Disordered Leptin signaling in the retrotrapezoid nucleus is associated with the impaired hypercapnic ventilatory response in obesity
Disordered Leptin signaling in the retrotrapezoid nucleus is associated with the impaired hypercapnic ventilatory response in obesity
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梯形后核中瘦素信号传导紊乱与肥胖患者高碳酸血症通气反应受损有关
DOI：
10.1016/j.lfs.2020.117994
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发表时间：
2020
期刊：
影响因子：
6.1
通讯作者：
Fang Yuan
中科院分区：
文献类型：
--
作者：
Ziqian Wei;Yinchao Hao;Hongxiao Yu;Luo Shi;Xinyi Jing;Xiang Zhang;Na Liu;Tao Li;Xiangjian Zhang;Fang Yuan
睡眠呼吸障碍的特征在于睡眠期间正常呼吸模式的中断。肥胖与通气不足或呼吸暂停密切相关，并成为睡眠呼吸障碍的主要危险因素。瘦素是一种由脂肪组织分泌的肽，与呼吸的中枢控制有关。后斜方核（RTN）神经元，一个关键的中枢呼吸化学感受器的候选人，激活，加强了中央驱动呼吸。在这里，我们问是否在RTN的瘦素信号紊乱是负责肥胖相关的通气不足。在饮食诱导的肥胖症（DIO）小鼠模型中，评估高碳酸血症缓解反应（HCVR）并检查RTN中的细胞瘦素信号传导。我们的主要研究结果表明，DIO小鼠表现出超重，高碳酸血症，高水平的血清和脑脊液瘦素。在暴露于室内空气期间，DIO小鼠表现出基础换气不足，呼吸模式快速而浅。CO2暴露可使DIO小鼠HCVR受损。此外，在DIO小鼠中，RTN中CO2激活的神经元的数量和ASK-2通道的表达都显著减少。此外，DIO小鼠RTN神经元存在瘦素信号转导障碍，包括瘦素激活的RTN神经元显著减少，磷酸化STAT 3下调和SOCS 3上调。总之，我们认为RTN中的Leptin/STAT 3/SOCS 3信号通路紊乱在肥胖相关的肺换气不足中起作用。
Sleep-disordered breathing is characterized by disruptions of normal breathing patterns during sleep. Obesity is closely related to hypoventilation or apnea and becomes a primary risk factor for sleep-disordered breathing. Leptin, a peptide secreted by adipose tissue, has been implicated in central control of breathing. Activation of the retrotrapezoid nucleus (RTN) neurons, a critical central respiratory chemoreceptor candidate, potentiates a central drive to breathing. Here, we ask whether the disordered leptin signaling in the RTN is responsible for obesity-related hypoventilation. In a diet induced obesity (DIO) mouse model, the hypercapnic ventilatory response (HCVR) was assessed and the cellular leptin signaling in the RTN was examined. Our main findings demonstrate that DIO mice exhibit overweight, hypercapnia, high levels of serum and cerebrospinal leptin. During exposure to room air, DIO mice manifest basal hypoventilation with a rapid and shallow breathing pattern. Exposure to CO2 elicits the impaired HCVR in DIO mice. In addition, both the number of CO2-activated neurons and expression of TASK-2 channels in the RTN are dramatically reduced in DIO mice. Moreover, there is leptin signaling disorder in RTN neurons in DIO mice, including a significant decrease in leptin-activated RTN neurons, downregulation of phosphorylated STAT3 and upregulation of SOCS3. Altogether, we suggest that the disordered leptin/STAT3/SOCS3 signaling pathway in the RTN plays a role in obesity-related hypoventilation.