Refeeding after fasting elicits insulin-dependent regulation of per2 and Rev-erbα with shifts in the liver clock

Yu Tahara, Makiko Otsuka, Yuta Fuse, Akiko Hirao, Shigenobu Shibata*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

107 Citations (Scopus)


The mammalian circadian clock is known to be entrained by both a daily light-dark cycle and daily feeding cycle. However, the mechanisms of feeding-induced entrainment are not as fully understood as those of light entrainment. To elucidate the first step of entrainment of the liver clock, we identified the circadian clock gene(s) that show both phase advance and acute change of gene expression during the early term of the daytime refeeding schedule in mice. The expressions of liver Per2 and Rev-erbα genes were phase-advanced within 1 day of refeeding. Additionally, the upregulation of Per2 mRNA and down-regulation of Rev-erbα mRNA were induced within 2 hours, not only by food intake but also by insulin injection in intact mice. These expression changes by food intake were not revealed in streptozotocin-treated insulin-deficient mice, but insulin injection was able to recover the impairment of Per2 and Rev-erbα gene expression. Furthermore, we demonstrated using an ex vivo luciferase monitoring system that insulin injection during the daytime causes a phase advance of liver Per2 expression rhythm in Per2::luciferase knock-in mice. In embryonic fibroblasts from Per2::luciferase knock-in mice, insulin infusion caused an acute increase of Per2 gene expression and a similar phase advance of Per2 expression rhythm. Our results indicate that an acute change of Per2 and Rev-erbα gene expression mediated by refeeding-induced insulin secretion is a critical step mediating the early phase of feeding-induced entrainment of the liver clock.

Original languageEnglish
Pages (from-to)230-240
Number of pages11
JournalJournal of Biological Rhythms
Issue number3
Publication statusPublished - 2011 Jun


  • Bmal1
  • Period2
  • circadian rhythms
  • food entrainment
  • insulin action
  • restricted feeding

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)


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