Role of leptin and orexin on control of breathing

瘦素和食欲素在呼吸控制中的作用

• 批准号: 14570533
• 负责人: NAKANO Hitoshi
• 金额: $ 2.11万
• 依托单位: Asahikawa Medical College
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570533/
• 关键词: obesity; leptin; orexin; control of breathing; sleep apnea syndrome; obesity hypoventilation; 代謝; 脳脊髄液

Leptin, synthesized in adipose tissue, suppresses food intake and increases sympathetic activity. On the other hand, orexin, produced mainly in lateral hypothalamus, stimulates food intake and may maintain arousal state. Although besides appetites both leptin and orexin are associated with the regulation of cardiovascular and autonomic function, roles of these peptides on control of breathing and metabolism remain unclear. Thus, we investigated the central action of leptin and orexin on resting ventilation, hypercapnic ventilatory response (HCVR) and metabolism in Zucker rats. The effects of leptin and orexin were tested in obese Zucker rat as a model of genetic obesity and its lean counterpart as a model of normal growth. A micro-polyethylene catheter was inserted into the lateral cerebroventricle several days before experimental date. Animals were anesthetized with intraperitoneal injection of urethane allowing to breath spontaneously. Ventilation (V_E) was measured by the barometric technique of plethysmography and VO_2 was calculated from inflow-outflow O_2 difference. After resting ventilation for 60 min, 9%CO_2 gas was challenged for 2 min (HCVR). Then after, either 10μg of orexin-A or 10μg of leptin was injected i.c.v. followed by the same protocol as above described was performed. The administration of leptin significantly increased V_T and V_E in lean rats, but not in obese rats. V_E/VO_2 and HCVR were unaffected by leptin in both groups. In lean rats, the administration of orexin significantly increased V_E, VO_2, resulting significant elevation in V_E/VO_2. Furthermore, orexin significantly augmented HCVR. We, therefore, conclude that leptin increases metabolic rate leading to a rise in ventilation under condition with a normal leptin receptor. On the other hand, orexin may stimulate resting ventilation and modulate central chemosensitivity directly via respiratory center.

瘦素在脂肪组织中合成，抑制食物摄入并增加交感神经活动。另一方面，食欲素主要在下丘脑外侧产生，刺激食物摄入并可能维持觉醒状态。尽管除了食欲之外，瘦素和食欲素都与心血管和自主神经功能的调节有关，但这些肽在控制呼吸和代谢方面的作用仍不清楚。因此，我们研究了瘦素和食欲素对 Zucker 大鼠静息通气、高碳酸血症通气反应 (HCVR) 和代谢的中枢作用。在肥胖 Zucker 大鼠（作为遗传性肥胖模型）和瘦素大鼠（作为正常生长模型）中测试了瘦素和食欲素的作用。在实验日期前几天将微型聚乙烯导管插入侧脑室。通过腹膜内注射乌拉坦麻醉动物，使其自主呼吸。通过体积描记法的气压技术测量通气量（V_E），并根据流入-流出O_2差值计算VO_2。静息通气60分钟后，挑战9%CO_2气体2分钟(HCVR)。然后，静脉注射 10μg 食欲素-A 或 10μg 瘦素。随后执行与上述相同的方案。瘦素的施用显着增加了瘦大鼠的 V_T 和 V_E，但对肥胖大鼠没有影响。两组中 V_E/VO_2 和 HCVR 均不受瘦素影响。在瘦大鼠中，给予食欲素显着增加 V_E、VO_2，导致 V_E/VO_2 显着升高。此外，食欲素显着增强 HCVR。因此，我们得出结论，在瘦素受体正常的情况下，瘦素会增加代谢率，导致通气量增加。另一方面，食欲素可以刺激静息通气并直接通过呼吸中枢调节中枢化学敏感性。