Abstract
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.
Highlights
Obesity became one of the major health concerns as it contributed to the growing prevalence of its related comorbidities, including insulin resistance (IR) and type 2 diabetes
The chronic inflammation has been identified by increased cytokines or chemokines expression, such as upregulated TNF-α, IL-6, and interferon (IFN) c, immune cell infiltration is a prominent feature of dysfunctional adipose tissue (AT), as well. ese immune cells include M1 and M2 polarization macrophages, effector and memory T cells, FoxP3+T regulatory cells, natural killer (NK), and NKT cells [7]
We first integrated three datasets including transcriptome data of adipose tissue between IRO and IS group to screen each dataset’s significant differently expressed genes (DEGs), and the commonly regulating network across three datasets was constructed to find the potential functional critical modules and hub genes participating in the immune cell infiltration induced AT dysfunction, and GSEA analysis was performed to test what kinds of pathogenesis pathways that screened hub genes were highly correlated
Summary
Obesity became one of the major health concerns as it contributed to the growing prevalence of its related comorbidities, including insulin resistance (IR) and type 2 diabetes. The chronic inflammation has been identified by increased cytokines or chemokines expression, such as upregulated TNF-α, IL-6, and interferon (IFN) c, immune cell infiltration is a prominent feature of dysfunctional adipose tissue (AT), as well. Low-grade chronic inflammation in dysfunctional adipose tissue links obesity with insulin resistance through the activation of tissue-infiltrating immune cells. We performed immunohistochemistry and immunofluorescence analysis to verify that the hub genes were associated with adipose tissue macrophages (ATM). GSEA analysis suggested high expression of the three hub genes was correlated with immune cells functional pathway’s activation. Is 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 Conclusions. is 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
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