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Journal of Lipid Research, Vol. 43, 936-943, June 2002
Copyright © 2002 by Lipid Research, Inc.
PPAR
suppresses insulin secretion and induces UCP2 in insulinoma cells
Departments of Medicine, Cell Biology and Physiology, Molecular Biology and Pharmacology, and the Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, MO
2 To whom correspondence should be addressed at the Division of Atherosclerosis, Nutrition, and Lipid Research, Washington University School of Medicine, Campus Box 8046, 660 South Euclid Avenue, St. Louis, MO 63110. e-mail: semenkov{at}im.wustl.edu
Fatty acids may promote type 2 diabetes by altering insulin secretion from pancreatic ß cells, a process known as lipotoxicity. The underlying mechanisms are poorly understood. To test the hypothesis that peroxisome proliferator-activated receptor 
(PPAR) has a direct effect on islet function, we treated INS-1 cells, an insulinoma cell line, with a PPAR adenovirus (AdPPAR) as well as the PPAR agonist clofibric acid. AdPPAR-infected INS-1 cells showed PPAR agonist- and fatty acid-dependent transactivation of a PPAR reporter gene. Treatment with either AdPPAR or clofibric acid increased both catalase activity (a marker of peroxisomal proliferation) and palmitate oxidation. AdPPAR induced carnitine-palmitoyl transferase-I (CPT-I) mRNA, but had no effect on insulin gene expression. AdPPAR treatment increased cellular triglyceride content but clofibric acid did not. Both AdPPAR and clofibric acid decreased basal and glucose-stimulated insulin secretion. Despite increasing fatty acid oxidation, AdPPAR did not increase cellular ATP content suggesting the stimulation of uncoupled respiration. Consistent with these observations, UCP2 expression doubled in PPAR-treated cells. Clofibric acid-induced suppression of glucose-simulated insulin secretion was prevented by the CPT-I inhibitor etomoxir.
These data suggest that PPAR-stimulated fatty acid oxidation can impair ß cell function.
Abbreviations: Ad, adenovirus; ETYA, 5,8,11,14-eicosatetrayonic acid; PPAR, peroxisome proliferator-activated receptor ; PPRE, peroxisome proliferator response element; UCP2, uncoupling protein-2; VLDL, very low density lipoprotein
Supplementary key words lipotoxicity • fatty acid oxidation • type 2 diabetes • ß cell failure • peroxisome proliferator-activated receptor
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