Interactome Analysis of Visceral Adipose Tissue Elucidates Gene Regulatory Networks and Novel Gene Candidates in Obesity

Abstract

ObjectiveVisceral adiposity is associated with increased proinflammatory activity, insulin resistance, diabetes risk and mortality rate. Numerous individual genes have been associated with obesity, but studies investigating gene-regulatory networks in human visceral obesity are lacking.MethodsWe analyzed gene-regulatory networks in human visceral adipose tissue (VAT) from 48 obese and 11 non-obese Chinese subjects using gene co-expression and network construction with RNA-sequencing data. We also conducted RNA interference-based tests on selected genes for adipocyte differentiation effects.ResultsA scale-free gene co-expression network was constructed from 360 differentially expressed genes between obese and non-obese VAT (absolute log fold-change >1, FDR<0.05) with edge probability >0.8. Gene regulatory network analysis identified candidate transcription factors associated with differentially expressed genes. Fifteen subnetworks (communities) displayed altered connectivity patterns between obese and non-obese networks. Genes in pro-inflammatory pathways showed increased network connectivities in obese VAT whereas the oxidative phosphorylation pathway displayed reduced connections (enrichment FDR<0.05). Functional screening via RNA interference identifiedSOX30andOSBPL3as potential network-derived gene candidates influencing adipocyte differentiation.ConclusionsThis interactome-based approach highlights the network architecture, identifies novel candidate genes, and leads to new hypotheses regarding network-assisted gene regulation in obese vs. non-obese VAT.What is already known about this subject?Visceral adipose tissue (VAT) is associated with increased levels of proinflammatory activity, insulin resistance, diabetes risk and mortality rate.Gene expression studies have identified candidate genes associated with proinflammatory function in VAT.What are the new findings in your manuscript?Using integrative network-science, we identified co-expression and gene regulatory networks that are differentially regulated in VAT samples from subjects with and without obesityWe used functional testing (adipocyte differentiation) to validate a subset of novel candidate genes with minimal prior reported associations to obesityHow might your results change the direction of research or the focus of clinical practiceNetwork biology-based investigation provides a new avenue to our understanding of gene function in visceral adiposityFunctional validation screen allows for the identification of novel gene candidates that may be targeted for the treatment of adipose tissue dysfunction in obesity