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 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 G LUT4 selectively in adipocytes of transgenic mice using the aP2 (fatty acid-binding protein) promoter/enhancer results in enhanced glucose t olerance and adipocyte hyperplasia. Here, we fed these GLUT4-overexpre ssing 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 a dipocytes in the development of insulin resistance and obesity, which are characteristic of high fat consumption. In nontransgenic mice, hig h 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, GLUT 4 is overexpressed 20-fold in white and 4-fold in brown adipose tissue . Glucose transport in epididymal adipocytes is increased 20-fold in t he 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 e ffects at the adipose cell level, glucose tolerance is not improved, p robably due to insulin resistance in skeletal muscle and liver, where the transgene is not expressed. During the low fat diet, transgenic mi ce have 80% more body lipid than nontransgenics. High fat feeding incr eases body lipid 76% and adipocyte size 65% in nontransgenic mice, but has no effect in transgenic mice. Thus, overexpression of GLUT4 selec tively in adipocytes protects against a further increase in adiposity. Furthermore, by using a heterologous promoter, high level overexpress ion of GLUT4 can be maintained even under metabolic conditions where i t is normally down-regulated in adipocytes. This overexpression result s in markedly increased glucose transport at the cellular level, but a dipose-specific GLUT4 overexpression does not prevent the decrease in glucose tolerance associated with high fat feeding.