Morton Nicholas M, Ramage Lynne, Seckl Jonathan R
Endocrinology Unit, University of Edinburgh, Molecular Medicine Centre, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, Scotland, United Kingdom.
Endocrinology. 2004 Jun;145(6):2707-12. doi: 10.1210/en.2003-1674. Epub 2004 Mar 25.
The enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) amplifies intracellular glucocorticoid action in vivo. 11beta-HSD-1 activity is increased in adipose tissues of obese humans and genetically obese rodents, providing a mechanistic basis for the similarities between metabolic disease arising from high circulating glucocorticoids (Cushing's syndrome) and idiopathic obesity/metabolic syndrome where plasma glucocorticoids are typically unaltered. Fat-specific overexpression of 11beta-HSD-1 produces a metabolic syndrome in mice, whereas 11beta-HSD-1 null mice resist high-fat diet (HF)-induced visceral obesity and its metabolic consequences. Here we compared the effects of chronic (18 wk) HF feeding on adipose 11beta-HSD-1 activity in strains of mice that are either resistant (A/J) or prone (C57BL/6J) to metabolic disease. 11beta-HSD-1 activity was highest in sc fat, followed by epididymal fat, with lowest activity in the mesenteric visceral depot of both strains. 11beta-HSD-1 activity was lower in white adipose tissues of A/J compared with C57BL/6J mice. Chronic HF feeding unexpectedly caused a down-regulation of 11beta-HSD-1 in adipose tissues of both strains, despite comparable adiposity. However, A/J mice down-regulated adipose 11beta-HSD-1 to a significantly lower level than C57BL/6J mice in white and thermogenic brown adipose tissues. We propose that a lower adipose 11beta-HSD-1 set point affords a metabolic protection to A/J mice. Adaptive down-regulation of adipose 11beta-HSD-1 in response to chronic HF represents a novel mechanism that may counteract metabolic disease.
11β-羟类固醇脱氢酶1型（11β-HSD-1）可在体内增强细胞内糖皮质激素的作用。在肥胖人类和遗传性肥胖啮齿动物的脂肪组织中，11β-HSD-1的活性会升高，这为高循环糖皮质激素引发的代谢疾病（库欣综合征）与特发性肥胖/代谢综合征（血浆糖皮质激素通常未改变）之间的相似性提供了一个机制基础。脂肪特异性过表达11β-HSD-1会在小鼠中产生代谢综合征，而11β-HSD-1基因敲除小鼠可抵抗高脂饮食（HF）诱导的内脏肥胖及其代谢后果。在此，我们比较了慢性（18周）HF喂养对代谢疾病抗性（A/J）或易感性（C57BL/6J）小鼠品系脂肪组织中11β-HSD-1活性的影响。11β-HSD-1活性在皮下脂肪中最高，其次是附睾脂肪，在两个品系的肠系膜内脏脂肪库中活性最低。与C57BL/6J小鼠相比，A/J小鼠白色脂肪组织中的11β-HSD-1活性较低。尽管肥胖程度相当，但慢性HF喂养意外导致两个品系脂肪组织中11β-HSD-1的下调。然而，在白色和产热棕色脂肪组织中，A/J小鼠脂肪组织中11β-HSD-1下调至显著低于C57BL/6J小鼠的水平。我们认为较低的脂肪11β-HSD-1设定点为A/J小鼠提供了代谢保护。脂肪组织中11β-HSD-1响应慢性HF的适应性下调代表了一种可能对抗代谢疾病的新机制。
