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

Abstract

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 PPARα activator (Wy-14,643) or a non-selective PPAR activator (bezafibrate) did not affect the expression of UCP-3 mRNA levels, whereas UCP-2 expression was slightly increased. In contrast, troglitazone, a thiazolidinedione which selectively activates PPARγ, strongly decreased UCP-3 and UCP-2 mRNA levels. Another thiazolidinedione, ciglitazone, had the same effect, but to a lower extent, suggesting that PPARγ 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 PPARα mRNA levels produced by this drug, linking the reduction in PPARα mRNA levels with the down-regulation of UCP mRNA in C2C12 myotubes after thiazolidinedione treatment.