Morton Nicholas M, Paterson Janice M, Masuzaki Hiroaki, Holmes Megan C, Staels Bart, Fievet Catherine, Walker Brian R, Flier Jeffrey S, Mullins John J, Seckl Jonathan R
Endocrinology Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, UK.
Diabetes. 2004 Apr;53(4):931-8. doi: 10.2337/diabetes.53.4.931.
The metabolic syndrome (visceral obesity, insulin resistance, type 2 diabetes, and dyslipidemia) resembles Cushing's Syndrome, but without elevated circulating glucocorticoid levels. An emerging concept suggests that the aberrantly elevated levels of the intracellular glucocorticoid reamplifying enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD-1) found in adipose tissue of obese humans and rodents underlies the phenotypic similarities between idiopathic and "Cushingoid" obesity. Transgenic overexpression of 11 beta-HSD-1 in adipose tissue reproduces a metabolic syndrome in mice, whereas 11 beta-HSD-1 deficiency or inhibition has beneficial metabolic effects, at least on liver metabolism. Here we report novel protective effects of 11 beta-HSD-1 deficiency on adipose function, distribution, and gene expression in vivo in 11 beta-HSD-1 nullizygous (11 beta-HSD-1(-/-)) mice. 11 beta-HSD-1(-/-) mice expressed lower resistin and tumor necrosis factor-alpha, but higher peroxisome proliferator-activated receptor-gamma, adiponectin, and uncoupling protein-2 mRNA levels in adipose, indicating insulin sensitization. Isolated 11 beta-HSD-1(-/-) adipocytes exhibited higher basal and insulin-stimulated glucose uptake. 11 beta-HSD-1(-/-) mice also exhibited reduced visceral fat accumulation upon high-fat feeding. High-fat-fed 11 beta-HSD-1(-/-) mice rederived onto the C57BL/6J strain resisted diabetes and weight gain despite consuming more calories. These data provide the first in vivo evidence that adipose 11 beta-HSD-1 deficiency beneficially alters adipose tissue distribution and function, complementing the reported effects of hepatic 11 beta-HSD-1 deficiency or inhibition.
代谢综合征（内脏性肥胖、胰岛素抵抗、2型糖尿病和血脂异常）类似于库欣综合征，但循环糖皮质激素水平并未升高。一个新出现的概念表明，在肥胖人类和啮齿动物的脂肪组织中发现的细胞内糖皮质激素再放大酶11β-羟基类固醇脱氢酶1型（11β-HSD-1）异常升高的水平是特发性肥胖和“类库欣样”肥胖之间表型相似性的基础。脂肪组织中11β-HSD-1的转基因过表达在小鼠中重现了代谢综合征，而11β-HSD-1缺乏或抑制至少对肝脏代谢具有有益的代谢作用。在此，我们报告了11β-HSD-1基因敲除（11β-HSD-1(-/-)）小鼠体内11β-HSD-1缺乏对脂肪功能、分布和基因表达的新的保护作用。11β-HSD-1(-/-)小鼠脂肪组织中抵抗素和肿瘤坏死因子-α表达较低，但过氧化物酶体增殖物激活受体-γ、脂联素和解偶联蛋白-2的mRNA水平较高，表明胰岛素敏感性增强。分离的11β-HSD-1(-/-)脂肪细胞表现出更高的基础葡萄糖摄取和胰岛素刺激的葡萄糖摄取。11β-HSD-1(-/-)小鼠在高脂喂养后内脏脂肪积累也减少。重新培育到C57BL/6J品系的高脂喂养11β-HSD-1(-/-)小鼠尽管摄入了更多热量，但仍能抵抗糖尿病和体重增加。这些数据提供了首个体内证据，表明脂肪组织11β-HSD-1缺乏有益地改变了脂肪组织的分布和功能，补充了已报道的肝脏11β-HSD-1缺乏或抑制的作用。
