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

Rona Aviram,Marina Golik,Vaishnavi Dandavate,Gad Asher,Gal Manella,Samer Hattar

doi:10.1371/journal.pbio.3001492

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.

Highlights

A fundamental facet of life on earth is exposure to a 24-hour rhythmic environment due to earth’s daily rotation
We found that the protein kinase AKT exhibits ultradian phosphorylation rhythms in Per1,2−/− mouse livers that are associated with ultradian gene expression
These ultradian rhythms were not detected in another clock mutant mouse model, namely Bmal1−/− mice, suggesting that they are not common to all clock mutant animals and raising the possibility that Bmal1 might be implicated in these rhythms

Summary

Introduction

A fundamental facet of life on earth is exposure to a 24-hour rhythmic environment due to earth’s daily rotation. Throughout evolution, 2 distinct adaptations, which enable organisms to cope with these pervasive daily oscillations, have emerged: (i) an acute response to rhythmic environmental cues through externally driven signaling cascades; and (ii) a proactive anticipatory mechanism that relies on an intrinsic circadian clock. The circadian clock is present in almost every cell of the body and functions based on a network of transcription–translation feedback loops [1,2]. The heterodimer of BMAL1 and CLOCK (or its paralog NPAS2) drives the expression of Period Foundation for the Promotion of Life Sciences, Adelis Foundation, Susan and Michael Stern. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Methods

Results

Conclusion