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

Uncoupling proteins (UCPs) are mitochondrial membrane proton transporters t hat uncouple oxidative phosphorylation by dissipating the proton gradient a cross the membrane. We have investigated regulation of the UCP3 gene in ske letal muscle and C2C12 muscle cells. UCP3 mRNA in mouse skeletal muscle is markedly increased by fasting and rapidly (within 4 h) decreased by re-feed ing. Methyl palmoxirate, which inhibits fatty acid uptake by mitochondria a nd increases blood free fatty acids, prevents the fall in UCP3 message leve l induced by re-feeding. These findings suggest that fatty acid or a metabo lite thereof, activates the UCP3 gene. Proof that fatty acid per se up-regu lates UCP3 mRNA was obtained with C2C12 muscle cells in culture. Thus, olei c acid activated expression of UCP3 mRNA in differentiated C2C12 myotubes i n a time and concentration-dependent manner. Moreover, BRL49653, a ligand f or the nuclear hormone receptor PPAR gamma induces expression of UCP3 mRNA suggesting that PPAR gamma may regulate transcription of the UCP3 gene, (C) 1999 Academic Press.