Dietary obesity-associated Hif1α activation in adipocytes restricts fatty acid oxidation and energy expenditure via suppression of the Sirt2-NAD+ system
Open Access
- 1 February 2012
- journal article
- Published by Cold Spring Harbor Laboratory in Genes & Development
- Vol. 26 (3), 259-270
- https://doi.org/10.1101/gad.180406.111
Abstract
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 1α (HIF1α). Here we report that, in mice, Hif1α activation in visceral white adipocytes is critical to maintain dietary obesity and associated pathologies, including glucose intolerance, insulin resistance, and cardiomyopathy. This function of Hif1α is linked to its capacity to suppress β-oxidation, in part, through transcriptional repression of sirtuin 2 (Sirt2) NAD+-dependent deacetylase. Reduced Sirt2 function directly translates into diminished deacetylation of PPARγ coactivator 1α (Pgc1α) and expression of β-oxidation and mitochondrial genes. Importantly, visceral adipose tissue from human obese subjects is characterized by high levels of HIF1α and low levels of SIRT2. Thus, by negatively regulating the Sirt2–Pgc1α regulatory axis, Hif1α negates adipocyte-intrinsic pathways of fatty acid catabolism, thereby creating a metabolic state supporting the development of obesity.Keywords
This publication has 40 references indexed in Scilit:
- Depot-Specific Differences and Insufficient Subcutaneous Adipose Tissue Angiogenesis in Human ObesityCirculation, 2011
- Cellular Metabolic Stress: Considering How Cells Respond to Nutrient ExcessMolecular Cell, 2010
- Adipose Tissue-specific Inhibition of Hypoxia-inducible Factor 1α Induces Obesity and Glucose Intolerance by Impeding Energy Expenditure in Mice*Published by Elsevier BV ,2010
- Diabetic cardiomyopathy, causes and effectsReviews in Endocrine and Metabolic Disorders, 2010
- Hypoxia-Inducible Factor 1α Induces Fibrosis and Insulin Resistance in White Adipose TissueMolecular and Cellular Biology, 2009
- Emerging role of adipose tissue hypoxia in obesity and insulin resistanceInternational Journal of Obesity, 2008
- The SIRT2 Deacetylase Regulates Autoacetylation of p300Molecular Cell, 2008
- Oxygen Sensing by Metazoans: The Central Role of the HIF Hydroxylase PathwayMolecular Cell, 2008
- SIRT2 Regulates Adipocyte Differentiation through FoxO1 Acetylation/DeacetylationCell Metabolism, 2007
- SIRT2 deacetylates FOXO3a in response to oxidative stress and caloric restrictionAging Cell, 2007