Genome-Wide DNA Methylation Changes Induced by High-Fat Diet and Methyl Donor Supplementation in Female Lupus Models: An Exploratory Study

This exploratory study investigated the interactive effects of dietary fat content and methyl-donor supplementation on genome-wide DNA methylation in adipose tissue of female lupus-prone NZBWF1/J mice. Thirty mice were randomly assigned to four groups for 12 weeks in a 2 × 2 factorial design: standard diet (SD, n = 7), high-fat diet (HFD, n = 7), standard diet supplemented (SDS, n = 8), and high-fat diet supplemented (HFDS, n = 8). The standard diet provided 4.2 kcal/g and the high-fat diet 6.6 kcal/g. Supplemented diets contained 8 mg/kg folic acid and 50 µg/kg vitamin B12. After a 10-h fast, subcutaneous adipose tissue was collected for genome-wide DNA methylation analysis using the Infinium Mouse Methylation BeadChip, followed by differential methylation and pathway enrichment analyses. The high-fat diet induced a distinct methylation profile with 90 differentially methylated CpGs (p < 0.05, Δβ ≥ 0.05). Enrichment analyses did not identify significantly overrepresented pathways. Diet × supplementation interaction analysis identified 31 CpGs with significant interaction effects (p < 0.01). Pathway enrichment analysis revealed overrepresentation of the IL-17 signaling pathway. Only one CpG overlapped between HFD-associated and interaction-associated loci, indicating largely distinct epigenetic responses to diet and supplementation. A high-fat diet induces widespread epigenetic remodeling in adipose tissue, while folic acid and vitamin B12 supplementation modulates inflammatory epigenetic pathways in a diet-dependent manner.