Lysophosphatidic acid inhibits adipocyte differentiation via lysophosphatidic acid 1 receptor-dependent down-regulation of peroxisome proliferator-activated receptor gamma2.
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.
Simon
Marie Françoise
MF
INSERM U586, Institut Louis Bugnard, Rangueil Hospital, BP84225, 31432 Toulouse, Cedex 4, France.
Daviaud
Danièle
D
Pradère
Jean Philippe
JP
Grès
Sandra
S
Guigné
Charlotte
C
Wabitsch
Martin
M
Chun
Jerold
J
Valet
Philippe
P
Saulnier-Blache
Jean Sébastien
JS
D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D015536:Down-Regulation; D050556:Fatty Acid-Binding Proteins; D005956:Glucose-6-Phosphate Isomerase / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008246:Lysophospholipids / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009000:Monocytes / Q000166:cytology; D009097:Multienzyme Complexes / Q000378:metabolism; D009841:Oligonucleotides / Q000235:genetics; D047495:PPAR gamma / Q000378:metabolism*; D043264:Phosphodiesterase I; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D013997:Time Factors; D014158:Transcription, Genetic; D014280:Triglycerides / Q000378:metabolism; D000099189:Lysophospholipase D
D002352:Carrier Proteins; D016895:Culture Media, Serum-Free; D050556:Fatty Acid-Binding Proteins; D005956:Glucose-6-Phosphate Isomerase; D006023:Glycoproteins; D007004:Hypoglycemic Agents; D008246:Lysophospholipids; D009097:Multienzyme Complexes; D009841:Oligonucleotides; D047495:PPAR gamma; D043264:Phosphodiesterase I; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; D012313:RNA; D012333:RNA, Messenger; D000077154:Rosiglitazone; D045162:Thiazolidinediones; D014280:Triglycerides; D000099189:Lysophospholipase D; C032881:lysophosphatidic acid