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

Abstract

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.

Figure 1.

Differentially expressed exosomal miRNAs were identified between the patients with obesity and the lean patients. (A) Heat map of DE-miRNAs in the GSE68885 dataset, which included subcutaneous adipose tissue samples obtained from patients with obesity and lean patients (red indicates high expression, green indicates low expression). (B) Heat map of DE-miRNAs in the GSE50574 dataset, which included visceral adipose tissue samples obtained from patients with obesity and lean patients (red indicates high expression, green indicates low expression). (C) The Venn diagram revealed the intersection of DE-miRNAs between subcutaneous and visceral adipose tissues. DE, differentially expressed; miRNA, microRNA.

Figure 2.

Regulatory network of shared exosomal hsa-microRNA-4517 between subcutaneous and visceral adipose tissues and associated target genes.

Figure 3.

Important genes associated with DE-miRNAs. (A) The regulatory association between the important DE-miRNA and its associated target gene in subcutaneous adipose tissues. (B) Regulatory associations between important DE-miRNAs and associated target genes in visceral adipose tissues. Diamonds represent miRNAs (yellow represents downregulated miRNAs; purple represents upregulated miRNAs); ovals represent DE target genes (red represents upregulated DE target genes; green represents downregulated DE target genes). DE, differentially expressed; miRNA, microRNA.