Deletion of LPCAT3 Promotes Enhanced Insulin Signaling in Skeletal Muscle

Abstract

Aberrant lipid metabolism has been linked to skeletal muscle insulin resistance. The exact identity of the lipid species that promote skeletal muscle insulin resistance among the human population remains unclear. In this study we utilized primary muscle cells isolated from lean-insulin sensitive (LN) or obese insulin-resistant (OB) individuals to characterize differences in the muscle lipidome free of contaminating cell types. OB muscles contained lower levels of various species of lysophospholipids (lyso-PLs) compared to LN, a finding that has never been previously described. RNAseq experiments in the same set of samples identified three genes involved in lyso-PL metabolism (PPAP2A, LPIN3, and LPCAT3) to have greater expression in OB vs. LN. Strikingly, lentivirus-mediated deletion of LPCAT3 in C2C12 myotubes resulted in increased insulin signaling (phosphorylation of IR, Akt, AS160) in the absence of, and at various concentrations of insulin. LPCAT3 deletion had no effect on cell morphology, myotube differentiation, fiber type, or abundance of enzymes of the electron transport chain. Future studies should focus on the cellular mechanisms by which LPCAT3 affects IR phosphorylation.