Collectively, our findings provide a new epigenetic pathomechanism in the regulation of the Slc2a4 gene in obesity in which dietary or endogenously derived FA may increase enhancer-associated DNA methylation in the Slc2a4 gene to partially cause a downregulation of Slc2a4 expression which ultimately reduces glucose uptake and contributes to insulin resistance. Here, SLC2A4 is linked to obesity due to melanocortin 4 receptor deficiency.