TRANSGENIC GLUT-4 OVEREXPRESSION IN FAT ENHANCES GLUCOSE-METABOLISM - PREFERENTIAL EFFECT ON FATTY-ACID SYNTHESIS
TRANSGENIC GLUT-4 OVEREXPRESSION IN FAT ENHANCES GLUCOSE-METABOLISM - PREFERENTIAL EFFECT ON FATTY-ACID SYNTHESIS
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DOI：
10.1152/ajpendo.1995.268.5.e956
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发表时间：
1995-05-01
影响因子：
5.1
通讯作者：
KAHN, BB
中科院分区：
文献类型：
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作者：
TOZZO, E;SHEPHERD, PR;KAHN, BB
GLUT-4的表达在正常人和肥胖及糖尿病患者之间差异很大。利用连接到人类GLUT-4基因的α P2启动子/增强子，我们创建了转基因小鼠，以研究脂肪细胞中GLUT-4选择性表达改变对葡萄糖稳态和身体成分的影响。在这里，我们研究了这些小鼠葡萄糖耐量和肥胖增强的分子机制。[U-C-14]葡萄糖与甘油三酯、甘油-甘油、甘油-脂肪酸、CO2和乳酸的掺入量在3、0.5和3 μ M葡萄糖孵育的脂肪细胞中被测量，无论是否最大程度地刺激胰岛素。在非转基因和转基因小鼠中，糖代谢的主要途径从示踪糖浓度下的脂肪生成转变为生理糖浓度下的糖酵解。在3 μ M葡萄糖培养的转基因脂肪细胞中，所有主要途径的代谢在不含胰岛素的情况下提高了8.6- 38倍，在有胰岛素的情况下提高了3- 13倍。在生理葡萄糖浓度下，转基因脂肪细胞对甘油三酯、二氧化碳和乳酸的组成代谢是非转基因脂肪细胞的两到三倍。与非转基因脂肪细胞相比，基础脂肪细胞的脂肪酸合成优先增加31倍，胰岛素刺激脂肪细胞的脂肪酸合成优先增加21倍。因此，转基因小鼠脂肪细胞中GLUT-4的过表达导致所有主要途径的糖代谢增加，但涉及脂肪形成的途径的调节存在差异。
GLUT-4 expression varies widely among normal humans and those with obesity and diabetes. Using the alpha P2 promoter/enhancer ligated to the human GLUT-4 gene, we created transgenic mice to study the impact of alterations in GLUT-4 expression selectively in adipocytes on glucose homeostasis and body composition. Here we investigate molecular mechanisms for enhanced glucose tolerance and obesity in these mice. [U-C-14]glucose incorporation into triglycerides, glyceride-glycerol, glyceride-fatty acids, CO2, and lactate was measured in adipocytes incubated at 3, 0.5, and 3 mu M glucose with or without maximally stimulating insulin. In nontransgenic and transgenic mice, the major pathway for glucose metabolism shifts from lipogenesis at tracer glucose concentration to glycolysis at physiological glucose concentration. In transgenic adipocytes incubated at 3 mu M glucose, metabolism via all major pathways is enhanced by 8.6- to 38-fold in the absence of insulin and 3- to 13-fold in the presence of insulin. At physiological glucose concentration, constitutive metabolism to triglycerides, CO2, and lactate is two- to threefold greater in transgenic than in nontransgenic adipocytes. De novo fatty acid synthesis is preferentially increased: 31-fold for basal and 21-fold for insulin-stimulated compared with nontransgenic adipocytes. Thus overexpression of GLUT-4 in adipocytes of transgenic mice results in increased glucose metabolism in all major pathways, with differential regulation of the pathways involved in lipogenesis.