New insights into estrogen effects in trophoblastic cells. Focus on leptin expression

YÉSICA GAMBINO; JULIETA L. MAYMÓ; ANTONIO PÉREZ-PÉREZ; JUAN CARLOS CALVO; VÍCTOR SÁNCHEZ-MARGALET; CECILIA L. VARONE

Geilo

Congreso; Reunión Anual de la International Federation of Placenta Associations; 2011

International Federation of Placenta Associations

Estradiol influences various aspects of placental function and fetal development as the regulation of implantation, placental development, fetal growth, onset of parturition, release of neuropeptides and glycoproteins, and leptin secretion. Leptin is a key hormone in trophoblast proliferation and survival. It regulates cell proliferation, inhibits apoptosis, stimulates protein synthesis, and regulates fetal growth and development. The mechanisms involved in regulation of placental leptin expression are still poorly understood. In the present study, we analyzed the effect of 17beta-estradiol (E2) on leptin expression in human placental cells. We have found a stimulatory effect of E2 on endogenous leptin expression in both BeWo choriocarcinoma cell line and human placental explants. E2 treatment enhanced leptin promoter activity, as evaluated by reporter plasmids. Deletion analysis showed that a minimal promoter region between -1951 and -1847 bp is both necessary and sufficient to achieve E2 effects. These effects involved estrogen receptors (ER), as the antagonist ICI 182,780 inhibited E2-induced leptin expression. Moreover, the overexpression of ERalpha, but not ERbeta, increased E2 effect on leptin promoter activity. E2 action probably involves membrane receptors too, as treatment with a membrane-constrained E2 conjugate, E-BSA, enhanced leptin expression. Furthermore, E2 and E-BSA rapidly activated different MAPKs and AKT signaling pathways. Inhibition of these pathways with dominant negative mutant kinases or pharmacologic inhibitors prevents E2 effect on leptin expression. On the other hand we demonstrated the presence of ERalpha associated to the plasma membrane of BeWo cells. We also showed that the downregulation of ERalpha level through a specific siRNA, decreased E-BSA effects on leptin expression, suggesting that E2 genomic and nongenomic actions could be mediated by this receptor. Taken together, our results provide new evidence on the mechanisms whereby E2 regulates placental leptin expression and support the importance of leptin in placental physiology