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AMPK Regulates the Circadian Clock by Cryptochrome Phosphorylation and Degradation

Science  16 Oct 2009:
Vol. 326, Issue 5951, pp. 437-440
DOI: 10.1126/science.1172156

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Coupling Clocks and Metabolism

Circadian clocks in mammals coordinate behavior and physiology with daily light-dark cycles by driving rhythmic transcription of thousands of genes. The master clock in the brain is set by light, but clocks in peripheral tissues, such as the liver, are set by daily feeding. Such coupling should allow tissues to “anticipate” food consumption and optimize the timing of metabolic processes, but how nutritional status is communicated to peripheral clocks is unclear. Studying cell culture models and mice, Lamia et al. (p. 437; see the Perspective by Suter and Schibler) show that the nutrient-responsive signaling molecule AMPK (AMP-activated protein kinase) provides metabolic information to circadian clocks by triggering phosphorylation and subsequent degradation of the clock component cryptochrome-1. Thus—cryptochromes, which originally evolved as blue-light photoreceptors in plants, act as chemical energy sensors in mammals.

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.

  • * These authors contributed equally to this work.

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