High fat feeding causes insulin resistance and a marked decrease in the expression of glucose transporters (Glut 4) in fat cells of rats.

With the identification of two different glucose transporter species in adipose cells it is crucial to determine the role of these transporters in the alterations in glucose transport activity associated with different metabolic and nutritional states. In the present study we assess levels of expression of Glut 1 and Glut 4 transporters and basal and insulin-stimulated glucose transport activity in adipocytes from Sprague-Dawley rats fed standard chow (control), combined liquid diet and standard chow (overfed), high fat diet, or energy-restricted diet for 7 weeks. High fat feeding was associated with relative postprandial hypoglycemia (P less than 0.05) and hypoinsulinemia (P less than 0.05). Although the high fat fed animals had lower body weights (P less than 0.05) than control rats, their body compositions showed obesity, with 36% heavier epididymal fat pads (P less than 0.05) and a 47% increase in adipocyte volume (P less than 0.05). Fat feeding caused a 78% reduction in insulin-stimulated glucose transport per adipocyte (P less than 0.05). In parallel we found 92% and 94% reductions in Glut 4 protein and mRNA per adipocyte, respectively, (P less than 0.01) in fat-fed rats. Substantial reductions were also seen in Glut 1 protein and mRNA per fat cell in the same rats (62% and 76%, respectively; P less than 0.05). However, the changes in Glut 1 expression were of the same magnitude as changes in the cytoskeletal protein beta-actin, reflecting a decreased expression of several proteins in this nutritional state. Even though overfeeding and energy restriction brought about opposite changes in adiposity, no significant alterations were demonstrated in glucose transport rate or glucose transporter expression. The impaired insulin-stimulated glucose transport in adipose cells from high fat-fed rats occurs in the presence of a dramatic decrease in the expression of the major insulin-responsive glucose transporter (Glut 4). The reduced gene expression may be caused by chronic hypoinsulinemia and may contribute to the insulin resistance observed in this state.