Integrative miRNA-mRNA Profiling of Adipose Tissue Unravels Transcriptional Circuits Induced by Sleep Fragmentation

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.

Upregulated expression of brain enzymatic markers of arachidonic and docosahexaenoic acid metabolism in a rat model of the metabolic syndrome

“…It is possible, however, that changes in eicosanoids or cytokines [65] occurred in specific brain regions such as the hippocampus, as reported in genetically diabetic mice, or that longer administration of the high-sucrose diet sufficient to initiate diabetes would increase whole brain cytokine levels [10]. However, consistent with the lack of significant changes in the three eicosanoids, we did not find significant changes in mRNA levels for COX-1, COX-2, 5- or 15-LOX in the high-sucrose fed rats, nor in TNF-α or GFAP mRNA, suggesting the absence of neuroinflammation, since transcription of these molecular markers occurs within transcriptional circuits related to neuroinflammation [67-69]. …”

Fragmented Sleep Accelerates Tumor Growth and Progression through Recruitment of Tumor-Associated Macrophages and TLR4 Signaling

“…Indeed, recent interest on the contribution of the adipose tissues surrounding tumors to tumor biological processes such as promotion of proliferation and invasion has recently emerged (43-45). Thus, altered sleep in the host may trigger a complex time-dependent cascade of activation and inactivation of biologically-relevant pathways both systemically and regionally (46), including peri-tumoral fat and intra-tumoral cellular substrates that cumulatively orchestrate changes in tumor growth and local invasiveness.…”

Association between Glucose Metabolism and Sleep-disordered Breathing during REM Sleep

“…While, NREMrelated SDB which is characterized by an overall higher frequency of respiratory disturbance may preferentially affect glucose tolerance and fasting hyperglycemia. (42,43), sympathetic stimulation (44,45), alteration in corticotropic regulation (46,47) and potentially other effects of selective REM-sleep deprivation.…”