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

2021 ◽  
Vol 12 ◽  
Author(s):  
Sara Andrade ◽  
Tiago Morais ◽  
Ionel Sandovici ◽  
Alexandre L. Seabra ◽  
Miguel Constância ◽  
...  
Keyword(s):  
Systematic Review ◽  
Dna Methylation ◽  
Adipose Tissue ◽  
Whole Blood ◽  
Intracellular Signaling ◽  
Phenotypic Variability ◽  
Normal Weight ◽  
Small Gtpases ◽  
Metabolic Complications ◽  
Epigenetic Marks

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.

scholarly journals DNMT1 maintains metabolic fitness of adipocytes through acting as an epigenetic safeguard of mitochondrial dynamics

2021 ◽  
Vol 118 (11) ◽  
pp. e2021073118
Author(s):  
Yoon Jeong Park ◽  
Sangseon Lee ◽  
Sangsoo Lim ◽  
Hahn Nahmgoong ◽  
Yul Ji ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Adipose Tissue ◽  
Energy Metabolism ◽  
Mitochondrial Dynamics ◽  
Ctcf Binding ◽  
Mitochondrial Bioenergetics ◽  
Metabolic Complications ◽  
Genetic Ablation ◽  
Adipocyte Hypertrophy ◽  
Metabolic Fitness

White adipose tissue (WAT) is a key regulator of systemic energy metabolism, and impaired WAT plasticity characterized by enlargement of preexisting adipocytes associates with WAT dysfunction, obesity, and metabolic complications. However, the mechanisms that retain proper adipose tissue plasticity required for metabolic fitness are unclear. Here, we comprehensively showed that adipocyte-specific DNA methylation, manifested in enhancers and CTCF sites, directs distal enhancer-mediated transcriptomic features required to conserve metabolic functions of white adipocytes. Particularly, genetic ablation of adipocyte Dnmt1, the major methylation writer, led to increased adiposity characterized by increased adipocyte hypertrophy along with reduced expansion of adipocyte precursors (APs). These effects of Dnmt1 deficiency provoked systemic hyperlipidemia and impaired energy metabolism both in lean and obese mice. Mechanistically, Dnmt1 deficiency abrogated mitochondrial bioenergetics by inhibiting mitochondrial fission and promoted aberrant lipid metabolism in adipocytes, rendering adipocyte hypertrophy and WAT dysfunction. Dnmt1-dependent DNA methylation prevented aberrant CTCF binding and, in turn, sustained the proper chromosome architecture to permit interactions between enhancer and dynamin-1–like protein gene Dnm1l (Drp1) in adipocytes. Also, adipose DNMT1 expression inversely correlated with adiposity and markers of metabolic health but positively correlated with AP-specific markers in obese human subjects. Thus, these findings support strategies utilizing Dnmt1 action on mitochondrial bioenergetics in adipocytes to combat obesity and related metabolic pathology.

scholarly journals DNA methylation in the adipose tissue and whole blood of Agent Orange-exposed Operation Ranch Hand veterans: a pilot study

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Matthew R. Rytel ◽  
Rondi Butler ◽  
Melissa Eliot ◽  
Joseph M. Braun ◽  
E. Andres Houseman ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Adipose Tissue ◽  
Pilot Study ◽  
Air Force ◽  
Whole Blood ◽  
Body Burden ◽  
Serum Levels ◽  
Agent Orange ◽  
Health Study ◽  
The Impact

Abstract Background Between 1962 and 1971, the US Air Force sprayed Agent Orange across Vietnam, exposing many soldiers to this dioxin-containing herbicide. Several negative health outcomes have been linked to Agent Orange exposure, but data is lacking on the effects this chemical has on the genome. Therefore, we sought to characterize the impact of Agent Orange exposure on DNA methylation in the whole blood and adipose tissue of veterans enrolled in the Air Force Health Study (AFHS). Methods We received adipose tissue (n = 37) and whole blood (n = 42) from veterans in the AFHS. Study participants were grouped as having low, moderate, or high TCDD body burden based on their previously measured serum levels of dioxin. DNA methylation was assessed using the Illumina 450 K platform. Results Epigenome-wide analysis indicated that there were no FDR-significantly methylated CpGs in either tissue with TCDD burden. However, 3 CpGs in the adipose tissue (contained within SLC9A3, LYNX1, and TNRC18) were marginally significantly (q < 0.1) hypomethylated, and 1 CpG in whole blood (contained within PTPRN2) was marginally significantly (q < 0.1) hypermethylated with high TCDD burden. Analysis for differentially methylated DNA regions yielded SLC9A3, among other regions in adipose tissue, to be significantly differentially methylated with higher TCDD burden. Comparing whole blood data to a study of dioxin exposed adults from Alabama identified a CpG within the gene SMO that was hypomethylated with dioxin exposure in both studies. Conclusion We found limited evidence of dioxin associated DNA methylation in adipose tissue and whole blood in this pilot study of Vietnam War veterans. Nevertheless, loci in the genes of SLC9A3 in adipose tissue, and PTPRN2 and SMO in whole blood, should be included in future exposure analyses.

DNA methylation of the Klf14 gene region in whole blood cells provides prediction for the chronic inflammation in the adipose tissue

2018 ◽  
Vol 497 (3) ◽  
pp. 908-915 ◽  
Author(s):  
Chihiro Iwaya ◽  
Hidetoshi Kitajima ◽  
Ken Yamamoto ◽  
Yasutaka Maeda ◽  
Noriyuki Sonoda ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Adipose Tissue ◽  
Chronic Inflammation ◽  
Whole Blood ◽  
Blood Cells ◽  
Gene Region ◽  
Whole Blood Cells

scholarly journals DNA Methylation in the Adipose Tissue and Whole Blood of Agent Orange-exposed Operation Ranch Hand Veterans

2020 ◽  
Author(s):  
Matthew Rae Rytel ◽  
Rondi Butler ◽  
Melissa Eliot ◽  
Joseph M. Braun ◽  
E. Andres Houseman ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Adipose Tissue ◽  
Vietnam War ◽  
Air Force ◽  
Whole Blood ◽  
Body Burden ◽  
Serum Levels ◽  
Agent Orange ◽  
Health Study ◽  
The Impact

Abstract BackgroundBetween 1962 and 1971, the US Air Force sprayed Agent Orange across Vietnam, exposing many soldiers to this dioxin-containing herbicide. Several negative health outcomes have been linked to Agent Orange exposure, but data is lacking on the effects this chemical has on the genome. Therefore, we sought to characterize the impact of Agent Orange exposure on DNA methylation in the whole blood and adipose tissue of veterans enrolled in the Air Force Health Study (AFHS). MethodsWe received adipose tissue (n=37) and whole blood (n=42) from veterans in the AFHS. Study participants were grouped as having low, moderate, or high TCDD body burden based on their previously measured serum levels of dioxin. DNA methylation was assessed using the Illumina 450K platform.ResultsEpigenome-wide analysis indicated that there were no FDR-significantly methylated CpGs in either tissue with TCDD burden. However, 3 CpGs in the adipose tissue (contained within SLC9A3, LYNX1, and TNRC18) were marginally significantly (q<0.1) hypomethylated, and 1 CpG in whole blood (contained within PTPRN2) was marginally significantly (q<0.1) hypermethylated with high TCDD burden. Analysis for differentially methylated DNA regions yielded SLC9A3, among other regions in adipose tissue, to be significantly differentially methylated with higher TCDD burden. Comparing whole blood data to a study of dioxin exposed adults from Alabama identified a CpG within the gene SMO that was hypomethylated with dioxin exposure in both studies. ConclusionWe found limited evidence of dioxin associated DNA methylation in adipose tissue and whole blood in this pilot study of Vietnam War veterans. Nevertheless, loci in the genes of SLC9A3 in adipose tissue, and PTPRN2 and SMO in whole blood, should be included in future exposure analyses.

scholarly journals DNA methylation of FKBP5 in South African women: associations with obesity and insulin resistance

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Tarryn Willmer ◽  
Julia H. Goedecke ◽  
Stephanie Dias ◽  
Johan Louw ◽  
Carmen Pheiffer
Keyword(s):  
Insulin Resistance ◽  
Dna Methylation ◽  
Adipose Tissue ◽  
South African ◽  
Hpa Axis ◽  
Normal Weight ◽  
African Women ◽  
Mrna Levels ◽  
South African Women ◽  
Subcutaneous Adipose

Abstract Background Disruption of the hypothalamic–pituitary–adrenal (HPA) axis, a neuroendocrine system associated with the stress response, has been hypothesized to contribute to obesity development. This may be mediated through epigenetic modulation of HPA axis-regulatory genes in response to metabolic stressors. The aim of this study was to investigate adipose tissue depot-specific DNA methylation differences in the glucocorticoid receptor (GR) and its co-chaperone, FK506-binding protein 51 kDa (FKBP5), both key modulators of the HPA axis. Methods Abdominal subcutaneous adipose tissue (ASAT) and gluteal subcutaneous adipose tissue (GSAT) biopsies were obtained from a sample of 27 obese and 27 normal weight urban-dwelling South African women. DNA methylation and gene expression were measured by pyrosequencing and quantitative real-time PCR, respectively. Spearman’s correlation coefficients, orthogonal partial least-squares discriminant analysis and multivariable linear regression were performed to evaluate the associations between DNA methylation, messenger RNA (mRNA) expression and key indices of obesity and metabolic dysfunction. Results Two CpG dinucleotides within intron 7 of FKBP5 were hypermethylated in both ASAT and GSAT in obese compared to normal weight women, while no differences in GR methylation were observed. Higher percentage methylation of the two FKBP5 CpG sites correlated with adiposity (body mass index and waist circumference), insulin resistance (homeostasis model for insulin resistance, fasting insulin and plasma adipokines) and systemic inflammation (c-reactive protein) in both adipose depots. GR and FKBP5 mRNA levels were lower in GSAT, but not ASAT, of obese compared to normal weight women. Moreover, FKBP5 mRNA levels were inversely correlated with DNA methylation and positively associated with adiposity, metabolic and inflammatory parameters. Conclusions These findings associate dysregulated FKBP5 methylation and mRNA expression with obesity and insulin resistance in South African women. Additional studies are required to assess the longitudinal association of FKBP5 with obesity and associated co-morbidities in large population-based samples. Graphical abstract

scholarly journals Changes in adipose tissue lipolysis gene expression and insulin sensitivity after weight loss

2020 ◽  
Vol 9 (2) ◽  
pp. 90-100 ◽  
Author(s):  
Monika Karczewska-Kupczewska ◽  
Agnieszka Nikołajuk ◽  
Radosław Majewski ◽  
Remigiusz Filarski ◽  
Magdalena Stefanowicz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Weight Loss ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Intervention Program ◽  
Dietary Intervention ◽  
Normal Weight ◽  
Control Group ◽  
Metabolic Complications ◽  
Obese Subjects

Objective Insulin resistance is a major pathophysiological link between obesity and its metabolic complications. Weight loss (WL) is an effective tool to prevent obesity-related diseases; however, the mechanisms of an improvement in insulin sensitivity (IS) after weight-reducing interventions are not completely understood. The aim of the present study was to analyze the relationships between IS and adipose tissue (AT) expression of the genes involved in the regulation of lipolysis in obese subjects after WL. Methods Fifty-two obese subjects underwent weight-reducing dietary intervention program. The control group comprised 20 normal-weight subjects, examined at baseline only. Hyperinsulinemic-euglycemic clamp and s.c. AT biopsy with subsequent gene expression analysis were performed before and after the program. Results AT expression of genes encoding lipases (PNPLA2, LIPE and MGLL) and lipid-droplet proteins enhancing (ABHD5) and inhibiting lipolysis (PLIN1 and CIDEA) were decreased in obese individuals in comparison with normal-weight individuals. The group of 38 obese participants completed dietary intervention program and clamp studies, which resulted in a significant WL and an improvement in mean IS. However, in nine subjects from this group IS did not improve in response to WL. AT expression of PNPLA2, LIPE and PLIN1 increased only in the group without IS improvement. Conclusions Excessive lipolysis may prevent an improvement in IS during WL. The change in AT PNPLA2 and LIPE expression was a negative predictor of the change in IS after WL.

scholarly journals Epigenetic findings in periodontitis in UK twins: a cross sectional study

2018 ◽  
Author(s):  
Yuko Kurushima ◽  
Pei-Chien Tsai ◽  
Juan Castillo Fernandez ◽  
Alexessander Couto Alves ◽  
Julia Sarah El-Sayed Moustafa ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Adipose Tissue ◽  
Periodontal Disease ◽  
Whole Blood ◽  
Chronic Periodontitis ◽  
P Value ◽  
Cross Sectional ◽  
Tissue Samples ◽  
Gingival Bleeding ◽  
Tooth Mobility

ABSTRACTBackgroundGenetic and environmental risk factors contribute to periodontal disease, but the underlying susceptibility pathways are not fully understood. Epigenetic mechanisms are malleable regulators of gene function that can change in response to genetic and environmental stimuli, thereby providing a potential mechanism for mediating risk effects in periodontitis. The aim of this study is to identify epigenetic changes across tissues that are associated with periodontal disease.MethodsSelf-reported gingival bleeding and history of gum disease, or tooth mobility, were used as indicators of periodontal disease. DNA methylation profiles were generated using the Infinium HumanMethylation450 BeadChip in whole blood, buccal, and adipose tissue samples from predominantly older female twins (mean age 58) from the TwinsUK cohort. Epigenome-wide association scans (EWAS) of gingival bleeding and tooth mobility were conducted in whole blood in 528 and 492 twins, respectively. Subsequently, targeted candidate gene analysis at 28 genomic regions was carried out testing for phenotype-methylation associations in 41 (tooth mobility) and 43 (gingival bleeding) buccal, and 501 (tooth mobility) and 556 (gingival bleeding) adipose DNA samples.ResultsEpigenome-wide analyses in blood identified one CpG-site (cg21245277 inZNF804A) associated with gingival bleeding (FDR=0.03, nominal p-value=7.17e-8), and 58 sites associated with tooth mobility (FDR<0.05) with the top signals inIQCEandXKR6. Epigenetic variation at 28 candidate regions (256 CpG-sites) for chronic periodontitis showed a strong enrichment for association with periodontal traits, and signals in eight genes (VDR, IL6ST, TMCO6, IL1RN, CD44, IL1B, WHAMM, andCXCL1) were significant in both traits. The methylation-phenotype association signals validated in buccal samples, and a subset (25%) also validated in adipose tissue.ConclusionsEpigenome-wide analyses in adult female twins identified specific DNA methylation changes linked to self-reported periodontal disease. Future work will explore the environmental basis and functional impact of these results to infer potential for strategic personalized treatments and prevention of chronic periodontitis.

scholarly journals Human adipocytes from the subcutaneous superficial layer have greater adipogenic potential and lower PPAR-γ DNA methylation levels than deep layer adipocytes

2016 ◽  
Vol 311 (2) ◽  
pp. C322-C329 ◽  
Author(s):  
Kentaro Kosaka ◽  
Yoshitaka Kubota ◽  
Naoki Adachi ◽  
Shinsuke Akita ◽  
Yoshitaro Sasahara ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Adipose Tissue ◽  
Cpg Island ◽  
Epigenetic Modification ◽  
Adipogenic Differentiation ◽  
Subcutaneous Fat ◽  
Adipocyte Size ◽  
Metabolic Complications ◽  
Differentiation Potential ◽  
Ppar Γ

Human subcutaneous fat tissue consists of two layers, superficial adipose tissue (SAT) and deep adipose tissue (DAT). Some recent reports suggest that a disproportionate accumulation of DAT is related to obesity-associated metabolic complications. However, the differences in adipocyte function between SAT and DAT are unclear. To clarify the differences in human adipocyte characteristics between SAT and DAT, human ceiling culture-derived proliferative adipocytes (ccdPAs) were primary cultured from SAT and DAT of three lean female patients. Differences in adipogenic differentiation potential and sensitivity to exogenous adipogenic factors were examined. Epigenetic modification of the CpG island DNA methylation levels of genes related to adipogenesis was measured. In histological analyses, the mean adipocyte size in SAT was significantly larger than that in DAT (8,741 ± 416 vs. 7,732 ± 213 μm2, P < 0.05). Primary cultured adipocytes from SAT showed significantly greater adipogenesis than did those of DAT. Sensitivity to partial adipogenic stimulation was significantly different between ccdPAs of SAT and DAT. Peroxisome proliferator-activated receptor-γ (PPAR-γ) protein expression and leptin protein secretion from ccdPAs were significantly higher in SAT than DAT. DNA methylation levels of PPAR-γ were significantly lower in ccdPAs of SAT than DAT. Adipocyte size was larger in SAT than DAT in vivo. This is consistent with the findings of an in vitro study that, compared with ccdPAs in DAT, ccdPAs in SAT have higher adipogenic potential and lower DNA methylation levels of PPAR-γ.

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