scholarly journals Identification of Three Significant Genes Associated with Immune Cells Infiltration in Dysfunctional Adipose Tissue-Induced Insulin-Resistance of Obese Patients via Comprehensive Bioinformatics Analysis

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Ming Zhai ◽  
Peipei Luan ◽  
Yefei Shi ◽  
Bo Li ◽  
Jianhua Kang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Correlation Analysis ◽  
Immune Cells ◽  
Plasma Cells ◽  
Immune Cell ◽  
Low Grade ◽  
Hub Genes ◽  
Bioinformatics Analyses ◽  
Adipose Tissue Macrophages

Background. Low-grade chronic inflammation in dysfunctional adipose tissue links obesity with insulin resistance through the activation of tissue-infiltrating immune cells. Numerous studies have reported on the pathogenesis of insulin-resistance. However, few studies focused on genes from genomic database. In this study, we would like to explore the correlation of genes and immune cells infiltration in adipose tissue via comprehensive bioinformatics analyses and experimental validation in mice and human adipose tissue. Methods. Gene Expression Omnibus (GEO) datasets (GSE27951, GSE55200, and GSE26637) of insulin-resistant individuals or type 2 diabetes patients and normal controls were downloaded to get differently expressed genes (DEGs), and GO and KEGG pathway analyses were performed. Subsequently, we integrated DEGs from three datasets and constructed commonly expressed DEGs’ PPI net-works across datasets. Center regulating module of DEGs and hub genes were screened through MCODE and cytoHubba in Cytoscape. Three most significant hub genes were further analyzed by GSEA analysis. Moreover, we verified the predicted hub genes by performing RT qPCR analysis in animals and human samples. Besides, the relative fraction of 22 immune cell types in adipose tissue was detected by using the deconvolution algorithm of CIBERSORT (Cell Type Identification by Estimating Relative Subsets of RNA Transcripts). Furthermore, based on the significantly changed types of immune cells, we performed correlation analysis between hub genes and immune cells. And, we performed immunohistochemistry and immunofluorescence analysis to verify that the hub genes were associated with adipose tissue macrophages (ATM). Results. Thirty DEGs were commonly expressed across three datasets, most of which were upregulated. DEGs mainly participated in the process of multiple immune cells’ infiltration. In protein-protein interaction network, we identified CSF1R, C1QC, and TYROBP as hub genes. GSEA analysis suggested high expression of the three hub genes was correlated with immune cells functional pathway’s activation. Immune cell infiltration and correlation analysis revealed that there were significant positive correlations between TYROBP and M0 macrophages, CSF1R and M0 macrophages, Plasma cells, and CD8 T cells. Finally, hub genes were associated with ATMs infiltration by experimental verification. Conclusions. This article revealed that CSF1R, C1QC, and TYROBP were potential hub genes associated with immune cells’ infiltration and the function of proinflammation, especially adipose tissue macrophages, in the progression of obesity-induced diabetes or insulin-resistance.

scholarly journals Identification of potential therapeutic targets for atherosclerosis by analysing the gene signature related to different immune cells and immune regulators in atheromatous plaques

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Yang Shen ◽  
Li-rong Xu ◽  
Xiao Tang ◽  
Chang-po Lin ◽  
Dong Yan ◽  
...  
Keyword(s):  
Immune Cells ◽  
Plasma Cells ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Gamma Delta ◽  
Hub Genes ◽  
Gene Set Enrichment ◽  
Bioinformatics Analyses ◽  
Immune Infiltration ◽  
Atheromatous Plaques

Abstract Background Atherosclerosis is a chronic inflammatory disease that affects multiple arteries. Numerous studies have shown the inherent immune diversity in atheromatous plaques and suggest that the dysfunction of different immune cells plays an important role in atherosclerosis. However, few comprehensive bioinformatics analyses have investigated the potential coordinators that might orchestrate different immune cells to exacerbate atherosclerosis. Methods Immune infiltration of 69 atheromatous plaques from different arterial beds in GSE100927 were explored by single-sample-gene-set enrichment analysis (presented as ssGSEA scores), ESTIMATE algorithm (presented as immune scores) and CIBERSORT algorithm (presented as relative fractions of 22 types of immune cells) to divide these plaques into ImmuneScoreL cluster (of low immune infiltration) and ImmuneScoreH cluster (of high immune infiltration). Subsequently, comprehensive bioinformatics analyses including differentially-expressed-genes (DEGs) analysis, protein–protein interaction networks analysis, hub genes analysis, Gene-Ontology-terms and KEGG pathway enrichment analysis, gene set enrichment analysis, analysis of expression profiles of immune-related genes, correlation analysis between DEGs and hub genes and immune cells were conducted. GSE28829 was analysed to cross-validate the results in GSE100927. Results Immune-related pathways, including interferon-related pathways and PD-1 signalling, were highly enriched in the ImmuneScoreH cluster. HLA-related (except for HLA-DRB6) and immune checkpoint genes (IDO1, PDCD-1, CD274(PD-L1), CD47), RORC, IFNGR1, STAT1 and JAK2 were upregulated in the ImmuneScoreH cluster, whereas FTO, CRY1, RORB, and PER1 were downregulated. Atheromatous plaques in the ImmuneScoreH cluster had higher proportions of M0 macrophages and gamma delta T cells but lower proportions of plasma cells and monocytes (p < 0.05). CAPG, CECR1, IL18, IGSF6, FBP1, HLA-DPA1 and MMP7 were commonly related to these immune cells. In addition, the advanced-stage carotid plaques in GSE28829 exhibited higher immune infiltration than early-stage carotid plaques. Conclusions Atheromatous plaques with higher immune scores were likely at a more clinically advanced stage. The progression of atherosclerosis might be related to CAPG, IGSF6, IL18, CECR1, FBP1, MMP7, FTO, CRY1, RORB, RORC, PER1, HLA-DPA1 and immune-related pathways (IFN-γ pathway and PD-1 signalling pathway). These genes and pathways might play important roles in regulating immune cells such as M0 macrophages, gamma delta T cells, plasma cells and monocytes and might serve as potential therapeutic targets for atherosclerosis.

scholarly journals Aerobic training reduces immune cell recruitment and cytokine levels in adipose tissue in obese mice

2019 ◽  
Vol 44 (5) ◽  
pp. 512-520 ◽  
Author(s):  
Débora Romualdo Lacerda ◽  
Michele Macedo Moraes ◽  
Albená Nunes-Silva ◽  
Kátia Anunciação Costa ◽  
Débora Fernandes Rodrigues ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Immune Cells ◽  
Aerobic Training ◽  
Immune Cell ◽  
Control Diet ◽  
Moderate Intensity ◽  
Low Grade ◽  
Carbohydrate Diet ◽  
Cytokine Levels ◽  
Low Grade Inflammation

Obesity is associated with an energy imbalance that results from excessive energy intake, low diet quality, and a sedentary lifestyle. The increased consumption of a high-refined carbohydrate (HC) diet is strongly related to higher adiposity and low-grade inflammation. Aerobic training is a well-known nonpharmacological intervention to treat obesity and metabolic disturbances. However, the mechanisms through which aerobic training ameliorates the low-grade inflammation induced by an HC diet should be further investigated. Our hypothesis herein was that aerobic training would decrease the recruitment of leukocytes in adipose tissue, thereby reducing the levels of cytokines and improving metabolism in mice fed an HC diet. Male Balb/c mice were assigned to the following groups: control diet/nontrained (C-NT), control diet/trained (C-T), high-refined carbohydrate diet/nontrained (HC-NT), and high-refined carbohydrate diet/trained (HC-T). Mice were submitted to moderate-intensity training sessions that consisted of running 60 min per day for 8 weeks. An intravital microscopy technique was performed in vivo in anesthetized mice to visualize the microvasculature of the adipose tissue. The HC diet induced obesity and increased the influx of immune cells into the adipose tissue. In contrast, HC-T mice presented a lower adiposity and adipocyte area. Furthermore, relative to HC-NT mice, HC-T mice showed increased resting energy expenditure, decreased recruitment of immune cells in the adipose tissue, reduced cytokine levels, and ameliorated hyperglycemia and fatty liver deposition. Collectively, our data enhance understanding about the anti-inflammatory effect of aerobic training and shed light on the adipose tissue-mediated mechanisms by which training promotes a healthier metabolic profile.

The role of innate immune cells in obese adipose tissue inflammation and development of insulin resistance

2013 ◽  
Vol 109 (03) ◽  
pp. 399-406 ◽  
Author(s):  
Triantafyllos Chavakis ◽  
Jindrich Chmelar ◽  
Kyoung-Jin Chung
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Immune Cells ◽  
Cytotoxic T Cells ◽  
Innate Immune ◽  
Low Grade ◽  
Innate Immune Cells ◽  
Metabolic Complications ◽  
Adaptive Immune Cells

SummaryObesity is characterised by a chronic state of low-grade inflammation in different tissues including the vasculature. There is a causal link between adipose tissue (AT) inflammation and obesity-related metabolic complications, such as the development of insulin resistance and subsequently of type 2 diabetes. Intense efforts in the recent years have aimed at dissecting the pathophysiology of AT inflammation. The role of both innate and adaptive immune cells, such as macrophages or cytotoxic T cells in AT inflammation has been demonstrated. Besides these cells, more leukocyte subpopulations have been recently implicated in obesity, including neutrophils and eosinophils, mast cells, natural killer cells or dendritic cells. The involvement of multiple leukocyte subpopulations underlines the complexity of obesity-associated AT inflammation. In this review, we discuss the role of innate immune cells in AT inflammation, obesity and related metabolic disorders.

scholarly journals Adipose Tissue in Obesity-Related Inflammation and Insulin Resistance: Cells, Cytokines, and Chemokines

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Kassem Makki ◽  
Philippe Froguel ◽  
Isabelle Wolowczuk
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Immune Cells ◽  
Metabolic Regulation ◽  
Immune Cell ◽  
Suppressor Cells ◽  
Cell Types ◽  
Immune Functions ◽  
Cytokines And Chemokines ◽  
Wide Range

Adipose tissue is a complex organ that comprises a wide range of cell types with diverse energy storage, metabolic regulation, and neuroendocrine and immune functions. Because it contains various immune cells, either adaptive (B and T lymphocytes; such as regulatory T cells) or innate (mostly macrophages and, more recently identified, myeloid-derived suppressor cells), the adipose tissue is now considered as a bona fide immune organ, at the cross-road between metabolism and immunity. Adipose tissue disorders, such as those encountered in obesity and lipodystrophy, cause alterations to adipose tissue distribution and function with broad effects on cytokine, chemokine, and hormone expression, on lipid storage, and on the composition of adipose-resident immune cell populations. The resulting changes appear to induce profound consequences for basal systemic inflammation and insulin sensitivity. The purpose of this review is to synthesize the current literature on adipose cell composition remodeling in obesity, which shows how adipose-resident immune cells regulate inflammation and insulin resistance—notably through cytokine and chemokine secretion—and highlights major research questions in the field.

scholarly journals Adipose tissue macrophages in aging-associated adipose tissue function

2021 ◽  
Vol 71 (1) ◽  
Author(s):  
Bangchao Lu ◽  
Liang Huang ◽  
Juan Cao ◽  
Lingling Li ◽  
Wenhui Wu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Therapeutic Targets ◽  
Visceral Adiposity ◽  
Low Grade ◽  
Recent Advances ◽  
Adipose Tissue Macrophages ◽  
Low Grade Inflammation

Abstract“Inflammaging” refers to the chronic, low-grade inflammation that characterizes aging. Aging, like obesity, is associated with visceral adiposity and insulin resistance. Adipose tissue macrophages (ATMs) have played a major role in obesity-associated inflammation and insulin resistance. Macrophages are elevated in adipose tissue in aging. However, the changes and also possibly functions of ATMs in aging and aging-related diseases are unclear. In this review, we will summarize recent advances in research on the role of adipose tissue macrophages with aging-associated insulin resistance and discuss their potential therapeutic targets for preventing and treating aging and aging-related diseases.

scholarly journals Leukocyte Heterogeneity in Adipose Tissue, Including in Obesity

2020 ◽  
Vol 126 (11) ◽  
pp. 1590-1612 ◽  
Author(s):  
Ada Weinstock ◽  
Hernandez Moura Silva ◽  
Kathryn J. Moore ◽  
Ann Marie Schmidt ◽  
Edward A. Fisher
Keyword(s):  
Adipose Tissue ◽  
Immune Cells ◽  
Immune Cell ◽  
Γδ T Cells ◽  
The United States ◽  
Low Grade ◽  
Obesity Prevalence ◽  
Cell Level ◽  
Mortality And Morbidity ◽  
Molecular Investigation

Adipose tissue (AT) plays a central role in both metabolic health and pathophysiology. Its expansion in obesity results in increased mortality and morbidity, with contributions to cardiovascular disease, diabetes mellitus, fatty liver disease, and cancer. Obesity prevalence is at an all-time high and is projected to be 50% in the United States by 2030. AT is home to a large variety of immune cells, which are critical to maintain normal tissue functions. For example, γδ T cells are fundamental for AT innervation and thermogenesis, and macrophages are required for recycling of lipids released by adipocytes. The expansion of visceral white AT promotes dysregulation of its immune cell composition and likely promotes low-grade chronic inflammation, which has been proposed to be the underlying cause for the complications of obesity. Interestingly, weight loss after obesity alters the AT immune compartment, which may account for the decreased risk of developing these complications. Recent technological advancements that allow molecular investigation on a single-cell level have led to the discovery of previously unappreciated heterogeneity in many organs and tissues. In this review, we will explore the heterogeneity of immune cells within the visceral white AT and their contributions to homeostasis and pathology.

scholarly journals CD40 deficiency in mice exacerbates obesity-induced adipose tissue inflammation, hepatic steatosis, and insulin resistance

2013 ◽  
Vol 304 (9) ◽  
pp. E951-E963 ◽  
Author(s):  
Chang-An Guo ◽  
Sophia Kogan ◽  
Shinya U. Amano ◽  
Mengxi Wang ◽  
Sezin Dagdeviren ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Hepatic Steatosis ◽  
Immune Cell ◽  
Ex Vivo ◽  
Liver Steatosis ◽  
Epididymal Adipose Tissue ◽  
Low Grade ◽  
Wild Type ◽  
Cytokine Levels

The pathophysiology of obesity and type 2 diabetes in rodents and humans is characterized by low-grade inflammation in adipose tissue and liver. The CD40 receptor and its ligand CD40L initiate immune cell signaling promoting inflammation, but conflicting data on CD40L-null mice confound its role in obesity-associated insulin resistance. Here, we demonstrate that CD40 receptor-deficient mice on a high-fat diet display the expected decrease in hepatic cytokine levels but paradoxically exhibit liver steatosis, insulin resistance, and glucose intolerance compared with their age-matched wild-type controls. Hyperinsulinemic-euglycemic clamp studies also demonstrated insulin resistance in glucose utilization by the CD40-null mice compared with wild-type mice. In contrast to liver, adipose tissue in CD40-deficient animals harbors elevated cytokine levels and infiltration of inflammatory cells, particularly macrophages and CD8+effector T cells. In addition, ex vivo explants of epididymal adipose tissue from CD40−/−mice display elevated basal and isoproterenol-stimulated lipolysis, suggesting a potential increase of lipid efflux from visceral fat to the liver. These findings reveal that 1) CD40-null mice represent an unusual model of hepatic steatosis with reduced hepatic inflammation, and 2) CD40 unexpectedly functions in adipose tissue to attenuate its inflammation in obesity, thereby protecting against hepatic steatosis.

scholarly journals Human Adipose Tissue Macrophages Are Enhanced but Changed to an Anti-Inflammatory Profile in Obesity

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Karen Fjeldborg ◽  
Steen B. Pedersen ◽  
Holger J. Møller ◽  
Tore Christiansen ◽  
Marianne Bennetzen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Human Adipose Tissue ◽  
Multivariate Regression Analysis ◽  
Low Grade ◽  
Macrophage Marker ◽  
Adipose Tissue Macrophages ◽  
Obese Subjects ◽  
Anti Inflammatory ◽  
Inflammatory Profile

Objective. Adipose tissue (AT) macrophages are increased in obesity and associated with low grade inflammation. We aimed to characterize the phenotype of AT macrophages in humans in relation to obesity and insulin resistance.Design. Gene-expression levels of general macrophage markers (CD68 and CD14), proinflammatory markers/M1 (TNF-α, MCP-1, and IL-6), and anti-inflammatory markers/M2 (CD163, CD206, and IL-10) were determined by RT-PCR in subcutaneous AT samples from lean and obese subjects. Insulin resistance was determined by HOMA-IR.Results. All the macrophage markers were elevated in the AT from obese compared to lean subjects (P<0.001). To determine the phenotype of the macrophages the level of CD14 was used to adjust the total number of macrophages. The relative expression of CD163 and IL-10 was elevated, and TNF-αand IL-6 were reduced in AT from obese subjects (allP<0.05). In a multivariate regression analysis CD163 was the only macrophage marker significantly associated with HOMA-IR (β: 0.57;P<0.05). Conclusion. Obesity is associated with elevated numbers of macrophages in the AT. Unexpectedly, the macrophages change phenotype by obesity, with a preponderance of M2 and a decrement of M1 markers in AT from obese subjects. Moreover, CD163 was the only macrophage marker associated with HOMA-IR after multiple adjustments.

Abstract 81: Absence of Macrophage microRNA-155 Affects Cardiac Metabolic and Inflammatory Remodeling Following Diabesotension and Protects Against Development of Heart Failure

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Monika Rech ◽  
Kristiaan Wouters ◽  
Julie Lecomte ◽  
Nicole Bitsch ◽  
Stephane Heymans ◽  
...  
Keyword(s):  
Heart Failure ◽  
Insulin Resistance ◽  
Adipose Tissue ◽  
Cardiac Dysfunction ◽  
Immune Cell ◽  
Interstitial Fibrosis ◽  
Uncoupling Protein ◽  
Chow Diet ◽  
Low Grade ◽  
Cardiac Inflammation

The co-existence of diabetes, obesity, hypertension - diabesotension - is a major burden in western societies and often culminates into heart failure (HF). Diabesotension is associated with a chronic status of low-grade inflammation, involving macrophage infiltration into adipose and cardiac tissues, local activation of inflammatory pathways and concomitant insulin-resistance. We showed that the microRNA miR-155 is a powerful modulator of hypertension-induced cardiac inflammation and HF. Here we hypothesize that absence of miR-155 in macrophages protects against adipose tissue and cardiac inflammation during diabesotension and thereby prevents insulin resistance and cardiac dysfunction. Male C57Bl/6J mice received a bone marrow transplantation of miR-155 WT (n=30) or miR-155 KO (n=30) donors with same genetic background. High fat (HFD; n=22/gr) or chow diet (n=8/gr) was given for 20 weeks. An HFD subgroup was subjected to pressure overload by angiotensin II (1.5mg/kg/d) for 4 weeks (HFD+PO; n=12/gr). Glycaemia, glucose tolerance test, cardiac MRI were performed after 16 and/or 20 weeks. Organs were stored for histology, RNA and FACS analysis. After 16 weeks of HFD, body weight (+11% WT; +14% KO; p<0.05) and glycaemia (+16% WT; +18% KO; p<0.05) increased compared to chow diet animals in both genotypes, confirming the status of obesity and pre-diabetes. Absence of macrophage miR-155 protected HFD-mice from glucose intolerance (at T15: WT 25.08; KO 18.15 mmol/L; p<0.05), suggesting that adipose tissue macrophages might contribute to insulin resistance. In addition, HFD+PO caused mild systolic dysfunction in WT but not in miR-155 KO animals compared to control (ejection fraction: -19% WT, p<0.05; -7% KO, n.s.). While cardiac interstitial fibrosis was not affected by absence of macrophage miR-155, cardiac CD45-positive leukocyte infiltration upon HFD+PO was abrogated. HFD+PO-induced cardiac expression of two PPAR-dependent metabolic genes, angiopoietin-like 4 and uncoupling protein 3, is repressed in the absence of macrophage miR-155. Our data suggest that macrophage miR-155 plays a role in the development of insulin resistance and cardiac dysfunction, possibly by affecting local immune cell function and metabolic programming.

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