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Macrophage-Secreted Factors Impair Human Adipogenesis: Involvement of Proinflammatory State in Preadipocytes

Institut National de la Santé et de la Recherche Médicale, Unité 755 Nutriomique (D.L., S.T., M.K., K.C.), 75004 Paris, France; University Pierre and Marie Curie-Paris 6 (D.L., S.T., M.K., K.C.), Faculty of Medicine Les Cordeliers, 75004 Paris, France; and AP-HP, Hôtel-Dieu Hospital (K.C.), Nutrition Department, 75004 Paris, France; and Cardiovascular Physiology Institute (A.M.), J.W. Goethe University, D-60385 Frankfurt/Main, Germany

Address all correspondence and requests for reprints to: Danièle Lacasa, Institut National de la Santé et de la Recherche Médicale, Unité 755 EA 3502, Service de Nutrition Hôtel Dieu, 1 place du parvis Notre Dame, 75004 Paris, France. E-mail: daniele.lacasa{at}ea3502.org.

Obesity is considered a chronic low-grade inflammatory state. The white adipose tissue produces a variety of inflammation-related proteins whose expression is increased in obese subjects. The nonadipose cell fraction, which includes infiltrated macrophages, is a determinant source of inflammation-related molecules within the adipose tissue. Our working hypothesis is that macrophage infiltration affects fat expansion through a paracrine action on adipocyte differentiation. Human primary preadipocytes were then differentiated in the presence of conditioned media obtained from macrophages differentiated from blood monocytes. Preadipocytes treated by macrophage-conditioned medium displayed marked reduction of adipogenesis as assessed by decreased cellular lipid accumulation and reduced gene expression of adipogenic and lipogenic markers. In addition to this effect, the activation of macrophages by lipopolysaccharides stimulated nuclear factor B signaling, increased gene expression and release of proinflammatory cytokines and chemokines, and induced preadipocyte proliferation. This phenomenon was associated with increased cyclin D1 gene expression and maintenance of the fibronectin-rich matrix. Anti-TNF neutralizing antibody inhibits the inflammatory state of preadipocytes positioning TNF as an important mediator of inflammation in preadipocytes. Strikingly, conditioned media produced by macrophages isolated from human adipose tissue exerted comparable effects with activated macrophages, i.e. decreased adipogenesis and increased inflammatory state in the preadipocytes. These data show that macrophage-secreted factors inhibit the formation of mature adipocytes, suggesting possible role in limiting adipose tissue expansion in humans.

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