Expression of PPARalpha modifies fatty acid effects on insulin secretion in uncoupling protein-2 knockout mice.
OBJECTIVE
In uncoupling protein-2 (UCP2) knockout (KO) mice, protection of beta cells from fatty acid exposure is dependent upon transcriptional events mediated by peroxisome proliferator-activated receptor-alpha (PPARalpha).


METHODS
PPARalpha expression was reduced in isolated islets from UCP2KO and wild-type (WT) mice with siRNA for PPARalpha (siPPARalpha) overnight. Some islets were also cultured with oleic or palmitic acid, then glucose stimulated insulin secretion (GSIS) was measured. Expression of genes was examined by quantitative RT-PCR or immunoblotting. PPARalpha activation was assessed by oligonucleotide consensus sequence binding.


RESULTS
siPPARalpha treatment reduced PPARalpha protein expression in KO and WT islets by >85%. In siPPARalpha-treated UCP2KO islets, PA but not OA treatment significantly decreased the insulin response to 16.5 mM glucose. In WT islets, siPPARalpha treatment did not modify GSIS in PA and OA exposed groups. In WT islets, PA treatment significantly increased UCP2 mRNA and protein expression. Both PA and OA treatment significantly increased PPARalpha expression in UCP2KO and WT islets but OA treatment augmented PPARalpha protein expression only in UCP2KO islets (p < 0.05). PA treatment induced carnitine palmitoyltransferase I, acyl CoA oxidase and malonyl CoA decarboxylase mRNA in UCP2KO islets.


CONCLUSIONS
These data show that the negative effect of saturated fatty acid on GSIS is mediated by PPARalpha/UCP2. Knockout of UCP2 protects beta-cells from PA exposure. However, in the absence of both UCP2 and PPARalpha even a short exposure (24 h) to PA significantly impairs GSIS.
Fatehi-Hassanabad
Zahra
Z
Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PE C1A 4P3, Canada. zfatehi@upei.ca
Chan
Catherine B
CB