Molecular mechanisms for dysfunction of obese adipose tissue focusing on the network of NADPH producing enzymes and intracellular glucocorticoid reactivating enzyme

细胞内糖皮质激素再激活酶11β-羟基类固醇脱氢酶1型（11β-HSD1）的表达和活性升高，导致肥胖脂肪组织功能障碍。虽然11β-HSD1在肥胖脂肪组织中的病理生理作用早已被研究，但11β-HSD1在肥胖脂肪组织中增强的机制仍不清楚。在这种情况下，在本研究中，我们研究了可能参与慢性炎症、氧化应激、神经酰胺信号和由戊糖途径组成的酶提供的NADPH。在小鼠肥胖脂肪组织培养的脂肪细胞和SVF细胞中，TNFα、IL-1β、LPS和神经酰胺增强了11β-HSD1的酶活性和表达。11β-HSD1的药理抑制和对11β-HSD1的RNA干扰减少了一系列促炎分子，并显著减弱了培养脂肪细胞中NF-kβ和MAPK炎症信号。在人类和小鼠中，肥胖脂肪组织中组成戊糖通路的酶的表达与肥胖程度成正比。脂肪细胞中戊糖通路成员葡萄糖-6-磷酸脱氢酶（G6PD）的强制表达增强了细胞内糖皮质激素的再扩增，并导致皮质醇分泌到介质中，这表明肥胖脂肪组织中11β-HSD1与NADPH提供之间存在功能联系。我们的数据强调了重扩增糖皮质激素的意想不到的作用和肥胖脂肪组织中11β-HSD1增强的分子基础。

Elevated expression and activity of the intracellular glucocorticoid reactivating enzyme, 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1), contribute to dysfunction of obese adipose tissue. Although the pathophysiologic role of 11β-HSD1 in obese adipose tissue has long been investigated, the mechanism whereby 11β-HSD1 is augmented in obese adipose tissue still remains obscure. In this context, in the present study, we investigated the possible involvement of chronic inflammation, oxidative stress, ceramide signals and NADPH provision from enzymes comprising of pentose pathways. In cultured adipocytes and SVF cells from obese adipose tissue from mice, enzyme activity and expression of 11β-HSD1 was augmented by TNFα, IL-1β, LPS and ceramide. Pharmacological inhibition of 11β-HSD1 and RNA interference against 11β-HSD1 reduced a line of pro-inflammatory molecules as well as substantially attenuated NF-kβ and MAPK inflammatory signaling in cultured adipocytes. Expression of enzymes comprising of pentose pathways was elevated in obese adipose tissue in proportion to the degree of obesity in both humans and mice. Forced expression of glucose-6-phosphate dehydrogenase (G6PD), a member of pentose pathways, in adipocytes augmented intracellular glucocorticoid reamplification and resultant secretion of cortisol into the media, indicating a functional link between 11β-HSD1 and NADPH provision in obese adipose tissue. Our data highlight an unexpected role of reamplified glucocorticoids and molecular basis for augmented 11β-HSD1 in obese adipose tissue.