Experimental evidence suggests that leptin operates on the tissues, including skeletal muscle, also by modulating gene expression. Using electrophoretic mobility shift assays, we have shown that physiological doses of leptin promptly increase the binding of C2C12 cell nuclear extracts to peroxisome proliferator-activated receptor (PPAR) response elements in oligonucleotide probes and that all three PPAR isoforms participate in DNA-binding complexes. We pre-treated C2C12 cells with AACOCF(3), a specific inhibitor of cytosolic phospholipase A(2) (cPLA(2)), an enzyme that supplies ligands to PPARs, and found that it abrogates leptin-induced PPAR DNA-binding activity. Leptin treatment significantly increased cPLA(2) activity, evaluated as the release of [H-3]arachidonic acid from pre-labelled C2C12 cells, as well as phosphorylation. Further, using MEK1 inhibitor PD-98059 we showed that leptin activates cPLA(2) through ERK induction. These results support a direct effect of leptin on skeletal Muscle cells, and suggest that the hormone may modulate muscle transcription also by precocious activation of PPARs through ERK cPLA(2) pathway. (c) 2005 Elsevier Inc. All rights reserved.