Kopecky J, Clarke G, Enerbäck S, Spiegelman B, Kozak L P
Jackson Laboratory, Bar Harbor, Maine 04609, USA.
J Clin Invest. 1995 Dec;96(6):2914-23. doi: 10.1172/JCI118363.
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 Avy genetically obese mice reductions in total body weight and subcutaneous fat stores were observed. Female transgenic Avy 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 approximately 80% of the mass of the tissue in Avy 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.
棕色脂肪特异性线粒体解偶联蛋白（UCP）通过使呼吸与氧化磷酸化解偶联提供了一种产热机制。有人提出，这种产热系统可以抵御肥胖。为了验证这一想法，我们构建了一种转基因小鼠，其中脂肪特异性aP2基因启动子指导Ucp在白色脂肪中表达，并使Ucp在棕色脂肪中组成性表达。转基因小鼠白色脂肪中的Ucp mRNA和免疫反应性UCP水平为棕色脂肪中正常测量水平的2 - 10%。在3月龄时观察到aP2 - Ucp C57BL/6J小鼠的皮下脂肪减少。当转基因在Avy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月龄的雌性转基因Avy小鼠体重为35克，与非转基因C57BL/6J小鼠体重无差异。性腺脂肪中一种新型脂肪细胞衍生物增加，该衍生物不积累脂质，在Avy转基因小鼠中约占组织质量的80%。aP2 - Ucp对棕色脂肪的一个主要作用是使内源基因表达降低多达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。
