Zheng Wen, Zhou Nan, Kuang Jiasi, Du Susu, Zhu Dandan, Ling Ru, Zhang Chunyang, Wang Yueshu, Zhou Wei, Li Xiaonan
Department of Child Health Care, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
Department of Child Health Care, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
J Nutr Biochem. 2025 Nov;145:110022. doi: 10.1016/j.jnutbio.2025.110022. Epub 2025 Jul 9.
This study evaluated the effects of postnatal overnutrition during lactation on hepatic DNA methylation patterns and their relationship with hepatic metabolic disorders. At postnatal day 3, male rats were randomly divided into normal litters (NL, 10 pups per litter) or small litters (SL, three pups per litter). Weight and insulin resistance were assessed at week 3 and week 13. Whole-genome bisulfite sequencing was used to detect alterations in hepatic DNA methylation levels, and enrichment analysis for differentially methylated genes (DMGs) was conducted. The methyl donor for DNA methylation, hepatic S-adenosylmethionine (SAMe), and serum methionine (Met) content were assessed by ELISA. The mRNA and protein expression levels of methionine adenosyltransferase I, alpha (Mat1a), a gene associated with SAMe synthesis, were examined. Rats that had postnatal overnutrition induced by small-litter rearing exhibited significant weight gain, insulin resistance and increased hepatic lipid deposition alongside reduced hepatic glycogen content. At week 3, the overall DNA methylation levels of the liver were notably reduced in the SL rats, with the differentially methylated regions (DMRs) primarily located in the genomic and intergenic regions. The DMGs were significantly enriched in the phosphatidylinositol (PI) and insulin resistance (IR) pathway. As the DNA methylation level decreased, the serum Met levels increased abnormally, while the hepatic SAMe content, glutathione (GSH) and Mat1a gene expression decreased significantly. Postnatal overnutrition leads to an aberrant hepatic DNA methylation pattern, which could contribute to persistent obesity and metabolic liver disorders by potentially regulating genes in the PI and IR pathways.
本研究评估了哺乳期产后营养过剩对肝脏DNA甲基化模式的影响及其与肝脏代谢紊乱的关系。在出生后第3天，将雄性大鼠随机分为正常窝仔组（NL，每窝10只幼仔）或小窝仔组（SL，每窝3只幼仔）。在第3周和第13周评估体重和胰岛素抵抗。采用全基因组亚硫酸氢盐测序检测肝脏DNA甲基化水平的变化，并对差异甲基化基因（DMG）进行富集分析。通过酶联免疫吸附测定法评估DNA甲基化的甲基供体、肝脏S-腺苷甲硫氨酸（SAMe）和血清蛋氨酸（Met）含量。检测与SAMe合成相关的基因——蛋氨酸腺苷转移酶Iα（Mat1a）的mRNA和蛋白表达水平。通过小窝仔饲养诱导产后营养过剩的大鼠表现出体重显著增加、胰岛素抵抗、肝脏脂质沉积增加以及肝脏糖原含量降低。在第3周，SL大鼠肝脏的总体DNA甲基化水平显著降低，差异甲基化区域（DMR）主要位于基因组和基因间区域。DMG在磷脂酰肌醇（PI）和胰岛素抵抗（IR）途径中显著富集。随着DNA甲基化水平降低，血清Met水平异常升高，而肝脏SAMe含量、谷胱甘肽（GSH）和Mat1a基因表达显著降低。产后营养过剩导致肝脏DNA甲基化模式异常，这可能通过潜在调节PI和IR途径中的基因导致持续性肥胖和代谢性肝脏疾病。
