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

Uncoupling proteins (UCPs) are mitochondrial membrane proton transporters that uncouple respiration from oxidative phosphorylation by dissipating the proton gradient across the membrane, We studied the direct effect of several peroxisome proliferator-activated receptor (PPAR) ligands on UCP-3 and UCP-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 activator (Wy-14,633) or a non-selective PPAR activator (bezafibrate) did not affect the expression of UCP-3 mRNA If, els, whereas UCP-2 expression was slightly increased, In contrast, troglitazone, a thiazolidinenione which selectively 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 presence of 0.5 mM oleic acid strongly increased UCP-3 mRNA levels and troglitazone addition failed to block the effect of this fatty acid. The drop in UCP expression after thiazolidinedione treatment correlated well with a reduction in PPAR alpha mRNA levels produced by this drug, linking the reduction 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 reserved.