11-Dehydrocorticosterone Causes Metabolic Syndrome, Which Is Prevented when 11β-HSD1 Is Knocked Out in Livers of Male Mice
11-Dehydrocorticosterone Causes Metabolic Syndrome, Which Is Prevented when 11β-HSD1 Is Knocked Out in Livers of Male Mice
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DOI：
10.1210/en.2013-1362
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发表时间：
2013-10-01
期刊：
影响因子：
4.8
通讯作者：
White, Anne
中科院分区：
文献类型：
--
作者：
Harno, Erika;Cottrell, Elizabeth C.;White, Anne
随着肥胖、2 型糖尿病和胰岛素抵抗水平的上升，代谢综合征变得越来越重要。代谢综合征与库欣综合征有许多共同特征，这引发了对过量糖皮质激素与代谢综合征之间联系的研究。事实上，11 β-羟基类固醇脱氢酶 1 型 (11 β-HSD1) 导致细胞内再生产生的糖皮质激素增加会导致胰岛素抵抗并增加肥胖，但这些代谢变化被认为是由于循环糖皮质激素增加所致。我们假设增加 11 beta-HSD1（11-脱氢皮质酮，11-DHC）底物会对代谢参数产生不利影响。我们发现，对雄性 C57BL/6J 小鼠长期给予 11-DHC 会导致循环糖皮质激素增加，并下调下丘脑-垂体-肾上腺轴。 11β-HSD1 衍生的皮质酮升高导致体重增加和肥胖增加，并产生明显的胰岛素抵抗。令人惊讶的是，给予 11-DHC 的肝脏特异性 11β-HSD1 敲除 (LKO) 小鼠没有表现出野生型小鼠中观察到的任何不良代谢影响。尽管 11-DHC 给药导致循环皮质酮升高（可能来自脂肪组织），但这种情况还是发生了。 11β-HSD1 整体缺失（整体敲除）的小鼠不受 11-DHC 治疗的影响，循环皮质酮没有增加，也没有表现出代谢损伤的迹象。总而言之，这些数据表明，在肝脏中缺乏 11β-HSD1 的情况下，即使循环糖皮质激素增加，小鼠也能免受 11-DHC 给药的代谢影响。这意味着肝脏来源的组织内糖皮质激素，而不是循环糖皮质激素，对代谢综合征的发展有显着贡献，并表明肝组织内的局部作用介导了这些作用。
Metabolic syndrome is growing in importance with the rising levels of obesity, type 2 diabetes, and insulin resistance. Metabolic syndrome shares many characteristics with Cushing's syndrome, which has led to investigation of the link between excess glucocorticoids and metabolic syndrome. Indeed, increased glucocorticoids from intracellular regeneration by 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) drives insulin resistance and increases adiposity, but these metabolic changes are assumed to be due to increased circulating glucocorticoids. We hypothesized that increasing the substrate for 11 beta-HSD1 (11-dehydrocorticosterone, 11-DHC) would adversely affect metabolic parameters. We found that chronic administration of 11-DHC to male C57BL/6J mice resulted in increased circulating glucocorticoids, and down-regulation of the hypothalamic-pituitary-adrenal axis. This elevated 11 beta-HSD1-derived corticosterone led to increased body weight gain and adiposity and produced marked insulin resistance. Surprisingly liver-specific 11 beta-HSD1 knockout (LKO) mice given 11-DHC did not show any of the adverse metabolic effects seen in wild-type mice. This occurred despite the 11-DHC administration resulting in elevated circulating corticosterone, presumably from adipose tissue. Mice with global deletion of 11 beta-HSD1 (global knockout) were unaffected by treatment with 11-DHC, having no increase in circulating corticosterone and exhibiting no signs of metabolic impairment. Taken to gether, these data show that in the absence of 11 beta-HSD1 in the liver, mice are protected from the metabolic effects of 11-DHC administration, even though circulating glucocorticoids are increased. This implies that liver-derived intratissue glucocorticoids, rather than circulating glucocorticoids, contribute significantly to the development of metabolic syndrome and suggest that local action within hepatic tissue mediates these effects.