Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha.
Diminished mitochondrial oxidative phosphorylation and aerobic capacity are associated with reduced longevity. We tested whether resveratrol (RSV), which is known to extend lifespan, impacts mitochondrial function and metabolic homeostasis. Treatment of mice with RSV significantly increased their aerobic capacity, as evidenced by their increased running time and consumption of oxygen in muscle fibers. RSV's effects were associated with an induction of genes for oxidative phosphorylation and mitochondrial biogenesis and were largely explained by an RSV-mediated decrease in PGC-1alpha acetylation and an increase in PGC-1alpha activity. This mechanism is consistent with RSV being a known activator of the protein deacetylase, SIRT1, and by the lack of effect of RSV in SIRT1(-/-) MEFs. Importantly, RSV treatment protected mice against diet-induced-obesity and insulin resistance. These pharmacological effects of RSV combined with the association of three Sirt1 SNPs and energy homeostasis in Finnish subjects implicates SIRT1 as a key regulator of energy and metabolic homeostasis.
Lagouge
Marie
M
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS / INSERM / ULP, 67404 Illkirch, France.
Argmann
Carmen
C
Gerhart-Hines
Zachary
Z
Meziane
Hamid
H
Lerin
Carles
C
Daussin
Frederic
F
Messadeq
Nadia
N
Milne
Jill
J
Lambert
Philip
P
Elliott
Peter
P
Geny
Bernard
B
Laakso
Markku
M
Puigserver
Pere
P
Auwerx
Johan
J
D000107:Acetylation; D000328:Adult; D000818:Animals; D004041:Dietary Fats / Q000008:administration & dosage; D004734:Energy Metabolism / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D008659:Metabolic Diseases / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008931:Mitochondria, Muscle / Q000502:physiology*; D009043:Motor Activity / Q000187:drug effects; D018485:Muscle Fibers, Skeletal / Q000502:physiology; D009765:Obesity / Q000517:prevention & control; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption / Q000187:drug effects; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020641:Polymorphism, Single Nucleotide; D000077185:Resveratrol; D056564:Sirtuin 1; D037761:Sirtuins / Q000235:genetics* / Q000378:metabolism*; D013047:Specific Pathogen-Free Organisms; D013267:Stilbenes / Q000494:pharmacology*; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors
D004041:Dietary Fats; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D013267:Stilbenes; D015534:Trans-Activators; D014157:Transcription Factors; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins; D000077185:Resveratrol