PPARα suppresses insulin secretion and induces UCP2 in insulinoma cells

• Published in: Journal of lipid research Vol. 43; no. 6; pp. 936 - 943
• Main Authors: Tordjman, Karen, Standley, Kara N., Bernal-Mizrachi, Carlos, Leone, Teresa C., Coleman, Trey, Kelly, Daniel P., Semenkovich, Clay F.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.06.2002; Elsevier
• Subjects: fatty acid oxidation; lipotoxicity; type 2 diabetes; β cell failure; type 2 diabetes; fatty acid oxidation; lipotoxicity; β cell failure
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1016/S0022-2275(20)30468-5

Fatty acids may promote type 2 diabetes by altering insulin secretion from pancreatic β cells, a process known as lipotoxicity. The underlying mechanisms are poorly understood. To test the hypothesis that peroxisome proliferator-activated receptor α (PPARα) has a direct effect on islet function, we treated INS-1 cells, an insulinoma cell line, with a PPARα adenovirus (AdPPARα) as well as the PPARα agonist clofibric acid. AdPPARα-infected INS-1 cells showed PPARα agonist- and fatty acid-dependent transactivation of a PPARα reporter gene. Treatment with either AdPPARα or clofibric acid increased both catalase activity (a marker of peroxisomal proliferation) and palmitate oxidation. AdPPARα induced carnitine-palmitoyl transferase-I (CPT-I) mRNA, but had no effect on insulin gene expression. AdPPARα treatment increased cellular triglyceride content but clofibric acid did not. Both AdPPARα and clofibric acid decreased basal and glucose-stimulated insulin secretion. Despite increasing fatty acid oxidation, AdPPARα did not increase cellular ATP content suggesting the stimulation of uncoupled respiration. Consistent with these observations, UCP2 expression doubled in PPARα-treated cells. Clofibric acid-induced suppression of glucose-simulated insulin secretion was prevented by the CPT-I inhibitor etomoxir. These data suggest that PPARα-stimulated fatty acid oxidation can impair β cell function.