Departments of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kitaku, Okayama, 700-8558, Japan.
Departments of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kitaku, Okayama, 700-8558, Japan.
J Steroid Biochem Mol Biol. 2018 Apr;178:82-88. doi: 10.1016/j.jsbmb.2017.11.004. Epub 2017 Nov 9.
The effects of incretins on ovarian steroidogenesis have not been clarified. In this study, we investigated the effects of incretins, including GIP and GLP-1, on ovarian steroidogenesis using rat primary granulosa cells. Treatment with incretins significantly suppressed progesterone synthesis in the presence of FSH, and the effect of GIP was more potent than that of GLP-1. In contrast, incretins had no significant effect on estrogen synthesis by rat granulosa cells. In accordance with the effects of incretins on steroidogenesis, GIP and GLP-1 suppressed the expression of progesterogenic factors and enzymes, including StAR, P450scc, 3βHSD, but not P450arom, and cellular cAMP synthesis induced by FSH. In addition, incretins moderately increased FSHR mRNA expression in granulosa cells. Of note, treatment with GIP, but not treatment with GLP-1, augmented Smad1/5/8 phosphorylation and transcription of the BMP target gene Id-1 induced by BMP-6 stimulation, suggesting that GIP upregulates BMP receptor signaling that can inhibit FSH-induced progesterone synthesis in rat granulosa cells. On the other hand, BMP-6 treatment suppressed the expression of GIP receptor but not that of GLP-1 receptor. Expression of the BMP type-I receptor ALK-3 was upregulated by treatment with GIP and GLP-1 and that of ALK-6 was also increased by GIP, while inhibitory Smad6 expression was impaired by GIP and GLP-1 in rat granulosa cells. Collectively, the results indicate that incretins, particularly GIP, impair FSH-induced progesterone production, at least in part, by upregulating BMP signaling in rat granulosa cells. The modulatory effects of incretins on endogenous BMP activity may be applicable to treatment of dysregulated steroidogenesis such as polycystic ovary syndrome.
肠促胰岛素对卵巢甾体激素生成的作用尚未阐明。在这项研究中，我们使用大鼠原代颗粒细胞研究了肠促胰岛素（包括 GIP 和 GLP-1）对卵巢甾体激素生成的影响。肠促胰岛素治疗显著抑制了 FSH 存在下孕激素的合成，且 GIP 的作用强于 GLP-1。相反，肠促胰岛素对大鼠颗粒细胞雌激素的合成没有显著影响。与肠促胰岛素对甾体激素生成的作用一致，GIP 和 GLP-1 抑制了孕激素生成因子和酶的表达，包括 StAR、P450scc、3βHSD，但不包括 P450arom，以及 FSH 诱导的细胞 cAMP 合成。此外，肠促胰岛素适度增加了颗粒细胞中的 FSHR mRNA 表达。值得注意的是，GIP 处理而非 GLP-1 处理增加了 BMP-6 刺激诱导的 Smad1/5/8 磷酸化和 BMP 靶基因 Id-1 的转录，表明 GIP 上调了 BMP 受体信号，可抑制大鼠颗粒细胞中 FSH 诱导的孕激素合成。另一方面，BMP-6 处理抑制了 GIP 受体而非 GLP-1 受体的表达。GIP 和 GLP-1 处理上调了 BMP Ⅰ型受体 ALK-3 的表达，GIP 还增加了 ALK-6 的表达，而 GIP 和 GLP-1 则损害了大鼠颗粒细胞中抑制性 Smad6 的表达。总之，这些结果表明，肠促胰岛素，特别是 GIP，通过上调大鼠颗粒细胞中的 BMP 信号至少部分地损害了 FSH 诱导的孕激素产生。肠促胰岛素对内源性 BMP 活性的调节作用可能适用于多囊卵巢综合征等甾体激素生成失调的治疗。
