Vascular and Hepatic Impact of Short-Term Intermittent Hypoxia in a Mouse Model of Metabolic Syndrome

BackgroundExperimental models of intermittent hypoxia (IH) have been developed during the last decade to investigate the consequences of obstructive sleep apnea. IH is usually associated with detrimental metabolic and vascular outcomes. However, paradoxical protective effects have also been described depending of IH patterns and durations applied in studies. We evaluated the impact of short-term IH on vascular and metabolic function in a diet-induced model of metabolic syndrome (MS).MethodsMice were fed either a standard diet or a high fat diet (HFD) for 8 weeks. During the final 14 days of each diet, animals were exposed to either IH (1 min cycle, FiO2 5% for 30s, FiO2 21% for 30s; 8 h/day) or intermittent air (FiO2 21%). Ex-vivo vascular reactivity in response to acetylcholine was assessed in aorta rings by myography. Glucose, insulin and leptin levels were assessed, as well as serum lipid profile, hepatic mitochondrial activity and tissue nitric oxide (NO) release.ResultsMice fed with HFD developed moderate markers of dysmetabolism mimicking MS, including increased epididymal fat, dyslipidemia, hepatic steatosis and endothelial dysfunction. HFD decreased mitochondrial complex I, II and IV activities and increased lactate dehydrogenase (LDH) activity in liver. IH applied to HFD mice induced a major increase in insulin and leptin levels and prevented endothelial dysfunction by restoring NO production. IH also restored mitochondrial complex I and IV activities, moderated the increase in LDH activity and liver triglyceride accumulation in HFD mice.ConclusionIn a mouse model of MS, short-term IH increases insulin and leptin levels, restores endothelial function and mitochondrial activity and limits liver lipid accumulation.

背景
近十年来，科研人员已构建间歇性低氧（intermittent hypoxia, IH）实验模型，用于探究阻塞性睡眠呼吸暂停所引发的各类后果。通常情况下，间歇性低氧会伴随代谢与血管功能的不良转归；但现有研究也报道了与其相悖的保护效应，且该效应取决于实验中采用的间歇性低氧模式与暴露时长。本研究旨在评估短期间歇性低氧对饮食诱导型代谢综合征（metabolic syndrome, MS）小鼠模型的血管与代谢功能的影响。
方法
实验小鼠分为两组，分别饲喂标准饲料与高脂饮食（high fat diet, HFD），持续8周。在每种饲料饲喂的最后14天期间，小鼠分别暴露于间歇性低氧（设置为1分钟循环：吸入氧分数FiO2为5%持续30秒、FiO2为21%持续30秒，每日暴露8小时）或间歇性空气（FiO2为21%）环境。采用肌动描记法检测主动脉环离体状态下对乙酰胆碱的血管反应性；同时检测小鼠的血糖、胰岛素与瘦素水平，以及血清脂质谱、肝脏线粒体活性与组织一氧化氮（nitric oxide, NO）释放量。
结果
饲喂高脂饮食的小鼠出现了模拟代谢综合征的中度代谢异常表型，包括附睾脂肪重量增加、血脂异常、肝脂肪变性以及内皮功能障碍。高脂饮食会降低肝脏线粒体复合物I、II与IV的活性，并升高肝脏乳酸脱氢酶（lactate dehydrogenase, LDH）的活性。对高脂饮食小鼠实施间歇性低氧干预后，其胰岛素与瘦素水平显著升高，且通过恢复一氧化氮生成改善了内皮功能障碍；同时，间歇性低氧还可恢复线粒体复合物I与IV的活性，缓解肝脏乳酸脱氢酶活性的升高，并减轻肝脏甘油三酯蓄积。
结论
在代谢综合征小鼠模型中，短期间歇性低氧可升高胰岛素与瘦素水平，恢复内皮功能与线粒体活性，并抑制肝脏脂质蓄积。