Activation of 5′-AMP-activated kinase with diabetes drug metformin induces casein kinase Iε (CKIε)-dependent degradation of clock protein mPer2

Hyun Um Jee, Shutong Yang, Shin Yamazaki, Hyeog Kang, Benoit Viollet, Marc Foretz, Jay H. Chung

Research output: Contribution to journalArticle

145 Scopus citations

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 Iε (CKIε), which by phosphorylating and inducing the degradation of the circadian clock component, mPer2, shortens the period length. AMPK phosphorylates Ser-389 of CKIε, resulting in increased CKIε 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 α2 knock-out mice. We conclude that metformin and AMPK have a previously unrecognized role in regulating the circadian rhythm.

Original languageEnglish (US)
Pages (from-to)20794-20798
Number of pages5
JournalJournal of Biological Chemistry
Volume282
Issue number29
DOIs
StatePublished - Jul 20 2007

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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