Role of fatty acid synthesis in the control of insulin-stimulated glucose utilization by rat adipocytes.

S K Fried,M Lavau,F X Pi-Sunyer

doi:10.1016/s0022-2275(20)37346-6

Abstract

A decreased capacity for fatty acid synthesis is associated with a decreased insulin effect on glucose metabolism in large fat cells and fat cells from rats fed a high-fat diet. We have investigated the relationship between these processes by specifically inhibiting fatty acid synthesis with (-)-hydroxycitrate (2.5 mM), an inhibitor of citrate cleavage enzyme, and cerulenin (0.05 mM), an inhibitor of fatty acid synthetase. (-)-Hydroxycitrate and cerulenin decreased maximally insulin-stimulated fatty acid synthesis from [6-(14)C]glucose to 10% and 25% of controls, respectively, while only (-)-hydroxycitrate decreased basal values. Oxidation of [1-(14)C]glucose in the presence of insulin was markedly depressed by each inhibitor. Thus, the percent increase over basal value was decreased from 540% in controls to 151% and 154% by (-)-hydroxycitrate and cerulenin, respectively. In contrast, oxidation of [6-(14)C]glucose was slightly enhanced by both inhibitors. Thus, oxidation of glucose via the pentose shunt was reduced, while Krebs cycle oxidation was unaffected. Basal and insulin-stimulated incorporation of [1-(14)C]glucose and [6-(14)C]glucose into glyceride-glycerol and basal lactate production was unchanged by the inhibition of fatty acid synthesis. Insulin-stimulated lactate production was halved by the inhibition of fatty acid synthesis. Total glucose utilization, as assessed by measuring the disappearance of glucose from the medium, was not detectably changed by inhibiting fatty acid synthesis under basal conditions, but insulin-stimulated values were decreased to 52% and 64% of control by (-)-hydroxycitrate and cerulenin, respectively. This occurred despite the fact that neither agent affected the initial rate of 2-deoxyglucose uptake, or glucose-6-phosphate dehydrogenase or 6-phosphogluconate dehydrogenase activities. These data therefore provide direct evidence that a limitation of the fatty acid synthetic pathway decreases the ability of insulin to stimulate both pentose shunt glucose oxidation and overall glucose utilization, but not Krebs cycle oxidation or glyceride-glycerol synthesis. The enzymatic capacity of the fat cell for fatty acid synthesis is therefore an important determinant of insulin-stimulated glucose utilization.-Fried, S. K., M. Lavau, and F. X. Pi-Sunyer. Role of fatty acid synthesis in the control of insulin-stimulated glucose utilization by rat adipocytes.

Highlights

M [6-'4C]glucose to 10% and 25% of controls, respectively, while only (-)-hydroxycitrate decreased basal values
Since the purpose of this study was to determine the effect of the specific inhibition of fatty acid synthesis on glucose utilization, it was important to determine first whether the inhibitors had any direct effect on the glucose transport process itself, or on the activities of the enzymes of the pentose pathway, since alterations in glucose metabolism via this pathway were expected.Neitherinhibitor of fatty acid synthesis significantly affected basal or maximally insulin-stimulated 2-deoxyglucose uptake,even after a1-hrpre-incubation
Total glucose utilization in the presence of inhibitors of fatty acid synthesis Glucose utilization was estimated by summing the incorporation of labeled glucose into all end-products (CO, fatty acids, glyceride-glycerol) and assuming that one mole of glucose forms two moles of lactate (i.e., lactatevalues are divided by 2, and added to the total incorporation of each label (Table 3)); and more directly, by measuring the disappearancoef glucose from the medium(Table4)

Summary

Introduction

M [6-'4C]glucose to 10% and 25% of controls, respectively, while only (-)-hydroxycitrate decreased basal values. As assessed by measuring the disappearance of glucose from the medium, was not detectably changed by inhibiting fatty acid synthesis under basal conditions, but insulin-stimulated valueswere decreased to 52% and64% of control by (-)-hydroxycitrate and cerulenin, respectively. This occurreddespitethe fact thatneither agent affected the initial rate of 2-deoxyglucose uptake,or glucose-6-phosphatedehydrogenaseor. 6-phosphogluconate dehydrogenase activities.l Thesedata provide direct evidence that a limitation of the fatty acid synthetic pathway decreases the ability of insulin to stimulate both pentose shunt glucose oxidation and overall glucose utilization, but not Krebs cycle oxidation or glyceride-glycerol synthesis. It is unknown which step(s) of glucose metabolism restricts glucose utilization by these fat cells

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