AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity

Abstract

AMP-activated protein kinase (AMPK) is a cellular energy sensor that helps coordinate glucose and lipid metabolism. Here, AMPK is shown to transcriptionally regulate genes involved in controlling energy metabolism in skeletal muscle by acting together with the NAD+-dependent deacetylase SIRT1. AMPK enhances SIRT1 activity by increasing cellular NAD+ levels. This results in the deacetylation and activation of the SIRT1 downstream target PGC-1α. AMP-activated protein kinase (AMPK) is shown to transcriptionally regulate genes involved in controlling energy metabolism in skeletal muscle by acting together with the NAD+-dependent deacetylase SIRT1. AMPK enhances SIRT1 activity by increasing cellular NAD+ levels, resulting in the deacetylation and activation of the SIRT1 downstream target PGC-1α. 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.