TRANSGENIC GLUT-4 OVEREXPRESSION IN FAT ENHANCES GLUCOSE-METABOLISM -PREFERENTIAL EFFECT ON FATTY-ACID SYNTHESIS

GLUT-4 expression varies widely among normal humans and those with obe sity 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 mechan isms for enhanced glucose tolerance and obesity in these mice. [U-C-14 ]glucose incorporation into triglycerides, glyceride-glycerol, glyceri de-fatty acids, CO2, and lactate was measured in adipocytes incubated at 3, 0.5, and 3 mu M glucose with or without maximally stimulating in sulin. In nontransgenic and transgenic mice, the major pathway for glu cose metabolism shifts from lipogenesis at tracer glucose concentratio n to glycolysis at physiological glucose concentration. In transgenic adipocytes incubated at 3 mu M glucose, metabolism via all major pathw ays 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 concentr ation, constitutive metabolism to triglycerides, CO2, and lactate is t wo- to threefold greater in transgenic than in nontransgenic adipocyte s. De novo fatty acid synthesis is preferentially increased: 31-fold f or basal and 21-fold for insulin-stimulated compared with nontransgeni c adipocytes. Thus overexpression of GLUT-4 in adipocytes of transgeni c mice results in increased glucose metabolism in all major pathways, with differential regulation of the pathways involved in lipogenesis.