Genome-wide DNA methylation pattern in visceral adipose tissue differentiates insulin-resistant from insulin-sensitive obese subjects

Abstract Objective The risk to develop type 2 diabetes increases with the amount of visceral adiposity presumably due to increased lipolysis and subsequent lipid accumulation in visceral organs. However, data describing the molecular regulation of these pathways in humans are rare. We tested if genes of the lipogenic and lipolytic pathways are associated with glucose intolerance independently of obesity in visceral adipose tissue (VAT) of obese subjects. Moreover, we studied DNA methylation of FASN (fatty acid synthase), that catalyses the synthesis of long-chain fatty acids, in VAT of the same subjects and whether it is associated with metabolic traits. Subjects and methods Visceral adipose tissue biopsies and blood samples were taken from 93 severely obese subjects undergoing bariatric surgery. Subjects were grouped in low HbA1c (L-HbA1c, HbA1c<6.5 %) and high HbA1c (H-HbA1c, HbA1c≥6.5 %) groups and expression of genes from the lipogenic and lipolytic pathways was analysed by TaqMan qPCR. DNA methylation of FASN was quantified by bisulfite-pyrosequencing. Results FASN expression was downregulated in visceral fat from subjects with high HbA1c (p = 0.00009). Expression of other lipogenetic (SCD, ELOVL6) or lipolytic genes (ADRB3, PNPLA2) and FABP4 was not changed. DNA methylation of FASN was increased at a regulatory ChoRE recognition site in the H-HbA1c-subgroup and correlated negatively with FASN mRNA (r = − 0.302, p = 0.0034) and positively with HbA1c (r = 0.296, p = 0.0040) and blood glucose (r = 0.363, p = 0.0005). Conclusions Epigenetic downregulation of FASN in visceral adipose tissue of obese subjects might contribute to limited de novo lipogenesis of important insulin sensitizing fatty acids and could thereby contribute to glucose intolerance and the development of type 2 diabetes independently of obesity.

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A Six Months Exercise Intervention Influences the Genome-wide DNA Methylation Pattern in Human Adipose Tissue

PLoS Genetics ◽

10.1371/journal.pgen.1003572 ◽

2013 ◽

Vol 9 (6) ◽

pp. e1003572 ◽

Cited By ~ 362

Author(s):

Tina Rönn ◽

Petr Volkov ◽

Cajsa Davegårdh ◽

Tasnim Dayeh ◽

Elin Hall ◽

...

Keyword(s):

Dna Methylation ◽

Adipose Tissue ◽

Exercise Intervention ◽

Human Adipose Tissue ◽

Methylation Pattern ◽

Genome Wide ◽

Dna Methylation Pattern

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Free-amino acid metabolic profiling of visceral adipose tissue from obese subjects

Amino Acids ◽

10.1007/s00726-020-02877-6 ◽

2020 ◽

Vol 52 (8) ◽

pp. 1125-1137

Author(s):

M. C. Piro ◽

M. Tesauro ◽

A. M. Lena ◽

P. Gentileschi ◽

G. Sica ◽

...

Keyword(s):

Adipose Tissue ◽

Amino Acid ◽

Free Amino Acid ◽

Visceral Adipose Tissue ◽

Metabolic Profiling ◽

Free Amino ◽

Obese Subjects ◽

Visceral Adipose

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Abstract 17843: Visceral Adipose Tissue Secretion of Adiponectin Decreases with Increased Body Mass Index

Circulation ◽

10.1161/circ.130.suppl_2.17843 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Lenore R Rengel ◽

Brittaney Obi ◽

Jon Gould ◽

Matthew Goldblatt ◽

Andrew Kastenmeier ◽

...

Keyword(s):

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Metabolic Health ◽

Metabolically Healthy Obese ◽

Obese Subjects ◽

Healthy Obese ◽

Metabolically Healthy ◽

Visceral Adipose ◽

Subcutaneous Adipose

Introduction: Peripheral adiposity is associated with better metabolic health and higher plasma adiponectin (ADPN) levels. Since ADPN is secreted mainly by adipose tissue (AT), it is intriguing that higher visceral adipose tissue (VAT) is associated with lower ADPN levels and poor metabolic health. Hypothesis: We hypothesized that various AT depots differ in their ability to secrete ADPN. Methods: Paired AT samples (VAT and subcutaneous adipose tissue (SAT)) were collected from 19 subjects (10 women, 15 obese) undergoing elective abdominal surgery. The samples were cultured and the supernatant was collected after 24 hours. ADPN levels released into the supernatant from VAT and SAT were measured using multiplex methods. Subjects were defined as obese or non-obese (NO) based on BMI > or ≤ 30kg/m2 respectively. Obese subjects were further classified as metabolically unhealthy obese (MUO) or metabolically healthy obese (MHO) based on presence or absence of type 2 diabetes mellitus, hypertension, or cardiovascular disease at the time of surgery. Results: Mean ADPN secretion levels from SAT and VAT were similar in NO subjects (17.3 ± 3.4 vs. 9.8 ± 13.0 ng/mL/mg, p=0.5) whereas the mean ADPN secretion was lower from VAT among obese subjects (15.9 ± 0.8 vs. 4.5 ± 0.2 ng/mL/mg, p=0.0002). ADPN secretion decreased from VAT (r=-0.16) and increased from SAT (r=0.33) with increased BMI (Fig.1). When MHO and MUO were compared, ADPN secretion from VAT in MHO was reduced only slightly (16.1 ± 8.2 vs. 4.0 ± 2.0 ng/mL/mg, p=0.07) whereas ADPN secretion was significantly reduced in MUO (15.9 ± 5.3 vs. 4.7 ± 4.6 ng/mL/mg, p=0.003). Conclusions: Reduced ADPN secretion from VAT in subjects with increasing BMI may explain lower circulating ADPN levels in obese individuals. Higher ADPN production from SAT and the relatively preserved secretion of ADPN from VAT may explain metabolic health in some obese individuals. Futures studies will help identify factors that control ADPN secretion from AT.

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24 The effect of bariatric surgery on DNA methylation in blood and omental visceral adipose tissue

10.1055/s-0041-1735683 ◽

2021 ◽

Author(s):

Luise Müller ◽

Lena Gras ◽

Anne Hoffmann ◽

Tobias Hagemann ◽

Stephan H. Bernhart ◽

...

Keyword(s):

Bariatric Surgery ◽

Dna Methylation ◽

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Visceral Adipose

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Reduced Biliverdin Reductase-A Expression in Visceral Adipose Tissue is Associated with Adipocyte Dysfunction and NAFLD in Human Obesity

International Journal of Molecular Sciences ◽

10.3390/ijms21239091 ◽

2020 ◽

Vol 21 (23) ◽

pp. 9091

Author(s):

Valentina Ceccarelli ◽

Ilaria Barchetta ◽

Flavia Agata Cimini ◽

Laura Bertoccini ◽

Caterina Chiappetta ◽

...

Keyword(s):

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Insulin Signalling ◽

Mrna Levels ◽

Gamma Glutamyl Transpeptidase ◽

Alcoholic Fatty Liver ◽

Biliverdin Reductase ◽

Omental Adipose Tissue ◽

Obese Subjects ◽

Visceral Adipose

Biliverdin reductase A (BVR-A) is an enzyme involved in the regulation of insulin signalling. Knockout (KO) mice for hepatic BVR-A, on a high-fat diet, develop more severe glucose impairment and hepato-steatosis than the wild type, whereas loss of adipocyte BVR-A is associated with increased visceral adipose tissue (VAT) inflammation and adipocyte size. However, BVR-A expression in human VAT has not been investigated. We evaluated BVR-A mRNA expression levels by real-time PCR in the intra-operative omental biopsy of 38 obese subjects and investigated the association with metabolic impairment, VAT dysfunction, and biopsy-proven non-alcoholic fatty liver disease (NAFLD). Individuals with lower VAT BVR-A mRNA levels had significantly greater VAT IL-8 and Caspase 3 expression than those with higher BVR-A. Lower VAT BVR-A mRNA levels were associated with an increased adipocytes’ size. An association between lower VAT BVR-A expression and higher plasma gamma-glutamyl transpeptidase was also observed. Reduced VAT BVR-A was associated with NAFLD with an odds ratio of 1.38 (95% confidence interval: 1.02–1.9; χ2 test) and with AUROC = 0.89 (p = 0.002, 95% CI = 0.76–1.0). In conclusion, reduced BVR-A expression in omental adipose tissue is associated with VAT dysfunction and NAFLD, suggesting a possible involvement of BVR-A in the regulation of VAT homeostasis in presence of obesity.

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ApoC-III and visceral adipose tissue contribute to paradoxically normal triglyceride levels in insulin-resistant African-American women

Nutrition & Metabolism ◽

10.1186/1743-7075-10-73 ◽

2013 ◽

Vol 10 (1) ◽

pp. 73 ◽

Cited By ~ 6

Author(s):

Anne E Sumner ◽

Jeremy D Furtado ◽

Amber B Courville ◽

Madia Ricks ◽

Novie Younger-Coleman ◽

...

Keyword(s):

Adipose Tissue ◽

African American ◽

African American Women ◽

Visceral Adipose Tissue ◽

American Women ◽

Insulin Resistant ◽

Normal Triglyceride ◽

Visceral Adipose

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Comparison of visceral adipose tissue DNA methylation and gene expression profiles in female adolescents with obesity

10.1101/728832 ◽

2019 ◽

Author(s):

Matthew D. Barberio ◽

Evan P. Nadler ◽

Samantha Sevilla ◽

Rosemary Lu ◽

Brennan Harmon ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Akt Signaling ◽

Adolescent Females ◽

Akt Signaling Pathway ◽

Visceral Adipose

AbstractBackgroundEpigenetic changes in visceral adipose tissue (VAT) with obesity and their effects on gene expression are poorly understood, especially during emergent obesity in youth. The current study tested the hypothesis that methylation and gene expression profiles of key growth factor and inflammatory pathways such as PI3K/AKT signaling are altered in VAT from obese compared to non-obese youth.MethodsVAT samples from adolescent females grouped as Lean (L; n=15; age=15±3 yrs, BMI=21.9±3.0 kg/m2) or Obese (Ob; n=15, age=16±2 yrs, BMI=45.8±9.8 kg/m2) were collected. Global methylation (n=20) and gene expression (N=30) patterns were profiled via microarray and interrogated for differences between groups by ANCOVA (p<0.05), followed by biological pathway analysis.ResultsOverlapping differences in methylation and gene expression in 317 genes were found in VAT from obese compared to lean groups. PI3K/AKT Signaling (p=1.83×10−6; 10/121 molecules in dataset/pathway) was significantly overrepresented in Ob VAT according to pathway analysis. mRNA upregulations in the PI3K/AKT Signaling Pathway genes TFAM (p=0.03; Fold change=1.8) and PPP2R5C (p=0.03, FC=2.6) were confirmed via qRT-PCR.ConclusionOur analyses show obesity-related differences in DNA methylation and gene expression in visceral adipose tissue of adolescent females. Specifically, we identified methylation site/gene expression pairs differentially regulated and mapped these differences to PI3K/AKT signaling, suggesting that PI3K/AKT signaling pathway dysfunction in obesity may be driven in part by obesity-related changes in DNA methylation.

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High Resolution Genome Wide DNA Methylation Analysis in a Large Trial Group Reveals a Novel Epigenetically Defined Subgroup of Myeloma Patients Characterized By Developmental Gene Hypermethylation

Blood ◽

10.1182/blood.v124.21.2189.2189 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2189-2189

Author(s):

Martin F Kaiser ◽

Alexander Murison ◽

Charlotte Pawlyn ◽

Eileen M Boyle ◽

David C Johnson ◽

...

Keyword(s):

Dna Methylation ◽

High Resolution ◽

Methylation Pattern ◽

Gene Set Enrichment Analysis ◽

Epigenetic Changes ◽

Dna Hypomethylation ◽

Dna Hypermethylation ◽

Epigenetic Programming ◽

Genome Wide ◽

Dna Methylation Pattern

Abstract Introduction Multiple myeloma is a clinically highly heterogeneous disease, which is reflected by both a complex genome and epigenome. Dynamic epigenetic changes are involved at several stages of myeloma biology, such as transformation and disease progression. Our previous genome wide epigenetic analyses identified prognostically relevant DNA hypermethylation at specific tumor suppressor genes (Kaiser MF et al., Blood 2013), indicating that specific epigenetic programming influences clinical behavior. This clinically relevant finding prompted further investigation of the epigenomic structure of myeloma and its interaction with genetic aberrations. Material and Methods Genome wide DNA methylation of CD138-purified myeloma cells from 464 patients enrolled in the NCRI Myeloma XI trial at presentation were analyzed using the high resolution 450k DNA methylation array platform (Illumina). In addition, 4 plasma cell leukemia (PCL) cases (two t(11;14) and two (4;14)) and 7 myeloma cell lines (HMCL) carrying different translocations were analysed. Analyses were performed in R Bioconductor packages after filtering and removal of low quality and non-uniquely mapping probes. Results Variation in genome wide DNA methylation was analyzed using unsupervised hierarchical clustering of the 10,000 most variable probes, which revealed epigenetically defined subgroups of disease. Presence of recurrent IGH translocations was strongly associated with specific epigenetic profiles. All 60 cases with t(4;14) clustered into two highly similar sub-clusters, confirming that overexpression of the H3K36 methyltransferase MMSET in t(4;14) has a defined and specific effect on the myeloma epigenome. Interestingly, HMCLs KMS-11 and LP-1, which carry t(4;14), MM1.S, a t(14;16) cell line with an E1099K MMSET activating mutation as well as two PCLs with t(4;14) all clustered in one sub-clade. The majority (59/85) of t(11;14) cases showed global DNA hypomethylation compared to t(4;14) cases and clustered in one subclade, indicating a epigenetic programming effect associated with CCND1, with a subgroup of t(11;14) cases showing a variable DNA methylation pattern. In addition to translocation-defined subgroups, a small cluster of samples with a distinct epigenetic profile was identified. In total 7 cases with a shared specific DNA methylation pattern (median inter-sample correlation 0.4) were identified. The group was characterized by DNA hypermethylation (4,341 hypermethylated regions vs. 750 hypomethylated regions) in comparison to all other cases. Intersection of regions hypermethylated in this subgroups with ENCODE datasets revealed mapping to poised enhancers and promoters in H1-hESC, indicating functionally relevant epigenetic changes. Gene set enrichment analysis (KEGG) demonstrated enrichment of developmental pathway genes, e.g. Hedgehog signaling (adj p=5x10exp-13), amongst others and all four HOX clusters were differentially methylated in this group. Of note, three of seven cases in this subgroup carried a t(11;14) and all t(11;14) or t(11;14)-like HMCLs clustered closely together with these patient cases, but not with the cluster carrying the majority of t(11;14) myeloma or t(11;14) PCLs. This potentially indicates that t(11;14) HMCL could be derived from a subgroup of patients with specific epigenetic characteristics. Conclusion Our results indicate that the recurrent IGH translocations are fundamentally involved in shaping the myeloma epigenome through either direct upregulation of epigenetic modifiers (e.g. MMSET) or through insufficiently understood mechanisms. However, developmental epigenetic processes seem to independently contribute to the complexity of the epigenome in some cases. This work provides important insights into the spectrum of epigenetic subgroups of myeloma and helps identify subgroups of disease that may benefit from specific epigenetic therapies currently being developed. Disclosures Walker: Onyx Pharmaceuticals: Consultancy, Honoraria.

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