Altered circadian clock as a novel therapeutic target for constant darkness-induced insulin resistance and hyperandrogenism of polycystic ovary syndrome
Altered circadian clock as a novel therapeutic target for constant darkness-induced insulin resistance and hyperandrogenism of polycystic ovary syndrome
复制标题
改变生物钟作为持续黑暗诱导的胰岛素抵抗和多囊卵巢综合征高雄激素血症的新治疗靶点。
DOI：
10.1016/j.trsl.2020.02.003
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发表时间：
2020-05-01
影响因子：
7.8
通讯作者：
Du, Yanzhi
中科院分区：
文献类型：
--
作者：
Li, Shang;Zhai, Junyu;Du, Yanzhi
生理时钟引起的代谢和生殖功能障碍及其与多囊卵巢综合征（PCOS）的关系的机制尚不清楚。在这里，我们解决了这个问题，使用大鼠与恒定的光或黑暗暴露8周和人类白细胞和血清的PCOS和非PCOS患者。此外，我们利用HepG 2细胞和KGN细胞来验证分子机制。持续黑暗导致的生物钟基因表达异常诱导了PCOS大鼠的代谢和生殖特征。暴露于持续黑暗后，大脑和肌肉ARNT样蛋白1（BMAL 1）减少通过葡萄糖转运蛋白4（GLUT 4）促进胰岛素抵抗，周期（PER）1和PER 2减少通过胰岛素样生长因子结合蛋白4（IGFBP 4）和性激素结合球蛋白（SHBG）促进雄激素过多。高胰岛素血症和高雄激素血症共同促进昼夜节律基因的异常表达和诱导卵巢颗粒细胞凋亡的双向联系。值得注意的是，黑暗处理大鼠的生物钟基因表达的改变与PCOS患者的生物钟基因表达相匹配。此外，褪黑激素治疗减轻高胰岛素血症和高雄激素血症的黑暗处理大鼠通过BMAL 1，PER 1，和PER 2。恢复正常的光/暗暴露2周通过BMAL 1逆转了这些条件。总之，我们的研究结果阐明了生物钟基因，特别是BMAL 1，PER 1和PER 2在PCOS中的关键功能，这可能有助于制定可行的预防和治疗策略。
The mechanisms underlying metabolic and reproductive dysfunction caused by arrhythmic circadian clock and their involvement in polycystic ovary syndrome (PCOS) are not understood. Here, we addressed this issue using rats with constant light or darkness exposure for 8 weeks and human leukocytes and serum of PCOS and non-PCOS patients. Additionally, we utilized HepG2 cells and KGN cells to verify the molecular mechanisms. The arrhythmic expressions of circadian clock genes due to constant darkness induced the metabolic and reproductive hallmarks of PCOS in rats. After exposure to constant darkness, decreased brain and muscle ARNT-like protein 1 (BMAL1) promoted insulin resistance via glucose transporter 4 (GLUT4), and decreased period (PER) 1 and PER2 promoted androgen excess via insulin-like growth factor-binding protein 4 (IGFBP4) and sex hormone binding globulin (SHBG) in the liver. Hyperinsulinemia and hyperandrogenism shared a bidirectional link promoting aberrant expression of circadian genes and inducing apoptosis of ovarian granulosa cells. Notably, the altered expressions of circadian clock genes in darkness-treated rats matched those of PCOS patients. Furthermore, melatonin treatment relieved the hyperinsulinemia and hyperandrogenism of darkness-treated rats via BMAL1, PER1 , and PER2. Restoring normal light/dark exposure for 2 weeks reversed these conditions via BMAL1. In conclusion, our findings elucidated the critical function of circadian clock genes, especially BMAL1, PER1, and PER2 in PCOS, which might aid the development of feasible preventive and therapeutic strategies for PCOS in women with biorhythm disorder.