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Macrophage-Secreted Factors Promote a Profibrotic Phenotype in Human Preadipocytes

Institut National de la Santé et de la Recherche Médicale (INSERM) (M.K., V.A., C.H., C.R., K.C., D.L.), Unité 872 Nutriomic, Université Pierre et Marie Curie (M.K., V.A., C.H., C.R., K.C., D.L.), Paris 6, Centre de Recherche des Cordeliers, and Université Paris Descartes (M.K., V.A., C.H., C.R., K.C., D.L.), Unité Mixte de Recherche S 872, Paris F-75006, France; and Assistance Publique-Hopitaux de Paris, Pitié Salpetrière Hospital (K.C.), Endocrinology and Nutrition Department, Paris F-75013, France

Address all correspondence and requests for reprints to: Lacasa Danièle, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 872, Centre de recherche des Cordeliers, 15 rue de l’école de Médecine, 75005 Paris, France. E-mail: daniele.lacasa{at}crc.jussieu.fr.

White adipose tissue (WAT) in obese humans is characterized by macrophage accumulation the effects of which on WAT biology are not fully understood. We previously demonstrated that macrophage-secreted factors impair preadipocyte differentiation and induce inflammation, and we described the excessive fibrotic deposition in WAT from obese individuals. Microarray analysis revealed significant overexpression of extracellular matrix (ECM) genes in inflammatory preadipocytes. We show here an organized deposition of fibronectin, collagen I, and tenascin-C and clustering of the ECM receptor 5 integrin, characterizing inflammatory preadipocytes. Anti-5 integrin-neutralizing antibody decreased proliferation of these cells, underlining the importance of the fibronectin/integrin partnership. Fibronectin-cultured preadipocytes exhibited increased proliferation and expression of both nuclear factor-B and cyclin D1. Small interfering RNA deletion of nuclear factor-B and cyclin D1 showed that these factors link preadipocyte proliferation with inflammation and ECM remodeling. Macrophage-secreted molecules increased preadipocyte migration through an increase in active/phosphorylated focal adhesion kinase. Gene expression and neutralizing antibody experiments suggest that inhibin β A, a TGF-β family member, is a major fibrotic factor. Interactions between preadipocytes and macrophages were favored in a three-dimensional collagen I matrix mimicking the fibrotic context of WAT. Cell-rich regions were immunostained for preadipocytes, proliferation, and macrophages in the vicinity of fibrotic WAT from obese individuals. In conclusion, an inflammatory environment leads to profound modifications of the human preadipocyte phenotype, producing fibrotic components with increased migration and proliferation. This phenomenon might play a role in facilitating the constitution of quiescent preadipocyte pools and eventually in the maintenance and aggravation of increased fat mass in obesity.

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