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TNF up-regulates apelin expression in human and mouse adipose tissue

Danièle Daviaud^*, Jérémie Boucher^*, Stéphane Gesta^*, Cédric Dray^*, Charlotte Guigne^*, Didier Quilliot, Ahmet Ayav, Olivier Ziegler, Christian Carpene^*, Jean-Sébastien Saulnier-Blache^*, Philippe Valet^* and Isabelle Castan-Laurell^*,1

^* INSERM, U586, Unité de recherches sur les obésités, Université Paul Sabatier, Institut Louis Bugnard IFR31, Toulouse, France; and

Service de diabétologie, Maladies métaboliques et nutrition, CHU de Nancy, Hôpital J. d’Arc, Nancy, France

¹Correspondence: FIR 31, Institut Louis Bugnard, BP 84 225 INSERM U586, Toulouse F-31432, Cedex 4, France. Email: isabelle.castan{at}toulouse.inserm.fr

ABSTRACT

We have recently identified apelin as a novel adipokine up-regulated by insulin and obesity. Since obesity and insulin resistance are associated with chronically elevated levels of both insulin and TNF, the present study was performed to investigate a putative regulation of apelin expression in adipocytes by TNF. Herein, we report a tight correlation between apelin and TNF expression in adipose tissue of lean and obese humans. Apelin regulation by TNF was further studied in cultured explants of human adipose tissue. The endogenous expression of TNF in adipocytes isolated from the explants was accompanied by a 6–9 h subsequent increase of apelin expression in adipocytes. This increase was reversed by inhibiting TNF expression with 100 µM isobutylmethylxanthine. In different mouse models of obesity, expression of both TNF and apelin was also significantly increased in adipocytes of obese mice. Furthermore, short-term exposure to an i.p. injection of TNF in C57Bl6/J mice induced an increase of apelin expression in adipose tissue as well as apelin plasma levels. Finally, a direct positive effect of TNF has been shown in differentiated 3T3F442A adipocytes on apelin expression and secretion. The signaling pathways of TNF for the induction of apelin were dependent of PI3-kinase, c-Jun NH2-terminal kinase (JNK), and MAPK but not PKC activation. All together, these findings suggest that apelin might be a candidate to better understand potential links between obesity and associated disorders such as inflammation and insulin resistance.—Daviaud, D., Boucher, J., Gesta, S., Dray, C., Guigne, C., Quilliot, D., Ayav, A., Ziegler, O., Carpene, C., Saulnier-Blache, J.-S., Valet, P., Castan-Laurell, I. TNF up-regulates apelin expression in human and mouse adipose tissue.

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