Journal of Lipid Research, Vol. 20, 8-21, January 1979
Copyright © 1979 by Lipid Research, Inc.

Mechanism of insulin resistance in adipocytes of rats fed a high-fat diet

M. Lavau , S. K. Fried , C. Susini , and P. Freychet

Division of Metabolism and Nutrition, St. Luke's Hospital Center, Columbia University, College of Physicians and Surgeons, New York, NY; Unité de Nutrition Humaine, U.1 INSERM, Hôpital Bichat, 75018 Paris; and Groupe de Recherches sur les Hormones Polypeptidiques et la Physiologie Endocrinienne, U.145 INSERM, Faculté de Médecine, Chemin de Vallombrose, Nice Cédex France

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 [1-¹⁴C]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 CO₂ 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.

Supplementary key words insulin binding • 2-deoxyglucose uptake • lipogenic enzymes • fatty acid synthesis • fat cell size

Submitted on February 3, 1978
Accepted on June 9, 1978

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