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

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 alpha, the present study was performed to investigate a putative regulation of apelin expression in adipocytes by TNF alpha. Herein, we report a tight correlation between apelin and TNF alpha expression in adipose tissue of lean and obese humans. Apelin regulation by TNF alpha was further studied in cultured explants of human adipose tissue. The endogenous expression of TNF alpha 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 alpha expression with 100 mu M isobutylmethylxanthine. In different mouse models of obesity, expression of both TNF alpha and apelin was also significantly increased in adipocytes of obese mice. Furthermore, short-term exposure to an i.p. injection of TNF alpha in C57B16/J mice induced an increase of apelin expression in adipose tissue as well as apelin plasma levels. Finally, a direct positive effect of TNF alpha has been shown in differentiated 3T3F442A adipocytes on apelin expression and secretion. The signaling pathways of TNF alpha 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.