Trends in Cell Biology
ForumTime to eat reveals the hierarchy of peripheral clocks
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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