Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation.
The 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.
Feige
Jérôme N
JN
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université Louis Pasteur, 67404, Illkirch, France.
Lagouge
Marie
M
Canto
Carles
C
Strehle
Axelle
A
Houten
Sander M
SM
Milne
Jill C
JC
Lambert
Philip D
PD
Mataki
Chikage
C
Elliott
Peter J
PJ
Auwerx
Johan
J
D000107:Acetylation; D000818:Animals; D004032:Diet; D004041:Dietary Fats / Q000008:administration & dosage; D004734:Energy Metabolism; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology* / Q000627:therapeutic use; D007333:Insulin Resistance / Q000502:physiology; D050356:Lipid Metabolism / Q000187:drug effects*; D008297:Male; D008659:Metabolic Diseases / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism*; D010084:Oxidation-Reduction; D010805:Physical Conditioning, Animal; D056564:Sirtuin 1; D037761:Sirtuins / Q000819:agonists / Q000235:genetics / Q000378:metabolism*
D004041:Dietary Fats; D006576:Heterocyclic Compounds, 4 or More Rings; C525422:SRT1720; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins