Shepherd P R, Gnudi L, Tozzo E, Yang H, Leach F, Kahn B B
Charles A. Dana Research Institute, Beth Israel Hospital, Boston, Massachusetts.
J Biol Chem. 1993 Oct 25;268(30):22243-6.
To gain insight into the molecular pathogenesis of obesity and specifically the role of nutrient partitioning in the development of obesity, we overexpressed the insulin-responsive glucose transporter (GLUT4) in transgenic mice under the control of the fat-specific aP2 fatty acid-binding protein promoter/enhancer. Two lines of transgenic mice were generated, which overexpressed GLUT4 6-9-fold in white fat and 3-5-fold in brown fat with no overexpression in other tissues. In vivo glucose tolerance was enhanced in transgenic mice. In isolated epididymal, parametrial, and subcutaneous adipose cells from transgenic mice, basal glucose transport was 20-34-fold greater than in nontransgenic littermates. Insulin-stimulated glucose transport was 2-4-fold greater in cells from transgenic mice. Total body lipid was increased 2-3-fold in transgenic mice overexpressing GLUT4 in fat. Surprisingly, fat cell size was unaltered and fat cell number was increased > 2-fold. This is the first animal model in which increased fat mass results solely from adipocyte hyperplasia and it will be a valuable model for understanding the mechanisms responsible for fat cell replication and/or differentiation in vivo.
为深入了解肥胖的分子发病机制，特别是营养分配在肥胖发展中的作用，我们在脂肪特异性aP2脂肪酸结合蛋白启动子/增强子的控制下，在转基因小鼠中过表达胰岛素反应性葡萄糖转运蛋白（GLUT4）。产生了两系转基因小鼠，其在白色脂肪中GLUT4过表达6 - 9倍，在棕色脂肪中过表达3 - 5倍，而在其他组织中无过表达。转基因小鼠的体内葡萄糖耐量增强。在来自转基因小鼠的分离的附睾、子宫旁和皮下脂肪细胞中，基础葡萄糖转运比非转基因同窝小鼠高20 - 34倍。胰岛素刺激的葡萄糖转运在转基因小鼠的细胞中高2 - 4倍。在脂肪中过表达GLUT4的转基因小鼠的全身脂质增加了2 - 3倍。令人惊讶的是，脂肪细胞大小未改变，脂肪细胞数量增加了2倍以上。这是第一个脂肪量增加仅由脂肪细胞增生导致的动物模型，它将成为理解体内脂肪细胞复制和/或分化机制的有价值模型。
