Adipose tissue depot specific promoter methylation of TMEM18

Epigenetic processes such as dynamic promoter methylation may play a role in obesity, fat distribution and its accompanied metabolic alterations. TMEM18 is a candidate gene for body mass index (BMI) comprising the second largest effect size among all loci identified so far via GWAS. We hypothesized that differential TMEM18 gene expression in visceral (VAT) and subcutaneous adipose tissue (SAT) may be a consequence of depot specific differential methylation at the TMEM18 promoter region. Differential methylation levels may confer fat depot specific correlations with measures of obesity and fat distribution. Here, we measured TMEM18 mRNA expression in VAT and SAT from 500 subjects. A total of 146 Caucasian individuals were investigated for differential methylation levels in VAT vs. SAT at three CpG sites. Subsequently, we tested for potential correlation of methylation levels with anthropometric and metabolic parameters. (1) In 500 individuals, we observed significantly decreased mRNA expression in SAT (paired t -test, P < 0.0001) compared to VAT with strongest effects in obese subjects. (2) We identified significantly higher methylation levels for the entire CpG locus in SAT (paired t -test, P = 0.00015). In 146 individuals, we detected positive correlations between CpG methylation levels in SAT with parameters of obesity and fat distribution (e.g., BMI, r = 0.173; P = 0.036; visceral fat area, r = 0.246; P = 0.004) and with metabolic traits ( P ≤ 0.05). However, these correlations did not withstand adjustment for covariates. Our data suggest an adipose tissue depot specific TMEM18 promoter methylation that may mediate inter-depot specific variance in TMEM18 mRNA expression. Key Messages Higher mean methylation across the entire CpG locus in SAT compared to VAT. Lower TMEM18 mRNA expression levels in SAT compared to VAT. TMEM18 mRNA expression levels are related to phenotypes of obesity and glucose metabolism.