Expression of the mitochondrial uncoupling protein gene from the aP2 gene promoter prevents genetic obesity
Expression of the mitochondrial uncoupling protein gene from the aP2 gene promoter prevents genetic obesity
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DOI：
10.1172/jci118363
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发表时间：
1995-12-01
影响因子：
15.9
通讯作者：
Kozak, LP
中科院分区：
文献类型：
--
作者：
Kopecky, J;Clarke, G;Kozak, LP
棕色脂肪特异性线粒体解偶联蛋白（UCP）提供了一种通过解偶联呼吸和氧化磷酸化产生热量的机制。有人认为，这种生热系统可以预防肥胖。为了测试这个想法，我们创建了一种转基因小鼠，其中脂肪特异性aP2基因启动子指导白色脂肪中的Ucp表达，并提供棕色脂肪中Ucp的组成型表达。转基因小鼠在白色脂肪中显示出Ucp mRNA和免疫反应性UCP，其水平为棕色脂肪中正常测量水平的2-10%。 aP2-Ucp C57BL/6J 小鼠在 3 个月龄时观察到皮下脂肪减少。当转基因在 A(vy) 遗传性肥胖小鼠中表达时，观察到总体重和皮下脂肪储存减少，13 个月龄的雌性转基因 A(vy) 小鼠体重为 35 克，与非转基因 C57BL/6J 小鼠的重量没有区别。性腺脂肪显示出一种新型脂肪细胞衍生物的增加，这种衍生物不会积累脂质，并且构成 A(vy) 转基因组织质量的 80%，aP2-Ucp 在棕色脂肪中的一个主要作用是减少内源基因表达多达 95%。结果表明，由 aP2 基因启动子合成的 UCP 具有产热活性，能够减少脂肪储存。
The brown fat-specific mitochondrial uncoupling protein (UCP) provides a mechanism for generating heat by uncoupling respiration and oxidative phosphorylation. It has been suggested that this system of thermogenesis can provide a defense against obesity. To test this idea, we created a transgenic mouse in which the fat-specific aP2 gene promoter directed Ucp expression in white fat and provided for the constitutive expression of Ucp in brown fat, Transgenic mice showed both Ucp mRNA and immunoreactive UCP in white fat at 2-10% the level normally measured in brown fat. A reduction in subcutaneous fat of aP2-Ucp C57BL/6J mice was observed at 3 mo of age. When the transgene was expressed in A(vy) genetically obese mice reductions in total body weight and subcutaneous fat stores were observed, Female transgenic A(vy) mice at 13 mo of age weighed 35 grams, a weight indistinguishable from nontransgenic C57BL/6J mice. Gonadal fat showed an increase in a novel adipocyte derivative that did not accumulate lipids and that constituted similar to 80% of the mass of the tissue in A(vy) transgenic, A major effect of aP2-Ucp in brown fat was to reduce endogenous gene expression by as much as 95%. The results suggest that UCP synthesized from the aP2 gene promoter is thermogenically active and capable of reducing fat stores.