Methylation of Tcf712 promoter by high-fat diet impairs β-cell function in mouse pancreatic islets

BACKGROUND The TCF7L2 (transcription factor 7 like 2) gene is strongly associated with type 2 diabetes risk. However, many people without the TCF7L2 at-risk allele develop T2D. The aim of this study was to investigate altered Tcf7l2 DNA methylation and gene expression caused by high-fat diets (HFDs). METHODS C57BL/6 mice were fed either an HFD or normal diet for 8 weeks, and intraperitoneal glucose tolerance tests were performed. Pancreatic islets were sorted for bisulfite sequencing polymerase chain reaction to determine DNA methylation status. We cloned the Tcf7l2 promoter, methylated it with methyltransferase, and transfected this construct into MIN-6 cells to confirm the effects of promoter methylation on Tcf7l2 expression. RESULTS Aberrant methylation at position -165 bp relative to the transcriptional start site of Tcf7l2 was present in mice fed an HFD. Accordingly, expression of Tcf7l2 mRNA and its corresponding protein was lower in the HFD group (P