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Submitted on May 23, 2006
Accepted on October 25, 2006
Inserm, U755 Nutriomique, 75004 Paris, France; University Pierre and Marie Curie-Paris 6, Faculty of Medicine Les Cordeliers, 75004 Paris, France; AP-HP, Hôtel-Dieu Hospital, Nutrition department, 1 Place du parvis Notre-Dame, 75004 Paris, France; Cardiovascular physiology Institute, J.W. Goethe University, Theodor Stern Kai 7, D-60385 Frankfurt/Main, Germany
* To whom correspondence should be addressed. 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 non-adipose 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 NF-
B signaling, increased gene expression and release of pro-inflammatory cytokines and chemokines, and induced preadipocyte proliferation. This phenomenom 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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