Abstract
Insulin's ability to stimulate glucose metabolism is severely diminished in the adipose tissue of rats fed a high-fat diet as compared to that of rats fed a low-fat diet. To elucidate the mechanism for this effect we have measured the binding of insulin, the hormone effect on 2-deoxyglucose uptake and the major pathways of [1-(14)C]glucose metabolism, and the activity of lipogenesis-related enzymes in adipocytes of rats fed a low- or high-fat diet for 7 days. Rats fed high- or low-fat diets bound equal amounts of insulin per adipocyte at all insulin concentrations tested. Basal and maximally insulin-stimulated 2-deoxyglucose uptake per fat cell were reduced in high-fat-fed rats. However, the insulin stimulation over basal was the same in both groups (230%). Submaximal doses of insulin produced equivalent increments of 2-deoxyglucose uptake in both groups, as would be predicted by the binding studies. The effect of both submaximal and maximal insulin concentration on the labeling of CO(2) and fatty acids was markedly decreased by high-fat feeding. The insulin response of the glyceride-glycerol pathway was less severely, though significantly, reduced. Acetyl CoA carboxylase and malic enzyme in adipocytes of high-fat-fed rats were reduced to 13% of the activity in the low-fat-fed rats. Glucose-6-phosphate and 6-phosphogluconate dehydrogenases were decreased to 20% and 34% of their activities in low-fat-fed rats, respectively. These reductions paralleled the changes in insulin-stimulated glucose oxidation and fatty acid synthesis. The data therefore strongly suggest that the blunted response of glucose metabolism to insulin in adipocytes of high-fat-fed rats is a result of a decreased intracellular capacity to utilize glucose for lipogenesis.
Highlights
Basal and maximally insulin-stimulated 2-deoxyglucose uptake per fat cell were reduced in high-fat-fed rats
The data strongly suggestthat the blunted response of glucosemetabolismtoinsulininadipocytesof high-fat-fed rats is a result of a decreased intracellular capacityto utilize glucose for lipogenesis
Thistissueexhibited an impaired glucose uptake in response to a maximal dose of insulin [2].We rezently confirmed this resistance to insulin in vitro and invivo, demonstrating that fattyacid synthesiswas strongly inhibited by fat feeding and remainednegligible even after in
Summary
Basal and maximally insulin-stimulated 2-deoxyglucose uptake per fat cell were reduced in high-fat-fed rats. The insulin stimulationover basal was the same in both groups (230%).Submaximal doses of insulinproduced equivalent increments of 2-deoxyglucose uptake in both groups, as would be predicted by the binding studies The effect of both submaximaland maximal insulinconcentration on the labeling of COz and fattyacids was markedly decreased by high-fat feeding. Acetyl CoA carboxylase and malic enzyme in adipocytes of high-fat-fed rats were reduced to 13%of the activity in the low-fat-fedrats.Glucose-6-phosphate and 6- These reductions paralleled the changes in insulin-stimulated glucose oxidation and fatty acid synthesis. I n contrasgt,lycerideglycerol labeling was stimulated to the same extent regardless of diet [4] This pathway specificity of the insulin resistanceis inconsistent with an impairmenot f hormone binding, but rather suggests that insulianction on the adiposetissue of fat-fed rats is limited by someintracelluladr efect. T h e responsiveness of the major pathways of glucose utilizationto insulin antdhe level of activity of some intracellular enzymes were measured and discussed in relationship to the pathogenesis of insulinresistance intheadipose tissue of high-fat-fed animals
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