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Title: The Alternative Epac/cAMP Pathway and the MAPK Pathway Mediate hCG Induction of Leptin in Placental Cells
Authors: Maymó, Julieta Lorena
Pérez Pérez, Antonio
Maskin, Bernardo
Dueñas, José Luis
Calvo, Juan Carlos
Sánchez Margalet, Victor
Varone, Cecilia Lorena
metadata.dc.contributor.authoraffiliation: [Maymó,JL; Calvo,JC ;Varone,CL] Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina. [Pérez Pérez,A; Sánchez Margalet,V] Departamento de Bioquímica Médica y Biología Molecular, Hospital Universitario Virgen Macarena. Facultad de Medicina, Universidad de Sevilla, Sevilla, España. [Maskin,B] Hospital Nacional Profesor Alejandro Posadas, Buenos Aires, Argentina. [Dueñas,JL] Servicio de Ginecología y Obstetricia, Hospital Universitario Virgen Macarena, Sevilla, España. [Calvo,JC] Instituto de Biología y Medicina Experimental (IBYME), Buenos Aires, Argentina
Keywords: Pleiotropic;reproduction;pregnancy;placenta;endogenous;leptin
metadata.dc.subject.mesh: Medical Subject Headings::Anatomy::Embryonic Structures::Placenta
Medical Subject Headings::Chemicals and Drugs::Biological Factors::Intercellular Signaling Peptides and Proteins::Adipokines::Leptin
Medical Subject Headings::Chemicals and Drugs::Hormones, Hormone Substitutes, and Hormone Antagonists::Hormones::Peptide Hormones::Gonadotropins::Chorionic Gonadotropin
Issue Date: 2-Oct-2012
Publisher: PLoS ONE
Abstract: Pleiotropic effects of leptin have been identified in reproduction and pregnancy, particularly in the placenta, where it works as an autocrine hormone. In this work, we demonstrated that human chorionic gonadotropin (hCG) added to JEG-3 cell line or to placental explants induces endogenous leptin expression. We also found that hCG increased cAMP intracellular levels in BeWo cells in a dose-dependent manner, stimulated cAMP response element (CRE) activity and the cotransfection with an expression plasmid of a dominant negative mutant of CREB caused a significant inhibition of hCG stimulation of leptin promoter activity. These results demonstrate that hCG indeed activates cAMP/PKA pathway, and that this pathway is involved in leptin expression. Nevertheless, we found leptin induction by hCG is dependent on cAMP levels. Treatment with (Bu)(2)cAMP in combination with low and non stimulatory hCG concentrations led to an increase in leptin expression, whereas stimulatory concentrations showed the opposite effect. We found that specific PKA inhibition by H89 caused a significant increase of hCG leptin induction, suggesting that probably high cAMP levels might inhibit hCG effect. It was found that hCG enhancement of leptin mRNA expression involved the MAPK pathway. In this work, we demonstrated that hCG leptin induction through the MAPK signaling pathway is inhibited by PKA. We observed that ERK1/2 phosphorylation increased when hCG treatment was combined with H89. In view of these results, the involvement of the alternative cAMP/Epac signaling pathway was studied. 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. In conclusion, we provide evidence suggesting that hCG induction of leptin gene expression in placenta is mediated not only by activation of the MAPK signaling pathway but also by the alternative cAMP/Epac signaling pathway.
Description: Journal Article; Research Support, Non-U.S. Gov't;
metadata.dc.identifier.doi: 10.1371/journal.pone.0046216
ISSN: 1932-6203 (Online)
Appears in Collections:01- Artículos - Hospital Virgen Macarena

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