Roy Arijit, Shin Mi-Kyung, Davaanyam Dashdulam, Williams Noah, Lee Sean M, Tang Wan-Yee, Polotsky Vsevolod Y
Department of Anesthesiology & Critical Care Medicine, The George Washington University, Washington, DC, USA.
Department of Surgery, Office of Clinical Research, The George Washington University, Washington, DC, USA.
J Physiol. 2025 Sep;603(17):4887-4905. doi: 10.1113/JP288722. Epub 2025 Aug 10.
Diet-induced obesity (DIO) is associated with increased circulating level of the hormone leptin. We have previously shown that leptin augments hypoxic ventilatory response in mice, and the response is abolished by carotid body (CB) denervation, and that leptin induces hypertension in DIO acting on transient receptor potential melastatin 7 (Trpm7) channels in CB. However CB chemosensory responses in DIO have not been sufficiently elucidated. The aim of this study was to examine the effects of DIO and leptin on carotid sinus nerve (CSN) activity and the role of Trpm7 at normoxic and hypoxic conditions. We measured afferent CSN activity using a novel ex vivo perfused CB preparation in four groups of mice on the C57BL/6J background: lean wild type, DIO wildtype, Trpm7-DIO transfected with adenoviral vectors harbouring Cre-recombinase and green fluorescent protein (Ad-Cre-GFP) or control GFP (Ad-GFP). Leptin augmented CSN responses to normoxic (PO = 100 Torr) and hypoxic (PO = 60 Torr) conditions. Compared to lean male mice, in DIO mice (a) CSN response to hypoxia was 50% greater, (b) leptin had a greater impact on CSN activity at normoxic and hypoxic conditions. Leptin-induced CSN activities were attenuated by Trpm7 antagonist FTY720 and by Trpm7 knockdown in CB. There was no significant difference between CB chemosensitivity response to leptin in male and female mice. We conclude that CB chemosensitivity is increased in DIO compared to lean mice, and CB Trpm7 channel could be a therapeutic target for obesity-related hypertension. KEY POINTS: We have developed a novel ex vivo perfused murine carotid body (CB) preparation to evaluate carotid sinus nerve (CSN) activity using physiologically relevant levels of PO at normoxic and hypoxic conditions. Diet-induced obesity (DIO) increases baseline (normoxic) CSN activity, independent of leptin. DIO augments CB hypoxic chemoreflex gain via leptin. The effect of leptin on CB hypoxic chemoreflex is completely abolished by a Trpm7 blocker FTY720 and prevented by Trpm7 knockdown in CB. FTY720 does not have any effect on CSN activity in the absence of leptin. Taken together our new findings provide direct evidence that obesity increases CB chemoreflex via the leptin-Trpm7 pathway.
饮食诱导的肥胖（DIO）与循环中瘦素水平升高有关。我们之前已经表明，瘦素可增强小鼠的低氧通气反应，且该反应可通过颈动脉体（CB）去神经支配而消除，并且瘦素通过作用于CB中的瞬时受体电位香草酸亚型7（Trpm7）通道在DIO中诱发高血压。然而，DIO中CB的化学感受反应尚未得到充分阐明。本研究的目的是在常氧和低氧条件下，研究DIO和瘦素对颈动脉窦神经（CSN）活动的影响以及Trpm7的作用。我们使用一种新型的离体灌注CB制剂，在四组C57BL/6J背景的小鼠中测量了CSN传入活动：瘦的野生型、DIO野生型、用携带Cre重组酶和绿色荧光蛋白的腺病毒载体转染的Trpm7-DIO（Ad-Cre-GFP）或对照GFP（Ad-GFP）。瘦素增强了CSN对常氧（PO = 100 Torr）和低氧（PO = 60 Torr）条件的反应。与瘦雄性小鼠相比，在DIO小鼠中：（a）CSN对低氧的反应增强了50%，（b）瘦素在常氧和低氧条件下对CSN活动有更大影响。瘦素诱导的CSN活动被Trpm7拮抗剂FTY720和CB中Trpm7的敲低所减弱。雄性和雌性小鼠对瘦素的CB化学感受反应之间没有显著差异。我们得出结论，与瘦小鼠相比，DIO中CB的化学感受性增加，并且CB Trpm7通道可能是肥胖相关高血压的治疗靶点。要点：我们开发了一种新型的离体灌注小鼠颈动脉体（CB）制剂，以在常氧和低氧条件下使用生理相关水平的PO来评估颈动脉窦神经（CSN）活动。饮食诱导的肥胖（DIO）增加基线（常氧）CSN活动，与瘦素无关。DIO通过瘦素增强CB低氧化学反射增益。瘦素对CB低氧化学反射的作用被Trpm7阻滞剂FTY720完全消除，并被CB中Trpm7的敲低所阻止。在没有瘦素的情况下，FTY720对CSN活动没有任何影响。综上所述，我们的新发现提供了直接证据，即肥胖通过瘦素-Trpm7途径增加CB化学反射。
