Increased adipose tissue expression of TLR8 in obese individuals with or without type-2 diabetes: significance in metabolic inflammation

Ahmad, Rasheed; Kochumon, Shihab; Thomas, Reeby; Atizado, Valerie; Sindhu, Sardar

doi:10.1186/s12950-016-0147-y

Cited by 32 publications

(26 citation statements)

References 44 publications

(42 reference statements)

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“…In line with this finding, increased expression of TLRs 1-9 and TLRs 11-13 was reported in two murine models of obesity [55]. Whereas in obese/T2D individuals, we have already reported the increased expression of several TLRs including TLR-2, -4, -7, -8, and -10 [28,[56][57][58]. The present data show the congruence between adipose tissue expression of IRF5 and most TLRs in obesity/T2D.…”

Section: Discussionsupporting

confidence: 91%

Enhanced Adipose Expression of Interferon Regulatory Factor (IRF)-5 Associates with the Signatures of Metabolic Inflammation in Diabetic Obese Patients

Sindhu

Kochumon

Thomas

et al. 2020

Cells

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Interferon regulatory factors (IRFs) are emerging as the metabolic transcriptional regulators in obesity/type-2 diabetes (T2D). IRF5 is implicated with macrophage polarization toward the inflammatory M1-phenotype, nonetheless, changes in the adipose expression of IRF5 in T2D and relationship of these changes with other markers of adipose inflammation remain unclear. Therefore, we determined the IRF5 gene expression in subcutaneous adipose tissue samples from 46 T2D patients including 35 obese (Body Mass Index/BMI 33.83 ± 0.42 kg/m 2 ) and 11 lean/overweight individuals (BMI 27.55 ± 0.46 kg/m 2 ) using real-time qRT-PCR. IRF5 protein expression was assessed using immunohistochemistry and confocal microscopy. Fasting plasma glucose, insulin, HbA1c, C-reactive protein, cholesterol, low-and high-density lipoproteins (LDL/HDL), and triglycerides were measured using commercial kits. IRF5 gene expression was compared with that of signature inflammatory markers and several clinico-metabolic indicators. The data (mean ± SEM) show the enhanced adipose IRF5 gene (p = 0.03) and protein (p = 0.05) expression in obese compared to lean/overweight diabetic patients. Adipose IRF5 transcripts in diabetic obese individuals associated positively with those of TNF-α, IL-18, IL-23A, CXCL8, CCL2, CCL7, CCR1/5, CD11c, CD68, CD86, TLR4/7/10, Dectin-1, FGL-2, MyD88, NF-κB, IRF3, and AML1 (p < 0.05). In diabetic lean/overweight subjects, IRF5 expression associated with BMI, body fat %age, glucose, insulin, homeostatic model assessment of insulin resistance (HOMA-IR, C-reactive protein (CRP), IL-5, and IL-1RL1 expression; while in all T2D patients, IRF5 expression correlated with that of IRF4, TLR2/8, and CD163. In conclusion, upregulated adipose tissue IRF5 expression in diabetic obese patients concurs with the inflammatory signatures and it may represent a potential marker for metabolic inflammation in obesity/T2D.

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Section: Discussionsupporting

confidence: 91%

Enhanced Adipose Expression of Interferon Regulatory Factor (IRF)-5 Associates with the Signatures of Metabolic Inflammation in Diabetic Obese Patients

Sindhu

Kochumon

Thomas

et al. 2020

Cells

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“…In agreement with this argument, it was shown that the visceral adipose tissue expression of several TLRs (TLR1, TLR4, TLR5, TLR8, TLR9, & TLR12) and downstream signaling molecules (MyD88, IRFs, NF-κB & STAT-1) was higher in diet-induced obese mice than leptin-deficient ob/ob mice [18]. Also in humans, increased expression of TLR2, TLR3, TLR4, TLR5, TLR7, and TLR8 was reported in obesity/T2D [14, 19, 20]. Among all TLRs, little is known about ligand(s) and function of TLR10.…”

Section: Discussionmentioning

confidence: 99%

Increased Expression of the Innate Immune Receptor TLR10 in Obesity and Type-2 Diabetes: Association with ROS-Mediated Oxidative Stress

Sindhu

Akhter

Kochumon

et al. 2018

Cell Physiol Biochem

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Background/Aims: Metabolic diseases such as obesity and type-2 diabetes (T2D) are known to be associated with chronic low-grade inflammation called metabolic inflammation together with an oxidative stress milieu found in the expanding adipose tissue. The innate immune Toll-like receptors (TLR) such as TLR2 and TLR4 have emerged as key players in metabolic inflammation; nonetheless, TLR10 expression in the adipose tissue and its significance in obesity/T2D remain unclear. Methods: TLR10 gene expression was determined in the adipose tissue samples from healthy non-diabetic and T2D individuals, 13 each, using real-time RT-PCR. TLR10 protein expression was determined by immunohistochemistry, confocal microscopy, and flow cytometry. Regarding in vitro studies, THP-1 cells, peripheral blood mononuclear cells (PBMC), or primary monocytes were treated with hydrogen peroxide (H₂O₂) for induction of reactive oxygen species (ROS)-mediated oxidative stress. Superoxide dismutase (SOD) activity was measured using a commercial kit. Data (mean±SEM) were compared using unpaired student’s t-test and P<0.05 was considered significant. Results: The adipose tissue TLR10 gene/protein expression was found to be significantly upregulated in obesity as well as T2D which correlated with body mass index (BMI). ROS-mediated oxidative stress induced high levels of TLR10 gene/protein expression in monocytic cells and PBMC. In these cells, oxidative stress induced a time-dependent increase in SOD activity. Pre-treatment of cells with anti-oxidants/ROS scavengers diminished the expression of TLR10. ROS-induced TLR10 expression involved the nuclear factor-kappaB (NF-κB)/mitogen activated protein kinase (MAPK) signaling as well as endoplasmic reticulum (ER) stress. H₂O₂-induced oxidative stress interacted synergistically with palmitate to trigger the expression of TLR10 which associated with enhanced expression of proinflammatory cytokines/chemokine. Conclusion: Oxidative stress induces the expression of TLR10 which may represent an immune marker for metabolic inflammation.

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“…For example, Sindhu et al ( 41 ) revealed that CD86 protein expression was significantly enhanced in adipose tissue samples obtained from patients with obesity. Furthermore, CD86 has been demonstrated to be positively correlated with the levels of pro-inflammatory cytokines in adipose tissues, including IL-18, IL-18R and TLR8 ( 42 , 43 ). Vitamin D supplementation, which decreases the expression of CD86 in the spleen, has been proposed as a treatment option to alleviate high-fat diet-induced obesity ( 44 ).…”

Section: Discussionmentioning

confidence: 99%

Screening of exosomal miRNAs derived from subcutaneous and visceral adipose tissues: Determination of targets for the treatment of obesity and associated metabolic disorders

Yang

Wei

et al. 2018

Mol Med Report

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Exosomal micro (mi)RNAs have been suggested to have important roles in abdominal obesity, and to be associated with metabolic alterations via posttranscriptional regulation of target genes. However, exosomal miRNA profiles in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) have rarely been investigated. In the present study, microarray data were obtained from the Gene Expression Omnibus database with the following accession numbers: GSE68885 (exosomal miRNAs in SAT obtained from seven patients with obesity and five lean patients), GSE50574 (exosomal miRNAs in VAT obtained from seven patients with obesity and five lean patients) and GSE29718 [mRNAs in SAT (obtained from seven patients with obesity and eight lean patients) and VAT (obtained from three patients with obesity and two lean patients)]. Differentially expressed (DE)-miRNAs and differentially expressed genes (DEGs) were identified using the Linear Models for Microarray Data method, and mRNA targets of DE-miRNAs were predicted using the miRWalk2.0 database. Potential functions of DE-miRNA target genes were determined using the Database for Annotation, Visualization and Integrated Discovery. As a result, 10 exosomal DE-miRNAs were identified in SAT between patients with obesity and lean patients, while 58 DE-miRNAs were identified in VAT between patients with obesity and lean patients. miRNA (miR)-4517 was revealed to be a downregulated exosomal miRNA between SAT and VAT, while the other DE-miRNAs were SAT-(e.g. hsa-miR-3156-5p and hsa-miR-4460) or VAT-(e.g. hsa-miR-582-5p, hsa-miR-566 and miR-548) specific. Following overlapping with the target genes of DE-miRNAs, only one DEG [cluster of differentiation 86 (CD86)] was identified in SAT samples, whereas 25 DEGs (e.g. fibroblast growth factor 2 (FGF2), FOS like 2, AP-1 transcription factor subunit (FOSL2); and adenosine monophosphate deaminase 3 (AMPD3)] were identified in VAT samples. CD86 was revealed to be regulated by hsa-miR-3156-5p; whereas FGF2, FOSL2 and AMPD3 were revealed to be regulated by hsa-miR-582-5p, hsa-miR-566 and miR-548, respectively. Functional enrichment analysis demonstrated that these target genes may be associated with inflammation. In conclusion, exosomal miRNAs may represent underlying therapeutic targets for the treatment of abdominal obesity and metabolic disorders via regulation of inflammatory genes.

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Increased adipose tissue expression of TLR8 in obese individuals with or without type-2 diabetes: significance in metabolic inflammation

Cited by 32 publications

References 44 publications

Enhanced Adipose Expression of Interferon Regulatory Factor (IRF)-5 Associates with the Signatures of Metabolic Inflammation in Diabetic Obese Patients

Enhanced Adipose Expression of Interferon Regulatory Factor (IRF)-5 Associates with the Signatures of Metabolic Inflammation in Diabetic Obese Patients

Increased Expression of the Innate Immune Receptor TLR10 in Obesity and Type-2 Diabetes: Association with ROS-Mediated Oxidative Stress

Screening of exosomal miRNAs derived from subcutaneous and visceral adipose tissues: Determination of targets for the treatment of obesity and associated metabolic disorders

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