title: Immune cell Toll-like receptor 4 mediates the development of obesity- and endotoxemia-associated adipose tissue fibrosis.
abstract: Adipose tissue fibrosis development blocks adipocyte hypertrophy and favors ectopic lipid accumulation. Here, we show that adipose tissue fibrosis is associated with obesity and insulin resistance in humans and mice. Kinetic studies in C3H mice fed a high-fat diet show activation of macrophages and progression of fibrosis along with adipocyte metabolic dysfunction and death. Adipose tissue fibrosis is attenuated by macrophage depletion. Impairment of Toll-like receptor 4 signaling protects mice from obesity-induced fibrosis. The presence of a functional Toll-like receptor 4 on adipose tissue hematopoietic cells is necessary for the initiation of adipose tissue fibrosis. Continuous low-dose infusion of the Toll-like receptor 4 ligand, lipopolysaccharide, promotes adipose tissue fibrosis. Ex vivo, lipopolysaccharide-mediated induction of fibrosis is prevented by antibodies against the profibrotic factor TGFβ1. Together, these results indicate that obesity and endotoxemia favor the development of adipose tissue fibrosis, a condition associated with insulin resistance, through immune cell Toll-like receptor 4.
authors.affiliation: Franco-Czech Laboratory for Clinical Research on Obesity, Inserm, 31432 Toulouse Cedex 4, France; Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases, UMR1048, Inserm, 31432 Toulouse Cedex 4, France; UMR1048, Paul Sabatier University, University of Toulouse, 31432 Toulouse Cedex 4, France.
authors.forename: Isabelle K
authors.initials: IK
authors.lastname: Vila
authors.affiliation: Franco-Czech Laboratory for Clinical Research on Obesity, Inserm, 31432 Toulouse Cedex 4, France; Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases, UMR1048, Inserm, 31432 Toulouse Cedex 4, France; UMR1048, Paul Sabatier University, University of Toulouse, 31432 Toulouse Cedex 4, France.
authors.forename: Pierre-Marie
authors.initials: PM
authors.lastname: Badin
authors.affiliation: Franco-Czech Laboratory for Clinical Research on Obesity, Inserm, 31432 Toulouse Cedex 4, France; Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases, UMR1048, Inserm, 31432 Toulouse Cedex 4, France; UMR1048, Paul Sabatier University, University of Toulouse, 31432 Toulouse Cedex 4, France.
authors.forename: Marie-Adeline
authors.initials: MA
authors.lastname: Marques
authors.affiliation: Franco-Czech Laboratory for Clinical Research on Obesity, Inserm, 31432 Toulouse Cedex 4, France; Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases, UMR1048, Inserm, 31432 Toulouse Cedex 4, France; UMR1048, Paul Sabatier University, University of Toulouse, 31432 Toulouse Cedex 4, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Monbrun
authors.affiliation: Franco-Czech Laboratory for Clinical Research on Obesity, Inserm, 31432 Toulouse Cedex 4, France; Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases, UMR1048, Inserm, 31432 Toulouse Cedex 4, France; UMR1048, Paul Sabatier University, University of Toulouse, 31432 Toulouse Cedex 4, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Lefort
authors.affiliation: Franco-Czech Laboratory for Clinical Research on Obesity, Inserm, 31432 Toulouse Cedex 4, France; Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases, UMR1048, Inserm, 31432 Toulouse Cedex 4, France; UMR1048, Paul Sabatier University, University of Toulouse, 31432 Toulouse Cedex 4, France.
authors.forename: Lucile
authors.initials: L
authors.lastname: Mir
authors.affiliation: Franco-Czech Laboratory for Clinical Research on Obesity, Inserm, 31432 Toulouse Cedex 4, France; Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases, UMR1048, Inserm, 31432 Toulouse Cedex 4, France; UMR1048, Paul Sabatier University, University of Toulouse, 31432 Toulouse Cedex 4, France.
authors.forename: Katie
authors.initials: K
authors.lastname: Louche
authors.affiliation: Franco-Czech Laboratory for Clinical Research on Obesity, Inserm, 31432 Toulouse Cedex 4, France; Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases, UMR1048, Inserm, 31432 Toulouse Cedex 4, France; UMR1048, Paul Sabatier University, University of Toulouse, 31432 Toulouse Cedex 4, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Bourlier
authors.affiliation: Franco-Czech Laboratory for Clinical Research on Obesity, Inserm, 31432 Toulouse Cedex 4, France; Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases, UMR1048, Inserm, 31432 Toulouse Cedex 4, France; UMR1048, Paul Sabatier University, University of Toulouse, 31432 Toulouse Cedex 4, France.
authors.forename: Balbine
authors.initials: B
authors.lastname: Roussel
authors.affiliation: Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases, UMR1048, Inserm, 31432 Toulouse Cedex 4, France; UMR1048, Paul Sabatier University, University of Toulouse, 31432 Toulouse Cedex 4, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Gui
authors.affiliation: UMR866, Inserm, 21000 Dijon, France; LabEx lipSTIC, Faculty of Medicine, University of Burgundy, 21000 Dijon, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Grober
authors.affiliation: Franco-Czech Laboratory for Clinical Research on Obesity, Third Faculty of Medicine, 100 00 Prague 10, Czech Republic; Department of Sport Medicine, Third Faculty of Medicine, Charles University, 100 00 Prague 10, Czech Republic.
authors.forename: Vladimír
authors.initials: V
authors.lastname: Štich
authors.affiliation: Franco-Czech Laboratory for Clinical Research on Obesity, Third Faculty of Medicine, 100 00 Prague 10, Czech Republic; Department of Sport Medicine, Third Faculty of Medicine, Charles University, 100 00 Prague 10, Czech Republic.
authors.forename: Lenka
authors.initials: L
authors.lastname: Rossmeislová
authors.affiliation: UMR1048, Paul Sabatier University, University of Toulouse, 31432 Toulouse Cedex 4, France; Laboratory of Vascular Network, Immune Cells, and Progenitor Cells in the Adipose Tissue, Institute of Metabolic and Cardiovascular Diseases, UMR1048, Inserm, 31432 Toulouse Cedex 4, France.
authors.forename: Alexia
authors.initials: A
authors.lastname: Zakaroff-Girard
authors.affiliation: UMR1048, Paul Sabatier University, University of Toulouse, 31432 Toulouse Cedex 4, France; Laboratory of Vascular Network, Immune Cells, and Progenitor Cells in the Adipose Tissue, Institute of Metabolic and Cardiovascular Diseases, UMR1048, Inserm, 31432 Toulouse Cedex 4, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Bouloumié
authors.affiliation: Franco-Czech Laboratory for Clinical Research on Obesity, Inserm, 31432 Toulouse Cedex 4, France; Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases, UMR1048, Inserm, 31432 Toulouse Cedex 4, France; UMR1048, Paul Sabatier University, University of Toulouse, 31432 Toulouse Cedex 4, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Viguerie
authors.affiliation: Franco-Czech Laboratory for Clinical Research on Obesity, Inserm, 31432 Toulouse Cedex 4, France; Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases, UMR1048, Inserm, 31432 Toulouse Cedex 4, France; UMR1048, Paul Sabatier University, University of Toulouse, 31432 Toulouse Cedex 4, France.
authors.forename: Cedric
authors.initials: C
authors.lastname: Moro
authors.affiliation: Franco-Czech Laboratory for Clinical Research on Obesity, Inserm, 31432 Toulouse Cedex 4, France; Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases, UMR1048, Inserm, 31432 Toulouse Cedex 4, France; UMR1048, Paul Sabatier University, University of Toulouse, 31432 Toulouse Cedex 4, France.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Tavernier
authors.affiliation: Franco-Czech Laboratory for Clinical Research on Obesity, Inserm, 31432 Toulouse Cedex 4, France; Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases, UMR1048, Inserm, 31432 Toulouse Cedex 4, France; UMR1048, Paul Sabatier University, University of Toulouse, 31432 Toulouse Cedex 4, France; Department of Clinical Biochemistry, Toulouse University Hospitals, 31059 Toulouse Cedex 9, France. Electronic address: dominique.langin@inserm.fr.
authors.forename: Dominique
authors.initials: D
authors.lastname: Langin
mesh_terms: D017667:Adipocytes / Q000378:metabolism / Q000473:pathology; D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007333:Insulin Resistance / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008809:Mice, Inbred C3H; D009765:Obesity / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4