Developmental Programming: Effect of Prenatal Steroid Excess on Intraovarian Components of Insulin Signaling Pathway and Related Proteins in Sheep
Developmental Programming: Effect of Prenatal Steroid Excess on Intraovarian Components of Insulin Signaling Pathway and Related Proteins in Sheep
复制标题
DOI：
10.1095/biolreprod.109.082719
复制
发表时间：
2010-06-01
影响因子：
3.6
通讯作者：
Padmanabhan, Vasantha
中科院分区：
文献类型：
--
作者：
Ortega, Hugo H.;Rey, Florencia;Padmanabhan, Vasantha
产前睾酮（T）过量增加卵巢卵泡募集，卵泡持续性，胰岛素抵抗和代偿性高胰岛素血症。考虑到胰岛素在卵巢生理学中的重要性，在本研究中，使用产前T-和二氢睾酮（DHT，一种非芳香化雄激素）治疗的母羊，我们测试了产前雄激素过量改变卵巢内胰岛素信号级联和代谢的假设对胰岛素信号有影响的介质。通过免疫组织化学方法测定胎儿（第90天和第140天）、青春期后（10个月）和成人（21个月）卵巢胰岛素受体（INSRB）、胰岛素受体底物1（IRS 1）、哺乳动物雷帕霉素靶蛋白（MTOR）、磷脂酰肌醇3-激酶（PIK 3）、过氧化物酶体增殖物激活受体-γ（PPARG）和脂联素蛋白的变化。结果表明，这些蛋白质表达在颗粒，卵泡膜，和间质室，与INSRB，IRS 1，PPARG，和脂联素增加与先进的卵泡分化。重要的是，产前T过量诱导PPARG和脂联素表达的年龄特异性变化，PPARG表达在胎儿期明显增加，而窦卵泡脂联素表达在成年期明显减少。比较产前T和DHT处理的女性的发育变化发现，对PPARG的影响是由T的雄激素作用编程的，而对脂联素的影响可能是由其雌激素作用。这些结果表明PPARG在产前T过量导致卵巢破坏的程序中发挥作用，包括窦卵泡脂联素表达的减少以及脂联素在卵泡持续存在和排卵失败中的贡献作用。
Prenatal testosterone (T) excess increases ovarian follicular recruitment, follicular persistence, insulin resistance, and compensatory hyperinsulinemia. Considering the importance of insulin in ovarian physiology, in this study, using prenatal T- and dihydrotestosterone (DHT, a nonaromatizable androgen)treated female sheep, we tested the hypothesis that prenatal androgen excess alters the intraovarian insulin signaling cascade and metabolic mediators that have an impact on insulin signaling. Changes in ovarian insulin receptor (INSRB), insulin receptor substrate 1 (IRS1), mammalian target of rapamycin (MTOR), phosphatidylinositol 3-kinase (PIK3), peroxisome proliferator-activated receptor-gamma (PPARG), and adiponectin proteins were determined at fetal (Days 90 and 140), postpubertal (10 mo), and adult (21 mo) ages by immunohistochemistry. Results indicated that these proteins were expressed in granulosa, theca, and stromal compartments, with INSRB, IRS1, PPARG, and adiponectin increasing in parallel with advanced follicular differentiation. Importantly, prenatal T excess induced age-specific changes in PPARG and adiponectin expression, with increased PPARG expression evident during fetal life and decreased antral follicular adiponectin expression during adult life. Comparison of developmental changes in prenatal T and DHT-treated females found that the effects on PPARG were programmed by androgenic actions of T, whereas the effects on adiponectin were likely by its estrogenic action. These results suggest a role for PPARG in the programming of ovarian disruptions by prenatal T excess, including a decrease in antral follicular adiponectin expression and a contributory role for adiponectin in follicular persistence and ovulatory failure.