Altered Adipose Tissue DNA Methylation Status in Metabolic Syndrome: Relationships Between Global DNA Methylation and Specific Methylation at Adipogenic, Lipid Metabolism and Inflammatory Candidate Genes and Metabolic Variables

Castellano‐Castillo, Daniel; Moreno-Indias, Isabel; Sánchez-Alcoholado, Lidia; Ramos‐Molina, Bruno; Alcaide-Torres, Juan; Morcillo, Sonsoles; Ocaña-Wilhelmi, Luis; Tinahones, Francisco J.; Cardona, Fernando

doi:10.3390/jcm8010087

Cited by 67 publications

(63 citation statements)

References 71 publications

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“…Deletion of SCD1 gene product in mice could effectively improve insulin sensitivity, reduce plasma non-HDL-cholesterol and triglyceride levels and liver lipid accumulation as well as increase bene cial HDL-cholesterol levels [49]. Daniel Castellano-Castillo et al also found that a negative relationship between SCD DNA methylation and BMI and the MetS index [50]. In the current study, we also noticed that SCD was mainly involved in fatty acid metabolism and biosynthesis of unsaturated fatty acids pathways.…”

Section: Discussionsupporting

confidence: 68%

Weighted gene co-expression network analysis to identify key modules and hub genes related to hyperlipidaemia

Liao

Zheng

Guan

et al. 2020

Preprint

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Background: The purpose of this study was to explore the potential molecular targets of hyperlipidaemia and the related molecular mechanisms.Methods: The microarray data set of GSE66676 obtained from patients with hyperlipidaemia was downloaded. The weighted gene co‑expression network (WGCNA) analysis was used to analyze the gene expression profile and royalblue module was considered as the highest correlation. Gene Ontology (GO) functional and Kyoto Encyclopedia of Genes and genomes (KEGG) pathway enrichment analyses were implemented for the identification of genes in the royalblue module using the Database for Annotation, Visualization and Integrated Discovery (DAVID) online tool (version 6.8; http://david.abcc.ncifcrf.gov). A protein-protein interaction (PPI) network was established by using the online STRING tool. Then, several hub genes were identified by the MCODE and cytoHubba plug-ins in Cytoscape software.Results: The significant module (royalblue) identified was associated with TC, TG and Non-HDL-C. GO and KEGG enrichment analyses revealed that the genes in the royalblue module were associated with carbon metabolism, steroid biosynthesis, fatty acid metabolism and biosynthesis of unsaturated fatty acids pathways. SQLE (degree = 17) was revealed as key molecules that associated with hypercholesterolemia (HCH) and SCD was revealed as key molecules that associated with hypertriglyceridemia (HTG). Meanwhile, RT-qPCR analysis also confirmed the above results based on our HCH/HTG samples.Conclusions: SQLE and SCD are related to hyperlipidaemia, SQLE/SCD may be new targets for cholesterol-lowering or triglyceride-lowering therapy, respectively.

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Section: Discussionsupporting

confidence: 68%

Weighted gene co-expression network analysis to identify key modules and hub genes related to hyperlipidaemia

Liao

Zheng

Guan

et al. 2020

Preprint

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“…Finally, limitations and critical aspects of the interpretation should be discussed one of which is that the analyses were on whole tissue samples instead of isolated adipocytes, as in other comparable studies [13,19,36,43] and due to the initially limited sample material available, protein expression analysis could not be performed here. It has been reported that in non-obese humans, macrophages can represent 10-25% of the immune cellular population in VAT, while in an obese condition this range is increased to 40-50% [26,30].…”

Section: Discussionmentioning

confidence: 99%

“…Various studies have described a direct relationship between visceral 2 of 13 adipose tissue (VAT) and the development of the pre-diabetic condition and diabetes. Mechanistically, this has been critically related to the inflammatory processes within adipose tissue, especially in visceral [13,14]. The particular pathophysiological role and precise mechanisms/factors within VAT for GDM are increasingly of interest.…”

Section: Introductionmentioning

confidence: 99%

“…Epigenetic alterations, especially of promoter methylation patterns, have been proposed as potential causes of insulin resistance, GDM, and obesity in a variety of aspects [2,13,16,17]. Therefore, in order to contribute to a better understanding of GDM pathophysiology, we sought to investigate the potential alterations of both TNF-α and/or SOCS3 mRNA expression and methylation in adipose tissues of women with GDM compared to pregnancies with normal glucose tolerance (NGT).…”

Section: Introductionmentioning

confidence: 99%

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Visceral Adipose Tissue Inflammatory Factors (TNF-Alpha, SOCS3) in Gestational Diabetes (GDM): Epigenetics as a Clue in GDM Pathophysiology

Rancourt

Ott

Ziska

et al. 2020

IJMS

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Gestational diabetes (GDM) is among the most challenging diseases in westernized countries, affecting mother and child, immediately and in later life. Obesity is a major risk factor for GDM. However, the impact visceral obesity and related epigenetics play for GDM etiopathogenesis have hardly been considered so far. Our recent findings within the prospective ‘EaCH’ cohort study of women with GDM or normal glucose tolerance (NGT), showed the role, critical factors of insulin resistance (i.e., adiponectin, insulin receptor) may have for GDM pathophysiology with epigenetically modified expression in subcutaneous (SAT) and visceral (VAT) adipose tissues. Here we investigated the expression and promoter methylation of key inflammatory candidates, tumor necrosis factor-alpha (TNF-α) and suppressor of cytokine signaling 3 (SOCS3) in maternal adipose tissues collected during caesarian section (GDM, n = 19; NGT, n = 22). The mRNA expression of TNF-α and SOCS3 was significantly increased in VAT, but not in SAT, of GDM patients vs. NGT, accompanied by specific alterations of respective promoter methylation patterns. In conclusion, we propose a critical role of VAT and visceral obesity for the pathogenesis of GDM, with epigenetic alterations of the expression of inflammatory factors as a potential factor.

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“…Visceral adipose tissue is a metabolically active endocrine organ that has been linked to the development of obesity and obesity-related comorbidities (23, 24). Understanding the epigenetic and molecular differences in VAT of adolescents with obesity in comparison to lean counterparts may help identify potential therapeutic targets and further inform our understanding of tissue dysfunction in obesity.…”

Section: Discussionmentioning

confidence: 99%

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

Barberio

Nadler

Sevilla

et al. 2019

Preprint

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Background: Epigenetic 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. Methods: VAT samples from adolescent females grouped as Lean (L; n=15; age=15±3 yrs, BMI=21.9±3.0 kg/m 2 ) or Obese (Ob; n=15, age=16±2 yrs, BMI=45.8±9.8 kg/m 2 ) 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. Results: Overlapping differences in methylation and gene expression in 317 genes were found in VAT from obese compared to lean groups. PI3K/AKT Signaling (p=1.83x10 -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. Conclusion: Our 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.Subjects. Adolescent (age 12-19) females grouped as either Lean (L; body mass index (BMI) <25; n=15) or Obese (Ob, BMI >35; n=15) were recruited to participate in this study. Three races (African-American, Caucasian and Hispanic) were represented in equal numbers (5 L; 5 Ob each). Lean patients were recruited from non-bariatric abdominal surgeries (appendectomies and cholecystectomies), while subjects with obesity were recruited prior to bariatric surgery at Children's National Medical Center. Known clinical diagnoses and medications at the time of surgery are listed below per group -N=1 per diagnosis/medication unless otherwise noted. Lean cohort: sickle cell anemia, localized peritonitis, ulcerative colitis, Crohn's disease, acid reflux, Remicade (n=2), Albuterol, and prednisone. Obese cohort: asthma (n=4), sleep apnea (n=3), insulin resistance, hypertension, polycystic ovary syndrome, appendicitis, cholecystitis, sickle cell trait, pseudotumor cerebri, hypothyroidism, albuterol, prednisone, Lisinopril, levothyroxine, and Diamox. Bariatric surgery patients had completed a protein-sparing modified fast (~1000 kcal/day; 50-60 g protein) for two weeks prior to their date of surgery. All operations took place after a minimum 12-hour overnight fasting per standard surgical practices. Patients provided assent and legal guardians signed written informed consents as approved by the Children's National Medical Center ...

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Altered Adipose Tissue DNA Methylation Status in Metabolic Syndrome: Relationships Between Global DNA Methylation and Specific Methylation at Adipogenic, Lipid Metabolism and Inflammatory Candidate Genes and Metabolic Variables

Cited by 67 publications

References 71 publications

Weighted gene co-expression network analysis to identify key modules and hub genes related to hyperlipidaemia

Weighted gene co-expression network analysis to identify key modules and hub genes related to hyperlipidaemia

Visceral Adipose Tissue Inflammatory Factors (TNF-Alpha, SOCS3) in Gestational Diabetes (GDM): Epigenetics as a Clue in GDM Pathophysiology

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

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