Studies in vitro indicate that group X secretory phospholipase A(2) (GX sPLA(2)) potently releases arachidonic acid (AA) and lysophosphatidylcholine from mammalian cell membranes. To define the function of GX sPLA(2) in vivo, our laboratory recently generated C57BL/6 mice with targeted deletion of GX sPLA(2) (GX(-/-) mice). When fed a normal rodent diet, GX(-/-) mice gained significantly more weight and had increased adiposity compared to GX(+/+) mice, which was not attributable to alterations in food consumption or energy expenditure. When treated with adipogenic stimuli ex vivo, stromal vascular cells isolated from adipose tissue of GX(-/-) mice accumulated significantly more (20%) triglyceride compared to cells from GX(+/+) mice. Conversely, overexpression of GX sPLA(2), but not catalytically inactive GX sPLA(2), resulted in a significant 50% reduction in triglyceride accumulation in OP9 adipocytes. The induction of genes encoding adipogenic proteins (PPARγ, SREBP-1c, SCD1, and FAS) was also significantly blunted by 50-80% in OP9 cells overexpressing GX sPLA(2). Activation of the liver X receptor (LXR), a nuclear receptor known to up-regulate adipogenic gene expression, was suppressed in 3T3-L1 and OP9 cells when GX sPLA(2) was overexpressed. Thus, hydrolytic products generated by GX sPLA(2) negatively regulate adipogenesis, possibly by suppressing LXR activation.