NF-κB induces transcriptional expression of proinflammatory genes and antiapoptotic genes. The two activities of NF-κB remain to be characterized in the mechanism of chronic inflammation in obesity. To address this issue, we inactivated NF-κB in adipose tissue by knocking out p65 (RelA) in mice (F-p65-KO) and examined the inflammation in lean and obese conditions. In the lean condition, KO mice exhibited a reduced inflammation in adipose tissue with a decrease in macrophage infiltration, M1 polarization, and proinflammatory cytokine expression. In the obese condition, KO mice had elevated inflammation with more macrophage infiltration, M1 polarization, and cytokine expression. In the mechanism of enhanced inflammation, adipocytes and macrophages exhibited an increase in cellular apoptosis, which was observed with more formation of crown-like structures (CLS) in fat tissue of KO mice. Body weight, glucose metabolism, and insulin sensitivity were not significantly altered in KO mice under the lean and obese conditions. A modest but significant reduction in body fat mass was observed in KO mice on HFD with an elevation in energy expenditure. The data suggest that in the control of adipose inflammation, NF-κB exhibits different activities in the lean vs. obese condition. NF-κB is required for expression of proinflammatory genes in the lean but not in the obese condition. NF-κB is required for inhibition of apoptosis in the obese condition, in which proinflammation is enhanced by NF-κB inactivation.

Lee JH, Gao Z, Ye J. Regulation of 11␤-HSD1 expression during adipose tissue expansion by hypoxia through different activities of NF-B and HIF-1␣. Am J Physiol Endocrinol Metab 304: E1035-E1041, 2013. First published March 19, 2013; doi:10.1152/ajpendo.00029.2013.-11␤-Hydroxysteroid dehydrogenase type 1 (11␤-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␤-HSD1 gene expression and its relationship to adipose angiogenesis are largely unknown. To address this issue, we examined 11␤-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␤-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␤-HSD1 expression was induced in mRNA and protein by hypoxia. Of the two transcription factors activated by hypoxia, the nuclear factor-B (NF-B) enhanced but the hypoxia inducible factor-1␣ (HIF-1␣) reduced 11␤-HSD1 expression. 11␤-HSD1 expression was elevated by NF-B in epididymal fat of aP2-p65 mice. The hypoxia-induced 11␤-HSD1 expression was attenuated by NF-B inactivation in p65-deficient cells but enhanced by HIF-1 inactivation in HIF-1␣-null cells. These data suggest that 11␤-HSD1 expression is upregulated by NF-B and downregulated by HIF-1␣. During AT expansion in DIO mice, the reduction of 11␤-HSD1 expression may reflect a dominant HIF-1␣ activity in the adipose tissue. This study suggests that NF-B may mediate the inflammatory cytokine signal to upregulate 11␤-HSD1 expression.11␤-hydroxysteroid dehydrogenase type 1; nuclear factor-B; hypoxiainducible factor-1␣; hypoxia; hyperinsulinemia; angiogenesis; inflammation; obesity; type 2 diabetes 11␤-HYDROXYSTEROID DEHYDROGENASE TYPE 1 (11␤-HSD1) that converts inactive glucocorticoids (GCs; cortisone and 11-dehydrocorticosterone) into active GCs (cortisol and corticosterone) plays a role in the pathogenesis of insulin resistance. Global inactivation of 11␤-HSD1 by gene knockout prevents insulin resistance and reduces hepatic gluconeogenesis in obese mice (21). 11␤-HSD1 overexpression in adipose tissue (AT) generates visceral obesity and systemic insulin resistance in transgenic mice (23). Liver-specific overexpression of 11␤-HSD1 leads to insulin resistance in the absence of obesity in mice (31). Conversely, global inactivation of the 11␤-HSD1 gene protects mice from diet-induced obesity (21,25,26). 11␤-HSD1 has been a drug target in the study of insulin resistance, and its inhibition using a pharmacological approach improves insulin sensitivity in diabetic mice (2). 11␤-HSD1 is expressed in many cell types, including adipocytes, and the expression is increased during adipocyte differentiation (7). 11␤-HSD1 elevation in adipocytes is proposed to be a common molecular etiology for visceral obe...

Hepatocyte growth factor (HGF) is expressed as an angiogenic factor in adipose tissue. However, the molecular mechanism of Hgf expression remains largely unknown in the tissue. We addressed the issue by studying Hgf expression in adipocytes and macrophages. Hgf was expressed more in the stromal-vascular fraction than the adipocyte fraction. The expression was fivefold more in macrophages than the stromal-vascular faction and was reduced by 50% after macrophage deletion in adipose tissue. The expression was reduced by differentiation in adipocytes and by tumor necrosis factor-α or lipopolysaccharide treatment in macrophages. The expression was suppressed by nuclear factor (NF)-κB in C57BL/6 mice with NF-κB p65 overexpression under the aP2 gene promoter (aP2-p65 mice) but enhanced by inactivation of NF-κB p65 in mouse embryonic fibroblasts. The Hgf gene promoter was suppressed by p65 overexpression, which blocked peroxisome proliferator-activated receptor-γ (PPARγ) interaction with RNA polymerase II. The p65 activity was abolished by knockdown of histone deacetylase 3. Hgf expression was upregulated by hypoxia in vitro and in vivo. Compared with vascular endothelial growth factor (Vegf), which was predominately expressed in mature adipocytes, Hgf was mainly expressed in nonadipocytes, suggesting that Hgf and Vegf may have different cell sources in adipose tissue. In mechanism, Hgf expression is inhibited by NF-κB through suppression of PPARγ function in the Hgf gene promoter. Both Hgf and Vegf are induced by hypoxia. The study provides a molecular mechanism for the difference of inflammation and hypoxia in the regulation of angiogenic factors.