AMP-activated protein kinase (AMPK) is a metabolic fuel gauge conserved along the evolutionary scale in eukaryotes that senses changes in the intracellular AMP/ATP ratio1. Recent evidence indicated an important role for AMPK in the therapeutic benefits of metformin2,3, thiazolidinediones4 and exercise5, which form the cornerstones of the clinical management of type 2 diabetes and associated metabolic disorders. In general, activation of AMPK acts to maintain cellular energy stores, switching on catabolic pathways that produce ATP, mostly by enhancing oxidative metabolism and mitochondrial biogenesis, while switching off anabolic pathways that consume ATP1. This regulation can take place acutely, through the regulation of fast post-translational events, but also by transcriptionally reprogramming the cell to meet energetic needs. Here we demonstrate that AMPK controls the expression of genes involved in energy metabolism in mouse skeletal muscle by acting in coordination with another metabolic sensor, the NAD+-dependent type III deacetylase SIRT1. AMPK enhances SIRT1 activity by increasing cellular NAD+ levels, resulting in the deacetylation and modulation of the activity of downstream SIRT1 targets that include the peroxisome proliferator-activated receptor-γ coactivator 1α and the forkhead box O1 (FOXO1) and O3 (FOXO3a) transcription factors. The AMPK-induced SIRT1-mediated deacetylation of these targets explains many of the convergent biological effects of AMPK and SIRT1 on energy metabolism.
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This work was supported by grants of CNRS, Ecole Polytechnique Fédérale de Lausanne, INSERM, ULP, NIH (DK59820 and DK069966), EU FP6 (EUGENE2; LSHM-CT-2004-512013) and EU Ideas programme (sirtuins; ERC-2008-AdG-23118). C.C. has been supported by grants of Fondation de la Recherche Medicale (FRM) and EMBO. J.N.F. was supported by a FEBS grant. The authors thank F. Foufelle and P. Ferre, B. Spiegelman, D. P. Kelly, S.-i. Imai, G. Hardie, C. Ammann (Topotarget) and F. Alt for providing materials, and members of the Auwerx and Puigserver laboratories for discussion.
Author Contributions C.C. designed and executed experiments, interpreted data and wrote the manuscript. Z.G.-H., J.C.M., J.N.F., M.L. and L.N. performed experiments and J.N.F. helped with writing. P.J.E. and P.P. provided crucial reagents and helped with data interpretation. J.A. supervised the design and interpretation of the experiments and participated in the writing of the manuscript.
[Competing Interests: P.P. consults for and J.C.M. and P.J.E. are employed by Sirtris, a subsidiary of GSK that develops drugs targeting sirtuins.]
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Cantó, C., Gerhart-Hines, Z., Feige, J. et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458, 1056–1060 (2009). https://doi.org/10.1038/nature07813
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