Abstract
Obstructive sleep apnea (OSA) is a prevalent condition and strongly associated with metabolic disorders. Sleep fragmentation (SF) is a major consequence of OSA, but its contribution to OSA-related morbidities is not known. We hypothesized that SF causes specific perturbations in transcriptional networks of visceral fat cells, leading to systemic metabolic disturbances. We simultaneously profiled visceral adipose tissue mRNA and miRNA expression in mice exposed to 6 hours of SF during sleep, and developed a new computational framework based on gene set enrichment and network analyses to merge these data. This approach leverages known gene product interactions and biologic pathways to interrogate large-scale gene expression profiling data. We found that SF induced the activation of several distinct pathways, including those involved in insulin regulation and diabetes. Our integrative methodology identified putative controllers and regulators of the metabolic response during SF. We functionally validated our findings by demonstrating altered glucose and lipid homeostasis in sleep-fragmented mice. This is the first study to link sleep fragmentation with widespread disruptions in visceral adipose tissue transcriptome, and presents a generalizable approach to integrate mRNA-miRNA information for systematic mapping of regulatory networks.
Highlights
Obstructive sleep apnea (OSA) is a highly prevalent disorder in adults and children [1,2,3] and associated with significant cognitive, metabolic, and cardiovascular morbidities [4,5,6,7,8]
We report on the first systematic effort to map the regulatory transcriptional landscape of visceral adipocytes in response to sleep fragmentation—a key pathophysiologic event in sleep apnea
We developed a framework for integrating mRNA-miRNA expression profiles based on gene set enrichment and network analyses
Summary
Obstructive sleep apnea (OSA) is a highly prevalent disorder in adults and children [1,2,3] and associated with significant cognitive, metabolic, and cardiovascular morbidities [4,5,6,7,8]. There is accumulating evidence that OSA is strongly linked to metabolic dysregulation, independent of obesity [9,10]. Fragmentation of sleep architecture is being recognized as an important contributor to OSA-related morbidities and can cause altered glucose homeostasis even in normal subjects [11]. SF may promote the adverse metabolic consequences of sleep apnea by perturbing normal visceral adipose tissue function and altering insulin sensitivity [12,13], but the biological effects of SF on fat tissue are not known. Since visceral fat tissue depots are critical regulators of metabolism [14,15], understanding the pathophysiologic consequences of SF on adipocyte biology is a crucial step in elucidating mechanisms linking OSA with metabolic dysregulation
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