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  3. Maternal obesity disrupts epigenetic reprogramming via peroxisomal-dependent phospholipid-methyl uncoupling during zygotic genome activation

Maternal obesity disrupts epigenetic reprogramming via peroxisomal-dependent phospholipid-methyl uncoupling during zygotic genome activation

  • Nat Commun. 2026 Mar 18;17(1):4706. doi: 10.1038/s41467-026-70492-2.
Xiao-Guohui Zhang # 1 2,  Lin-Li Yang # 1 2 3,  Xie Feng # 1,  Yu-Wei Zhang # 2,  Lei Guo # 1,  Sun-Xing Huang # 4,  Tie-Gang Meng 1,  Pei-Ying Li 1 2,  Lei-Ning Chen 1 2,  Rui-Bao Su 1,  Jun-Yu Ma 1,  Xiao-Yan Fan 1,  Jia-Li Su 5,  Yue-Fan Wang 5,  Lan-Fang Luo 5,  Qing-Yuan Sun 6,  Shyh-Chang Ng 7,  Shi-Ming Luo 8,  Xiang-Hong Ou 9 10
Affiliations

Affiliations

  • 1 Guangzhou Key Laboratory of Metabolic Diseases and Reproductive Health, Guangdong-Hong Kong Metabolism & Reproduction Joint Laboratory, Reproductive Medicine Center, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, China.
  • 2 The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.
  • 3 Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • 4 Reproductive Medicine Center, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
  • 5 State Key Laboratory of Stem Cell and Reproduction Biology, Institute of Zoology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing, China.
  • 6 Guangzhou Key Laboratory of Metabolic Diseases and Reproductive Health, Guangdong-Hong Kong Metabolism & Reproduction Joint Laboratory, Reproductive Medicine Center, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, China. [email protected].
  • 7 State Key Laboratory of Stem Cell and Reproduction Biology, Institute of Zoology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • 8 Guangzhou Key Laboratory of Metabolic Diseases and Reproductive Health, Guangdong-Hong Kong Metabolism & Reproduction Joint Laboratory, Reproductive Medicine Center, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, China. [email protected].
  • 9 Guangzhou Key Laboratory of Metabolic Diseases and Reproductive Health, Guangdong-Hong Kong Metabolism & Reproduction Joint Laboratory, Reproductive Medicine Center, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, China. [email protected].
  • 10 The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China. [email protected].
  • # Contributed equally.
PMID: 41851092 DOI: 10.1038/s41467-026-70492-2
Abstract

Maternal obesity is known to cause systemic lipid dysregulation, yet its effect on lipid reprogramming during the maternal-to-zygotic transition (MZT) remains unknown. Here we show that obesity disrupts very-long-chain fatty acids (VLCFAs) storage in oocytes and downregulates PEX13, impairing peroxisomal protein import in 2-cell embryos. Normally, peroxisomal β-oxidation converts oocyte-stored VLCFAs into medium- and long-chain fatty acids, which fuel triglyceride synthesis and drive phosphatidylethanolamine (PE) methylation to phosphatidylcholine (PC). This metabolic flux consumes methyl donors to facilitate H3K4me3 erasure and zygotic genome activation (ZGA). In obese mice, VLCFAs deficiency and PEX13 dysfunction lead to metabolic-epigenetic uncoupling, depleting lipid droplets and sustaining H3K4me3, thereby suppressing ZGA and blastocyst development. Importantly, supplying long-chain fatty acids or overexpressing PEMT restore the phospholipid-methyl cycle, rescuing epigenetic reprogramming and embryonic development. Our findings establish peroxisomal β-oxidation as a metabolic-epigenetic nexus essential for MZT and reveal a phospholipid-methyl coupling mechanism underlying obesity-associated embry development, offering novel therapeutic entry points to improve fertility in metabolic disorders.

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