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Cell Rep. 2014 May 22;7(4):1116-29. doi: 10.1016/j.celrep.2014.03.062. Epub 2014 May 1.

Immune cell Toll-like receptor 4 mediates the development of obesity- and endotoxemia-associated adipose tissue fibrosis.

Author information

1
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.
2
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.
3
UMR866, Inserm, 21000 Dijon, France; LabEx lipSTIC, Faculty of Medicine, University of Burgundy, 21000 Dijon, France.
4
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.
5
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.
6
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.

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.

PMID:
24794440
DOI:
10.1016/j.celrep.2014.03.062
[Indexed for MEDLINE]
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