Feige, Jérôme NLagouge, MarieCanto, CarlesStrehle, AxelleHouten, Sander MMilne, Jill CLambert, Philip DMataki, ChikageElliott, Peter JAuwerx, Johan2009-04-022009-04-022009-04-02200810.1016/j.cmet.2008.08.017https://infoscience.epfl.ch/handle/20.500.14299/36641WOS:0002606753000031376719046567The NAD(+)-dependent deacetylase SIRT1 controls metabolic processes in response to low nutrient availability. We report the metabolic phenotype of mice treated with SRT1720, a specific and potent synthetic activator of SIRT1 that is devoid of direct action on AMPK. SRT1720 administration robustly enhances endurance running performance and strongly protects from diet-induced obesity and insulin resistance by enhancing oxidative metabolism in skeletal muscle, liver, and brown adipose tissue. These metabolic effects of SRT1720 are mediated by the induction of a genetic network controlling fatty acid oxidation through a multifaceted mechanism that involves the direct deacetylation of PGC-1alpha, FOXO1, and p53 and the indirect stimulation of AMPK signaling through a global metabolic adaptation mimicking low energy levels. Combined with our previous work on resveratrol, the current study further validates SIRT1 as a target for the treatment of metabolic disorders and characterizes the mechanisms underlying the therapeutic potential of SIRT1 activation.text::journal::journal article::research article