Leptin prevents apoptosis and promotes growth of trophoblastic cells from human placenta

VICTOR SÁNCHEZ-MARGALET; ANTONIO PÉREZ-PÉREZ; CECILIA VARONE; JULIETA MAYMÓ; JOSÉ LUIS DUEÑAS; RAIMUNDO GOBERNA.

Washington DC, U.S.A.

Congreso; AACC Annual Meeting 2008; 2008

American Association of Clinical Chemistry (AACC).

Leptin, the peripheral signal produced by the adipocyte to regulate energy metabolism, can also be produced by placenta, where it may have a role as an autocrine hormone. There is previous evidence that leptin levels are increased during pregnancy and come back to normal levels after delivery. Leptin may be a marker of placental function as well as placental stress conditions such as preeclampsia.Objective: In the present work we aimed to study the proliferative and antiapoptotic effect of leptin in placenta, by using the JEG-3 choriocarcinoma cell line, as well as trophoblastic cells from human placenta explants.Methods: The trophic effect of leptin was studied by thymidine incorporation and cell counting. We have assayed the early phase of apoptosis, triggered by the lack of serum, by using annexin V-PI labeling and flow cytometric analysis, as well as the late phase of apoptosis by studing the activation of caspase-3. We have also studied the major signaling pathways known to be triggered by the leptin receptor, and we have investigated the relative importance of these pathways in the trophic effect of leptin by using pharmacologic inhibitors.Results: We have found that leptin promotes the survival, growth and proliferation of trophoblastic cells. Leptin stimulates JAK-STAT pathway by promoting JAK2 and STAT3 tyrosine phosphorylation in placenta. We have also demonstrated the activation of MAPK pathway by studying phosphorylation of MEK and MAPK (Erk1/2). PI3K pathway is also triggered by leptin stimulation as assessed by the study of PKB phosphorylation. These signaling pathways were confirmed in trophoblastic cells obtained from placenta of healthy donors. The effect of leptin on JEG-3 survival was completely reversed by blocking p42/44 MAPK activation employing the MEK inhibitor PD98059, whereas it was not affected by PI3K inhibition using Wortmannin.Conclusion: Leptin promotes cell survival, growth and proliferation of trophoblastic cells from human placenta by stimulating leptin receptor signaling. These data suggest that the leptin and leptin receptor may be good markers for the study of the function of the placenta in pregnancy, and the measurement of leptin and leptin receptor may be useful in the monitoring of pregnancy in different pathological conditions such as diabetes, preeclampsia or placental insufficiency.