A Pathway-Based Analysis on the Effects of Obstructive Sleep Apnea in Modulating Visceral Fat Transcriptome

Rationale: Obstructive sleep apnea (OSA) has been associated with metabolic dysregulation and systemic inflammation. This may be due to pathophysiologic effects of OSA on visceral adipose tissue. We sought to assess the transcriptional consequences of OSA on adipocytes by utilizing pathway-focused analyses. Methods: Patients scheduled to undergo ventral hernia repair surgery were recruited to wear a portable home sleep monitor for 2 nights prior to surgery. Visceral fat biopsies were obtained intraoperatively. RNA was extracted and whole-genome expression profiling was performed. Gene Set Enrichment Analysis (GSEA) was used to identify curated gene sets that were differentially enriched in OSA subjects. Network analysis was applied to a select set of highly enriched pathways. Results: Ten patients with OSA and 8 control subjects were recruited. There were no differences in age, gender, or body mass index between the 2 groups, but the OSA subjects had a significantly higher respiratory disturbance index (19.2 vs. 0.6, P = 0.05) and worse hypoxemia (minimum oxygen saturation 79.7% vs. 87.8%, P < 0.001). GSEA identified a number of gene sets up-regulated in adipose tissue of OSA patients, including the pro-inflammatory NF-kB pathway and the proteolytic ubiquitin/proteasome module. A critical metabolic pathway, the peroxisome proliferator-activated receptor (PPAR), was down-regulated in subjects with OSA. Network analysis linked members of these modules together and identified regulatory hubs. Conclusions: OSA is associated with alterations in visceral fat gene expression. Pathway-based network analysis highlighted perturbations in several key pathways whose coordinated interactions may contribute to the metabolic dysregulation observed in this complex disorder.