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

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 acid (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, VLCFA 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 restores the phospholipid-methyl cycle, rescuing epigenetic reprogramming and 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. Overall design: control embryo compared with siAcox1-2-cell embryo of H3K4me3 modification by CUT&Tag