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.
Chronic sleep fragmentation (SF) induces obesity in mice and increased proliferation and differentiation of adipocyte progenitors (AP) in visceral white adipose tissue (VWAT) that are mediated by increased Nox2 activity. In addition, enhanced migration of bone marrow mesenchymal stem cells from the systemic circulation into VWAT, along with AP differentiation, proliferation, and adipocyte formation occur in SF-exposed wild-type but not in oxidase 2 (Nox2) null mice. Thus, Nox2 may provide a therapeutic target to prevent obesity in the context of sleep disorders.
Obstructive sleep apnea (OSA) is a prevalent disorder characterized by intermittent hypoxia (IH) during sleep. OSA is strongly associated with obesity and dysregulation of metabolism-yet the molecular pathways linking the effects of IH on adipocyte biology remain unknown. We hypothesized that exposure to IH would activate distinct, time-dependent transcriptional programs in visceral adipose tissue of mice. We exposed 36 mice to IH or normoxia for up to 13 days. We transcriptionally profiled visceral fat tissue harvested from the animals and performed functional enrichment and network analysis on differentially expressed genes. We identified over 3,000 genes with significant expression patterns during the time course of IH exposure. The most enriched pathways mapped to metabolic processes, mitochondrion, and oxidative stress responses. We confirmed the pathophysiological relevance of these findings by demonstrating that mice exposed to chronic IH developed dyslipidemia and underwent significant lipid and protein oxidation within their visceral adipose depots. We applied gene-gene interaction network analysis to identify critical controllers of IH-induced transcriptional programs in adipocytes-these network hubs represent putative targets to modulate the effects of chronic IH on adipose tissue. Our approach to integrate computational methods with gene expression profiling of visceral fat tissue during IH exposure shows promise in helping unravel the mechanistic links between OSA and adipocyte biology.
Alzheimer's disease (AD) is an irreversible, progressive brain disorder that slowly destroys the memory and the thinking skills, and eventually the ability to carry out the simplest tasks. This has motivated lots of scientists to search for an ultimate treatment or cure for this serious disease. There are various causes & risk factors which cause AD and are the reasons for its progression. The drugs used in AD are usually a combination between different classes but never those of the same class such as Acetyl cholinesterase inhibitors which increase the availability of acetylcholine & NMDA receptors antagonists such as memantine. Most of the currently used drugs are mainly used to treat the symptoms, but lately some drugs have shown some promise in both treating & curing AD such as Aducanumab which is in the fi nal phases of the clinical trials that resulted in the clearing of Amyloid plaques affecting cells communication. Since there are newly discovered causes of the disease, there are various other approaches in dealing with AD which will be discussed thoroughly in this review article.
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