Adipose Tissue Epigenetic Profile in Obesity-Related Dysglycemia - A Systematic Review

Abstract

BackgroundObesity is a major risk factor for dysglycemic disorders, including type 2 diabetes (T2D). However, there is wide phenotypic variation in metabolic profiles. Tissue-specific epigenetic modifications could be partially accountable for the observed phenotypic variability.ScopeThe aim of this systematic review was to summarize the available data on epigenetic signatures in human adipose tissue (AT) that characterize overweight or obesity-related insulin resistance (IR) and dysglycemia states and to identify potential underlying mechanisms through the use of unbiased bioinformatics approaches.MethodsOriginal data published in the last decade concerning the comparison of epigenetic marks in human AT of individuals with metabolically unhealthy overweight/obesity (MUHO) versus normal weight individuals or individuals with metabolically healthy overweight/obesity (MHO) was assessed. Furthermore, association of these epigenetic marks with IR/dysglycemic traits, including T2D, was compiled.ResultsWe catalogued more than two thousand differentially methylated regions (DMRs; above the cut-off of 5%) in the AT of individuals with MUHO compared to individuals with MHO. These DNA methylation changes were less likely to occur around the promoter regions and were enriched at loci implicated in intracellular signaling (signal transduction mediated by small GTPases, ERK1/2 signaling and intracellular trafficking). We also identified a network of seven transcription factors that may play an important role in targeting DNA methylation changes to specific genes in the AT of subjects with MUHO, contributing to the pathogeny of obesity-related IR/T2D. Furthermore, we found differentially methylated CpG sites at 8 genes that were present in AT and whole blood, suggesting that DMRs in whole blood could be potentially used as accessible biomarkers of MUHO.ConclusionsThe overall evidence linking epigenetic alterations in key tissues such AT to metabolic complications in human obesity is still very limited, highlighting the need for further studies, particularly those focusing on epigenetic marks other than DNA methylation. Our initial analysis suggests that DNA methylation patterns can potentially discriminate between MUHO from MHO and provide new clues into why some people with obesity are less susceptible to dysglycemia. Identifying AT-specific epigenetic targets could also lead to novel approaches to modify the progression of individuals with obesity towards metabolic disease.Systematic Review RegistrationPROSPERO, identifier CRD42021227237.

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.…”

“…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. 14,15 However, all of these studies did not provide potential candidates to better predict the pathways implicated in the transition from MHO to MUO.…”

DNA Methylation Mediates the Association Between Individual and Neighborhood Social Disadvantage and Cardiovascular Risk Factors

“…The protein encoded by DPEP2 has been shown to modulate macrophage inflammation ( 88 ), and is upregulated in subcutaneous white adipose tissue in obese women with type 2 diabetes ( 89 ). The most highly ranked MESA eQTM was cg19103704, which is associated with expression of the proteasome 26S subunit, ATPase 4 ( PSMC4 ), a subunit of perilipin-2 which regulates intracellular lipid metabolism in macrophages, and the fc fragment of IgG binding protein ( FCGBP ), both of which have been associated with obesity ( 90 , 91 ).…”

Changes in adiposity over the life course and gene expression in postmenopausal women

“… 52 More than 2000 differentially methylated regions in adipose tissue of individuals with unhealthy overweight/obesity versus normal‐weight individuals or individuals with metabolically healthy overweight/obesity have been identified. 53 However, the epigenetic evidence for long‐term change of obesity from age 10 to postmenopause is lacking. Future studies can integrate genetic and epigenetic data to elucidate the underlying mechanisms driving early life adiposity.…”

“…Epigenetic dysregulation during early development may increase the risk of obesity 52 . More than 2000 differentially methylated regions in adipose tissue of individuals with unhealthy overweight/obesity versus normal‐weight individuals or individuals with metabolically healthy overweight/obesity have been identified 53 . However, the epigenetic evidence for long‐term change of obesity from age 10 to postmenopause is lacking.…”