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

Abstract

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.

摘要

多囊卵巢综合征通常是一种以胰岛素抵抗（IR）为特征的系统性疾病。ATF4参与能量稳态和葡萄糖代谢的调节, 但其在PCOS的作用机制尚不清楚。在本研究中, 我们发现ATF4在肥胖和胰岛素抵抗的PCOS患者的人颗粒细胞中有高表达。因此, 我们采用Spearman相关分析来进一步探讨ATF4的表达与PCOS患者中的肥胖、脂代谢紊乱或胰岛素抵抗的相关性。发现ATF4的增加是PCOS中脂肪堆积和胰岛素信号转导异常的重要触发因素。在培养的KGN细胞中, 胰岛素对ATF4的mRNA和蛋白质的表达有正向调节作用。AFT4的过表达显著地抑制胰岛素刺激的AKT的磷酸化。综上所述, 基于PCOS的发生和发展, 我们的发现提供了一个新的分子机制, 这意味着AFT4可能是PCOS治疗的一个新的分子靶点。

The Chinese abstracts are translated by Prof. Dr. Xiangyan Ruan and her team: Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, China.

Keywords:

• PCOS
• ATF4
• obesity
• lipid metabolism
• IR

Acknowledgments

We thank all research volunteers for participating in the study, and the clinicians and embryologists of Center for Reproductive Medicine of Ren Ji Hospital for their excellent assistance.

Disclosure statement

The authors report no conflict of interest.

Additional information

Funding

This work was partly supported by grants from the National Natural Science Foundation (No.81671414 and 81490743), the National Key Research and Development Program of China (No.2017YFC1001002), Shanghai Municipal Education Commission–Gaofeng Clinical Medicine (No.20152510), and Shanghai Commission of Science and Technology (No.17DZ2271100).