Abstract
BackgroundObesity has been linked to an increased risk of female infertility. Leptin, an adipocytokine which is elevated during obesity, may influence gonadal function through modulating steroidogenesis in granulosa cells.MethodsThe effect of leptin on progesterone production in simian virus 40 immortalized granulosa (SVOG) cells was examined by Enzyme linked immunosorbent assay (ELISA). The effect of leptin on the expression of the steroidogenic enzymes (StAR, P450scc, 3betaHSD) in SVOG cells was examined by real-time PCR and Western blotting. The mRNA expression of leptin receptor isoforms in SVOG cells were examined by using PCR. SVOG cells were co-treated with leptin and specific pharmacological inhibitors to identify the signaling pathways involved in leptin-reduced progesterone production. Silencing RNA against leptin receptor was used to determine that the inhibition of leptin on cAMP-induced steroidogenesis acts in a leptin receptor-dependent manner.Results and ConclusionIn the present study, we investigated the cellular mechanisms underlying leptin-regulated steroidogenesis in human granulosa cells. We show that leptin inhibits 8-bromo cAMP-stimulated progesterone production in a concentration-dependent manner. Furthermore, we show that leptin inhibits expression of the cAMP-stimulated steroidogenic acute regulatory (StAR) protein, the rate limiting de novo protein in progesterone synthesis. Leptin induces the activation of ERK1/2, p38 and JNK but only the ERK1/2 (PD98059) and p38 (SB203580) inhibitors attenuate the leptin-induced inhibition of cAMP-stimulated StAR protein expression and progesterone production. These data suggest that the leptin-induced MAPK signal transduction pathway interferes with cAMP/PKA-stimulated steroidogenesis in human granulosa cells. Moreover, siRNA mediated knock-down of the endogenous leptin receptor attenuates the effect of leptin on cAMP-induced StAR protein expression and progesterone production, suggesting that the effect of leptin on steroidogenesis in granulosa cells is receptor dependent. In summary, leptin acts through the MAPK pathway to downregulate cAMP-induced StAR protein expression and progesterone production in immortalized human granulosa cells. These results suggest a possible mechanism by which gonadal steroidogenesis could be suppressed in obese women.
Highlights
Obesity has been linked to an increased risk of female infertility
We found that treatment of immortalized granulosa cells with increasing doses of leptin inhibited 8-bromo cAMP-induced steroidogenesis with downregulation of the de novo produced steroidogenic acute regulatory (StAR) protein
Leptin attenuates the 8-bromo cAMP-stimulated progesterone production in human granulosa cells The gonadotropin-stimulated progesterone production in granulosa and luteal cell is critical for normal uterine function, establishment and maintenance of pregnancy, and mammary gland development [1,12]
Summary
Obesity has been linked to an increased risk of female infertility. The major function of the female gonad is to differentiate and release mature oocytes for fertilization and successful propagation of the species. The follicular maturation, ovulation and corpus luteum function of mammalian ovaries is regulated by the interaction between gonadotropin releasing hormone, gonadotropins, ovarian sex steroids and a variety of peptide hormones [1]. Dysfunction in the biosynthesis of sex steroid hormones could impair normal ovarian function or even cause infertility. A key hormone in energy homeostasis and neuroendocrine function, has a permissive role in initiating puberty and is crucial in the pathogenesis of reproductive dysfunction in several disease states of energy imbalance [2]. Accumulating evidence suggests that increased leptin levels contribute to the pathogenesis of reproductive abnormalities including infertility, polycystic ovary syndrome (PCOS), anovulation, disruption of the menstrual cycle, hyperinsulinemia and many other conditions [4,5,6]
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