Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
Dental School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo 14040-904, Brazil.
Int J Mol Sci. 2021 Jun 23;22(13):6742. doi: 10.3390/ijms22136742.
Obstructive sleep apnea (OSA) is recurrent obstruction of the upper airway due to the loss of upper airway muscle tone during sleep. OSA is highly prevalent, especially in obesity. There is no pharmacotherapy for OSA. Previous studies have demonstrated the role of leptin, an adipose-tissue-produced hormone, as a potent respiratory stimulant. Leptin signaling via a long functional isoform of leptin receptor, LEPR, in the nucleus of the solitary tract (NTS), has been implicated in control of breathing. We hypothesized that leptin acts on LEPR positive neurons in the NTS to increase ventilation and maintain upper airway patency during sleep in obese mice. We expressed designer receptors exclusively activated by designer drugs (DREADD) selectively in the LEPR positive neurons of the NTS of -Cre-GFP mice with diet-induced obesity (DIO) and examined the effect of DREADD ligand, J60, on tongue muscle activity and breathing during sleep. J60 was a potent activator of LEPR positive NTS neurons, but did not stimulate breathing or upper airway muscles during NREM and REM sleep. We conclude that, in DIO mice, the stimulating effects of leptin on breathing during sleep are independent of LEPR signaling in the NTS.
阻塞性睡眠呼吸暂停（OSA）是由于睡眠中上气道肌肉张力丧失而导致的上气道反复阻塞。OSA 患病率很高，尤其是在肥胖人群中。目前还没有针对 OSA 的药物治疗。先前的研究表明，瘦素作为一种由脂肪组织产生的激素，在呼吸刺激方面发挥着重要作用。瘦素通过长功能型瘦素受体（LEPR）在孤束核（NTS）中的信号转导，与呼吸控制有关。我们假设瘦素作用于 NTS 中的 LEPR 阳性神经元，增加通气并维持肥胖小鼠睡眠时上气道的通畅性。我们利用 -Cre-GFP 肥胖小鼠，通过饮食诱导肥胖（DIO），选择性地在 LEPR 阳性神经元中表达设计受体专门被设计药物激活（DREADD），并研究了 DREADD 配体 J60 在睡眠期间对舌肌活动和呼吸的影响。J60 是 LEPR 阳性 NTS 神经元的有效激活剂，但在 NREM 和 REM 睡眠期间不会刺激呼吸或上气道肌肉。我们的结论是，在 DIO 小鼠中，瘦素在睡眠期间对呼吸的刺激作用不依赖于 NTS 中的 LEPR 信号转导。
