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)2cAMP 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.
Highlights
The major role of the placenta is to establish a crosstalk between maternal and fetal circulations
We have previously observed that treatment of trophoblastic cells with (Bu)2cAMP causes a complete loss of human chorionic gonadotropin (hCG) leptin induction [18]
Cotransfection with CREBM1 caused a significant inhibition of hCG stimulation of leptin promoter activity, with a 112-fold reduction compared with hCG treatment
Summary
The major role of the placenta is to establish a crosstalk between maternal and fetal circulations. The placenta works as an endocrine tissue that produces steroids, peptide hormones, growth factors and cytokines that are crucial for the establishment and maintenance of pregnancy. The synthesis and secretion of leptin as well as its functional receptors by trophoblast cells have been widely demonstrated [7,8], suggesting that leptin may act through a paracrine or autocrine mechanism. In this way, previous studies have demonstrated the interactions between leptin and some placental hormones, implicating leptin as a modulator of placental endocrine function [9]. Leptin stimulates the process of proliferation and protein synthesis, and inhibits apoptosis [10,11,12,13] in human trophoblastic cells
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