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.

Franco Czech Laboratory for Clinical Research on Obesity 3rd Faculty of Medicine 100 00 Prague 10 Czech Republic; Department of Sport Medicine 3rd Faculty of Medicine Charles University 100 00 Prague 10 Czech Republic

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

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

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

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

UMR866 Inserm 21000 Dijon France; LabEx lipSTIC Faculty of Medicine University of Burgundy 21000 Dijon France

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Irf5 deficiency in macrophages promotes beneficial adipose tissue expansion and insulin sensitivity during obesity