Caloric restriction prevents inheritance of polycystic ovary syndrome through oocyte-mediated DNA methylation reprogramming

Yue Liu; Yi Dong; Yonghui Jiang; Shan Han; Xin Liu; Xin Xu; Aiqing Zhu; Zihe Zhao; Yuan Gao; Yang Zou; Chuanxin Zhang; Yuehong Bian; Yuqing Zhang; Jiang Liu; Shigang Zhao; Han Zhao; Zi-Jiang Chen

doi:10.1016/j.cmet.2025.01.014

Caloric restriction prevents inheritance of polycystic ovary syndrome through oocyte-mediated DNA methylation reprogramming

Cell Metab. 2025 Apr 1;37(4):920-935.e6. doi: 10.1016/j.cmet.2025.01.014. Epub 2025 Feb 21.

Authors

Yue Liu¹, Yi Dong², Yonghui Jiang², Shan Han², Xin Liu², Xin Xu², Aiqing Zhu², Zihe Zhao², Yuan Gao², Yang Zou², Chuanxin Zhang², Yuehong Bian², Yuqing Zhang², Jiang Liu³, Shigang Zhao⁴, Han Zhao⁵, Zi-Jiang Chen⁶

Affiliations

¹ State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, The Second Hospital, Institute of Women, Children and Reproductive Health, Shandong University, Jinan 250012, Shandong, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan 250012, Shandong, China; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan 250012, Shandong, China; Center for Reproductive Medicine, Gusu School, The First Affiliated Hospital of Nanjing Medical University/Jiangsu Province Hospital, Nanjing 212028, Jiangsu, China.
² State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, The Second Hospital, Institute of Women, Children and Reproductive Health, Shandong University, Jinan 250012, Shandong, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan 250012, Shandong, China; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan 250012, Shandong, China.
³ Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China.
⁴ State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, The Second Hospital, Institute of Women, Children and Reproductive Health, Shandong University, Jinan 250012, Shandong, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan 250012, Shandong, China; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan 250012, Shandong, China; Shandong Technology Innovation Center for Reproductive Health, Jinan 250012, Shandong, China; Shandong Provincial Clinical Research Center for Reproductive Health, Jinan 250012, Shandong, China; Shandong Key Laboratory of Reproductive Research and Birth Defect Prevention, Jinan 250012, Shandong, China; Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No. 2021RU001), Jinan 250012, Shandong, China. Electronic address: zsg0108@126.com.
⁵ State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, The Second Hospital, Institute of Women, Children and Reproductive Health, Shandong University, Jinan 250012, Shandong, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan 250012, Shandong, China; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan 250012, Shandong, China; Center for Reproductive Medicine, Gusu School, The First Affiliated Hospital of Nanjing Medical University/Jiangsu Province Hospital, Nanjing 212028, Jiangsu, China; Shandong Technology Innovation Center for Reproductive Health, Jinan 250012, Shandong, China; Shandong Provincial Clinical Research Center for Reproductive Health, Jinan 250012, Shandong, China; Shandong Key Laboratory of Reproductive Research and Birth Defect Prevention, Jinan 250012, Shandong, China; Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No. 2021RU001), Jinan 250012, Shandong, China. Electronic address: hanzh80@sdu.edu.cn.
⁶ State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, The Second Hospital, Institute of Women, Children and Reproductive Health, Shandong University, Jinan 250012, Shandong, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan 250012, Shandong, China; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan 250012, Shandong, China; Shandong Technology Innovation Center for Reproductive Health, Jinan 250012, Shandong, China; Shandong Provincial Clinical Research Center for Reproductive Health, Jinan 250012, Shandong, China; Shandong Key Laboratory of Reproductive Research and Birth Defect Prevention, Jinan 250012, Shandong, China; Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No. 2021RU001), Jinan 250012, Shandong, China; Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai 200025, China; Department of Reproductive Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.

PMID: 39986273
DOI: 10.1016/j.cmet.2025.01.014

Abstract

Polycystic ovary syndrome (PCOS) is a prevalent metabolic and reproductive endocrine disorder with strong heritability. However, the independent role of oocytes in mediating this heritability remains unclear. Utilizing in vitro fertilization-embryo transfer and surrogacy, we demonstrated that oocytes from androgen-exposed mice (F1) transmitted PCOS-like traits to F2 and F3 generations. Notably, caloric restriction (CR) in F1 or F2 effectively prevented this transmission by restoring disrupted DNA methylation in oocyte genes related to insulin secretion and AMPK signaling pathways. Further detection in adult tissues of offspring revealed dysregulated DNA methylation and expression of those genes (e.g., Adcy3, Gnas, and Srebf1) were reversed by maternal CR. Moreover, similar benefits of CR were observed in aberrant embryonic methylome of women with PCOS. These findings elucidate the essential role of CR in preventing PCOS transmission via methylation reprogramming, emphasizing the importance of preconception metabolic management for women with PCOS.

Keywords: ADCY3; DNA methylation; GCK; GNAS; PCOS; SREBF1; caloric restriction; embryo; oocyte; transgenerational inheritance.

MeSH terms

Animals
Caloric Restriction*
DNA Methylation*
Female
Humans
Mice
Mice, Inbred C57BL
Oocytes* / metabolism
Polycystic Ovary Syndrome* / genetics
Polycystic Ovary Syndrome* / metabolism
Polycystic Ovary Syndrome* / prevention & control