Leptin-Mediated Activation of Human Platelets: Involvement of a Leptin Receptor and Phosphodiesterase 3A Cellular Signaling Complex.

Leptin, a 16-KDa peptide-hormone produced primarily by adipocytes, was reported previously to promote platelet aggregation by a yet undefined mechanism. In this study, we investigated the effect of leptin on human platelet activation and delineate a molecular basis for this effect. Thus, we report that leptin potentiates ADP-induced platelet aggregation and directly stimulates adhesion of platelets to fibronectin. Using a combination of pharmacological and biochemical approaches we demonstrate that leptin mediates these effects by activating a signaling cascade that includes the leptin receptor (OB-R) and the kinases Jak2, phosphatidylinositol 3-kinase (PI3K) and protein kinase B (PKB/Akt). Consistent with an important role for PKB-mediated phosphorylation and activation of the dominant cAMP hydrolyzing phosphodiesterase, phosphodiesterase 3A (PDE3A), in this system, incubation of platelets with leptin activated PDE3A and stimulated a PKB-mediated phosphorylation of PDE3A. A selective PDE3 inhibitor, cilostamide, attenuated leptin effects in these cells. While leptin did not alter platelet cAMP levels, our identification of an OB-R/PDE3A complex is consistent with leptin acting locally to regulate a “pool” of cAMP that controls platelet activity. This is the first report of leptin-induced platelet adhesion which provides a mechanistic basis for this potentially important effect of this peptide hormone.