DNA Hypermethylation of the Serotonin Receptor Type-2A Gene Is Associated with a Worse Response to a Weight Loss Intervention in Subjects with Metabolic Syndrome

Abstract

Understanding the regulation of gene activities depending on DNA methylation has been the subject of much recent study. However, although polymorphisms of the HTR2A gene have been associated with both obesity and psychiatric disorders, the role of HTR2A gene methylation in these illnesses remains uncertain. The aim of this study was to evaluate the association of HTR2A gene promoter methylation levels in white blood cells (WBC) with obesity traits and depressive symptoms in individuals with metabolic syndrome (MetS) enrolled in a behavioural weight loss programme. Analyses were based on 41 volunteers (mean age 49 ± 1 year) recruited within the RESMENA study. Depressive symptoms (as determined using the Beck Depression Inventory), anthropometric and biochemical measurements were analysed at the beginning and after six months of weight loss treatment. At baseline, DNA from WBC was isolated and cytosine methylation in the HTR2A gene promoter was quantified by a microarray approach. In the whole-study sample, a positive association of HTR2A gene methylation with waist circumference and insulin levels was detected at baseline. Obesity measures significantly improved after six months of dietary treatment, where a lower mean HTR2A gene methylation at baseline was associated with major reductions in body weight, BMI and fat mass after the treatment. Moreover, mean HTR2A gene methylation at baseline significantly predicted the decrease in depressive symptoms after the weight loss treatment. In conclusion, this study provides newer evidence that hypermethylation of the HTR2A gene in WBC at baseline is significantly associated with a worse response to a weight-loss intervention and with a lower decrease in depressive symptoms after the dietary treatment in subjects with MetS.

A systematic review of studies of DNA methylation in the context of a weight loss intervention

“…Specifically, at baseline, high-responder dieters showed lower promoter methylation levels of LEP (-47%, p < 0.05) [16] and TNF-α (-39%, p = 0.071 [16], r = 0.74; p = 0.021 [19]) than the nonresponder group, while obese men who regained weight after the diet showed higher methylation within POMC (+26%; p = 0.020) and lower methylation of NPY (-22%; p = 0.033) compared with nonregainers [20]. In addition, lower HTR2A methylation (low ≤ 0.556; medium = 0.557-0.585) [28] and higher methylation of SERPINE-1 (>7%) [26], ATP10A (r = 0.42) and CD44 (r = 0.3) at baseline was associated with greater weight loss [27], while end point methylation of the WT1 promoter was higher (+3-9%) in high versus low responders [27].…”

“…Six candidate-gene approach studies and two EWAS analyzed baseline and/or end point DNAm in high versus low responders to the dietary or GBP intervention to identify DNAm biomarkers of weight loss response [16,20,[26][27][28][31][32][33]. Studies of DNAm biomarkers measure epigenetic markers that vary between different individuals, but which are stable and potentially permanent, within the same individual.…”

“…Six diet intervention studies aimed at identifying DNAm biomarkers of weight loss response by analyzing baseline and/or end point methylation differences between high versus low responders to the diet, or in weight regainers versus nonregainers (hereafter referred to as 'biomarker studies') [16,[19][20][26][27][28]. These biomarker studies indicate that baseline methylation of TNF-α, LEP [16,19], POMC, NPY [20], SERPINE-1 [26], HTR2A [28], WT1, ATP10A and CD44 [27] can predict weight loss response at end point.…”

“…Six diet intervention studies aimed at identifying DNAm biomarkers of weight loss response by analyzing baseline and/or end point methylation differences between high versus low responders to the diet, or in weight regainers versus nonregainers (hereafter referred to as 'biomarker studies') [16,[19][20][26][27][28]. These biomarker studies indicate that baseline methylation of TNF-α, LEP [16,19], POMC, NPY [20], SERPINE-1 [26], HTR2A [28], WT1, ATP10A and CD44 [27] can predict weight loss response at end point. Specifically, at baseline, high-responder dieters showed lower promoter methylation levels of LEP (-47%, p < 0.05) [16] and TNF-α (-39%, p = 0.071 [16], r = 0.74; p = 0.021 [19]) than the nonresponder group, while obese men who regained weight after the diet showed higher methylation within POMC (+26%; p = 0.020) and lower methylation of NPY (-22%; p = 0.033) compared with nonregainers [20].…”

Peripheral Blood Cells, a Transcriptomic Tool in Nutrigenomic and Obesity Studies: Current State of the Art

“…In the same line, Perez‐Corango et al. showed that the methylations levels of HTR2A in PBC at baseline are associated with the ability to respond to weight‐loss programs, in the sense that those obese subjects with hypermethylations of this gene are worse responders (Perez‐Cornago, Mansego, Zulet, & Martinez, ). Interestingly, in addition to weight loss, weight regain can also be predicted by transcriptional‐based biomarkers in PBC.…”