Epigenetic Biomarkers of Transition from Metabolically Healthy Obesity to Metabolically Unhealthy Obesity Phenotype: A Prospective Study

Abstract

Background: Identifying those parameters that could potentially predict the deterioration of metabolically healthy phenotype is a matter of debate. In this field, epigenetics, in particular DNA methylation deserves special attention. Results: The aim of the present study was to analyze the long-term evolution of methylation patterns in a subset of metabolically healthy subjects in order to search for epigenetic markers that could predict the progression to an unhealthy state. Twenty-six CpG sites were significantly differentially methylated, both at baseline and 11-year follow-up. These sites were related to 19 genes or pseudogenes; a more in-depth analysis of the methylation sites of these genes showed that CYP2E1 had 50% of the collected CpG sites differently methylated between stable metabolically healthy obesity (MHO) and unstable MHO, followed by HLA-DRB1 (33%), ZBTB45 (16%), HOOK3 (14%), PLCZ1 (14%), SLC1A1 (12%), MUC2 (12%), ZFPM2 (12.5%) and HLA-DQB2 (8%). Pathway analysis of the selected 26 CpG sites showed enrichment in pathways linked to th1 and th2 activation, antigen presentation, allograft rejection signals and metabolic processes. Higher methylation levels in the cg20707527 (ZFPM2) could have a protective effect against the progression to unstable MHO (OR: 0.21, 95%CI (0.067–0.667), p < 0.0001), whilst higher methylation levels in cg11445109 (CYP2E1) would increase the progression to MUO; OR: 2.72, 95%CI (1.094–6.796), p < 0.0014; respectively). Conclusions: DNA methylation status is associated with the stability/worsening of MHO phenotype. Two potential biomarkers of the transition to an unhealthy state were identified and deserve further investigation (cg20707527 and cg11445109). Moreover, the described differences in methylation could alter immune system-related pathways, highlighting these pathways as therapeutic targets to prevent metabolic deterioration in MHO patients.

Epigenetic changes in the metabolically healthy obese: A case‐control versus a prospective study

“…7 Recently, our group identified in a prospective study two differentially methylated positions located in the ZFPM2 and CYP2E1 genes, closely associated with the transition from MHO to MUO state. 8 A recent metaanalysis conducted by Andrade et al (2021) found more than 2000 DMRs in the adipose tissue of individuals with MUO compared to individuals with MHO, as our study reported. 14 There are several genes that overlapped our DMRs, such as FLRT, FRMPD4 PSMD5, NKX or LRRC, suggesting a similar effect in obesity.…”

“…A prospective study carried out by Gallardo‐Escribano et al (2020) reported that several metabolic genes ( LPL , SCD , SREBF1 , LXR ) were epigenetically altered in the MHO group after 12 months of follow‐up 7 . Recently, our group identified in a prospective study two differentially methylated positions located in the ZFPM2 and CYP2E1 genes, closely associated with the transition from MHO to MUO state 8 . A recent meta‐analysis conducted by Andrade et al (2021) found more than 2000 DMRs in the adipose tissue of individuals with MUO compared to individuals with MHO, as our study reported 14 …”

“…5 However, until now, only a few studies have been conducted to understand the epigenetic changes in individuals with MHO and MUO. [6][7][8] Therefore, we hypothesized that epigenetic changes may be involved in the development and the transition from MHO to MUO phenotype. Consequently, the aim of this study was to analyze the epigenome-wide DNA methylation study in peripheral blood mononuclear cells (PMBCs) from participants with MHO and MUO, by using two study designs, such as case-control and prospective approaches.…”

“…Epigenetic mechanisms might be implicated in the regulation of several metabolic disorders 5 . However, until now, only a few studies have been conducted to understand the epigenetic changes in individuals with MHO and MUO 6‐8 …”

ZNF384: A Potential Therapeutic Target for Psoriasis and Alzheimer’s Disease Through Inflammation and Metabolism

“…Here, we focus on its functions in immune and metabolic systems, which may commonly impact psoriasis and AD through peripheral blood. Previous clinical trials implicated that hypermethylated ZFPM2 protects against the occurrence and progression of metabolic complications in obesity and could affect immunity-related pathways ( 56 ). Meanwhile, some research implicated that decreasing ZFPM2 enhances insulin sensitivity via upregulating PPARA expression ( 57 , 58 ).…”