Immune Cell Toll-like Receptor 4 Mediates the Development of Obesity- and Endotoxemia-Associated Adipose Tissue Fibrosis

• DOI: 10.1016/j.celrep.2014.03.062
• Publication Date: 2014-05-01T11:48:31Z
• Authors: Isabelle K. Vila; Pierre-Marie Badin; Marie-Adeline Mar...; Laurent Monbrun; Corinne Lefort; Lucile Mir; Katie Louche; Virginie Bourlier; Balbine Roussel; Philippe Gui; Jacques Grober; Vladimír Štich; Lenka Rossmeislová; Alexia Zakaroff-G...; Anne Bouloumié; Nathalie Viguerie; Cedric Moro; Geneviève Tavernier; Dominique Langin
• Keywords: MESH: Signal Transduction; MESH: Inflammation; Lipopolysaccharides; [SDV.IMM] Life Sciences [q-bio]/Immunology; QH301-705.5; 610; Diet, High-Fat; Mice; 03 medical and health sciences; MESH: Diet; Adipocytes; MESH: Obesity; Animals; Humans; MESH: Animals; Obesity; Biology (General); MESH: Mice, Inbred C3H; MESH: Mice; MESH: Adipocytes; Inflammation; 2. Zero hunger; Mice, Inbred C3H; 0303 health sciences; MESH: Humans; Animal; MESH: Toll-Like Receptor 4; Inbred C3H; Fibrosis; Endotoxemia; 3. Good health; Toll-Like Receptor 4; High-Fat; MESH: Diet, High-Fat; MESH: Insulin Resistance; Disease Models, Animal; Adipose Tissue; MESH: Endotoxemia; MESH: Fibrosis; [SDV.IMM]Life Sciences [q-bio]/Immunology; MESH: Disease Models; MESH: Disease Models, Animal; MESH: Lipopolysaccharides; Insulin Resistance; MESH: Adipose Tissue; Signal Transduction

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.