Healthy Aging Korean Medical Research Center, School of Korean Medicine, Pusan National University, Yangsan 50612, Korea.
Division of Longevity and Biofunctional Medicine, School of Korean Medicine, Pusan National University, Yangsan 50612, Korea.
Int J Mol Sci. 2019 Apr 29;20(9):2109. doi: 10.3390/ijms20092109.
Endogenous cannabinoids (ECs) are lipid-signaling molecules that specifically bind to cannabinoid receptor types 1 and 2 (CB1R and CB2R) and are highly expressed in central and many peripheral tissues under pathological conditions. Activation of hepatic CB1R is associated with obesity, insulin resistance, and impaired metabolic function, owing to increased energy intake and storage, impaired glucose and lipid metabolism, and enhanced oxidative stress and inflammatory responses. Additionally, blocking peripheral CB1R improves insulin sensitivity and glucose metabolism and also reduces hepatic steatosis and body weight in obese mice. Thus, targeting EC receptors, especially CB1R, may provide a potential therapeutic strategy against obesity and insulin resistance. There are many CB1R antagonists, including inverse agonists and natural compounds that target CB1R and can reduce body weight, adiposity, and hepatic steatosis, and those that improve insulin sensitivity and reverse leptin resistance. Recently, the use of CB1R antagonists was suspended due to adverse central effects, and this caused a major setback in the development of CB1R antagonists. Recent studies, however, have focused on development of antagonists lacking adverse effects. In this review, we detail the important role of CB1R in hepatic insulin resistance and the possible underlying mechanisms, and the therapeutic potential of CB1R targeting is also discussed.
内源性大麻素（ECs）是脂类信号分子，特异性结合大麻素受体 1 型和 2 型（CB1R 和 CB2R），在病理条件下高度表达于中枢和许多外周组织。肝 CB1R 的激活与肥胖、胰岛素抵抗和代谢功能受损有关，原因是能量摄入和储存增加、葡萄糖和脂质代谢受损、氧化应激和炎症反应增强。此外，阻断外周 CB1R 可改善胰岛素敏感性和葡萄糖代谢，并减少肥胖小鼠的肝脂肪变性和体重。因此，针对 EC 受体，特别是 CB1R，可能为肥胖和胰岛素抵抗提供一种潜在的治疗策略。有许多 CB1R 拮抗剂，包括针对 CB1R 的反向激动剂和天然化合物，可降低体重、体脂和肝脂肪变性，并提高胰岛素敏感性和逆转瘦素抵抗。最近，由于中枢副作用，CB1R 拮抗剂的使用被暂停，这对 CB1R 拮抗剂的开发造成了重大挫折。然而，最近的研究集中于开发无不良反应的拮抗剂。在这篇综述中，我们详细介绍了 CB1R 在肝胰岛素抵抗中的重要作用及其可能的潜在机制，并讨论了针对 CB1R 的治疗潜力。
