AMPK Regulates the Circadian Clock by Cryptochrome Phosphorylation and Degradation

TLDR

Circadian clocks coordinate daily physiological processes by rhythmic gene transcription, with the brain clock set by light and peripheral clocks, such as the liver, entrained by food, though the mechanisms remain unclear. In mouse fibroblasts and livers, AMPK phosphorylates and destabilizes CRY1, with rhythmic activity inversely correlated to CRY1 nuclear levels, and genetic disruption of AMPK alters peripheral clocks, demonstrating that AMPK-mediated phosphorylation allows cryptochrome to convey nutrient signals to circadian rhythms.

Abstract

Circadian clocks coordinate behavioral and physiological processes with daily light-dark cycles by driving rhythmic transcription of thousands of genes. Whereas the master clock in the brain is set by light, pacemakers in peripheral organs, such as the liver, are reset by food availability, although the setting, or "entrainment," mechanisms remain mysterious. Studying mouse fibroblasts, we demonstrated that the nutrient-responsive adenosine monophosphate-activated protein kinase (AMPK) phosphorylates and destabilizes the clock component cryptochrome 1 (CRY1). In mouse livers, AMPK activity and nuclear localization were rhythmic and inversely correlated with CRY1 nuclear protein abundance. Stimulation of AMPK destabilized cryptochromes and altered circadian rhythms, and mice in which the AMPK pathway was genetically disrupted showed alterations in peripheral clocks. Thus, phosphorylation by AMPK enables cryptochrome to transduce nutrient signals to circadian clocks in mammalian peripheral organs.