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 AMPKa1 is essential for circadian rhythm. Mice deficient in AMPKa1 have abnormal circadian rhythm of behavior and gene expression. We demonstrated that fibroblasts lacking AMPK also have abnormal forskolin-induced circadian rhythm. Thus, the role of AMPK in circadian rhythm is cell-autonomous. The expression of PGC-1a, a downstream target of AMPK, lacks circadian rhythm in the absence of AMPK and PGC-1a is required for circadian rhythm. Resveratrol has been shown to have metabolically beneficial effects in animals with diet induced obesity. We discovered that the beneficial effects of resveratrol is abrogated in AMPK knockout mice. Our work suggests that the metabolic effects of resveratrol are mediated through AMPK rather than Sirt1.
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