Hindbrain cocaine- and amphetamine-regulated transcript induces hypothermia mediated by GLP-1 receptors.
Hindbrain cocaine- and amphetamine-regulated transcript induces hypothermia mediated by GLP-1 receptors.
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DOI：
10.1523/jneurosci.6144-08.2009
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发表时间：
2009-05-27
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影响因子：
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通讯作者：
Grill HJ
中科院分区：
文献类型：
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作者：
Skibicka KP;Alhadeff AL;Grill HJ
可卡因和安非他明调节的转录肽（CART）广泛分布在整个轴突，包括与能量平衡相关的区域。CART作为分解代谢神经肽的分类是基于其对进食的抑制作用、与弓状核POMC神经元的共表达以及对其能量消耗作用的有限分析。在这里，我们调查是否：1）CART的尾侧脑干递送产生能量、心血管和血糖效应，2）这些效应需要前脑-尾侧脑干神经通信，3）GLP-1受体（GLP-1 R）有助于介导CART诱导的效应。在第4次注射CART（0.1、1.0和2.0µg）的大鼠中测量核心温度（Tc）、心率（HR）、活动和血糖。在生理记录期间禁食，并返回过夜测量摄入量和体重。CART诱导长期（> 6小时）;体温过低; 1.0和2.0µg剂量的TC下降1.5 ℃和1.6 ℃。后脑CART应用减少了食物摄入量和体重，并增加了血糖水平;未观察到HR或活动的变化。上丘去脑消除了在完整大鼠中观察到的对后脑心室CART的低温反应，表明前脑处理是低温所必需的。在对照大鼠中，GLP-1 R拮抗剂（exendin-9-39）预处理减轻了CART体温过低和摄食量减少，表明GLP-1 R激活有助于后脑CART的体温过低和摄食量减少效应，而GLP-1 R阻断剂未改变CART诱导的高血糖症。数据揭示了CART在温度调节中的新功能，并为未来研究低温效应的临床潜力提供了可能性。
Cocaine- and amphetamine-regulated transcript peptides (CART) are widely distributed throughout the neuraxis, including regions associated with energy balance. CART’s classification as a catabolic neuropeptide is based on its inhibitory effects on feeding, co-expression with arcuate nucleus POMC neurons, and on limited analysis of its energy expenditure effects. Here we investigate whether: 1) caudal brainstem delivery of CART produces energetic, cardiovascular and glycemic effects, 2) forebrain – caudal brainstem neural communication is required for those effects and 3) GLP-1 receptors (GLP-1R) contribute to the mediation of CART-induced effects. Core temperature (Tc), heart rate (HR), activity and blood glucose were measured in rats injected 4th v. with CART (0.1, 1.0 and 2.0µg). Food was withheld during physiologic recording and returned for overnight measurement of intake and body weight. CART induced a long-lasting (> 6h); hypothermia; a 1.5°C and 1.6°C drop in TC for the 1.0 and 2.0µg doses. Hindbrain CART application reduced food intake and body weight and increased blood glucose levels; no change in HR or activity was observed. Supracollicular decerebration eliminated the hypothermic response observed in intact rats to hindbrain ventricular CART, suggesting that forebrain processing is required for hypothermia. Pretreatment with the GLP-1R antagonist (exendin-9-39) in control rats attenuated CART hypothermia and hypophagia, indicating that GLP-1R activation contributes to hypothermic and hypophagic effects of hindbrain CART while CART-induced hyperglycemia was not altered by GLP-1R blockade. Data reveal a novel function of CART in temperature regulation and open possibilities for future studies on the clinical potential of the hypothermic effect.