| First Author | Krishnan J | Year | 2012 |
| Journal | Genes Dev | Volume | 26 |
| Issue | 3 | Pages | 259-70 |
| PubMed ID | 22302938 | Mgi Jnum | J:181338 |
| Mgi Id | MGI:5311062 | Doi | 10.1101/gad.180406.111 |
| Citation | Krishnan J, et al. (2012) Dietary obesity-associated Hif1alpha activation in adipocytes restricts fatty acid oxidation and energy expenditure via suppression of the Sirt2-NAD+ system. Genes Dev 26(3):259-70 |
| abstractText | 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 1alpha (HIF1alpha). Here we report that, in mice, Hif1alpha activation in visceral white adipocytes is critical to maintain dietary obesity and associated pathologies, including glucose intolerance, insulin resistance, and cardiomyopathy. This function of Hif1alpha is linked to its capacity to suppress beta-oxidation, in part, through transcriptional repression of sirtuin 2 (Sirt2) NAD(+)-dependent deacetylase. Reduced Sirt2 function directly translates into diminished deacetylation of PPARgamma coactivator 1alpha (Pgc1alpha) and expression of beta-oxidation and mitochondrial genes. Importantly, visceral adipose tissue from human obese subjects is characterized by high levels of HIF1alpha and low levels of SIRT2. Thus, by negatively regulating the Sirt2-Pgc1alpha regulatory axis, Hif1alpha negates adipocyte-intrinsic pathways of fatty acid catabolism, thereby creating a metabolic state supporting the development of obesity. |
