Lysophosphatidic acid inhibits adipocyte differentiation via lysophosphatidic acid 1 receptor-dependent down-regulation of peroxisome proliferator-activated receptor γ2

Abstract

Lysophosphatidic acid (LPA) is a bioactive phospholipid acting via specific G protein-coupled receptors that is synthesized at the extracellular face of adipocytes by a secreted lysophospholipase D (autotaxin). Preadipocytes mainly express the LPA1 receptor subtype, and LPA increases their proliferation. In monocytes and CV1 cells LPA was recently reported to bind and activate peroxisome proliferator-activated receptor γ (PPARγ), a transcription factor also known to play a pivotal role in adipogenesis. Here we show that, unlike the PPARγ agonist rosiglitazone, LPA was unable to increase transcription of PPARγ-sensitive genes (PEPCK and ALBP) in the mouse preadipose cell line 3T3F442A. In contrast, treatment with LPA decreased PPARγ2 expression, impaired the response of PPARγ-sensitive genes to rosiglitazone, reduced triglyceride accumulation, and reduced the expression of adipocyte mRNA markers. The anti-adipogenic activity of LPA was also observed in the human SGBS (Simpson-Golabi-Behmel syndrome) preadipocyte cell line, as well as in primary preadipocytes isolated from wild type mice. Conversely, the anti-adipogenic activity of LPA was not observed in primary preadipocytes from LPA1 receptor knock-out mice, which, in parallel, exhibited a higher adiposity than wild type mice. In conclusion, LPA does not behave as a potent PPARγ agonist in adipocytes but, conversely, inhibits PPARγ expression and adipogenesis via LPA1 receptor activation. The local production of LPA may exert a tonic inhibitory effect on the development of adipose tissue. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.