Peroxisome proliferator-activated receptor alpha (PPARalpha) potentiates, whereas PPARgamma attenuates, glucose-stimulated insulin secretion in pancreatic beta-cells.
Fatty acids (FAs) are known to be important regulators of insulin secretion from pancreatic beta-cells. FA-coenzyme A esters have been shown to directly stimulate the secretion process, whereas long-term exposure of beta-cells to FAs compromises glucose-stimulated insulin secretion (GSIS) by mechanisms unknown to date. It has been speculated that some of these long-term effects are mediated by members of the peroxisome proliferator-activated receptor (PPAR) family via an induction of uncoupling protein-2 (UCP2). In this study we show that adenoviral coexpression of PPARalpha and retinoid X receptor alpha (RXRalpha) in INS-1E beta-cells synergistically and in a dose- and ligand-dependent manner increases the expression of known PPARalpha target genes and enhances FA uptake and beta-oxidation. In contrast, ectopic expression of PPARgamma/RXRalpha increases FA uptake and deposition as triacylglycerides. Although the expression of PPARalpha/RXRalpha leads to the induction of UCP2 mRNA and protein, this is not accompanied by reduced hyperpolarization of the mitochondrial membrane, indicating that under these conditions, increased UCP2 expression is insufficient for dissipation of the mitochondrial proton gradient. Importantly, whereas expression of PPARgamma/RXRalpha attenuates GSIS, the expression of PPARalpha/RXRalpha potentiates GSIS in rat islets and INS-1E cells without affecting the mitochondrial membrane potential. These results show a strong subtype specificity of the two PPAR subtypes alpha and gamma on lipid partitioning and insulin secretion when systematically compared in a beta-cell context.
Ravnskjaer
Kim
K
Department of Biochemistry and Molecular Biology University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark.
Boergesen
Michael
M
Rubi
Blanca
B
Larsen
Jan K
JK
Nielsen
Tina
T
Fridriksson
Jakob
J
Maechler
Pierre
P
Mandrup
Susanne
S
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D017931:DNA Primers; D017930:Genes, Reporter; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007340:Insulinoma; D007473:Ion Channels; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000235:genetics; D024101:Mitochondrial Proteins / Q000235:genetics; D009539:Nicotinic Acids / Q000494:pharmacology; D019301:Oleic Acid / Q000378:metabolism; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000235:genetics / Q000502:physiology*; D047495:PPAR gamma / Q000235:genetics / Q000502:physiology*; D010190:Pancreatic Neoplasms; D016133:Polymerase Chain Reaction; D011743:Pyrimidines / Q000494:pharmacology; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D051381:Rats; D047490:Retinoid X Receptor alpha / Q000235:genetics; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D000071246:Uncoupling Protein 2
D017931:DNA Primers; D007328:Insulin; D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D009539:Nicotinic Acids; D047493:PPAR alpha; D047495:PPAR gamma; D011743:Pyrimidines; D047490:Retinoid X Receptor alpha; D013764:Tetrahydronaphthalenes; C000604391:Ucp2 protein, rat; D000071246:Uncoupling Protein 2; D019301:Oleic Acid; D012313:RNA; C006253:pirinixic acid; D005947:Glucose; C095104:LG 100268