Brain glucagon-like peptide-1 regulates arterial blood flow, heart rate, and insulin sensitivity
Brain glucagon-like peptide-1 regulates arterial blood flow, heart rate, and insulin sensitivity
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DOI：
10.2337/db08-0121
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发表时间：
2008-10-01
期刊：
影响因子：
7.7
通讯作者：
Burcelin, Remy
中科院分区：
文献类型：
--
作者：
Cabou, Cendrine;Campistron, Gerard;Burcelin, Remy
目的：确定脑胰高血糖素样肽（GLP）-1在代谢和心血管功能控制中的重要性和作用机制。GLP-1是一种响应口服葡萄糖吸收而分泌的肠道激素，可调节葡萄糖代谢和心血管功能。GLP-1也产生于大脑中，其对代谢和心血管稳态的中枢调节的贡献仍不完全了解。在基础状态下或在高胰岛素血症性高血糖钳夹/高血糖钳夹期间，将激动剂毒蜥外泌肽-4（Ex 4）递送到脑的侧脑室中。连续记录股动脉血流量、全身胰岛素刺激的葡萄糖利用率和心率。Ex 4的连续3-h脑输注降低了在高胰岛素血症-高血糖状况下夹紧的清醒自由活动小鼠中的股动脉血流量和全身葡萄糖利用率，仅证明这种作用是严格葡萄糖依赖性的。然而，心率保持不变。GLP-1受体（GLP-1 R）拮抗剂毒蜥外泌肽-9（Ex 9）的中枢输注显著减弱了Ex 4的代谢和血管效应，并在GLP-1受体敲除小鼠中完全消除。在对照和Ex 4输注小鼠中观察到代谢率与血管流量之间存在相关性，而在Ex 9和GLP-1 R敲除小鼠中则消失。此外，下丘脑一氧化氮合酶活性和活性氧（ROS）的浓度也降低了GLP-1 R依赖的方式，而谷胱甘肽的抗氧化能力增加。中枢GLP-1激活迷走神经活动，并与ROS供体互补剂量依赖性逆转脑GLP-1信号对外周血流量的影响。结论-我们的数据表明，中枢GLP-1信号是集成高血糖心血管和代谢反应的电路的重要组成部分。
OBJECTIVE-To ascertain the importance and mechanisms underlying the role of brain glucagon-like peptide (GLP)-1 in the control of metabolic and cardiovascular function. GLP-1 is a gut hormone secreted in response to oral glucose absorption that regulates glucose metabolism and cardiovascular function. GLP-1 is also produced in the brain, where its contribution to central regulation of metabolic and cardiovascular homeostasis remains incompletely understood.RESEARCH DESIGN AND METHODS-Awake free-moving mice were infused with the GLP-1 receptor. agonist exendin-4 (Ex4) into the lateral ventricle of the brain in the basal state or during hyperinsulinemic eu-/hyperglycemic clamps. Arterial femoral blood flow, whole-body insulin-stimulated glucose utilization, and heart rates were continuously recorded.RESULTS-A continuous 3-h brain infusion of Ex4 decreased femoral arterial blood flow and whole-body glucose utilization in the awake free-moving mouse clamped in a hyperinsulinemic-hyperglycemic condition, only demonstrating that this effect was strictly glucose dependent. However, the heart rate remained unchanged. The metabolic and vascular effects of Ex4 were markedly attenuated by central infusion of the GLP-1 receptor (GLP-1R) antagonist exendin-9 (Ex9) and totally abolished in GLP-1 receptor knockout mice. A correlation was observed between the metabolic rate and the vascular flow in control and Ex4-infused mice, which disappeared in Ex9 and GLP-1R knockout mice. Moreover, hypothalamic nitric oxide synthase activity and the concentration of reactive oxygen species (ROS) were also reduced in a GLP-1R-dependent manner, whereas the glutathione antioxidant capacity was increased. Central GLP-1 activated vagus nerve activity, and complementation with ROS donor dose-dependently reversed the effect of brain GLP-1 signaling on peripheral blood flow.CONCLUSIONS-Our data demonstrate that central GLP-1 signaling is an essential component of circuits integrating cardiovascular and metabolic responses to hyperglycemia.