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r, di tu b N lmmember of the sirtuin family, Sir2, was originally discovered as a silencing factor, functioning as a sensor of the metabolic activity of the cell to influence gene transcription, DNA repair, this point, however, it remains unclear what the molecular defect underlying the main phenotype in SIRT6-deficient mice is, namely the lethal hypoglycemia. Critically, it is not knownrecombination, and life span (Haigis and Guarente, 2006; Longo and Kennedy, 2006). Later studies identified Sir2 as an NAD+-whether SIRT6 is directly or indirectly involved in the modulation of glucose metabolism.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