Expression array from SIRT6WT and SIRT6KO muscle. Mus musculus

SIRT6 is a member of a highly conserved family of NAD+-dependent deacetylases with various roles in metabolism, stress resistance, and life span. SIRT6- deficient mice develop normally but succumb to a lethal hypoglycemia early in life; however, the mechanism underlying this hypoglycemia remained unclear. Here, we demonstrate that SIRT6 functions as a histone H3K9 deacetylase to control the expres- sion of multiple glycolytic genes. Specifically, SIRT6 appears to function as a corepressor of the transcrip- tion factor Hif1a, a critical regulator of nutrient stress responses. Consistent with this notion, SIRT6-defi- cient cells exhibit increased Hif1a activity and show increased glucose uptake with upregulation of glycolysis and diminished mitochondrial respiration. Our studies uncover a role for the chromatin factor SIRT6 as a master regulator of glucose homeostasis and may provide the basis for novel therapeutic approaches against metabolic diseases, such as diabetes and obesity. Overall design: RNA was prepared from muscle of three SIRT6 wild type and KO mice, and hybridized onto an Affymetrix GeneChip Mouse Genome 430 2.0 Array.