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

摘要

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.