Association of weight regain with specific methylation levels in the NPY and POMC promoters in leukocytes of obese men: A translational study

Specific methylation of appetite-related genes in leukocytes could serve as a useful biomarker to predict weight regain after an energy restriction program. We aimed to evaluate whether the pre-intervention DNA methylation patterns involved in the epigenetic control of appetite-regulatory genes in leukocytes are associated with the weight regain process. Eighteen men who lost ≥ 5% of body weight after an 8-week nutritional intervention were categorized as “regainers” (≥ 10% weight regain) and “non-regainers” (< 10% weight regain) 32 weeks after stopping dieting. At baseline, leukocytes were isolated and DNA was analyzed for epigenetic methylation patterns of appetite-related gene promoters by MALDI-TOF mass spectrometry. Regainers showed higher methylation levels than non-regainers in proopiomelanocortin (POMC) CpG sites + 136 bp and + 138 bp (fold change from non-regainers = 26%; p = 0.020) and lower methylation of the whole analyzed region of neuropeptide Y (NPY; fold change from non-regainers = − 22%; p = 0.033), as well as of several individual NPY-promoter CpG sites. Importantly, total baseline NPY methylation was associated with weight-loss regain (r = − 0.76; p < 0.001), baseline plasma ghrelin levels (r = 0.60; p = 0.011) and leptin/ghrelin ratio (r = − 0.52; p = 0.046). Lower methylation levels of POMC CpG sites + 136 bp and + 138 bp were associated with success in weight-loss maintenance (odds ratio = 0.042 [95% CI 0.01-0.57]; p = 0.018), whereas lower total methylation levels in NPY promoter were associated with higher risk of weight regain (odds ratio = 14.0 [95% CI 1.13-172]; p = 0.039). Therefore, the study of leukocyte methylation levels reflects a putative epigenetic regulation of NPY and POMC, which might be implicated in the weight regain process and be used as biomarkers for predicting weight regain after dieting.