Ultradian rhythms of AKT phosphorylation and gene expression emerge in the absence of the circadian clock components Per1 and Per2

PLoS Biol. 2021 Dec 30;19(12):e3001492. doi: 10.1371/journal.pbio.3001492. eCollection 2021 Dec.

Abstract

Rhythmicity of biological processes can be elicited either in response to environmental cycles or driven by endogenous oscillators. In mammals, the circadian clock drives about 24-hour rhythms of multitude metabolic and physiological processes in anticipation to environmental daily oscillations. Also at the intersection of environment and metabolism is the protein kinase-AKT. It conveys extracellular signals, primarily feeding-related signals, to regulate various key cellular functions. Previous studies in mice identified rhythmicity in AKT activation (pAKT) with elevated levels in the fed state. However, it is still unknown whether rhythmic AKT activation can be driven through intrinsic mechanisms. Here, we inspected temporal changes in pAKT levels both in cultured cells and animal models. In cultured cells, pAKT levels showed circadian oscillations similar to those observed in livers of wild-type mice under free-running conditions. Unexpectedly, in livers of Per1,2-/- but not of Bmal1-/- mice we detected ultradian (about 16 hours) oscillations of pAKT levels. Importantly, the liver transcriptome of Per1,2-/- mice also showed ultradian rhythms, corresponding to pAKT rhythmicity and consisting of AKT-related genes and regulators. Overall, our findings reveal ultradian rhythms in liver gene expression and AKT phosphorylation that emerge in the absence of environmental rhythms and Per1,2-/- genes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Circadian Clocks / genetics
  • Gene Expression / genetics
  • Gene Expression Regulation / genetics*
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Period Circadian Proteins / genetics
  • Period Circadian Proteins / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Transcription Factors / metabolism
  • Transcriptome / genetics
  • Ultradian Rhythm / genetics*

Substances

  • Per1 protein, mouse
  • Per2 protein, mouse
  • Period Circadian Proteins
  • Transcription Factors
  • Proto-Oncogene Proteins c-akt

Grants and funding

G.A. is supported by the European Research Council (ERC-2017 CIRCOMMUNICATION 770869), Abisch Frenkel Foundation for the Promotion of Life Sciences, Adelis Foundation, Susan and Michael Stern. R.A. is recipient of fellowship from the Azrieli Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.