Augmentation of Leptin Synthesis and Secretion Through Activation of Protein Kinases A and C in Cultured Human Trophoblastic Cells¹

Abstract

Leptin is a fat cell-derived hormone that regulates food intake and energy expenditure. We previously demonstrated that leptin is produced by nonadipose cells, i.e. by placental trophoblasts. We also reported that a human trophoblastic cell line, BeWo cells, expresses leptin gene and secretes leptin into culture media. To elucidate the regulatory mechanisms of leptin production by human trophoblasts, we investigated synthesis and secretion of leptin in BeWo cells and in explant cultures of human placental tissue. Leptin production and gene expression in BeWo cells were increased by treatment with forskolin. The forskolin-induced increase in leptin production was completely suppressed by H89, an inhibitor of protein kinase A. Leptin production and gene expression in BeWo cells were increased by treatment with phorbol myristate acetate (PMA). The PMA-induced increase in leptin production was completely suppressed by H7 and staurosporine, both of which are inhibitors of protein kinase C. Leptin secretion from first trimester chorionic tissue was approximately 50-fold greater than that from term placental tissue. Leptin production and gene expression in explant cultures of placental tissue at both stages of pregnancy were augmented markedly by treatment with forskolin or PMA. The present study demonstrated augmentation of leptin production by protein kinase A and protein kinase C in cultured human trophoblasts, thereby leading to a better understanding of the regulatory mechanisms of leptin production in human trophoblasts in vivo.

Involvement of leptin in the molecular physiology of the placenta

“…Moreover, cAMP increased leptin promoter activity and leptin mRNA transcription . The stimulatory cAMP effect on the leptin expression was also reported in several cells such as glioma cells, pituitary tumor cells (Morash et al 2000, Li et al 2001, breast cancer cells (O'Neil et al 2001), gastric cells (Goiot et al 2005) and placental chorionic tissue (Yura et al 1998).…”

“…However, several experiments have evidenced that cAMP affects some cellular processes independently on PKA (Renstrom et al 1997, Cass et al 1999, Staples et al 2001. It was demonstrated that in BeWo cells and human-term placental tissue, leptin secretion is augmented by forskolin, an activator of PKA (Yura et al 1998). On the other hand, cAMP is known to alter human trophoblast function as demonstrated in numerous in vitro studies of normal and transformed trophoblast cells (Strauss et al 1992).…”