Upregulation of placental leptin by human chorionic gonadotropin

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

ENDOCRINOLOGY

The Endocrine Society

Lugar: MD EEUU; Año: 2009 vol. 150 p. 304 - 313

0013-7227

Leptin, the 16000 MW protein product of the obese gene, was originally considered as an adipocyte-derived signaling molecule for the central control of metabolism. However, leptin has been suggested to be involved in other functions during pregnancy, particularly in placenta, where it was found to be expressed. In the present work, we have found that recombinant human chorionic gonadotropin (hCG) added to BeWo choriocarcinoma cell line showed a stimulatory effect on endogenous leptin expression, when analysed by Western blot. This effect was time and dose-dependent. Maximal effect was achieved at 100 IU hCG/ml. Moreover, hCG treatment enhanced leptin promoter activity up to 12.9 times, evaluated by transient transfection with a plasmid construction containing different promoter regions and the reporter gene luciferase. This effect was dose-dependent and evidenced with all the promoter regions analyzed, regardless of length. Similar results were obtained with placental explants thus indicating physiological relevance. Since hCG signal transduction usually involves cAMP signaling, this pathway was analyzed. Contrarily, we found that dibutyril cAMP counteracted hCG effect on leptin expression. Furthermore, cotransfection with the catalytic subunit of PKA and/or the transcription factor CREB repressed leptin expression. Thereafter we determined that hCG effect could be partially blocked by pharmacologic inhibition of MAP kinase pathway with 50 mM PD98059 but not by the inhibition of the PI3K pathway with 0.1 mM Wortmannin. Moreover, hCG treatment promoted MEK and ERK1/ERK2 phosphorylation in placental cells. Finally, cotransfection with a dominant negative mutant of MAPK blocked the hCG-mediated activation of leptin expression. In conclusion, we provide some evidence suggesting that hCG induces leptin expression in trophoblastic cells probably involving the MAPK signal transduction pathway.