AMPK Regulates the Circadian Clock by Cryptochrome Phosphorylation and Degradation

Overview

Journal Science

Specialty Science

Date 2009 Oct 17

PMID 19833968

Citations 458

Authors

Katja A Lamia

Uma M Sachdeva

Luciano DiTacchio

Elliot C Williams

Jacqueline G Alvarez

Daniel F Egan

Debbie S Vasquez

Henry Juguilon

Satchidananda Panda

Reuben J Shaw

Craig B Thompson

Ronald M Evans

Affiliations

Soon will be listed here.

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.

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References

Stephan F, Zucker I . Circadian rhythms in drinking behavior and locomotor activity of rats are eliminated by hypothalamic lesions. Proc Natl Acad Sci U S A. 1972; 69(6):1583-6. PMC: 426753. DOI: 10.1073/pnas.69.6.1583. View

DAVIES S, Carling D, Munday M, Hardie D . Diurnal rhythm of phosphorylation of rat liver acetyl-CoA carboxylase by the AMP-activated protein kinase, demonstrated using freeze-clamping. Effects of high fat diets. Eur J Biochem. 1992; 203(3):615-23. DOI: 10.1111/j.1432-1033.1992.tb16591.x. View

Gatfield D, Schibler U . Physiology. Proteasomes keep the circadian clock ticking. Science. 2007; 316(5828):1135-6. DOI: 10.1126/science.1144165. View

Witters L, Kemp B, Means A . Chutes and Ladders: the search for protein kinases that act on AMPK. Trends Biochem Sci. 2005; 31(1):13-6. DOI: 10.1016/j.tibs.2005.11.009. View

Minokoshi Y, Alquier T, Furukawa N, Kim Y, Lee A, Xue B . AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature. 2004; 428(6982):569-74. DOI: 10.1038/nature02440. View

Stokkan K, Yamazaki S, Tei H, Sakaki Y, Menaker M . Entrainment of the circadian clock in the liver by feeding. Science. 2001; 291(5503):490-3. DOI: 10.1126/science.291.5503.490. View

Damiola F, Le Minh N, Preitner N, Kornmann B, Schibler U . Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. Genes Dev. 2000; 14(23):2950-61. PMC: 317100. DOI: 10.1101/gad.183500. View

Suzuki A, Okamoto S, Lee S, Saito K, Shiuchi T, Minokoshi Y . Leptin stimulates fatty acid oxidation and peroxisome proliferator-activated receptor alpha gene expression in mouse C2C12 myoblasts by changing the subcellular localization of the alpha2 form of AMP-activated protein kinase. Mol Cell Biol. 2007; 27(12):4317-27. PMC: 1900064. DOI: 10.1128/MCB.02222-06. View

Grahame Hardie D . The AMP-activated protein kinase pathway--new players upstream and downstream. J Cell Sci. 2004; 117(Pt 23):5479-87. DOI: 10.1242/jcs.01540. View

10.

Grahame Hardie D . AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol. 2007; 8(10):774-85. DOI: 10.1038/nrm2249. View

11.

Rudic R, McNamara P, Curtis A, Boston R, Panda S, Hogenesch J . BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis. PLoS Biol. 2004; 2(11):e377. PMC: 524471. DOI: 10.1371/journal.pbio.0020377. View

12.

Viollet B, Andreelli F, Jorgensen S, Perrin C, Geloen A, Flamez D . The AMP-activated protein kinase alpha2 catalytic subunit controls whole-body insulin sensitivity. J Clin Invest. 2003; 111(1):91-8. PMC: 151837. DOI: 10.1172/JCI16567. View

13.

Yamazaki S, Numano R, Abe M, Hida A, Takahashi R, Ueda M . Resetting central and peripheral circadian oscillators in transgenic rats. Science. 2000; 288(5466):682-5. DOI: 10.1126/science.288.5466.682. View

14.

Andersson U, Filipsson K, Abbott C, Woods A, Smith K, Bloom S . AMP-activated protein kinase plays a role in the control of food intake. J Biol Chem. 2004; 279(13):12005-8. DOI: 10.1074/jbc.C300557200. View

15.

Hirota T, Okano T, Kokame K, Shirotani-Ikejima H, Miyata T, Fukada Y . Glucose down-regulates Per1 and Per2 mRNA levels and induces circadian gene expression in cultured Rat-1 fibroblasts. J Biol Chem. 2002; 277(46):44244-51. DOI: 10.1074/jbc.M206233200. View

16.

Gwinn D, Shackelford D, Egan D, Mihaylova M, Mery A, Vasquez D . AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell. 2008; 30(2):214-26. PMC: 2674027. DOI: 10.1016/j.molcel.2008.03.003. View

17.

Schibler U, Ripperger J, Brown S . Peripheral circadian oscillators in mammals: time and food. J Biol Rhythms. 2003; 18(3):250-60. DOI: 10.1177/0748730403018003007. View

18.

Green C, Takahashi J, Bass J . The meter of metabolism. Cell. 2008; 134(5):728-42. PMC: 3760165. DOI: 10.1016/j.cell.2008.08.022. View

19.

Narkar V, Downes M, Yu R, Embler E, Wang Y, Banayo E . AMPK and PPARdelta agonists are exercise mimetics. Cell. 2008; 134(3):405-15. PMC: 2706130. DOI: 10.1016/j.cell.2008.06.051. View

20.

Lamia K, Storch K, Weitz C . Physiological significance of a peripheral tissue circadian clock. Proc Natl Acad Sci U S A. 2008; 105(39):15172-7. PMC: 2532700. DOI: 10.1073/pnas.0806717105. View