An Epigenetic Signature in Adipose Tissue Is Linked to Nicotinamide N‐Methyltransferase Gene Expression

Scope The enzyme nicotinamide N‐methyltransferase (NNMT) is a major methyltransferase in adipose tissue. We hypothesized an epigenetic signature in association with NNMT gene expression in adipose tissue. Methods and results The global human methylome was analyzed in visceral adipose tissue (VAT) from morbidly obese patients using the Infinium Human Methylation 450 BeadChip array (discovery cohort: n = 11). The findings were confirmed in two additional independent cohorts (cohort 1: n = 60; BMI 20–60 kg m−2 and cohort 2: n = 40; BMI > 40 kg m−2) and validated after weight loss (using microarray data). Among the genes associated with the largest methylation fold change were genes related to metabolic processes, proliferation, inflammation, and extracellular matrix remodeling, such as COL23A1, PLEC1, FBXO21, STEAP3, RGS12, IGDCC3, FOXK2, and ORAI2. In fact, the results showed 577 differentially methylated CpG sites (DMCpGs) associated with the NNMT expression levels, with low methylation levels paralleling high NNMT expression. The expression of FBXO21 and FOXK2 was specifically modified after weight loss concomitantly with a decrease in NNMT expression and inflammation‐related genes. Interestingly, the adipose tissue NNMT gene expression correlated with markers of adipose tissue inflammation. Conclusions The expression of NNMT in VAT is associated with a specific methylome signature involving genes linked to adipose tissue metabolic pathophysiology. This study is the first to investigate the global methylome of VAT obtained from morbidly obese patients in association with the expression of nicotinamide N‐methyltransferase (NNMT). Higher NNMT expression is associated with lower global DNA methylation in visceral adipose tissue from morbidly obese patients. The genes mapped by the NNMT‐related DMCpG sites belong to a family of genes involved in adipose tissue pathophysiology. The expression of the differentially methylated genes changes in the expected direction after bariatric‐induced weight loss parallel to NNMT.