PPARalpha suppresses insulin secretion and induces UCP2 in insulinoma cells.
Fatty acids may promote type 2 diabetes by altering insulin secretion from pancreatic beta cells, a process known as lipotoxicity. The underlying mechanisms are poorly understood. To test the hypothesis that peroxisome proliferator-activated receptor alpha (PPARalpha) has a direct effect on islet function, we treated INS-1 cells, an insulinoma cell line, with a PPARalpha adenovirus (AdPPARalpha) as well as the PPARalpha agonist clofibric acid. AdPPARalpha-infected INS-1 cells showed PPARalpha agonist- and fatty acid-dependent transactivation of a PPARalpha reporter gene. Treatment with either AdPPARalpha or clofibric acid increased both catalase activity (a marker of peroxisomal proliferation) and palmitate oxidation. AdPPARalpha induced carnitine-palmitoyl transferase-I (CPT-I) mRNA, but had no effect on insulin gene expression. AdPPARalpha treatment increased cellular triglyceride content but clofibric acid did not. Both AdPPARalpha and clofibric acid decreased basal and glucose-stimulated insulin secretion. Despite increasing fatty acid oxidation, AdPPARalpha did not increase cellular ATP content suggesting the stimulation of uncoupled respiration. Consistent with these observations, UCP2 expression doubled in PPARalpha-treated cells. Clofibric acid-induced suppression of glucose-simulated insulin secretion was prevented by the CPT-I inhibitor etomoxir. These data suggest that PPARalpha-stimulated fatty acid oxidation can impair beta cell function.
Tordjman
Karen
K
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Standley
Kara N
KN
Bernal-Mizrachi
Carlos
C
Leone
Teresa C
TC
Coleman
Trey
T
Kelly
Daniel P
DP
Semenkovich
Clay F
CF
D000255:Adenosine Triphosphate / Q000378:metabolism; D000256:Adenoviridae; D000818:Animals; D002374:Catalase / Q000378:metabolism; D002995:Clofibric Acid / Q000378:metabolism; D004852:Epoxy Compounds / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005822:Genetic Vectors; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007340:Insulinoma / Q000378:metabolism*; D007473:Ion Channels; D026901:Membrane Transport Proteins; D051379:Mice; D024101:Mitochondrial Proteins; D014176:Protein Biosynthesis; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014280:Triglycerides / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000071246:Uncoupling Protein 2
D004852:Epoxy Compounds; D005227:Fatty Acids; D007328:Insulin; D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014280:Triglycerides; C000604390:Ucp2 protein, mouse; C000604391:Ucp2 protein, rat; D000071246:Uncoupling Protein 2; D002995:Clofibric Acid; D000255:Adenosine Triphosphate; D002374:Catalase; D005947:Glucose; C054207:etomoxir