1. Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 67404 Illkirch, France
2. Ecole Polytechnique Fédérale de Lausanne, CH1015 Lausanne, Switzerland
3. Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
4. Sirtris Pharmaceuticals Inc., Cambridge, Massachusetts 02139, USA
5. Institut Clinique de la Souris, BP10142, 67404 Illkirch, France

Correspondence to: Johan Auwerx^1,2,5 Correspondence and requests for materials should be addressed to J.A. (Email: admin.auwerx@epfl.ch).

Abstract

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 metformin^{2, 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- coactivator 1 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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