Department of Physiology, Hebei Medical University, Shijiazhuang, Hebei 050017, China; School of Nursing, Hebei Medical University, Shijiazhuang, Hebei 050000, China.
Department of Physiology, Hebei Medical University, Shijiazhuang, Hebei 050017, China; Functional Laboratory, Experimental Center for Teaching, Hebei Medical University, Shijiazhuang, Hebei 050000, China.
Life Sci. 2020 Sep 15;257:117994. doi: 10.1016/j.lfs.2020.117994. Epub 2020 Jun 20.
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 CO elicits the impaired HCVR in DIO mice. In addition, both the number of CO-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.
睡眠呼吸障碍的特征是睡眠期间正常呼吸模式的中断。肥胖与低通气或呼吸暂停密切相关，成为睡眠呼吸障碍的主要危险因素。瘦素是脂肪组织分泌的一种肽，它与呼吸的中枢控制有关。激活延髓网状核（RTN）神经元，这是一个关键的中枢呼吸化学感受器候选者，增强了呼吸的中枢驱动力。在这里，我们询问 RTN 中紊乱的瘦素信号是否是肥胖相关低通气的原因。在饮食诱导肥胖（DIO）小鼠模型中，评估了高碳酸血症通气反应（HCVR），并检查了 RTN 中的细胞瘦素信号。我们的主要发现表明，DIO 小鼠表现出超重、高碳酸血症、血清和脑脊液瘦素水平升高。在暴露于室内空气时，DIO 小鼠表现出基础低通气，呼吸模式快速而浅。暴露于 CO 会导致 DIO 小鼠 HCVR 受损。此外，DIO 小鼠 RTN 中的 CO 激活神经元的数量和 TASK-2 通道的表达都显著减少。此外，DIO 小鼠 RTN 神经元中的瘦素信号紊乱，包括瘦素激活的 RTN 神经元数量显著减少、磷酸化 STAT3 下调和 SOCS3 上调。总之，我们认为 RTN 中的紊乱的瘦素/STAT3/SOCS3 信号通路在肥胖相关低通气中起作用。
