title: Adipose-specific disruption of autotaxin enhances nutritional fattening and reduces plasma lysophosphatidic acid.
abstract: Autotaxin (ATX) is a secreted lysophospholipase D that generates the lipid mediator lysophosphatidic acid (LPA). ATX is secreted by adipose tissue and its expression is enhanced in obese/insulin-resistant individuals. Here, we analyzed the specific contribution of adipose-ATX to fat expansion associated with nutritional obesity and its consequences on plasma LPA levels. We established ATX(F/F)/aP2-Cre (FATX-KO) transgenic mice carrying a null ATX allele specifically in adipose tissue. FATX-KO mice and their control littermates were fed either a normal or a high-fat diet (HFD) (45% fat) for 13 weeks. FATX-KO mice showed a strong decrease (up to 90%) in ATX expression in white and brown adipose tissue, but not in other ATX-expressing organs. This was associated with a 38% reduction in plasma LPA levels. When fed an HFD, FATX-KO mice showed a higher fat mass and a higher adipocyte size than control mice although food intake was unchanged. This was associated with increased expression of peroxisome proliferator-activated receptor (PPAR)γ2 and of PPAR-sensitive genes (aP2, adiponectin, leptin, glut-1) in subcutaneous white adipose tissue, as well as in an increased tolerance to glucose. These results show that adipose-ATX is a negative regulator of fat mass expansion in response to an HFD and contributes to plasma LPA levels.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Toulouse, Cedex 4, France; Université de Toulouse, UPS, Institut de Médecine Moléculaire de Rangueil, IFR150, BP84225, Toulouse, France.
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Dusaulcy
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Toulouse, Cedex 4, France; Université de Toulouse, UPS, Institut de Médecine Moléculaire de Rangueil, IFR150, BP84225, Toulouse, France.
authors.forename: Chloé
authors.initials: C
authors.lastname: Rancoule
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Toulouse, Cedex 4, France; Université de Toulouse, UPS, Institut de Médecine Moléculaire de Rangueil, IFR150, BP84225, Toulouse, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Grès
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Toulouse, Cedex 4, France; Université de Toulouse, UPS, Institut de Médecine Moléculaire de Rangueil, IFR150, BP84225, Toulouse, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Wanecq
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Toulouse, Cedex 4, France; Université de Toulouse, UPS, Institut de Médecine Moléculaire de Rangueil, IFR150, BP84225, Toulouse, France.
authors.forename: André
authors.initials: A
authors.lastname: Colom
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Toulouse, Cedex 4, France; Université de Toulouse, UPS, Institut de Médecine Moléculaire de Rangueil, IFR150, BP84225, Toulouse, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Guigné
authors.affiliation: Division of Cell Biology and Center for Biomedical Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Laurens A
authors.initials: LA
authors.lastname: van Meeteren
authors.affiliation: Division of Cell Biology and Center for Biomedical Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Wouter H
authors.initials: WH
authors.lastname: Moolenaar
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Toulouse, Cedex 4, France; Université de Toulouse, UPS, Institut de Médecine Moléculaire de Rangueil, IFR150, BP84225, Toulouse, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Valet
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Toulouse, Cedex 4, France; Université de Toulouse, UPS, Institut de Médecine Moléculaire de Rangueil, IFR150, BP84225, Toulouse, France. Electronic address: Jean-Sebastien.Saulnier-Blache@inserm.fr.
authors.forename: Jean Sébastien
authors.initials: JS
authors.lastname: Saulnier-Blache
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000378:metabolism* / Q000503:physiopathology; D052436:Adipose Tissue, White / Q000378:metabolism* / Q000503:physiopathology; D050154:Adiposity; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D048429:Cell Size; D004041:Dietary Fats / Q000009:adverse effects / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D018703:Founder Effect; D017353:Gene Deletion; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood; D008246:Lysophospholipids / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000172:deficiency / Q000235:genetics; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D043264:Phosphodiesterase I / Q000172:deficiency / Q000235:genetics; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases / Q000172:deficiency / Q000235:genetics; D000099189:Lysophospholipase D
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D007328:Insulin; D008246:Lysophospholipids; D009097:Multienzyme Complexes; D047495:PPAR gamma; D043264:Phosphodiesterase I; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; D000099189:Lysophospholipase D; C032881:lysophosphatidic acid