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

ABSTRACT Objective Visceral 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. Methods We 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. Results A scale-free gene co-expression network was constructed from 360 differentially expressed genes between obese and non-obese VAT (absolute log fold-change >1, FDR0.8. 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 identified SOX30 and OSBPL3 as potential network-derived gene candidates influencing adipocyte differentiation. Conclusions This 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 obesity We used functional testing (adipocyte differentiation) to validate a subset of novel candidate genes with minimal prior reported associations to obesity How might your results change the direction of research or the focus of clinical practice Network biology-based investigation provides a new avenue to our understanding of gene function in visceral adiposity Functional validation screen allows for the identification of novel gene candidates that may be targeted for the treatment of adipose tissue dysfunction in obesity