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J. Biol. Chem., Vol. 282, Issue 29, 20794-20798, July 20, 2007

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Activation of 5'-AMP-activated Kinase with Diabetes Drug Metformin Induces Casein Kinase I (CKI)-dependent Degradation of Clock Protein mPer2^*

Jee Hyun Um, Shutong Yang, Shin Yamazaki, Hyeog Kang, Benoit Viollet^¶||**, Marc Foretz^¶¶, and Jay H. Chung¹

From the Laboratory of Biochemical Genetics, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, the Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee 37235-1634, the ^¶Institut Cochin, Département Endocrinologie Métabolisme et Cancer, Paris, F-75014 France, the ^||Inserm, U567, Paris, F-75014 France, the^**CNRS, UMR 8104, Paris, F-75014 France, and the Université Paris 5, FacultédeMédecine René Descartes, UM 3, Paris, F-75014 France, INSERM, U567, Paris F-75014, France, and ^¶¶Institut Cochin, Université Paris Descartes, CNRS, UMR 8104, Paris F-75014, France

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 I (CKI), which by phosphorylating and inducing the degradation of the circadian clock component, mPer2, shortens the period length. AMPK phosphorylates Ser-389 of CKI, resulting in increased CKI 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 2 knock-out mice. We conclude that metformin and AMPK have a previously unrecognized role in regulating the circadian rhythm.

Received for publication, April 11, 2007 , and in revised form, May 16, 2007.

^* This work was supported by the Intramural Research Program, National Institutes of Health, National Heart Lung and Blood Institute. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: NHLBI, National Institutes of Health, Bldg. 10, Rm. 7D14, Laboratory of Biochemical Genetics, 10 Center Dr., Bethesda, MD 20892. Tel.: 301-496-3075; Fax: 301-480-4557; E-mail: chungj{at}nhlbi.nih.gov.

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