Prolonged Exposures to Intermittent Hypoxia Promote Visceral White Adipose Tissue Inflammation in a Murine Model of Severe Sleep Apnea: Effect of Normoxic Recovery.
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).



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.



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.



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.
Sections of Pediatric Sleep Medicine and Pulmonology, Department of Pediatrics, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Chicago, IL.
Alex
A
Gileles-Hillel
Sections of Pediatric Sleep Medicine and Pulmonology, Department of Pediatrics, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Chicago, IL.
Isaac
I
Almendros
Sections of Pediatric Sleep Medicine and Pulmonology, Department of Pediatrics, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Chicago, IL.
Abdelnaby
A
Khalyfa
Department of Medicine, Section of Pulmonary and Critical Care, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Chicago, IL.
Recep
R
Nigdelioglu
Sections of Pediatric Sleep Medicine and Pulmonology, Department of Pediatrics, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Chicago, IL.
Zhuanhong
Z
Qiao
Department of Medicine, Section of Pulmonary and Critical Care, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Chicago, IL.
Robert B
RB
Hamanaka
Department of Medicine, Section of Pulmonary and Critical Care, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Chicago, IL.
Gökhan M
GM
Mutlu
Sections of Pediatric Sleep Medicine and Pulmonology, Department of Pediatrics, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Chicago, IL.
Mahzad
M
Akbarpour
Sections of Pediatric Sleep Medicine and Pulmonology, Department of Pediatrics, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Chicago, IL.
David
D
Gozal
D000388:Air; D000818:Animals; D001835:Body Weight; D002452:Cell Count; D004195:Disease Models, Animal; D000860:Hypoxia / Q000150:complications* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D007249:Inflammation / Q000150:complications / Q000378:metabolism / Q000473:pathology; D007333:Insulin Resistance; D050152:Intra-Abdominal Fat / Q000378:metabolism* / Q000473:pathology*; D008264:Macrophages / Q000166:cytology; D008297:Male; D024821:Metabolic Syndrome / Q000150:complications; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000150:complications; D009929:Organ Size; D010100:Oxygen / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000032:analysis / Q000378:metabolism; D020181:Sleep Apnea, Obstructive / Q000150:complications* / Q000378:metabolism / Q000473:pathology*; D013997:Time Factors
D017382:Reactive Oxygen Species; D010100:Oxygen
insulin resistance; intermittent hypoxia; macrophages; metabolic dysfunction; sleep apnea.