In DIO mice, abnormal methylation was observed in three loci in mouse RNF43 of pancreatic exocrine cells, contrasting with unaltered CpG islands in KRAS, CDKN2A, TP53, SMAD4 and GNAS. Obesity alone was unlikely to induce aberrant methylation in these genes; therefore, the prominent contribution of these genes in PC arose from genetic alterations: mutations/deletions. The gene discussed is SMAD4; the disease is obesity due to melanocortin 4 receptor deficiency.