Beijing Institute of Pharmacology and Toxicology, Beijing 100850, PR China; State Key Laboratory of Toxicology and Medical Countermeasures, Beijing 100850, China.
Beijing Institute of Pharmacology and Toxicology, Beijing 100850, PR China.
Eur J Pharmacol. 2017 Nov 5;814:232-239. doi: 10.1016/j.ejphar.2017.08.030. Epub 2017 Aug 26.
As a key insulin target tissue for maintaining systemic glucose homeostasis, the liver plays important roles in improving obesity-associated insulin intolerance via selective cannabinoid CB receptor antagonism/inverse agonism. However, it is unclear whether this receptor inverse agonism affects hepatic glucose metabolism. MJ08 is a novel cannabinoid CB receptor antagonist/inverse agonist that has superior inverse agonism over the well-known antagonist/inverse agonist, SR141716 (rimonabant). MJ08 remarkably elevates fasting blood glucose independent of inhibition of insulin release in mice. In the current study, MJ08 was used to investigate the mechanism by which liver cannabinoid CB receptor inverse activation regulates hepatic glucose metabolism. MJ08 stimulated hepatic glucose production (HGP) in a dose-dependent manner and promoted gluconeogenic gene expression in perfused rat liver. SR141716 exhibited similar but weaker effects. The cannabinoid CB receptor agonist (WIN 55,212-2), Gs protein-cyclic AMP (cAMP)-dependent pathway inhibitors (NF449 and H89), β-adrenoceptor antagonist (propranolol), and peripheral sympathetic inhibitor (reserpine) could antagonize MJ08-induced HGP. Furthermore, MJ08 and SR141716 induced monoamine neurotransmitter (noradrenaline) release and increased cAMP content significantly in perfused liver, although only a slight increase was observed in primary cultured hepatocytes. These results indicate that local liver cannabinoid CB receptor inverse agonism via hepatic sympathetic innervation is responsible for the HGP induced by MJ08. Thus, high inverse agonistic activity could increase fasting blood glucose levels and should be avoided in the development of peripheral cannabinoid CB receptor-targeted weight-loss drugs.
作为维持全身葡萄糖稳态的关键胰岛素靶组织，肝脏在通过选择性大麻素 CB 受体拮抗/反向激动改善肥胖相关胰岛素抵抗方面发挥重要作用。然而，尚不清楚这种受体反向激动是否会影响肝葡萄糖代谢。MJ08 是一种新型大麻素 CB 受体拮抗剂/反向激动剂，其反向激动作用优于著名的拮抗剂/反向激动剂 SR141716（利莫那班）。MJ08 可显著升高空腹血糖，而不抑制小鼠胰岛素释放。在本研究中，MJ08 被用于研究肝脏大麻素 CB 受体反向激活调节肝葡萄糖代谢的机制。MJ08 以剂量依赖的方式刺激肝葡萄糖生成（HGP），并促进灌流大鼠肝中糖异生基因的表达。SR141716 表现出类似但较弱的作用。大麻素 CB 受体激动剂（WIN 55,212-2）、G 蛋白-cAMP（cAMP）依赖性途径抑制剂（NF449 和 H89）、β-肾上腺素能受体拮抗剂（普萘洛尔）和外周交感神经抑制剂（利血平）可拮抗 MJ08 诱导的 HGP。此外，MJ08 和 SR141716 诱导单胺神经递质（去甲肾上腺素）释放，并显著增加灌流肝脏中的 cAMP 含量，尽管在原代培养的肝细胞中仅观察到轻微增加。这些结果表明，通过肝交感神经支配的局部肝大麻素 CB 受体反向激动作用是 MJ08 诱导的 HGP 的原因。因此，高反向激动活性可能会增加空腹血糖水平，在外周大麻素 CB 受体靶向减肥药物的开发中应避免使用。
