Lysophosphatidic Acid Inhibits Adipocyte Differentiation via Lysophosphatidic Acid 1 Receptor-dependent Down-regulation of Peroxisome Proliferator-activated Receptor γ2

Jean Philippe Pradère,Martin Wabitsch,Philippe Valet,Danièle Daviaud,Jean Sébastien Saulnier-Blache,Sandra Grès,Jerold Chun,Charlotte Guigné,Marie Françoise Simon

doi:10.1074/jbc.m412585200

Jean Philippe Pradère, Martin Wabitsch + Show 7 more

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https://doi.org/10.1074/jbc.m412585200

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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 LPA(1) receptor subtype, and LPA increases their proliferation. In monocytes and CV1 cells LPA was recently reported to bind and activate peroxisome proliferator-activated receptor gamma (PPARgamma), a transcription factor also known to play a pivotal role in adipogenesis. Here we show that, unlike the PPARgamma agonist rosiglitazone, LPA was unable to increase transcription of PPARgamma-sensitive genes (PEPCK and ALBP) in the mouse preadipose cell line 3T3F442A. In contrast, treatment with LPA decreased PPARgamma2 expression, impaired the response of PPARgamma-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 LPA(1) receptor knock-out mice, which, in parallel, exhibited a higher adiposity than wild type mice. In conclusion, LPA does not behave as a potent PPARgamma agonist in adipocytes but, conversely, inhibits PPARgamma expression and adipogenesis via LPA(1) receptor activation. The local production of LPA may exert a tonic inhibitory effect on the development of adipose tissue.

Highlights

Enlargement of adipose tissue is conditioned by the ability of adipocytes to store triglycerides as well as by the ability of preadipocytes to differentiate into adipocytes
The recruitment of new fat cells in adipose tissue requires the differentiation of preadipocytes into adipocytes, TABLE II Blood parameters of wild type (WT) and LPA1-KO mice
Factors locally produced in adipose tissue by adipocytes could contribute to the regulation of adipogenesis by exerting paracrine actions on preadipocytes

Summary

Introduction

Enlargement of adipose tissue is conditioned by the ability of adipocytes to store triglycerides as well as by the ability of preadipocytes to differentiate into adipocytes (adipogenesis). Identifying the factors that control and/or regulate PPAR␥ activity and adipogenesis is of major interest for understanding the normal growth and the pathologic growth of adipose tissue. LPA1 (edg-2 in the former nomenclature) was the first identified LPA receptor subtype It is abundantly expressed in the central nervous system but is present in numerous peripheral tissues. Extracellular LPA activates the mitogen-activated protein kinases ERK1 and ERK2 and increases the proliferation of growing 3T3F442A preadipocytes, which mainly express the LPA1 receptor subtype [5, 8]. The possible influence of this regulation on in vivo enlargement of adipose tissue is conditioned by the ability of preadipocytes to differentiate into adipocytes

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