HIGH-LEVEL OVEREXPRESSION OF GLUCOSE TRANSPORTER-4 DRIVEN BY AN ADIPOSE-SPECIFIC PROMOTER IS MAINTAINED IN TRANSGENIC MICE ON A HIGH-FAT DIET, BUT DOES NOT PREVENT IMPAIRED GLUCOSE-TOLERANCE
HIGH-LEVEL OVEREXPRESSION OF GLUCOSE TRANSPORTER-4 DRIVEN BY AN ADIPOSE-SPECIFIC PROMOTER IS MAINTAINED IN TRANSGENIC MICE ON A HIGH-FAT DIET, BUT DOES NOT PREVENT IMPAIRED GLUCOSE-TOLERANCE
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DOI：
10.1210/en.136.3.995
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发表时间：
1995-03-01
期刊：
影响因子：
4.8
通讯作者：
KAHN, BB
中科院分区：
文献类型：
--
作者：
GNUDI, L;TOZZO, E;KAHN, BB
高脂肪喂养与胰岛素作用受损、肥胖体组成和脂肪细胞中葡萄糖转运蛋白4（GLUT 4）表达下调相关。我们最近发现，使用aP 2（脂肪酸结合蛋白）启动子/增强子在转基因小鼠的脂肪细胞中选择性过表达GLUT 4导致葡萄糖耐量增强和脂肪细胞增生。在这里，我们给这些GLUT 4过表达的转基因小鼠喂食高脂肪（55%）或低脂肪（10%）饮食13-15周，以确定脂肪细胞中GLUT 4表达的改变在胰岛素抵抗和肥胖症发展中的作用，这是高脂肪消耗的特征。在非转基因小鼠中，高脂肪喂养导致白色和棕色脂肪组织中GLUT 4水平降低45-50%，同时胰岛素刺激的葡萄糖转运也相应降低。在接受低脂饮食的转基因小鼠中，GLUT 4在白色脂肪组织中过表达20倍，在棕色脂肪组织中过表达4倍。附睾脂肪细胞的葡萄糖转运在基础状态下增加20倍，在胰岛素刺激状态下增加6倍。即使在转基因小鼠喂食高脂肪饮食后，其脂肪细胞中的GLUT 4表达和葡萄糖转运仍然比接受相同饮食的非转基因小鼠高14至30倍。尽管在脂肪细胞水平上有这些显著的效果，但葡萄糖耐量没有改善，这可能是由于骨骼肌和肝脏中的胰岛素抵抗，其中转基因不表达。在低脂肪饮食期间，转基因小鼠的身体脂质比非转基因小鼠多80%。高脂肪喂养使非转基因小鼠的身体脂质增加76%，脂肪细胞大小增加65%，但对转基因小鼠没有影响。因此，在脂肪细胞中选择性地过表达GLUT 4可以防止肥胖的进一步增加。此外，通过使用异源启动子，即使在脂肪细胞中GLUT 4通常下调的代谢条件下，也可以维持GLUT 4的高水平过表达。这种过表达导致细胞水平上葡萄糖转运的显著增加，但脂肪特异性GLUT 4过表达并不能阻止与高脂喂养相关的葡萄糖耐量降低。
High fat feeding is associated with impaired insulin action, an obese body composition, and down-regulation of glucose transporter-4 (GLUT4) expression in adipocytes. We recently showed that overexpression of GLUT4 selectively in adipocytes of transgenic mice using the aP2 (fatty acid-binding protein) promoter/enhancer results in enhanced glucose tolerance and adipocyte hyperplasia. Here, we fed these GLUT4-overexpressing transgenic mice a high fat (55%) or a low fat (10%) diet for 13-15 weeks to determine the role of alterations in GLUT4 expression in adipocytes in the development of insulin resistance and obesity, which are characteristic of high fat consumption. In nontransgenic mice, high fat feeding results in 45-50% reduction of GLUT4 levels in white and brown adipose tissue, with a parallel decrease in insulin-stimulated glucose transport. In transgenic mice receiving the low fat diet, GLUT4 is overexpressed 20-fold in white and 4-fold in brown adipose tissue. Glucose transport in epididymal adipocytes is increased 20-fold in the basal state and 6-fold in the insulin-stimulated state. Even after transgenic mice are fed a high fat diet, GLUT4 expression and glucose transport in their adipocytes remains 14- to 30-fold greater than that in nontransgenic mice receiving the same diet. Despite these marked effects at the adipose cell level, glucose tolerance is not improved, probably due to insulin resistance in skeletal muscle and liver, where the transgene is not expressed. During the low fat diet, transgenic mice have 80% more body lipid than nontransgenics. High fat feeding increases body lipid 76% and adipocyte size 65% in nontransgenic mice, but has no effect in transgenic mice. Thus, overexpression of GLUT4 selectively in adipocytes protects against a further increase in adiposity. Furthermore, by using a heterologous promoter, high level overexpression of GLUT4 can be maintained even under metabolic conditions where it is normally down-regulated in adipocytes. This overexpression results in markedly increased glucose transport at the cellular level, but adipose-specific GLUT4 overexpression does not prevent the decrease in glucose tolerance associated with high fat feeding.