leptin-下丘脑-JAK2/STAT3通路介导肥胖间歇性缺氧/复氧过程能量平衡变化的研究

Obesity is an important inducing and concomitant factor for obstructive sleep apnea (OSA) syndrome. Clinical studies have shown that OSA patients tend to be more obese; however, effective CPAP treatment did not reduce but increased the weight of OSA patients, especially in obese subjects: It is confusing which the direction of energy balance change is in obese individuals with chronic intermittent hypoxia (CIH). Leptin ,secreted mainly by fat mass, plays a role in regulating body weight and energy balance through the central signal pathway of hypothalamic arcuate nucleus (ARC).Recently, animal experiments have shown that acute intermittent hypoxia (AIH) results in changes in body energy balance, including food intake and body weight ,and directly mediated by the leptin signal pathway in the brain. It is not known whether leptin played a direct role in mediating the changes of energy regulation in obese individuals following chronic intermittent hypoxia (CIH), who usually have higher serum leptin level and remain a status of leptin resistance. To determine this , measurements of body weight, behavior and plasma hormones associated with body energy balance will be compared in diet induced obese (DIO) and leptin deficient Sprague Dawley(SD) rats after exposure to CIH , reoxygenation after CIH or normoxic condition . The ARC will be removed to determine potential alterations in signaling in hypothalamic JAK2/STAT3 feeding pathway in both RNA and protein levels.

肥胖是阻塞性睡眠呼吸暂停综合征重要的诱发和伴随因素。临床研究表明，OSA患者趋向更加肥胖；而有效的CPAP治疗并未减轻反而增加OSA患者体重,在肥胖者中尤甚：慢性间歇性缺氧（CIH）对肥胖者能量平衡的调控方向存在争议。主要由脂肪分泌的leptin通过下丘脑弓状核中枢信号途径发挥调节体重和能量平衡的作用。动物实验表明，急性间歇性缺氧（AIH）可引起体重减轻和摄食减少，且由中枢leptin信号通路介导。而肥胖者通常有leptin抵抗，中枢leptin信号途径是否仍在肥胖者CIH中介导能量调控变化尚不清楚。本项目通过观察饮食诱导的leptin抵抗肥胖小鼠在常氧、间歇性缺氧和缺氧复氧后体重、摄食等的变化以及leptin-下丘脑-JAK2/STAT3通路在受体和受体后水平mRNA、蛋白表达差异，以期明确慢性间歇性缺氧/复氧过程对肥胖者的能量代谢影响及相关机制，为理清肥胖和OSA的相互关系提供依据。

阻塞性睡眠呼吸暂停低通气综合征和肥胖是心血管和代谢合发症的高危因素，但慢性间歇性缺氧（CIH）对肥胖者能量平衡的调控方向及相关作用机制尚不清楚。本研究中建立了饮食诱导肥胖的大鼠模型，对不同氧气暴露条件下的代谢指标和中枢瘦素信号通路分子进行了检测，发现IH组大鼠饮水摄食量及体重增加，血清瘦素、IL-6和Ang-II水平升高，下丘脑POMC、OBRB及STAT3表达减少，这些改变均在复氧治疗后有所好转。以上结果表明CIH 对肥胖动物具有增加体重和摄食的作用，并通过中枢Leptin-JAK2-STAT3信号途径调控肥胖个体的能量平衡方向，为阐明OSA和肥胖的相互作用以及OSA患者的体重管理提供实验依据。此外，还发现IH导致肥胖大鼠肠道菌群多样性增加，主要是梭菌目的富集和乳杆菌属的丰度下降，并上调了与宿主能量代谢相关的功能途径；其中梭状芽胞杆菌、瘤胃球菌和产布拉特菌与体重增长、瘦素抵抗和炎症反应正相关，而乳杆菌有助于降低代谢风险，提供了靶向微生物治疗的新思路。