Ye Tian, members of the Southwest Center for Circadian Metabolism for discussion and support, and Xiaojie Liu for assistance with graphical illustrations. We apologize to colleagues whose work was not cited due to space limits.

Declaration of interests

The authors declare no competing interests.

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    The liver and adipose tissue are entrained readily to inverted feeding, whereas the heart, kidneys, quadriceps, and lungs are resistant to varying degrees. These findings have revealed the differential responsiveness of peripheral clocks to food entrainment in different tissues [14], which suggests that TRE may only function in peripheral tissues, or for specific tissue functions that can be entrained by meal timing. In addition, the liver clock is dispensable for the anti-hepatic steatosis activity of TRE in obese mice [26].

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