Molecular and Cellular Endocrinology 175 (2001) 81 – 92 Chemokines control fat accumulation and leptin secretion by cultured human adipocytes C.C. Gerhardt 1 , I.A. Romero 2 , R. Cancello, L. Camoin, A.D. Strosberg * CNRS UPR 0415, Institut Cochin de Ge ´ne ´tique Mole ´culaire, 22 rue Me ´chain, 75014 Paris, France Received 10 August 2000; accepted 5 January 2001 Abstract In addition to their role in inflammation, cytokines like TNF have been reported to regulate the adipose tissue function suggesting a role for these soluble mediators in metabolism. However, it is not known whether adipocytes have the capacity to secrete chemokines, a group of low molecular weight inflammatory mediators that control leukocyte migration into tissues. Here we show that primary cultures of human preadipocytes constitutively produce three chemokines, interleukin-8 (IL-8), macrophage inflammatory protein-1 (MIP-1) and monocyte chemotactic protein-1 (MCP-1), while their level of expression is low in mature adipocytes. Upon TNF treatment, the expression of all the three chemokines is upregulated in adipocytes differentiated in vitro. In addition, we describe the presence of seven different chemokine receptors, mainly in mature adipocytes, both in vitro and in human fat tissue sections. Prolonged stimulation of cultured human adipocytes with exogenous chemokines leads to a decrease in lipid content in association with the downregulation of PPAR mRNA expression. Moreover, chemokines positively control the secretion of leptin, a hormone that regulates appetite, by a post-transcriptional mechanism. These findings reveal a new role for chemokines in the regulation of adipose tissue and suggest a novel therapeutic basis for the treatment of obesity, diabetes and cachexia. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: IL-8; MCP-1; MIP1; Chemokine receptors; Leptin; Insulin; Adipocytes; Obesity www.elsevier.com/locate/mce 1. Introduction Adipocytes are considered to play a key role in the control of body mass both in normal weight-controlled situations and in conditions where there is a loss of control of body weight, including increased (obesity) or decreased (cachexia) body fat. It is becoming increas- ingly clear that either circulating or locally produced soluble factors regulate adipose tissue metabolism. Anti-adipogenic circulating cytokines have been sug- gested as mediators of the process of cachexia (Matthys and Billiau, 1997), although conclusive data supporting a role in human disease are often lacking. In addition, the finding that adipocytes are secretory cells and that adipocyte-secreted factors regulate adipocyte biology has gained support over the past few years (Hotamis- ligil et al., 1993; Mohamed-Ali et al., 1998). Adipocyte- secreted factors include, amongst others, a variety of inflammatory cytokines, such as tumor necrosis factor  (TNF), interferon , interleukins -1 and -6, trans- forming growth factor  and leukemia inhibitory fac- tor, that control the adipocyte function. Among these, TNF has been the focus of major attention as a central mediator in the development of obesity (re- viewed by Bullo-Bonet et al., 1999). TNF has been shown to induce insulin resistance (Hotamisligil et al., 1994), to inhibit adipocyte differentiation (Torti et al., 1989) and to disrupt leptin homeostasis (Kirchgessner et al., 1997). Abbreiations: IL-8, interleukin-8; MCP-1, monocyte chemotactic protein-1; MIP-1, macrophage inflammatory protein-1; PPAR, peroxisome proliferator activated receptor ; TNF, tumor necrosis factor . * Corresponding author. Tel. +33-1-40516415; fax: +33-1- 40516430. E-mail address: storsberg@icgm.cochin.inserm.fr (A.D. Strosberg). 1 Present address: Unilever Research Vlaardingen, The Nether- lands. C.C. Gerhardt and I.A. Romero contributed equally to the work. 2 Present address: Department of Biological Sciences, The Open University, Walton Hall, Milton Keynes MK7 6AA, United King- dom. C.C. Gerhardt and I.A. Romero contributed equally to the work. 0303-7207/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII:S0303-7207(01)00394-X