title: Activation of 5'-AMP-activated kinase with diabetes drug metformin induces casein kinase Iepsilon (CKIepsilon)-dependent degradation of clock protein mPer2.
abstract: Metformin is one of the most commonly used first line drugs for type II diabetes. Metformin lowers serum glucose levels by activating 5'-AMP-activated kinase (AMPK), which maintains energy homeostasis by directly sensing the AMP/ATP ratio. AMPK plays a central role in food intake and energy metabolism through its activities in central nervous system and peripheral tissues. Since food intake and energy metabolism is synchronized to the light-dark (LD) cycle of the environment, we investigated the possibility that AMPK may affect circadian rhythm. We discovered that the circadian period of Rat-1 fibroblasts treated with metformin was shortened by 1 h. One of the regulators of the period length is casein kinase Iepsilon (CKIepsilon), which by phosphorylating and inducing the degradation of the circadian clock component, mPer2, shortens the period length. AMPK phosphorylates Ser-389 of CKIepsilon, resulting in increased CKIepsilon activity and degradation of mPer2. In peripheral tissues, injection of metformin leads to mPer2 degradation and a phase advance in the circadian expression pattern of clock genes in wild-type mice but not in AMPK alpha2 knock-out mice. We conclude that metformin and AMPK have a previously unrecognized role in regulating the circadian rhythm.
authors.affiliation: Laboratory of Biochemical Genetics, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Jee Hyun
authors.initials: JH
authors.lastname: Um
authors.forename: Shutong
authors.initials: S
authors.lastname: Yang
authors.forename: Shin
authors.initials: S
authors.lastname: Yamazaki
authors.forename: Hyeog
authors.initials: H
authors.lastname: Kang
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.forename: Marc
authors.initials: M
authors.lastname: Foretz
authors.forename: Jay H
authors.initials: JH
authors.lastname: Chung
mesh_terms: D055372:AMP-Activated Protein Kinases; D000595:Amino Acid Sequence; D000818:Animals; D048149:Casein Kinase 1 epsilon / Q000737:chemistry*; D018797:Cell Cycle Proteins / Q000378:metabolism / Q000502:physiology*; D002940:Circadian Rhythm; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D056950:Period Circadian Proteins; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*
chemical_list: D018797:Cell Cycle Proteins; D007004:Hypoglycemic Agents; D009097:Multienzyme Complexes; D009687:Nuclear Proteins; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D014157:Transcription Factors; D008687:Metformin; D048149:Casein Kinase 1 epsilon; C526181:PRKAA2 protein, human; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases