scholarly journals Integrative analysis of glucometabolic traits, adipose tissue DNA methylation and gene expression identifies epigenetic regulatory mechanisms of insulin resistance and obesity in African Americans

2020 ◽  
Author(s):  
Ada Admin ◽  
Neeraj K. Sharma ◽  
Mary E. Comeau ◽  
Dennis Montoya ◽  
Matteo Pellegrini ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Dna Methylation ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
African Americans ◽  
Association Studies ◽  
Regulation Of Gene Expression ◽  
Transcript Level ◽  
Matsuda Index

Decline in insulin sensitivity due to dysfunction of adipose tissue (AT) is one of the earliest pathogenic events in Type 2 Diabetes. We hypothesize that differential DNA methylation (DNAm) controls insulin sensitivity and obesity by modulating transcript expression in AT. Integrating AT DNAm profiles with transcript profile data measured in a cohort of 230 African Americans from AAGMEx cohort, we performed <i>cis</i>-expression quantitative trait methylation (<i>cis</i>-eQTM) analysis to identify epigenetic regulatory loci for glucometabolic trait-associated transcripts. We identified significantly associated CpG-regions for 82 transcripts (FDR-P<0.05). The strongest eQTM locus was observed for the proopiomelanocortin (<i>POMC</i>; r= -0.632, P= 4.70X10<sup>-27</sup>) gene. Epigenome-wide association studies (EWAS) further identified 155, 46, and 168 CpG regions associated (FDR-P <0.05) with Matsuda index, S<sub>I</sub> and BMI, respectively. Intersection of EWAS, transcript level to trait association, and eQTM results, followed by causal inference test identified significant eQTM loci for 23 genes that were also associated with Matsuda index, S<sub>I </sub>and/or BMI in EWAS. These associated genes include <i>FERMT3</i>, <i>ITGAM</i>, <i>ITGAX</i>, and <i>POMC</i>. In summary, applying an integrative multi-omics approach, our study provides evidence for DNAm-mediated regulation of gene expression at both previously identified and novel loci for many key AT transcripts influencing insulin resistance and obesity.

scholarly journals Integrative analysis of glucometabolic traits, adipose tissue DNA methylation and gene expression identifies epigenetic regulatory mechanisms of insulin resistance and obesity in African Americans

2020 ◽  
Author(s):  
Ada Admin ◽  
Neeraj K. Sharma ◽  
Mary E. Comeau ◽  
Dennis Montoya ◽  
Matteo Pellegrini ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Dna Methylation ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
African Americans ◽  
Association Studies ◽  
Regulation Of Gene Expression ◽  
Transcript Level ◽  
Matsuda Index

Decline in insulin sensitivity due to dysfunction of adipose tissue (AT) is one of the earliest pathogenic events in Type 2 Diabetes. We hypothesize that differential DNA methylation (DNAm) controls insulin sensitivity and obesity by modulating transcript expression in AT. Integrating AT DNAm profiles with transcript profile data measured in a cohort of 230 African Americans from AAGMEx cohort, we performed <i>cis</i>-expression quantitative trait methylation (<i>cis</i>-eQTM) analysis to identify epigenetic regulatory loci for glucometabolic trait-associated transcripts. We identified significantly associated CpG-regions for 82 transcripts (FDR-P<0.05). The strongest eQTM locus was observed for the proopiomelanocortin (<i>POMC</i>; r= -0.632, P= 4.70X10<sup>-27</sup>) gene. Epigenome-wide association studies (EWAS) further identified 155, 46, and 168 CpG regions associated (FDR-P <0.05) with Matsuda index, S<sub>I</sub> and BMI, respectively. Intersection of EWAS, transcript level to trait association, and eQTM results, followed by causal inference test identified significant eQTM loci for 23 genes that were also associated with Matsuda index, S<sub>I </sub>and/or BMI in EWAS. These associated genes include <i>FERMT3</i>, <i>ITGAM</i>, <i>ITGAX</i>, and <i>POMC</i>. In summary, applying an integrative multi-omics approach, our study provides evidence for DNAm-mediated regulation of gene expression at both previously identified and novel loci for many key AT transcripts influencing insulin resistance and obesity.

scholarly journals Associations between plasma branched-chain amino acids, β-aminoisobutyric acid and body composition

2016 ◽  
Vol 5 ◽  
Author(s):  
Annemarie Rietman ◽  
Takara L. Stanley ◽  
Clary Clish ◽  
Vamsi Mootha ◽  
Marco Mensink ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Amino Acids ◽  
Body Composition ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Cardiometabolic Risk ◽  
Branched Chain Amino Acids ◽  
Multivariate Modelling ◽  
Matsuda Index ◽  
Branched Chain

AbstractPlasma branched-chain amino acids (BCAA) are elevated in obesity and associated with increased cardiometabolic risk. β-Aminoisobutyric acid (B-AIBA), a recently identified small molecule metabolite, is associated with decreased cardiometabolic risk. Therefore, we investigated the association of BCAA and B-AIBA with each other and with detailed body composition parameters, including abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT). A cross-sectional study was carried out with lean (n 15) and obese (n 33) men and women. Detailed metabolic evaluations, including measures of body composition, insulin sensitivity and plasma metabolomics were completed. Plasma BCAA were higher (1·6 (se 0·08) (×107) v. 1·3 (se 0·06) (×107) arbitrary units; P = 0·005) in obese v. lean subjects. BCAA were positively associated with VAT (R 0·49; P = 0·0006) and trended to an association with SAT (R 0·29; P = 0·052). The association between BCAA and VAT, but not SAT, remained significant after controlling for age, sex and race on multivariate modelling (P < 0·05). BCAA were also associated with parameters of insulin sensitivity (Matsuda index: R −0·50, P = 0·0004; glucose AUC: R 0·53, P < 0·001). BCAA were not associated with B-AIBA (R −0·04; P = 0·79). B-AIBA was negatively associated with SAT (R −0·37; P = 0·01) but only trended to an association with VAT (R 0·27; P = 0·07). However, neither relationship remained significant after multivariate modelling (P > 0·05). Plasma B-AIBA was associated with parameters of insulin sensitivity (Matsuda index R 0·36, P = 0·01; glucose AUC: R −0·30, P = 0·04). Plasma BCAA levels were positively correlated with VAT and markers of insulin resistance. The results suggest a possible complex role of adipose tissue in BCAA homeostasis and insulin resistance.

scholarly journals Dynamic Strength Training Improves Insulin Sensitivity without Altering Plasma Levels and Gene Expression of Adipokines in Subcutaneous Adipose Tissue in Obese Men

2006 ◽  
Vol 91 (12) ◽  
pp. 5107-5112 ◽  
Author(s):  
E. Klimcakova ◽  
J. Polak ◽  
C. Moro ◽  
J. Hejnova ◽  
M. Majercik ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Strength Training ◽  
Plasma Levels ◽  
Dynamic Strength ◽  
Whole Body ◽  
Obese Subjects ◽  
Dynamic Strength Training

Abstract Context: Obesity is characterized by a low-grade inflammatory state, which could play a role in insulin resistance. Dynamic strength training improves insulin sensitivity. Objective: The objective of this study was to investigate, in obese subjects, whether the insulin sensitizing effect of dynamic strength training is associated with changes in plasma levels and gene expression of adipokines potentially involved in the development of insulin resistance. Design: Twelve obese male subjects were investigated before and at the end of 3 months of dynamic strength training. Insulin sensitivity was evaluated using euglycemic-hyperinsulinemic clamp. Blood samples and needle biopsy samples of sc abdominal adipose tissue were obtained. The plasma levels and adipose tissue mRNA levels of adiponectin, leptin, IL-1β, IL-6, and TNF-α were determined. Results: The training induced an increase in the whole-body glucose disposal rate by 24% (P = 0.04). The body weight was not altered during the training. Plasma levels of leptin decreased during the training (16.6 ± 6.3 vs. 13.1 ± 5.7 ng/ml) by 21% (P &lt; 0.02), whereas no change in plasma levels of other adipokines and C-reactive protein was observed. Gene expression of the investigated adipokines was not changed in sc adipose tissue during the training. Conclusions: In obese subjects, the dynamic strength training resulted in an improvement of whole-body insulin sensitivity. The increase in insulin sensitivity was not associated with training-induced modifications of plasma levels or adipose tissue gene expression of adipokines supposedly involved in the development of insulin resistance.

scholarly journals Omics Approaches in Adipose Tissue and Skeletal Muscle Addressing the Role of Extracellular Matrix in Obesity and Metabolic Dysfunction

2021 ◽  
Vol 22 (5) ◽  
pp. 2756
Author(s):  
Augusto Anguita-Ruiz ◽  
Mireia Bustos-Aibar ◽  
Julio Plaza-Díaz ◽  
Andrea Mendez-Gutierrez ◽  
Jesús Alcalá-Fdez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Dna Methylation ◽  
Extracellular Matrix ◽  
Adipose Tissue ◽  
Association Studies ◽  
Epigenetic Mechanism ◽  
Biological Traits ◽  
Metabolic Dysfunction ◽  
Ecm Remodeling

Extracellular matrix (ECM) remodeling plays important roles in both white adipose tissue (WAT) and the skeletal muscle (SM) metabolism. Excessive adipocyte hypertrophy causes fibrosis, inflammation, and metabolic dysfunction in adipose tissue, as well as impaired adipogenesis. Similarly, disturbed ECM remodeling in SM has metabolic consequences such as decreased insulin sensitivity. Most of described ECM molecular alterations have been associated with DNA sequence variation, alterations in gene expression patterns, and epigenetic modifications. Among others, the most important epigenetic mechanism by which cells are able to modulate their gene expression is DNA methylation. Epigenome-Wide Association Studies (EWAS) have become a powerful approach to identify DNA methylation variation associated with biological traits in humans. Likewise, Genome-Wide Association Studies (GWAS) and gene expression microarrays have allowed the study of whole-genome genetics and transcriptomics patterns in obesity and metabolic diseases. The aim of this review is to explore the molecular basis of ECM in WAT and SM remodeling in obesity and the consequences of metabolic complications. For that purpose, we reviewed scientific literature including all omics approaches reporting genetic, epigenetic, and transcriptomic (GWAS, EWAS, and RNA-seq or cDNA arrays) ECM-related alterations in WAT and SM as associated with metabolic dysfunction and obesity.

scholarly journals Intermuscular adipose tissue directly modulates skeletal muscle insulin sensitivity in humans

2019 ◽  
Vol 316 (5) ◽  
pp. E866-E879 ◽  
Author(s):  
Stephan Sachs ◽  
Simona Zarini ◽  
Darcy E. Kahn ◽  
Kathleen A. Harrison ◽  
Leigh Perreault ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Matrix Proteins ◽  
Muscle Insulin Resistance ◽  
Intermuscular Adipose Tissue ◽  
Skeletal Muscle Insulin Resistance ◽  
Skeletal Muscle Insulin Sensitivity

Intermuscular adipose tissue (IMAT) is negatively related to insulin sensitivity, but a causal role of IMAT in the development of insulin resistance is unknown. IMAT was sampled in humans to test for the ability to induce insulin resistance in vitro and characterize gene expression to uncover how IMAT may promote skeletal muscle insulin resistance. Human primary muscle cells were incubated with conditioned media from IMAT, visceral (VAT), or subcutaneous adipose tissue (SAT) to evaluate changes in insulin sensitivity. RNAseq analysis was performed on IMAT with gene expression compared with skeletal muscle and SAT, and relationships to insulin sensitivity were determined in men and women spanning a wide range of insulin sensitivity measured by hyperinsulinemic-euglycemic clamp. Conditioned media from IMAT and VAT decreased insulin sensitivity similarly compared with SAT. Multidimensional scaling analysis revealed distinct gene expression patterns in IMAT compared with SAT and muscle. Pathway analysis revealed that IMAT expression of genes in insulin signaling, oxidative phosphorylation, and peroxisomal metabolism related positively to donor insulin sensitivity, whereas expression of macrophage markers, inflammatory cytokines, and secreted extracellular matrix proteins were negatively related to insulin sensitivity. Perilipin 5 gene expression suggested greater IMAT lipolysis in insulin-resistant individuals. Combined, these data show that factors secreted from IMAT modulate muscle insulin sensitivity, possibly via secretion of inflammatory cytokines and extracellular matrix proteins, and by increasing local FFA concentration in humans. These data suggest IMAT may be an important regulator of skeletal muscle insulin sensitivity and could be a novel therapeutic target for skeletal muscle insulin resistance.

Influence of TNF-α and IL-6 infusions on insulin sensitivity and expression of IL-18 in humans

2006 ◽  
Vol 291 (1) ◽  
pp. E108-E114 ◽  
Author(s):  
Rikke Krogh-Madsen ◽  
Peter Plomgaard ◽  
Kirsten Møller ◽  
Bettina Mittendorfer ◽  
Bente K. Pedersen
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Muscle Tissue ◽  
Plasma Concentrations ◽  
Whole Body ◽  
Euglycemic Hyperinsulinemic Clamp ◽  
Tnf Α

Inflammation is associated with insulin resistance, and both tumor necrosis factor (TNF)-α and interleukin (IL)-6 may affect glucose uptake. TNF induces insulin resistance, whereas the role of IL-6 is controversial. High plasma levels of IL-18 are associated with insulin resistance in epidemiological studies. We investigated the effects of TNF and IL-6 on IL-18 gene expression in skeletal muscle and adipose tissue. Nine human volunteers underwent three consecutive interventions, receiving an infusion of recombinant human (rh)IL-6, rhTNF, and saline. Insulin sensitivity was assessed by measurement of whole body glucose uptake with the stable isotope tracer method during a euglycemic hyperinsulinemic clamp (20 mU·min−1·kg−1), which was initiated 1 h after the IL-6-TNF-saline infusion. Cytokine responses were measured in plasma, muscle, and fat biopsies. Plasma concentrations of TNF and IL-6 increased 10- and 38-fold, respectively, during the cytokine infusions. Whole body insulin-mediated glucose uptake was significantly reduced during TNF infusion but remained unchanged during IL-6 infusion. TNF induced IL-18 gene expression in muscle tissue, but not in adipose tissue, whereas IL-6 infusion had no effect on IL-18 gene expression in either tissue. We conclude that TNF-induced insulin resistance of whole body glucose uptake is associated with increased IL-18 gene expression in muscle tissue, indicating that TNF and IL-18 interact, and both may have important regulatory roles in the pathogenesis of insulin resistance.

scholarly journals CREB pathway links PGE2 signaling with macrophage polarization

2015 ◽  
Vol 112 (51) ◽  
pp. 15642-15647 ◽  
Author(s):  
Bing Luan ◽  
Young-Sil Yoon ◽  
John Le Lay ◽  
Klaus H. Kaestner ◽  
Susan Hedrick ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Adipose Tissue ◽  
Immune System ◽  
Insulin Sensitivity ◽  
Innate Immune System ◽  
Marker Gene ◽  
Innate Immune ◽  
M2 Polarization ◽  
Marker Gene Expression

Obesity is thought to promote insulin resistance in part via activation of the innate immune system. Increases in proinflammatory cytokine production by M1 macrophages inhibit insulin signaling in white adipose tissue. In contrast, M2 macrophages have been found to enhance insulin sensitivity in part by reducing adipose tissue inflammation. The paracrine hormone prostaglandin E2 (PGE2) enhances M2 polarization in part through activation of the cAMP pathway, although the underlying mechanism is unclear. Here we show that PGE2 stimulates M2 polarization via the cyclic AMP-responsive element binding (CREB)-mediated induction of Krupple-like factor 4 (KLF4). Targeted disruption of CREB or the cAMP-regulated transcriptional coactivators 2 and 3 (CRTC2/3) in macrophages down-regulated M2 marker gene expression and promoted insulin resistance in the context of high-fat diet feeding. As re-expression of KLF4 rescued M2 marker gene expression in CREB-depleted cells, our results demonstrate the importance of the CREB/CRTC pathway in maintaining insulin sensitivity in white adipose tissue via its effects on the innate immune system.

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