The regulation of uncoupling protein-2 gene expression by omega-6 polyunsaturated fatty acids in human skeletal muscle cells involves multiple pathways, including the nuclear receptor peroxisome proliferator-activated receptor beta

Fatty acids have been postulated to regulate uncoupling protein (UCP) gene expression in skeletal muscle in, vivo, We have identified, at least in par t, the mechanism by which polyunsaturated fatty acids increase UCP-2 expres sion in primary culture of human muscle cells, omega -6 fatty acids and ara chidonic acid induced a 3-fold rise in UCP-2 mRNA levels possibly through t ranscriptional activation. This effect was prevented by indomethacin and mi micked by prostaglandin (PG) E-2 and carbaprostacyclin PGI(2), consistent w ith a cyclooxygenase-mediated process. Incubation of myotubes for 6 h with 100 muM arachidonic acid resulted in a 150-fold increase in PGE(2) and a 15 -fold increase in PGE(2) in the culture medium. Consistent with a role of c AMP and protein kinase A, both prostaglandins induced a marked accumulation of cAMP in human myotubes, and forskolin reproduced the effect of arachido nic acid on UCP-2 mRNA expression. Inhibition of protein kinase A with H-89 suppressed the effect of PGE(2), whereas cPGI(2) and arachidonic acid were still able to increase ucp-2 gene expression, suggesting additional mechan isms. We found, however, that the MAP kinase pathway was not involved, Pros taglandins, particularly PGI(2), are potent activators of the peroxisome pr oliferator-activated receptors, A specific agonist of peroxisome proliferat or-activated receptor (PPAR) beta (L165041) increased UCP-2 mRNA levels in myotubes, whereas activation of PPAR alpha or PPAR gamma was ineffective. T hese results suggest thus that ucp-2 gene expression is regulated by omega -6 fatty acids in human muscle cells through mechanisms involving at least protein kinase A and the nuclear receptor PPAR beta.