title: Regulation of 11β-HSD1 expression during adipose tissue expansion by hypoxia through different activities of NF-κB and HIF-1α.
abstract: 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is involved in the pathogenesis of type 2 diabetes by generating active glucocorticoids (cortisol and corticosterone) that are strong inhibitors of angiogenesis. However, the mechanism of 11β-HSD1 gene expression and its relationship to adipose angiogenesis are largely unknown. To address this issue, we examined 11β-HSD1 expression in visceral and subcutaneous adipose tissue (AT) of diet-induced obese (DIO) mice during weight gain and investigated the gene regulation by hypoxia in vitro. 11β-HSD1 mRNA was reduced in the adipose tissues during weight gain in DIO mice, and the reduction was associated with an elevated expression of angiogenic factors. In vitro, 11β-HSD1 expression was induced in mRNA and protein by hypoxia. Of the two transcription factors activated by hypoxia, the nuclear factor-κB (NF-κB) enhanced but the hypoxia inducible factor-1α (HIF-1α) reduced 11β-HSD1 expression. 11β-HSD1 expression was elevated by NF-κB in epididymal fat of aP2-p65 mice. The hypoxia-induced 11β-HSD1 expression was attenuated by NF-κB inactivation in p65-deficient cells but enhanced by HIF-1 inactivation in HIF-1α-null cells. These data suggest that 11β-HSD1 expression is upregulated by NF-κB and downregulated by HIF-1α. During AT expansion in DIO mice, the reduction of 11β-HSD1 expression may reflect a dominant HIF-1α activity in the adipose tissue. This study suggests that NF-κB may mediate the inflammatory cytokine signal to upregulate 11β-HSD1 expression.
authors.affiliation: Pennington Biomedical Research Center, Louisiana State University System, 6400 Perkins Road, Baton Rouge, LA 70808, USA.
authors.forename: Jong Han
authors.initials: JH
authors.lastname: Lee
authors.forename: Zhanguo
authors.initials: Z
authors.lastname: Gao
authors.forename: Jianping
authors.initials: J
authors.lastname: Ye
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D041721:3T3-L1 Cells; D000818:Animals; D015153:Blotting, Western; D015687:Cell Hypoxia / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D050152:Intra-Abdominal Fat / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D009765:Obesity / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D050151:Subcutaneous Fat / Q000201:enzymology / Q000378:metabolism*; D015430:Weight Gain / Q000502:physiology
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D012333:RNA, Messenger; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1
keywords: 11β-hydroxysteroid dehydrogenase type 1; angiogenesis; hyperinsulinemia; hypoxia; hypoxia-inducible factor-1α; inflammation; nuclear factor-κB; obesity; type 2 diabetes