Down-regulation of uncoupling protein-3 and-2 by thiazolidinediones in C2C12 myotubes

Uncoupling proteins (UCPs) are mitochondrial membrane proton transporters t hat uncouple respiration from oxidative phosphorylation by dissipating the proton gradient across the membrane, We studied the direct effect of severa l peroxisome proliferator-activated receptor (PPAR) ligands on UCP-3 and UC P-2 mRNA expression in C2C12 myotubes for 24 h, In the absence of exogenous fatty acids, treatment of C2C12 cells with a selective PPAR alpha activato r (Wy-14,633) or a non-selective PPAR activator (bezafibrate) did not affec t the expression of UCP-3 mRNA If, els, whereas UCP-2 expression was slight ly increased, In contrast, troglitazone, a thiazolidinenione which selectiv ely activates PPAR gamma, strongly decreased UCP-3 and UCP-2. mRNA levels, Another thiazolidinedione, ciglitazone, had the same effect, but to a lower extent, suggesting that PPAR gamma activation is involved, Further, the pr esence of 0.5 mM oleic acid strongly increased UCP-3 mRNA levels and trogli tazone addition failed to block the effect of this fatty acid. The drop in UCP expression after thiazolidinedione treatment correlated well with a red uction in PPAR alpha mRNA levels produced by this drug, linking the reducti on in PPAR alpha mRNA levels with the down-regulation of UCP mRNA in C2C12 myotubes after thiazolidinedione treatment. (C) 2000 Federation of European Biochemical Societies, Published by Elsevier Science B.V. All rights reser ved.