Annual Report HS02243-01 ? The ability to sense energy level is crucial for responding to metabolic stress such as energy deprivation. In eukaryotic cells, 5 AMP-activated kinase (AMPK), which maintains energy homeostasis by directly sensing the AMP/ATP ratio is an important energy sensor. AMPK plays a central role in food intake and energy metabolism through its activities in CNS 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 hr. 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 AMPK activator 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 knockout mice. We conclude that AMPK has a previously unrecognized role in regulating the circadian rhythm.
Showing the most recent 10 out of 16 publications
