Studies on the effects of lipids on skeletal muscle cells rarely examine the effects of lysophospholipids. Through our recent studies, we identified select forms of phospholipids, such as alkyl-LPA, as ligands for the intracellular receptor peroxisome proliferator-activated receptor gamma (PPAR gamma). PPAR gamma is a nuclear hormone receptor implicated in many human diseases, including diabetes and obesity. We previously showed that alkyl-LPA is a specific agonist of PPAR gamma. However, the mechanism by which the alkyl-LPA-PPAR gamma axis affects skeletal muscle cells is poorly defined. Our objective in the present study was to determine whether alkyl-LPA and PPAR gamma activation promotes glucose uptake in skeletal muscle cells. Our findings indicate that PPAR gamma 1 mRNA is more abundant than PPAR gamma 2 mRNA in C2C12 cells. We showed that alkyl-LPA (3 mu M) significantly activated PPAR gamma and increased intracellular glucose levels in skeletal muscle cells. We also showed that incubation of C2C12 cells with alkyl-LPA led to lipid accumulation in the cells. These findings suggest that alkyl-LPA activates PPAR gamma and stimulates glucose uptake in the absence of insulin in C2C12 cells. This may contribute to the plasma glucose-lowering effect in the treatment of insulin resistance. (C) 2013 Elsevier Inc. All rights reserved.