CB1 receptor blockade counters age-induced insulin resistance and metabolic dysfunction.
CB1 receptor blockade counters age-induced insulin resistance and metabolic dysfunction.
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DOI：
10.1111/acel.12438
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发表时间：
2016-04
期刊：
影响因子：
7.8
通讯作者：
Hundal HS
中科院分区：
文献类型：
--
作者：
Lipina C;Vaanholt LM;Davidova A;Mitchell SE;Storey-Gordon E;Hambly C;Irving AJ;Speakman JR;Hundal HS
内源性大麻素系统可以通过调节摄食行为以及外周能量储存和利用来调节能量动态平衡。重要的是，它的许多代谢活动是通过大麻素1型受体(CB1R)介导的，CB1R的过度激活与肥胖和代谢功能受损有关。在此，我们探讨了选择性CB1R反向激动剂利莫那班对幼龄(4月龄)和老年(17月龄)成年雄性C57BL/6小鼠主要代谢参数的影响。每天服用利莫那班14天后，幼年和老年小鼠的摄食量短暂减少；然而，老年动物的厌食反应更深刻，与身体脂肪质量的实质性减少不谋而合。值得注意的是，老年骨骼肌和肝脏对胰岛素敏感性的降低与CB1R mRNA丰度的增加是一致的。值得注意的是，利莫那班被证明可以改善老年成年小鼠的葡萄糖耐量，提高骨骼肌和肝脏的胰岛素敏感性，但不是年轻的成年小鼠。此外，利莫那班介导的老年脂肪组织的胰岛素敏化与低度炎症和抑制的造脂基因表达的改善是一致的。总体而言，我们的发现表明CB1R在衰老相关的胰岛素抵抗和代谢功能障碍中发挥关键作用，并强调CB1R阻断是对抗与衰老相关的代谢紊乱的潜在策略。
The endocannabinoid system can modulate energy homeostasis by regulating feeding behaviour as well as peripheral energy storage and utilization. Importantly, many of its metabolic actions are mediated through the cannabinoid type 1 receptor (CB1R), whose hyperactivation is associated with obesity and impaired metabolic function. Herein, we explored the effects of administering rimonabant, a selective CB1R inverse agonist, upon key metabolic parameters in young (4 month old) and aged (17 month old) adult male C57BL/6 mice. Daily treatment with rimonabant for 14 days transiently reduced food intake in young and aged mice; however, the anorectic response was more profound in aged animals, coinciding with a substantive loss in body fat mass. Notably, reduced insulin sensitivity in aged skeletal muscle and liver concurred with increased CB1R mRNA abundance. Strikingly, rimonabant was shown to improve glucose tolerance and enhance skeletal muscle and liver insulin sensitivity in aged, but not young, adult mice. Moreover, rimonabant‐mediated insulin sensitization in aged adipose tissue coincided with amelioration of low‐grade inflammation and repressed lipogenic gene expression. Collectively, our findings indicate a key role for CB1R in aging‐related insulin resistance and metabolic dysfunction and highlight CB1R blockade as a potential strategy for combating metabolic disorders associated with aging.