Epigenome-wide association in adipose tissue from the METSIM cohort

ABSTRACTMost epigenome-wide association studies to date have been conducted in blood. However, metabolic syndrome is mediated by a dysregulation of adiposity and therefore it is critical to study adipose tissue in order to understand the effects of this syndrome on epigenomes. To determine if natural variation in DNA methylation was associated with metabolic syndrome traits, we profiled global methylation levels in subcutaneous abdominal adipose tissue. We measured association between 32 clinical traits related to diabetes and obesity in 201 people from the Metabolic Syndrome In Men cohort. We performed epigenome-wide association studies between DNA methylation levels and traits, and identified associations for 13 clinical traits in 21 loci. We prioritized candidate genes in these loci using eQTL, and identified 18 high confidence candidate genes, including known and novel genes associated with diabetes and obesity traits. Using methylation deconvolution, we examined which cell types may be mediating the associations, and concluded that most of the loci we identified were specific to adipocytes. We determined whether the abundance of cell types varies with metabolic traits, and found that macrophages increased in abundance with the severity of metabolic syndrome traits. Finally, we developed a DNA methylation based biomarker to assess type II diabetes risk in adipose tissue. In conclusion, our results demonstrate that profiling DNA methylation in adipose tissue is a powerful tool for understanding the molecular effects of metabolic syndrome on adipose tissue, and can be used in conjunction with traditional genetic analyses to further characterize this disorder.

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Subcutaneous abdominal adipose tissue is associated with the metabolic syndrome in Asian Indians independent of intra-abdominal and total body fat

Heart ◽

10.1136/hrt.2009.183236 ◽

2010 ◽

Vol 96 (8) ◽

pp. 579-583 ◽

Cited By ~ 50

Author(s):

K. Goel ◽

A. Misra ◽

N. K. Vikram ◽

P. Poddar ◽

N. Gupta

Keyword(s):

Metabolic Syndrome ◽

Adipose Tissue ◽

Body Fat ◽

Asian Indians ◽

Abdominal Adipose Tissue ◽

The Metabolic Syndrome ◽

Total Body Fat ◽

Total Body ◽

Subcutaneous Abdominal Adipose Tissue

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Abstract 1124: CD40L Induces Inflammation in Adipose Tissue - a Potential Link Between the Metabolic Syndrome and Atherosclerosis

Circulation ◽

10.1161/circ.116.suppl_16.ii_226-b ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Anna Missiou ◽

Isabel Platzer ◽

Sandra Ernst ◽

Uwe Schonbeck ◽

Peter Libby ◽

...

Keyword(s):

Metabolic Syndrome ◽

Endothelial Cells ◽

Adipose Tissue ◽

Cardiovascular Risk ◽

Inflammatory Cytokine ◽

Inflammatory Responses ◽

Human Adipose Tissue ◽

Cell Types ◽

High Cardiovascular Risk ◽

The Metabolic Syndrome

Background: CD40L figures prominently as marker and mediator of atherosclerosis and its clinical complications. Recent data also demonstrate an association between CD40L and the metabolic syndrome. In the light of these data we hypothesized a functional pro-inflammatory role of CD40L in adipose tissue that provokes systemic pro-inflammatory responses and potentially mediates some of the high cardiovascular risk associated with the metabolic syndrome. Methods and Results: Adipocytes and preadipocytes isolated from adipose tissue obtained from bariatic surgery did not express CD40L but its receptor CD40 as assessed by PCR and immunohistochemistry. Furthermore, sections of human adipose tissue from obese donors contained more macrophages and T cells colocalizing with CD40L than those from lean controls. Stimulation of both adipocytes and preadipocytes with recombinant CD40L resulted in a concentration- and time-dependent release of the pro-inflammatory cytokine IL-6, the chemokines MCP -1 and IL-8 as well as the inhibitor of fibrinolysis PAI-1 into the supernatant as quantified by ELISA. Membranes isolated from a Murine cell line overexpressing human CD40L reproduced these pro-inflammatory effects compared to respective controls. Interestingly, fenofibrate but neither rosiglitazone, metformin, nor atorvastatin attenuated the CD40L-inducible expression of these pro-atherogenic mediators. Finally, supernatants from adipocytes and preadipocytes stimulated with CD40L activated endothelial cells and macrophages, typical cell types resident in atherosclerotic lesions, as assessed by FACS for tissue factor, Mac-1, and ICAM-1, respectively. Conclusions: Our data suggest that CD40L induces inflammatory cytokine production in adipose tissue resulting in activation of endothelial cells and macrophages. This new mechanism may contribute to the high cardiovascular risk of patients suffering from the metabolic syndrome.

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DNA methylation of candidate genes in peripheral blood from patients with type 2 diabetes or the metabolic syndrome

PLoS ONE ◽

10.1371/journal.pone.0180955 ◽

2017 ◽

Vol 12 (7) ◽

pp. e0180955 ◽

Cited By ~ 11

Author(s):

Sanne D. van Otterdijk ◽

Alexandra M. Binder ◽

Katarzyna Szarc vel Szic ◽

Julia Schwald ◽

Karin B. Michels

Keyword(s):

Type 2 Diabetes ◽

Metabolic Syndrome ◽

Dna Methylation ◽

Candidate Genes ◽

Peripheral Blood ◽

The Metabolic Syndrome

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Adipose Tissue LPL Methylation is Associated with Triglyceride Concentrations in the Metabolic Syndrome

Clinical Chemistry ◽

10.1373/clinchem.2017.277921 ◽

2018 ◽

Vol 64 (1) ◽

pp. 210-218 ◽

Cited By ~ 15

Author(s):

Daniel Castellano-Castillo ◽

Isabel Moreno-Indias ◽

José Carlos Fernández-García ◽

Juan Alcaide-Torres ◽

Inmaculada Moreno-Santos ◽

...

Keyword(s):

Gene Expression ◽

Metabolic Syndrome ◽

Dna Methylation ◽

Adipose Tissue ◽

Cpg Island ◽

Methylation Status ◽

The Metabolic Syndrome ◽

Postprandial Triglycerides ◽

Gene And Protein Expression ◽

Lpl Gene

Abstract BACKGROUND DNA methylation is one of the epigenetic mechanisms that regulate gene expression. DNA methylation may be modified by environmental and nutritional factors. Thus, epigenetics could potentially provide a mechanism to explain the etiology of metabolic disorders, such as metabolic syndrome (MetS). The aim of this study was to analyze the level of DNA methylation of several lipoprotein lipase (LPL)-promoter-CpG dinucleotides in a CpG island region and relate this to the gene and protein expression levels in human visceral adipose tissue (VAT) from individuals with and without MetS. METHODS VAT samples were collected from laparoscopic surgical patients without and with MetS, and levels of LPL mRNA, LPL protein, and LPL DNA methylation were measured by qPCR, western blot, and pyrosequencing. Biochemical and anthropometric variables were analyzed. Individuals included in a subset underwent a dietary fat challenge test, and levels of postprandial triglycerides were determined. RESULTS We found higher levels of DNA methylation in MetS patients but lower gene expression and protein levels. There was a negative association between LPL methylation and LPL gene expression. We found a positive association between LPL methylation status and abnormalities of the metabolic profile and basal and postprandial triglycerides, whereas LPL gene expression was negatively associated with these abnormalities. CONCLUSIONS We demonstrate that LPL methylation may be influenced by the degree of metabolic disturbances and could be involved in triglyceride metabolism, promoting hypertriglyceridemia and subsequent associated disorders, such as MetS.

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Altered subcutaneous abdominal adipose tissue lipid synthesis in obese, insulin-resistant humans

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00194.2013 ◽

2013 ◽

Vol 305 (8) ◽

pp. E999-E1006 ◽

Cited By ~ 17

Author(s):

Demidmaa Tuvdendorj ◽

Manisha Chandalia ◽

Tumurbaatar Batbayar ◽

Manish Saraf ◽

Carine Beysen ◽

...

Keyword(s):

Metabolic Syndrome ◽

Adipose Tissue ◽

Nonesterified Fatty Acid ◽

Oral Glucose ◽

Large Variability ◽

Abdominal Adipose Tissue ◽

The Metabolic Syndrome ◽

Wide Range ◽

Obese Subjects ◽

Subcutaneous Abdominal Adipose Tissue

The purpose of this study was to evaluate the variability of subcutaneous abdominal adipose tissue (AT) dynamics in obese subjects with a wide range of insulin sensitivity (IS) and the correlation between these two metabolic measures. Ten obese (BMI 30–40 kg/m2) nondiabetic subjects with ( n = 6) and without ( n = 4) the metabolic syndrome were studied following a 12-wk 2H2O labeling period. Subcutaneous abdominal AT biopsies were collected. Deuterium incorporation into triglyceride (TG)-glycerol and TG-palmitate were measured by gas chromatography-mass spectrometry for the calculation of fractional TG synthesis ( fTG) and fractional de novo lipogenesis ( fDNL). Muscle IS and insulin-mediated nonesterified fatty acid (NEFA) suppression (a measure for adipose IS) indexes were derived from the oral glucose tolerance test (OGTT). The ability of subcutaneous abdominal AT to synthesize lipids varied significantly in obese subjects ( fTG range 7–28%, fDNL range 1.1–4.6%) with significantly lower values (>35% reduction) for both parameters in obese with the metabolic syndrome. fTG correlated positively with muscle IS ( r = 0.64, P = 0.04) and inversely with NEFA suppression during the OGTT ( r = −0.69, P = 0.03). These results demonstrate a large variability in subcutaneous abdominal AT lipid turnover in obesity. Moreover, a reduced capacity for subcutaneous abdominal AT fat storage is associated with muscle and adipose tissue insulin resistance as well as with the metabolic syndrome, thus identifying a form of obesity at heightened risk for type 2 diabetes and cardiovascular disease.

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Abstract 3672: Loss of Perivascular Adipocyte Paracrine Function Leads to Increased Vascular Tone and Glucose Intolerance in Hypertension

Circulation ◽

10.1161/circ.118.suppl_18.s_463-b ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Kaivan Khavandi ◽

Adam Greenstein ◽

Sarah Withers ◽

Kazuhiko Sonoyama ◽

Sarah Lewis ◽

...

Keyword(s):

Oxidative Stress ◽

Metabolic Syndrome ◽

Adipose Tissue ◽

Vascular Tone ◽

Tnf Alpha ◽

Perivascular Adipose Tissue ◽

The Metabolic Syndrome ◽

Adipocyte Cell ◽

Therapeutic Opportunity

In order to investigate the contribution of perivascular adipose tissue (PVAT) to arterial function, a total of 55 small arteries harvested from 35 skin biopsies of patients with Metabolic Syndrome and matched controls were mounted as ring preparations in a wire myograph. Contractility to cumulative doses of Norepinephrine in the presence or absence of PVAT showed an anticontractile effect in arteries from healthy volunteers (p=0.009), which was lost in patients with Metabolic Syndrome. Bioassay studies confirmed that PVAT releases a hydrophilic anticontractile factor in health, which is absent in obesity. Using a soluble fragment of the human Type 1 receptor, we identified that the anticontractile factor was adiponectin, which is the sole mediator of vasodilation, acting by increasing endothelial bioavailability of nitric oxide. Significant endothelial dysfunction was observed in patients with Metabolic Syndrome (p<0.001). Quantitative image analysis of adipose tissue revealed significantly increased adipocyte cell size in patients with Metabolic Syndrome, compared with healthy controls (p<0.006). There was immunohistochemical evidence of inflammation with upregulation of TNF-alpha receptor 1 in these patients (p<0.001). Application of exogenous TNF-alpha abolished the anticontractile effect of PVAT by reducing adiponectin bioavailability. Oxidative stress also induced by cytokines TNF-alpha and IL-6 but not IL-1, reduced adiponectin production from PVAT and increased basal tone. When the obese microenvironment was replicated in vitro by inflicting hypoxia on PVAT, adiponectin activity was lost but then rescued by incubation with cytokine antagonists. Further application of the adiponectin receptor fragment abolished PVAT relaxation. We conclude that in healthy arteries, PVAT releases adiponectin which reduces vascular tone. In obesity, this is lost by a cascade of adipocyte hypertrophy, hypoxia, inflammation and oxidative stress. The resulting vasoconstriction contributes to hypertension, hypertriglyceridaemia and insulin resistance. Direct targeting of adiponectin release from PVAT therefore provides a novel therapeutic opportunity in the Metabolic Syndrome.

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