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Leptin Promotes Cell Proliferation and Survival of Trophoblastic Cells¹

Departamento de Química Biológica,³ Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, 1428 Buenos Aires, Argentina Departamento de Bioquímica Médica y Biología Molecular,⁴ Facultad de Medicina, Hospital Universitario Virgen Macarena, Universidad de Sevilla, 41009 Sevilla, España Instituto de Biología y Medicina Experimental (IBYME),⁵ 1428 Buenos Aires, Argentina

ABSTRACT

Leptin, the 16-kDa 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. In the present work, we studied a possible effect of leptin on trophoblastic cell proliferation, survival, and apoptosis. Recombinant human leptin added to JEG-3 and BeWo choriocarcinoma cell lines showed a stimulatory effect on cell proliferation up to 3 and 2.4 times, respectively, measured by ³H-thymidine incorporation and cell counting. These effects were time and dose dependent. Maximal effect was achieved at 250 ng leptin/ml for JEG-3 cells and 50 ng leptin/ml for BeWo cells. Moreover, by inhibiting endogenous leptin expression with 2 µM of an antisense oligonucleotide (AS), cell proliferation was diminished. We analyzed cell population distribution during the different stages of cell cycle by fluorescence-activated cell sorting, and we found that leptin treatment displaced the cells towards a G2/M phase. We also found that leptin upregulated cyclin D1 expression, one of the key cell cycle-signaling proteins. Since proliferation and death processes are intimately related, the effect of leptin on cell apoptosis was investigated. Treatment with 2 µM leptin AS increased the number of apoptotic cells 60 times, as assessed by annexin V-fluorescein isothiocyanate/propidium iodide staining, and the caspase-3 activity was increased more than 2 fold. This effect was prevented by the addition of 100 ng leptin/ml. In conclusion, we provide evidence that suggests that leptin is a trophic and mitogenic factor for trophoblastic cells by virtue of its inhibiting apoptosis and promoting proliferation.

apoptosis, growth factors, leptin, mechanisms of hormone action, placenta

¹Supported by Universidad de Buenos Aires grant UBACYT X048, Consejería de Educación y Ciencia CTS151, Junta de Andalucía, España, and PIP5402 from CONICET.

Correspondence: ²Cecilia L. Varone, Departamento de Química Biológica, Ciudad Universitaria Pabellón 2 piso 4 (1428), Buenos Aires, Argentina. FAX: 54 11 4576 3342; e-mail: cvarone{at}qb.fcen.uba.ar

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