title: Regulation of HIF-1{alpha} activity in adipose tissue by obesity-associated factors: adipogenesis, insulin, and hypoxia.
abstract: The transcription factor HIF-1α 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-1α activity in response to obesity-associated factors, such as adipogenesis, insulin, and hypoxia. In adipose tissue, both HIF-1α mRNA and protein were increased by obesity. The underlying mechanism was investigated in 3T3-L1 adipocytes. HIF-1α mRNA and protein were augmented by adipocyte differentiation. In differentiated adipocytes, insulin further enhanced HIF-1α in both levels. Hypoxia enhanced only HIF-1α protein, not mRNA. PI3K and mTOR activities are required for the HIF-1α expression. Function of HIF-1α protein was investigated in the regulation of VEGF gene transcription. ChIP assay shows that HIF-1α 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-1α protein levels, but only two (adipogenesis and insulin) are able to enhance HIF-1α mRNA activity. Adipose tissue HIF-1α activity is influenced by multiple signals, including adipogenesis, insulin, and hypoxia in obesity. The transcriptional activity of HIF-1α is inhibited by HDAC3-SMRT corepressor in the VEGF gene promoter.
authors.affiliation: Pennington Biomedical Research Center, Louisiana State University System, 6400 Perkins Rd., Baton Rouge, LA 70808, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: He
authors.forename: Zhanguo
authors.initials: Z
authors.lastname: Gao
authors.forename: Jun
authors.initials: J
authors.lastname: Yin
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.forename: Zhong
authors.initials: Z
authors.lastname: Yun
authors.forename: Jianping
authors.initials: J
authors.lastname: Ye
mesh_terms: D017667:Adipocytes / Q000378:metabolism / Q000502:physiology; D050156:Adipogenesis / Q000502:physiology*; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D006655:Histone Deacetylases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D000860:Hypoxia / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology*; D008156:Luciferases / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D056985:Nuclear Receptor Co-Repressor 2 / Q000096:biosynthesis / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*; D000099186:Histone Deacetylase 3
chemical_list: D006655:Histone Deacetylases; D007004:Hypoglycemic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007328:Insulin; D008156:Luciferases; D056985:Nuclear Receptor Co-Repressor 2; D019869:Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A; D000099186:Histone Deacetylase 3; C497443:Hif1a protein, mouse; C539131:Ncor2 protein, mouse