PPARα suppresses insulin secretion and induces UCP2 in insulinoma cells

Karen Tordjman, Kara N. Standley, Carlos Bernal-Mizrachi, Teresa C. Leone, Trey Coleman, Daniel P. Kelly, Clay F. Semenkovich

Research output: Contribution to journalArticle

72 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)936-943
Number of pages8
JournalJournal of lipid research
Volume43
Issue number6
StatePublished - 2002

Keywords

  • Fatty acid oxidation
  • Lipotoxicity
  • Peroxisome proliferator-activated receptor α
  • Type 2 diabetes
  • β cell failure

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    Tordjman, K., Standley, K. N., Bernal-Mizrachi, C., Leone, T. C., Coleman, T., Kelly, D. P., & Semenkovich, C. F. (2002). PPARα suppresses insulin secretion and induces UCP2 in insulinoma cells. Journal of lipid research, 43(6), 936-943.