Peripheral endocannabinoid signaling controls hyperphagia in western diet-induced obesity.
Peripheral endocannabinoid signaling controls hyperphagia in western diet-induced obesity.
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DOI：
10.1016/j.physbeh.2016.12.044
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发表时间：
2017-03-15
影响因子：
2.9
通讯作者：
DiPatrizio NV
中科院分区：
文献类型：
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作者：
Argueta DA;DiPatrizio NV
大脑和外周的内源性大麻素系统在控制食物摄入和能量平衡方面发挥着重要作用。我们报道称，在大鼠小肠上部，品尝膳食脂肪会导致内源性大麻素、2-花生四烯酰-sn-甘油（2-AG）和花生四烯酸乙醇胺水平升高，并且对这种局部信号传导事件的药理抑制会剂量依赖性地阻断脂肪的假喂养。我们现在研究了外周内源性大麻素信号传导在与小鼠长期食用西式饮食（[WD]，即高脂肪和蔗糖）相关的食欲亢进中的作用。在 WD 或标准啮齿动物饲料 (SD) 维持 60 天的雄性 C57BL/6Tac 小鼠中评估喂养模式，并通过药理学干预研究 CB1R 外周内源性大麻素信号在控制食物摄入中的作用。此外，通过液相色谱结合串联质谱分析小鼠上段小肠和循环中的内源性大麻素、2-AG 和 anandamide 的水平，以评估内源性大麻素信号传导中与饮食相关的变化以及对食物摄入的潜在影响。与饲喂 SD 的对照小鼠相比，饲喂 WD 60 天的小鼠体重、每日热量摄入、平均膳食量和饲喂率均出现大幅增加。使用外周限制性中性大麻素 CB1 受体拮抗剂 AM6545 (10mg/kg) 抑制外周 CB1R，在 6 小时的测试中显着减少了 WD 的摄入量，但未能改变小鼠的 SD 摄入量。 AM6545 将 WD 摄入量、平均膳食量和进食率标准化至 SD 对照小鼠的水平。这些结果表明 WD 小鼠外周 CB1R 的内源性活性对于驱动食欲亢进至关重要。为了支持这一假设，与 SC 小鼠相比，随意喂养的 WD 小鼠的空肠粘膜和血浆中 2-AG 和 anandamide 的水平有所增加。此外，与 SC 小鼠相比，WD 小鼠中内源性大麻素系统主要成分（即大麻素受体、内源性大麻素生物合成和降解酶）的基因表达失调。我们的结果表明，与 WD 诱导的肥胖相关的食欲亢进是由外周 CB1R 处内源性大麻素信号增强所驱动的。
The endocannabinoid system in the brain and periphery plays a major role in controlling food intake and energy balance. We reported that tasting dietary fats was met with increased levels of the endocannabinoids, 2-arachidonoyl-sn-glycerol (2-AG) and anandamide, in the rat upper small intestine, and pharmacological inhibition of this local signaling event dose-dependently blocked sham feeding of fats. We now investigated the contribution of peripheral endocannabinoid signaling in hyperphagia associated with chronic consumption of a western-style diet in mice ([WD] i.e., high fat and sucrose). Feeding patterns were assessed in male C57BL/6Tac mice maintained for 60 days on WD or a standard rodent chow (SD), and the role for peripheral endocannabinoid signaling at CB1Rs in controlling food intake was investigated via pharmacological interventions. In addition, levels of the endocannabinoids, 2-AG and anandamide, in the upper small intestine and circulation of mice were analyzed via liquid chromatography coupled to tandem mass spectrometry to evaluate diet-related changes in endocannabinoid signaling and the potential impact on food intake. Mice fed WD for 60 days exhibited large increases in body weight, daily caloric intake, average meal size, and rate of feeding when compared to control mice fed SD. Inhibiting peripheral CB1Rs with the peripherally-restricted neutral cannabinoid CB1 receptor antagonist, AM6545 (10mg/kg), significantly reduced intake of WD during a 6 h test, but failed to modify intake of SD in mice. AM6545 normalized intake of WD, average meal size, and rate of feeding to levels found in SD control mice. These results suggest that endogenous activity at peripheral CB1Rs in WD mice is critical for driving hyperphagia. In support of this hypothesis, levels of 2-AG and anandamide in both, jejunum mucosa and plasma, of ad-libitum fed WD mice increased when compared to SC mice. Furthermore, expression of genes for primary components of the endocannabinoid system (i.e., cannabinoid receptors, and endocannabinoid biosynthetic and degradative enzymes) was dysregulated in WD mice when compared to SC mice. Our results suggest that hyperphagia associated with WD-induced obesity is driven by enhanced endocannabinoid signaling at peripheral CB1Rs.