Novel adipose tissue-mediated resistance to diet-induced visceral obesity in 11β-hydroxysteroid dehydrogenase type 1-deficient mice
Novel adipose tissue-mediated resistance to diet-induced visceral obesity in 11β-hydroxysteroid dehydrogenase type 1-deficient mice
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DOI：
10.2337/diabetes.53.4.931
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发表时间：
2004-04-01
期刊：
影响因子：
7.7
通讯作者：
Seckl, JR
中科院分区：
文献类型：
--
作者：
Morton, NM;Paterson, JM;Seckl, JR
代谢综合征(内脏肥胖、胰岛素抵抗、2型糖尿病和血脂异常)类似于库欣综合征，但没有循环糖皮质激素水平升高。一个新的概念表明，在肥胖者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(11β-HSD-1)水平异常升高，这是特发性肥胖和库辛戈德样肥胖之间表型相似的基础。在脂肪组织中转基因过表达11β-HSD-1会在小鼠中复制代谢综合征，而11β-HSD-1缺乏或抑制会对代谢产生有益的影响，至少对肝脏代谢有影响。在这里，我们报道了11β-HSD-1缺陷对11β-HSD-1缺失(11β-HSD-1(-/-))小鼠体内脂肪功能、分布和基因表达的新保护作用。11beta-HSD-1(-/-)小鼠脂肪组织中抵抗素和肿瘤坏死因子-α水平较低，而过氧化体增殖物激活受体-γ、脂联素和解偶联蛋白-2的mRNA水平较高，提示胰岛素增敏。分离的11beta-HSD-1(-/-)脂肪细胞表现出更高的基础葡萄糖摄取率和胰岛素刺激的葡萄糖摄取率。11beta-HSD-1(-/-)小鼠在高脂饮食时内脏脂肪积聚也减少。高脂肪喂养的11β-HSD-1(-/-)小鼠重新获得C57BL/6J品系，尽管消耗了更多卡路里，但仍能抵抗糖尿病和体重增加。这些数据提供了第一个活体证据，表明脂肪11β-HSD-1缺乏有益于改变脂肪组织的分布和功能，补充了已报道的肝脏11β-HSD-1缺乏或抑制的影响。
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 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) found in adipose tissue of obese humans and rodents underlies the phenotypic similarities between idiopathic and "Cushingoid" obesity. Transgenic overexpression of 11beta-HSD-1 in adipose tissue reproduces a metabolic syndrome in mice, whereas 11beta-HSD-1 deficiency or inhibition has beneficial metabolic effects, at least on liver metabolism. Here we report novel protective effects of 11beta-HSD-1 deficiency on adipose function, distribution, and gene expression in vivo in 11beta-HSD-1 nullizygous (11beta-HSD-1(-/-)) mice. 11beta-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 11beta-HSD-1(-/-) adipocytes exhibited higher basal and insulin-stimulated glucose uptake. 11beta-HSD-1(-/-) mice also exhibited reduced visceral fat accumulation upon high-fat feeding. High-fat-fed 11beta-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 11beta-HSD-1 deficiency beneficially alters adipose tissue distribution and function, complementing the reported effects of hepatic 11beta-HSD-1 deficiency or inhibition.