Abstract
Female reproduction depends on the metabolic status, especially during the period of folliculogenesis. Even though it is believed that melatonin can improve oocyte competence, there is still limited knowledge of how it can modulate metabolic processes during folliculogenesis and which signaling pathways are involved in regulating gene expression. To investigate the effects of melatonin on metabolic signals during the antral stage of follicular development, human granulosa-like tumor cells (KGN) were treated with melatonin or forskolin, and gene expression was analyzed with RNA-seq technology. Following appropriate normalization and the application of a fold change cut-off of 1.5 (FC 1.5, p ≤ 0.05), 1009 and 922 genes were identified as differentially expressed in response to melatonin and forskolin, respectively. Analysis of major upstream regulators suggested that melatonin may activate PKB/mTOR signaling pathways to program the metabolism of KGN cells to support slower growth and differentiation and to prevent follicular atresia. Similarly, PKA activation through stimulation of cAMP synthesis with FSK seemed to exert the same effects as melatonin in reducing follicular growth and regulating differentiation. This study suggests that melatonin may act through PKA and PKB simultaneously in human granulosa cells to prevent follicular atresia and early luteinization at the antral stage.
Highlights
Female reproduction is sensitive to the metabolic status, nutrition intake during gestation, and in the period of gametogenesis [1]
Our results suggest that PKA activation, through cAMP accumulation in response to FSK or other cAMP-inducing hormones, such as LH or prostaglandins, may control ovarian processes during the periovulatory period to improve granulosa cell survival and prevent follicular atresia (Figure 2)
The results of this study suggest that melatonin supplementation in a dominant-like plateau phase follicular context may activate PKB/mTOR signaling to program granulosa cell metabolism during the switch in the hormone-dependent state and following the FSH decline
Summary
Female reproduction is sensitive to the metabolic status, nutrition intake during gestation, and in the period of gametogenesis [1]. In mono-ovulatory species, one single oocyte, usually from the largest growing follicle, is ovulated at each cycle This process is well established and requires close coordination between the oocyte and the surrounding somatic cells, such as granulosa cells. Gap junctional channels mediate the transfer of metabolites, ions, and signaling molecules between these cells [2] These metabolic interactions between the oocyte and granulosa cells have long been studied since they are involved in the control of meiotic resumption [3,4]. The oocyte acquires its maturation competence during folliculogenesis, when the bidirectional communication between somatic cells and the oocyte creates an intrafollicular microenvironment that maintains the growth of primordial follicles into antral follicles, from which one is selected to ovulate a high-quality oocyte. This microenvironment depends on the maternal metabolic environment, which can affect the oocyte epigenetic and metabolic programming throughout follicular growth [5]
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