复氧改善间歇性缺氧所致的肥胖大鼠下丘脑瘦素反应性降低  

Reoxygenation improves reduced hypothalamic leptin responsiveness induced by intermittent hypoxia in obese rats

作　　者：董梦璐 朱恬 马俊文 杜晓红[3] 冯媛[1,4,5] DONG Menglu;ZHU Tian;MA Junwen;DU Xiaohong;FENG Yuan(Department of Psychiatry(Sleep Medicine Center),School of Basic Medical Science,Southern Medical University,Guangzhou 510515,China;First School of Clinical Medicine,Southern Medical University,Guangzhou 510515,China;Department of Anesthesiology,Second Affiliated Hospital of Nanchang University,Nanchang 330000,China;Institute of Brain Disease,Nanfang Hospital,School of Basic Medical Science,Southern Medical University,Guangzhou 510515,China;Guangdong Provincial Key Laboratory of Proteomics,School of Basic Medical Science,Southern Medical University,Guangzhou 510515,China)

机构地区：[1]南方医科大学南方医院精神心理科(睡眠医学中心),广东广州510515 [2]南方医科大学第一临床医学院,广东广州510515 [3]南昌大学第二附属医院麻醉科,江西南昌330000 [4]南方医科大学南方医院脑病研究院,广东广州510515 [5]南方医科大学基础医学院广东省蛋白质组学重点实验室,广东广州510515

出　　处：《南方医科大学学报》2024年第9期1696-1703,共8页Journal of Southern Medical University

基　　金：国家自然科学基金(81900089)。

摘　　要：目的使用饮食诱导肥胖(DIO)大鼠模型,探索间歇性缺氧-复氧(IHR)对肥胖大鼠体质量、食水摄入量、循环代谢因子和中枢瘦素注射反应的影响。方法通过12周高脂饮食(HFD)喂养建立DIO大鼠模型,将其随机分为3组并继续HFD喂养:常氧组(NM,n=15)、间歇性缺氧组(IH:6%O2,30周期/h,8 h/d,4周,n=15),IHR组(缺氧2周后复氧2周,n=15)。记录大鼠体质量、饮食饮水情况,检测循环瘦素、IL-6、Ang-II含量。IHR干预结束后,大鼠接受4μg瘦素侧脑室注射,1 h后处死取材下丘脑及肝脏。通过免疫组化观察下丘脑POMC、FRA-1、FRA-2表达,Western blotting检测下丘脑POMC、pSTAT3、LepR表达,RT-PCR检测下丘脑和肝脏中LepR mRNA含量,对比各组大鼠下丘脑瘦素受体(LepR)及下游通路蛋白的变化。结果IH暴露导致DIO大鼠体质量(P=0.001)和摄食量(P=0.001)增加,全身炎症因子升高(瘦素P=0.004;IL-6 P=0.008;Ang-II P<0.001)。IH抑制下丘脑食欲抑制肽POMC表达(P<0.001 vs NM组),降低反映瘦素反应性神经元活性的FRA-1表达(P<0.001 vs NM组),抑制对瘦素响应的pSTAT3表达(瘦素+vs瘦素-,P=0.241),降低对外源性瘦素给药的反应性(P<0.001 vs NM组),并下调下丘脑和肝脏LepR mRNA含量(P<0.001 vs NM组)。经过2周的复氧治疗后,IH加剧的体质量增加和代谢紊乱能够得到改善,下丘脑瘦素反应性也有所提高。结论IH可能通过下调LepR表达损害下丘脑瘦素信号传导,从而促进肥胖大鼠增重,这可以通过复氧治疗得到改善。Objective To evaluate the effects of intermittent hypoxia-reoxygenation(IHR)on body weight,diet and water intake,circulating metabolites,and responses to central leptin injection in a rat model of diet-induced obesity(DIO).Methods Rat models of DIO established by 12-week high-fat diet(HFD)feeding were randomized into normoxia group(n=15),intermittent hypoxia group(6%O2,30 cycles/h,8 h/day for 4 weeks;n=15),and IHR group(2 weeks of intermittent hypoxia followed by 2 weeks of reoxygenation;n=15).Body weight,diet and water intake of the rats were recorded,and circulating leptin,IL-6,and Ang-II levels were detected.After IHR treatment,the rats received intracerebroventricular injection of 4μg leptin,and the hypothalamus and liver were taken 1 h later for detecting POMC,FRA-1 and FRA-2 expressions in the hypothalamus using immunohistochemistry,POMC,pSTAT3 and LepR expressions in the hypothalamus using Western blotting,and LepR mRNA expression in the hypothalamus and liver using RT-PCR.Results The rats in intermittent hypoxia group showed significantly increased weight gain,food intake and elevated systemic inflammatory cytokine levels.Intermittent hypoxia obviously inhibited the expression of POMC,lowered the expressions of FRA-1 and pSTAT3,reduced the responsiveness of the rats to exogenous leptin,and downregulated the mRNA and protein expression of LepR.Two weeks of reoxygenation treatment obviously reduced intermittent hypoxia-induced weight gain and metabolic disorder and improved leptin sensitivity of the rats.Conclusion Prolonged intermittent hypoxia impairs hypothalamic leptin signaling by downregulating LepR expression to promote weight gain in obese rats,which can be improved by reoxygenation treatment.

关 键 词：间歇性缺氧 阻塞性睡眠呼吸暂停 肥胖 瘦素 复氧 

分 类 号：R589.2[医药卫生—内分泌]