Hypoxic regulation of adipocyte gene expression

Recent studies have demonstrated the importance of adipose tissue hypoxia in the pathogenesis of obesity-related insulin resistance. In vivo data from mice indicate that white adipocytes become hypertrophic during obesity leading to impaired adipose tissue blood flow and hypoxia. Such effects contribute to dysfunctional adipose tissue, ultimately resulting in local inflammation and insulin resistance. Other studies suggest that white adipocytes are unable to mount a compensatory angiogenic response to hypoxic stress; instead the tissues become inflamed and fibrotic. Brown adipose tissue, however, is highly vascularized, likely due to a greater production of angiogenic factors. In the present study, the role of brown-selective nuclear factors, Peroxisome ProliferatorActivated Receptor-gamma Coactivator-1alpha (PGC-1alpha) and PGC-1beta in regulating the angiogenic response of brown adipocytes to hypoxia was investigated. Studies from our lab have shown that activation of Peroxisome Proliferator-Activated Receptor-gamma (PPARgamma) by treatment of white adipocytes with synthetic ligands (thiazolidinediones) causes induction of brown adipocyte-specific genes including PGC-1alpha. Consequently, the potential role of PPARy and thiazolidinediones in regulating expression of vascular endothelial growth factor (VEGF) as well as other hypoxia responsive genes was assessed. The role of the NAD+-dependent deacetylase, Silent Information Regulator-2 homolog-1 (SIRT1) was also analyzed since its activity is responsive to the redox state of the cell.;When exposed to hypoxia, PGC-1alpha knockout adipocytes showed similar activation of hypoxia-induced target genes as observed in control brown adipocytes. However, when brown adipocytes with both PGC-1alpha and PGC-1beta knocked down were exposed to hypoxia, a reduction in the activation of hypoxia target genes, including VEGF, was observed.;Knockdown of SIRT1 in white preadipocytes enhanced their differentiation and induced a subset of hypoxia-target genes also able to be induced by agonist-activated PPARgamma. Conversely, genes coding for inflammatory cytokines, also known targets of hypoxia, were found to be repressed by SIRT1 knockdown or agonist-activated PPARgamma. These data highlight a possible switch from a white fat phenotype to a more vascularized and less dysfunctional brown fat phenotype in response to attenuating SIRT1 or enhancing PPARgamma activity.;These results suggest that PPARgamma and SIRT1 play vital roles in the response of the adipocyte to hypoxia, which includes induction of brown fat-selective genes such as PGC-1alpha in white adipocytes, facilitating a better response to a hypoxic challenge with an appropriate level of angiogenesis.