Dietary obesity is a major factor in the development of type 2 diabetes and is associated with intra-adipose tissue hypoxia and activation of hypoxia-inducible factor 1a (HIF1a). Here we report that, in mice, Hif1a activation in visceral white adipocytes is critical to maintain dietary obesity and associated pathologies, including glucose intolerance, insulin resistance, and cardiomyopathy. This function of Hif1a is linked to its capacity to suppress b-oxidation, in part, through transcriptional repression of sirtuin 2 (Sirt2) NAD + -dependent deacetylase. Reduced Sirt2 function directly translates into diminished deacetylation of PPARg coactivator 1a (Pgc1a) and expression of b-oxidation and mitochondrial genes. Importantly, visceral adipose tissue from human obese subjects is characterized by high levels of HIF1a and low levels of SIRT2. Thus, by negatively regulating the Sirt2-Pgc1a regulatory axis, Hif1a negates adipocyte-intrinsic pathways of fatty acid catabolism, thereby creating a metabolic state supporting the development of obesity.