Khalyfa Abdelnaby, Qiao Zhuanhong, Gileles-Hillel Alex, Khalyfa Ahamed A, Akbarpour Mahzad, Popko Brian, Gozal David
1 Section of Pediatric Sleep Medicine, Department of Pediatrics, and.
2 Department of Neurology, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Chicago, Illinois.
Am J Respir Cell Mol Biol. 2017 Oct;57(4):477-486. doi: 10.1165/rcmb.2017-0057OC.
Intermittent hypoxia (IH) induces activation of the integrated stress response (ISR), but its role in IH-induced visceral white adipose tissue (vWAT) insulin resistance is unknown. CHOP is activated by chronic ISR, whereas GADD34 dephosphorylates the subunit of translation initiation factor 2 (eIF2α), leading to termination of the ISR. We hypothesized that CHOP/Gadd34 null mice would not manifest evidence of insulin resistance after IH exposures. Eight-week-old CHOP/GADD34 (double mutant [DM]) and wild-type (WT) littermates were randomly assigned to IH or room air (RA) exposures for 6 weeks. Glucose and insulin tolerance tests were performed, and regulatory T cells (Tregs) and macrophages in vWAT were assessed. Phosphorylated eIF2α:total eIF2α, ATF4, XBP1 expression, and insulin-induced pAKT/AKT expression changes were examined in vWATs. Single GADD34 and PERK mice were also evaluated. Body weight and vWAT mass were reduced in DM and WT mice after IH. M1/M2 macrophages and inflammatory macrophages (Ly-6c) were significantly increased in WT vWAT but remained unchanged in DM mice. Tregs were significantly decreased in WT vWAT but not in DM mice. Systemic insulin and glucose tolerance tests revealed insulin resistance in IH-WT but not in IH-DM mice. Similarly, decreased pAKT/AKT responses to exogenous insulin emerged in IH-WT compared with RA-WT mice, whereas no significant differences emerged in IH-DM compared with DM-RA. Chronic ISR activation appears to contribute to the insulin resistance and vWAT inflammation that characteristically emerge after long-term IH exposures in a murine model of obstructive sleep apnea.
间歇性低氧（IH）可诱导整合应激反应（ISR）激活，但其在IH诱导的内脏白色脂肪组织（vWAT）胰岛素抵抗中的作用尚不清楚。CHOP由慢性ISR激活，而GADD34使翻译起始因子2（eIF2α）亚基去磷酸化，导致ISR终止。我们假设CHOP/Gadd34基因敲除小鼠在暴露于IH后不会出现胰岛素抵抗的迹象。将8周龄的CHOP/GADD34（双突变体[DM]）和野生型（WT）同窝小鼠随机分为两组，分别暴露于IH或常氧（RA）环境中6周。进行葡萄糖和胰岛素耐量试验，并评估vWAT中的调节性T细胞（Tregs）和巨噬细胞。检测vWAT中磷酸化eIF2α与总eIF2α的比值、ATF4、XBP1的表达以及胰岛素诱导的pAKT/AKT表达变化。还评估了单GADD34和PERK小鼠。IH后，DM和WT小鼠的体重和vWAT质量均降低。WT vWAT中的M1/M2巨噬细胞和炎性巨噬细胞（Ly-6c）显著增加，但DM小鼠中保持不变。WT vWAT中的Tregs显著减少，但DM小鼠中未减少。全身胰岛素和葡萄糖耐量试验显示，IH-WT小鼠存在胰岛素抵抗，而IH-DM小鼠不存在。同样，与RA-WT小鼠相比，IH-WT小鼠对外源胰岛素的pAKT/AKT反应降低，而与DM-RA相比，IH-DM小鼠无显著差异。在阻塞性睡眠呼吸暂停小鼠模型中，长期暴露于IH后，慢性ISR激活似乎导致了胰岛素抵抗和vWAT炎症。
