Up-regulation of uncoupling protein-3 by fatty acid in C2C12 myotubes

Uncoupling proteins (UCPs) are mitochondrial membrane proton transporters that uncouple oxidative phosphorylation by dissipating the proton gradient across the membrane. We have investigated regulation of the UCP3 gene in skeletal muscle and C2C12 muscle cells. UCP3 mRNA in mouse skeletal muscle is markedly increased by fasting and rapidly (within 4 h) decreased by re-feeding. Methyl palmoxirate, which inhibits fatty acid uptake by mitochondria and increases blood free fatty acids, prevents the fall in UCP3 message level induced by re-feeding. These findings suggest that fatty acid or a metabolite thereof, activates the UCP3 gene. Proof that fatty acid per se up-regulates UCP3 mRNA was obtained with C2C12 muscle cells in culture. Thus, oleic acid activated expression of UCP3 mRNA in differentiated C2C12 myotubes in a time and concentration-dependent manner. Moreover, BRL49653, a ligand for the nuclear hormone receptor PPARgamma induces expression of UCP3 mRNA suggesting that PPARgamma may regulate transcription of the UCP3 gene.