Regulation of HIF-1α activity in adipose tissue by obesity-associated factors: adipogenesis, insulin, and hypoxia

Regulation of HIF-1 alpha activity in adipose tissue by obesity-associated factors: adipogenesis, insulin, and hypoxia. Am J Physiol Endocrinol Metab 300: E877-E885, 2011. First published February 22, 2011; doi: 10.1152/ajpendo.00626.2010.-The transcription factor HIF-1 alpha activity is increased in adipose tissue to contribute to chronic inflammation in obesity. However, its upstream and downstream events remain to be characterized in adipose tissue in obesity. We addressed this issue by investigating adipocyte HIF-1 alpha activity in response to obesity-associated factors, such as adipogenesis, insulin, and hypoxia. In adipose tissue, both HIF-1 alpha mRNA and protein were increased by obesity. The underlying mechanism was investigated in 3T3-L1 adipocytes. HIF-1 alpha mRNA and protein were augmented by adipocyte differentiation. In differentiated adipocytes, insulin further enhanced HIF-1 alpha in both levels. Hypoxia enhanced only HIF-1 alpha protein, not mRNA. PI3K and mTOR activities are required for the HIF-1 alpha expression. Function of HIF-1 alpha protein was investigated in the regulation of VEGF gene transcription. ChIP assay shows that HIF-1 alpha binds to the proximal hypoxia response element in the VEGF gene promoter, and its function is inhibited by a corepressor composed of HDAC3 and SMRT. These observations suggest that of the three obesity-associated factors, all of them are able to augment HIF-1 alpha protein levels, but only two (adipogenesis and insulin) are able to enhance HIF-1 alpha mRNA activity. Adipose tissue HIF-1 alpha activity is influenced by multiple signals, including adipogenesis, insulin, and hypoxia in obesity. The transcriptional activity of HIF-1 alpha is inhibited by HDAC3-SMRT corepressor in the VEGF gene promoter.