Metabolic benefits from Sirt1 and Sirt1 activators.

PURPOSE OF REVIEW: To evaluate the role of mammalian Sirt1 and Sirt1 activators in the protection from metabolic disorders such as diet-induced obesity, diabetes type 2, or nonalcoholic fatty liver disease.

RECENT FINDINGS: Sirtuins are highly conserved nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases that are activated by NAD+ and inhibited by NAD in its reduced form (NADH). Sirtuins act as cellular energy sensors that deacetylate numerous proteins involved in energy and glucose homeostasis, which in turn induce a wide range of physiological changes that counteract detrimental effects of metabolic stressors.

SUMMARY: Sirt1 targets numerous proteins, including peroxisome proliferator-activated receptor (PPAR)-gamma, PPAR-gamma coactivator (PGC)-1alpha, uncoupling protein 2 (UCP2), and nuclear factor-kappa B, which play key roles in various metabolic disorders. This review summarizes these key targets of Sirt1 and the physiological relevance of those interactions. Also, new results on Sirt1-knockout and overexpressor mouse models are presented to substantiate metabolic benefits from Sirt1 activation. Finally, this review gives an overview on recent efforts to activate Sirt1 pharmacologically by using resveratrol or small-molecule Sirt1 activators with improved biopotency.