AMPK Regulates the Circadian Clock by Cryptochrome Phosphorylation and Degradation
By Katja A. Lamia, U. Sachdeva, Luciano DiTacchio, E. C. Williams, J. G. Alvarez, Daniel F Egan, Debbie S. Vasquez, Henry Juguilon, Satchidananda Panda, R. Shaw and 2 more. Science, 2009
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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. The protein kinase AMPK couples circadian clocks and metabolism in mammals through effects on a cryptochrome protein. 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.
Subfields: Endocrine and Autonomic Systems, Plant Science
View Paper: https://www.semanticscholar.org/paper/1f34e5c13e1836ca303e5ece7cd297e5061ffdd7
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In Endocrine and Autonomic Systems
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Citations in the corpus
- Time restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high fat diet (2012, neutral): “During fasting, AMPK phosphorylates a circadian repressor CRY (Lamia et al., 2009) and targets it for subsequent degradation, thus preventing it from repressing CLOCK:BMAL1 target genes, such as Rev-erba, Per, and Cry.”
- Molecular components of the Mammalian circadian clock. (2013, background): “CRY1 is phosphorylated by AMPK1 and CRY2 by a sequential DYRK1A/GSK-3β cascade (Lamia et al. 2009; Harada et al. 2005; Kurabayashi et al. 2010).”
- Fasting, circadian rhythms, and time restricted feeding in healthy lifespan (2016, neutral): “CRY and promotes its degradation (Lamia et al., 2009).”
- Metabolic regulation of epigenetics (2012, background): “In mice and cells where AMPK pathway is deficient, the peripheral circadian clock is disrupted (Lamia et al., 2009; Um et al., 2011).”
- Timing to perfection: the biology of central and peripheral circadian clocks. (2012, background): “It can directly phosphorylate CRY1, leading to destabilization and degradation of this core clock protein (Lamia et al., 2009) and consequently affecting the negative limb of the circadian clock mechanism (Figure 4).”