MULTIPLE SIGNALS ARE NEEDED TO REGULATE LEPTIN EXPRESSION IN PLACENTAL CELLS

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

Foz de Iguazú

Simposio; V Latin american symposium on maternal fetal interaction and placenta; 2013

MULTIPLE SIGNALS ARE NEEDED TO REGULATE LEPTIN EXPRESSION IN PLACENTAL CELLS. J Maymóa, Y Gambinoa, A Pérez-Pérezb, JL Dueñasc, B Maskind, JC Calvoa, V Sánchez-Margaletb and C Varonea aDepto. de Química Biológica, FCEN UBA, IQUIBICEN CONICET, Buenos Aires, Argentina. bDepto. de Bioquímica Médica y Biología Molecular. Universidad de Sevilla, Sevilla, España. cHospital Virgen Macarena, Sevilla, España. dHospital Nacional A Posadas, Buenos Aires, Argentina. Leptin is a key hormone in placental physiology. It regulates trophoblast proliferation, inhibits apoptosis, stimulates protein synthesis, and regulates fetal growth and development. The mechanisms involved in the regulation of placental leptin expression are not fully understood. In the present study, we analyzed the mechanisms of hCG and 17beta-estradiol (E2) in the induction of leptin expression in human placental cells. We have found that hCG enhancement of leptin expression involved the MAPK pathway. This induction is inhibited by PKA as we observed that ERK1/2 phosphorylation increased when hCG treatment was combined with H89. We observed that a cAMP analogue that specifically activates Epac (CPT-OMe) stimulated leptin expression by hCG. In addition, the overexpression of Epac and Rap1 proteins increased leptin promoter activity and enhanced hCG effect.  Finally we found that the alternative Epac/cAMP pathway and the MAPK pathway mediate hCG induction of leptin expression in placental cells. On the other hand, we found that E2 action probably involves membrane receptors, as treatment with a membrane-constrained E2 conjugate, E-BSA, enhanced leptin expression and rapidly activated different MAPKs and AKT signaling pathways. Inhibition of these pathways with dominant negative mutant kinases or pharmacologic inhibitors prevented E2 effect on leptin expression. We also demonstrated the presence of ERalpha associated to the plasma membrane of BeWo cells. We also found 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. Finally we have also found that CREB, NFkB, Sp1 and AP1 transcription factors modulated leptin induction by E2. These results improve the comprehension of leptin function during pregnancy and further support the importance of leptin in pregnancy.