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AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation

Katja A Lamia1, Uma M Sachdeva, Luciano DiTacchio

  • 1Gene Expression Laboratory, the Salk Institute, La Jolla, CA 92037, USA.

Science (New York, N.Y.)
|October 17, 2009
PubMed

Insights

Nutrient-responsive adenosine monophosphate-activated protein kinase (AMPK) phosphorylates and destabilizes cryptochrome 1 (CRY1), a key clock component. This mechanism helps peripheral organs, like the liver, synchronize their circadian rhythms with nutrient availability.

Area of Science:

  • Chronobiology
  • Molecular Biology
  • Metabolism

Background:

  • Circadian clocks regulate daily rhythms in behavior and physiology, synchronized by light in the brain and nutrient availability in peripheral organs.
  • The precise mechanisms by which peripheral circadian clocks, like the liver clock, are entrained by nutrient signals remain largely unknown.
  • Cryptochrome 1 (CRY1) is a crucial component of the molecular clockwork underlying circadian rhythms.

Purpose of the Study:

  • To investigate the role of nutrient-responsive signaling pathways in regulating peripheral circadian clocks.
  • To elucidate the molecular mechanisms by which nutrient availability entrains peripheral organ pacemakers.
  • To determine if adenosine monophosphate-activated protein kinase (AMPK) influences the stability and function of the circadian clock component CRY1.

Main Methods:

  • Utilized mouse fibroblasts to study the interaction between AMPK and CRY1.
  • Investigated rhythmic AMPK activity and CRY1 nuclear abundance in mouse livers.
  • Employed genetic disruption of the AMPK pathway in mice to assess its impact on peripheral clocks.
  • Stimulated AMPK activity to observe its effects on cryptochrome stability and circadian rhythms.

Main Results:

  • Demonstrated that AMPK phosphorylates and destabilizes CRY1 in mouse fibroblasts.
  • Observed rhythmic AMPK activity and inverse correlation with nuclear CRY1 abundance in mouse livers.
  • Showed that AMPK stimulation destabilizes cryptochromes and disrupts circadian rhythms.
  • Found that genetic disruption of the AMPK pathway leads to altered peripheral clock function in mice.

Conclusions:

  • AMPK-mediated phosphorylation of CRY1 serves as a critical mechanism for transducing nutrient signals to peripheral circadian clocks in mammals.
  • This pathway highlights a direct link between cellular energy status and the regulation of circadian timing in peripheral organs.
  • Understanding this nutrient-clock interaction is vital for comprehending metabolic health and circadian disruption-related diseases.

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