Prolonged Exposures to Intermittent Hypoxia Promote Visceral White Adipose Tissue Inflammation in a Murine Model of Severe Sleep Apnea: Effect of Normoxic Recovery.
Study Objective
Increased visceral white adipose tissue (vWAT) mass results in infiltration of inflammatory macrophages that drive inflammation and insulin resistance. Patients with obstructive sleep apnea (OSA) suffer from increased prevalence of obesity, insulin resistance, and metabolic syndrome. Murine models of intermittent hypoxia (IH) mimicking moderate-severe OSA manifest insulin resistance following short-term IH. We examined in mice the effect of long-term IH on the inflammatory cellular changes within vWAT and the potential effect of normoxic recovery (IH-R).


Methods
Male C57BL/6J mice were subjected to IH for 20 weeks, and a subset was allowed to recover in room air (RA) for 6 or 12 weeks (IH-R). Stromal vascular fraction was isolated from epididymal vWAT and mesenteric vWAT depots, and single-cell suspensions were prepared for flow cytometry analyses, reactive oxygen species (ROS), and metabolic assays.


Results
IH reduced body weight and vWAT mass and IH-R resulted in catch-up weight and vWAT mass. IH-exposed vWAT exhibited increased macrophage counts (ATMs) that were only partially improved in IH-R. IH also caused a proinflammatory shift in ATMs (increased Ly6c(hi)(+) and CD36(+) ATMs). These changes were accompanied by increased vWAT insulin resistance with only partial improvements in IH-R. In addition, ATMs exhibited increased ROS production, altered metabolism, and changes in electron transport chain, which were only partially improved in IH-R.


Conclusion
Prolonged exposures to IH during the sleep period induce pronounced vWAT inflammation and insulin resistance despite concomitant vWAT mass reductions. These changes are only partially reversible after 3 months of normoxic recovery. Thus, long-lasting OSA may preclude complete reversibility of metabolic changes.
['Gileles-Hillel|Alex|A|', 'Almendros|Isaac|I|', 'Khalyfa|Abdelnaby|A|', 'Nigdelioglu|Recep|R|', 'Qiao|Zhuanhong|Z|', 'Hamanaka|Robert B|RB|', 'Mutlu|Gökhan M|GM|', 'Akbarpour|Mahzad|M|', 'Gozal|David|D|']
D000388:Air D000818:Animals D001835:Body Weight D002452:Cell Count D004195:Disease Models, Animal D000860:Hypoxia D007249:Inflammation D007333:Insulin Resistance D050152:Intra-Abdominal Fat D008264:Macrophages D008297:Male D024821:Metabolic Syndrome D051379:Mice D008810:Mice, Inbred C57BL D009765:Obesity D009929:Organ Size D010100:Oxygen D017382:Reactive Oxygen Species D020181:Sleep Apnea, Obstructive D013997:Time Factors
intermittent hypoxia macrophages insulin resistance metabolic dysfunction sleep apnea.