Activating transcriptional factor 4 correlated with obesity and insulin resistance in polycystic ovary syndrome

PCOS is a systemic disorder that is commonly characterized by insulin resistance (IR). ATF4 participates in the regulation of energy homeostasis and glucose metabolism, but its role in PCOS remains unclear. In this study, we found that ATF4 was highly expressed in human granulosa cells (hGCs) of PCOS patients with obesity and IR. Thus, we performed Spearman's correlation analysis to further investigate the correlation between ATF4 expression and obesity, lipometabolic disorders, or IR in PCOS. We found that increased ATF4 was an important trigger for lipid accumulation and abnormal insulin signal transduction in PCOS. In cultured KGN cells, insulin positively regulated the mRNA and protein abundance of ATF4. Overexpression of ATF4 significantly impaired insulin-stimulated phosphorylation of AKT. Collectively, our findings provided a novel insight into the molecular mechanisms underlying the occurrence and development of PCOS, implying that ATF4 may be a new molecular target for PCOS therapy.

多囊卵巢综合征（Polycystic Ovary Syndrome, PCOS）是一类以胰岛素抵抗（insulin resistance, IR）为典型特征的全身性代谢紊乱。激活转录因子4（Activating Transcription Factor 4, ATF4）参与能量稳态与糖代谢的调控，但其在多囊卵巢综合征中的作用仍未明确。本研究发现，合并肥胖与胰岛素抵抗的多囊卵巢综合征患者的人颗粒细胞（human granulosa cells, hGCs）中，ATF4呈高表达状态。为此，我们通过斯皮尔曼相关性分析，进一步探究了多囊卵巢综合征患者体内ATF4表达水平与肥胖、脂代谢紊乱及胰岛素抵抗之间的相关性。结果显示，ATF4表达升高是多囊卵巢综合征患者出现脂质堆积与胰岛素信号转导异常的重要诱因。在体外培养的KGN细胞中，胰岛素可正向调控ATF4的mRNA与蛋白表达丰度。ATF4过表达则可显著削弱胰岛素介导的AKT磷酸化过程。综上，本研究结果为多囊卵巢综合征发生发展的潜在分子机制提供了全新的研究视角，提示ATF4或可成为多囊卵巢综合征治疗的新型分子靶点。