Early postnatal overnutrition as a contributor to metabolic dysregulation: insights into hepatic epigenetic mechanisms.

Abstract

Objective: This study evaluated the effects of postnatal overnutrition during lactation on hepatic DNA methylation patterns and their relationship with hepatic metabolic disorders.

Methods: At postnatal day 3, male rats were randomly divided into normal litters (NL, 10 pups per litter) or small litters (SL, 3 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.

Results: 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.

Conclusion: 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.