Regulation of 11β-HSD1 expression during adipose tissue expansion by hypoxia through different activities of NF-κB and HIF-1α

11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-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 11 beta-HSD1 gene expression and its relationship to adipose angiogenesis are largely unknown. To address this issue, we examined 11 beta-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. 11 beta-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, 11 beta-HSD1 expression was induced in mRNA and protein by hypoxia. Of the two transcription factors activated by hypoxia, the nuclear factor-kappa B (NF-kappa B) enhanced but the hypoxia inducible factor-1 alpha (HIF-1 alpha) reduced 11 beta-HSD1 expression. 11 beta-HSD1 expression was elevated by NF-kappa B in epididymal fat of aP2-p65 mice. The hypoxia-induced 11 beta-HSD1 expression was attenuated by NF-kappa B inactivation in p65-deficient cells but enhanced by HIF-1 inactivation in HIF-1 alpha-null cells. These data suggest that 11 beta-HSD1 expression is upregulated by NF-kappa B and downregulated by HIF-1 alpha. During AT expansion in DIO mice, the reduction of 11 beta-HSD1 expression may reflect a dominant HIF-1 alpha activity in the adipose tissue. This study suggests that NF-kappa B may mediate the inflammatory cytokine signal to upregulate 11 beta-HSD1 expression.