Adipocyte-specific glucocorticoid inactivation protects against diet-induced obesity
Adipocyte-specific glucocorticoid inactivation protects against diet-induced obesity
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DOI：
10.2337/diabetes.54.4.1023
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发表时间：
2005-04-01
期刊：
影响因子：
7.7
通讯作者：
Flier, JS
中科院分区：
文献类型：
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作者：
Kershaw, EE;Morton, NM;Flier, JS
局部糖皮质激素（GC）的作用取决于细胞内11个β -羟基类固醇脱氢酶（11 β hsd）对GC的代谢。11 β HSD1激活GCs，而11 β HSD2使GCs失活。通过转基因过表达11 β HSD1对脂肪细胞特异性扩增GCs可在小鼠中产生内脏性肥胖和代谢综合征。为了确定脂肪细胞特异性失活的GCs是否能防止这种表型，我们建立了一个转基因模型，在小鼠脂肪细胞脂肪酸结合蛋白（aP2）启动子（aP2-h11 β HSD2）的控制下表达人11 β HSD2。转基因小鼠仅在脂肪组织中增加了11 β - HSD2的表达和活性，其中皮下脂肪组织的表达和活性最高，而GC暴露的全身指标不变。转基因小鼠在高脂肪饮食中抵抗体重增加是由于减少了脂肪堆积。这种能量平衡的改善与减少食物摄入、增加能量消耗、改善葡萄糖耐量和胰岛素敏感性有关。转基因小鼠脂肪组织基因表达的特点是瘦素和抵抗素的表达减少，脂联素、过氧化物酶体增殖物激活受体γ和解偶联蛋白2的表达增加。这些数据表明，在能量稳态和代谢综合征方面，脂肪组织中活性gc的减少是有利代谢表型的重要决定因素。
Local glucocorticoid (GC) action depends on intracellular GC metabolism by 11 beta-hydroxysteroid dehydrogenases (11 beta HSDs). 11 beta HSD1 activates GCs, while 11 beta HSD2 inactivates GCs. Adipocyte-specific amplification of GCs through transgenic overexpression of 11 beta HSD1 produces visceral obesity and the metabolic syndrome in mice. To determine whether adipocytespecific inactivation of GCs protects against this phenotype, we created a transgenic model in which human 11 beta HSD2 is expressed under the control of the murine adipocyte fatty acid binding protein (aP2) promoter (aP2-h11 beta HSD2). Transgenic mice have increased 11 beta HSD2 expression and activity exclusively in adipose tissue, with the highest levels in subcutaneous adipose tissue, while systemic indexes of GC exposure are unchanged. Transgenic mice resist weight gain on high-fat diet due to reduced fat mass accumulation. This improved energy balance is associated with decreased food intake, increased energy expenditure, and improved glucose tolerance and insulin sensitivity. Adipose tissue gene expression in transgenic mice is characterized by decreased expression of leptin and resistin and increased expression of adiponectin, peroxisome proliferator-activated receptor gamma, and uncoupling protein 2. These data suggest that reduction of active GCs exclusively in adipose tissue is an important determinant of a favorable metabolic phenotype with respect to energy homeostasis and the metabolic syndrome.