Insulin post-transcriptionally modulates Bmal1 protein to affect the hepatic circadian clock

Nat Commun. 2016 Aug 31;7:12696. doi: 10.1038/ncomms12696.

Abstract

Although food availability is a potent synchronizer of the peripheral circadian clock in mammals, the underlying mechanisms are unclear. Here, we show that hepatic Bmal1, a core transcription activator of the molecular clock, is post-transcriptionally regulated by signals from insulin, an important hormone that is temporally controlled by feeding. Insulin promotes postprandial Akt-mediated Ser42-phosphorylation of Bmal1 to induce its dissociation from DNA, interaction with 14-3-3 protein and subsequently nuclear exclusion, which results in the suppression of Bmal1 transcriptional activity. Inverted feeding cycles not only shift the phase of daily insulin oscillation, but also elevate the amplitude due to food overconsumption. This enhanced and reversed insulin signalling initiates the reset of clock gene rhythms by altering Bmal1 nuclear accumulation in mouse liver. These results reveal the molecular mechanism of insulin signalling in regulating peripheral circadian rhythms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ARNTL Transcription Factors / genetics
  • ARNTL Transcription Factors / metabolism*
  • Animals
  • CLOCK Proteins / genetics
  • CLOCK Proteins / metabolism
  • Cell Line
  • Cell Nucleus / metabolism
  • Circadian Clocks / physiology*
  • Feeding Behavior / physiology*
  • Hepatocytes / metabolism
  • Humans
  • Insulin / metabolism*
  • Liver / cytology
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphorylation / physiology
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA Processing, Post-Transcriptional / physiology
  • RNA, Messenger / metabolism
  • Serine / metabolism
  • Signal Transduction / physiology

Substances

  • ARNTL Transcription Factors
  • ARNTL protein, human
  • Arntl protein, mouse
  • Insulin
  • RNA, Messenger
  • Serine
  • CLOCK Proteins
  • Akt2 protein, mouse
  • Proto-Oncogene Proteins c-akt