TY - JOUR
T1 - Activation of 5′-AMP-activated kinase with diabetes drug metformin induces casein kinase Iε (CKIε)-dependent degradation of clock protein mPer2
AU - Jee, Hyun Um
AU - Yang, Shutong
AU - Yamazaki, Shin
AU - Kang, Hyeog
AU - Viollet, Benoit
AU - Foretz, Marc
AU - Chung, Jay H.
PY - 2007/7/20
Y1 - 2007/7/20
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.C700070200
DO - 10.1074/jbc.C700070200
M3 - Article
C2 - 17525164
AN - SCOPUS:34547127625
SN - 0021-9258
VL - 282
SP - 20794
EP - 20798
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 29
ER -