Wargent Edward T, Kepczynska Malgorzata, Zaibi Mohamed Sghaier, Hislop David C, Arch Jonathan R S, Stocker Claire J
Institute of Translational Medicine, University of Buckingham, Buckingham, United Kingdom.
Medical School, University of Buckingham, Buckingham, United Kingdom.
PeerJ. 2020 Aug 24;8:e9811. doi: 10.7717/peerj.9811. eCollection 2020.
The insulin-sensitizing phytocannabinoid, Δ(9)-tetrahydrocannabivarin (THCV) can signal partly via G-protein coupled receptor-55 (GPR55 behaving as either an agonist or an antagonist depending on the assay). The cannabinoid receptor type 1 (CB1R) inverse agonist rimonabant is also a GPR55 agonist under some conditions. Previous studies have shown varied effects of deletion of GPR55 on energy balance and glucose homeostasis in mice. The contribution of signalling via GPR55 to the metabolic effects of THCV and rimonabant has been little studied.
In a preliminary experiment, energy balance and glucose homeostasis were studied in GPR55 knockout and wild-type mice fed on both standard chow (to 20 weeks of age) and high fat diets (from 6 to 15 weeks of age). In the main experiment, all mice were fed on the high fat diet (from 6 to 14 weeks of age). In addition to replicating the preliminary experiment, the effects of once daily administration of THCV (15 mg kg po) and rimonabant (10 mg kg po) were compared in the two genotypes.
There was no effect of genotype on absolute body weight or weight gain, body composition measured by either dual-energy X-ray absorptiometry or Nuclear Magnetic Resonance (NMR), fat pad weights, food intake, energy expenditure, locomotor activity, glucose tolerance or insulin tolerance in mice fed on chow. When the mice were fed a high fat diet, there was again no effect of genotype on these various aspects of energy balance. However, in both experiments, glucose tolerance was worse in the knockout than the wild-type mice. Genotype did not affect insulin tolerance in either experiment. Weight loss in rimonabant- and THCV-treated mice was lower in knockout than in wild-type mice, but surprisingly there was no detectable effect of genotype on the effects of the drugs on any aspect of glucose homeostasis after taking into account the effect of genotype in vehicle-treated mice.
Our two experiments differ from those reported by others in finding impaired glucose tolerance in GPR55 knockout mice in the absence of any effect on body weight, body composition, locomotor activity or energy expenditure. Nor could we detect any effect of genotype on insulin tolerance, so the possibility that GPR55 regulates glucose-stimulated insulin secretion merits further investigation. By contrast with the genotype effect in untreated mice, we found that THCV and rimonabant reduced weight gain, and this effect was in part mediated by GPR55.
具有胰岛素增敏作用的植物大麻素Δ⁹ - 四氢大麻酚酸（THCV）可部分通过G蛋白偶联受体55（GPR55）发挥信号传导作用，在不同检测方法中GPR55表现为激动剂或拮抗剂。大麻素1型受体（CB1R）反向激动剂利莫那班在某些情况下也是GPR55激动剂。先前的研究表明，敲除GPR55对小鼠能量平衡和葡萄糖稳态有不同影响。通过GPR55信号传导对THCV和利莫那班代谢作用的贡献鲜有研究。
在一项初步实验中，对喂食标准饲料（至20周龄）和高脂饮食（6至15周龄）的GPR55基因敲除小鼠和野生型小鼠的能量平衡和葡萄糖稳态进行了研究。在主要实验中，所有小鼠均喂食高脂饮食（6至14周龄）。除重复初步实验外，还比较了两种基因型小鼠每日一次给予THCV（15 mg/kg口服）和利莫那班（10 mg/kg口服）的效果。
对于喂食普通饲料的小鼠而言，基因型对绝对体重、体重增加、通过双能X线吸收法或核磁共振（NMR）测量的身体组成、脂肪垫重量、食物摄入量、能量消耗、运动活动、葡萄糖耐量或胰岛素耐量均无影响。当小鼠喂食高脂饮食时，基因型对能量平衡的这些不同方面同样没有影响。然而，在两个实验中，基因敲除小鼠的葡萄糖耐量均比野生型小鼠差。在任一实验中，基因型均不影响胰岛素耐量。利莫那班和THCV治疗的小鼠中，基因敲除小鼠的体重减轻低于野生型小鼠，但令人惊讶的是，在考虑溶媒处理小鼠的基因型影响后，未检测到基因型对药物在葡萄糖稳态任何方面的影响产生作用。
我们的两项实验与其他研究报告不同，发现GPR55基因敲除小鼠存在葡萄糖耐量受损，而对体重、身体组成、运动活动或能量消耗无任何影响。我们也未检测到基因型对胰岛素耐量有任何影响，因此GPR5是否调节葡萄糖刺激的胰岛素分泌值得进一步研究。与未处理小鼠的基因型效应相反，我们发现THCV和利莫那班可减轻体重增加，且这一效应部分由GPR55介导。
