The cannabinoid ligand LH-21 reduces anxiety and improves glucose handling in diet-induced obese pre-diabetic mice

Abstract

LH-21 is a triazol derivative that has been described as a low-permeant neutral CB1 antagonist, though its pharmacology is still unclear. It has been associated with anti-obesity actions in obese rats. However, its role in preventing type 2 diabetes (T2D) onset have not been studied yet. Given CB1 receptors remain as potential pharmacological targets to fight against obesity and T2D, we wanted to explore the metabolic impact of this compound in an animal model of obesity and pre-diabetes as well as the lack of relevant actions in related central processes such as anxiety. C57BL/6J mice were rendered obese and pre-diabetic by feeding a high-fat diet for 15 weeks and then treated with LH-21 or vehicle for two weeks. Food intake, body weight and glucose handling were assessed, together with other relevant parameters. Behavioural performance was evaluated by the open field test and the elevated plus maze. LH-21 did not affect food intake nor body weight but it improved glucose handling, displaying tissue-specific beneficial actions. Unexpectedly, LH-21 induced anxiolysis and reverted obesity-induced anxiety, apparently through GPR55 receptor. These results suggest that LH-21 can be a new candidate to fight against diabetes onset. Indeed, this compound shows potential in counteracting obesity-related anxiety.

LH‐21 and abnormal cannabidiol improve β‐cell function in isolated human and mouse islets through GPR55‐dependent and ‐independent signalling

“…There is a growing body of evidence suggesting that the endocannabinoid system has a role in the regulation of cell proliferation and apoptosis . We have previously reported that CB1 and CB2 agonists protect mouse islets from apoptosis, and we recently demonstrated that LH‐21 delivery to pre‐diabetic mice has anti‐inflammatory and cytoprotective effects . In the present study we showed that LH‐21 has direct anti‐apoptotic effects in isolated human and mouse islets and the use of islets from GPR55 −/− mice indicated that, as for stimulation of insulin secretion and [Ca 2+ ] i , this was GPR55‐mediated.…”

“…Since LH‐21, an inverse agonist/neutral antagonist of CB1, shows structural similarities with AM251 and rimonabant, we investigated whether its activation of islet GPR55 could underlie at least some of its reported positive effects on glucose management . An earlier study used a static incubation protocol to show that the CB1 antagonists AM251 and JD‐5037 increased insulin release from human islets, and in the present study we employed perifusion experiments to demonstrate that LH‐21 also promoted insulin secretion from human islets.…”

“…Treatment of rats with LH‐21 for 10 days resulted in a significant upregulation of GPR55 expression in visceral adipose tissue, suggesting involvement of peripheral GPR55‐related regulatory mechanisms in its effects . We have recently demonstrated that LH‐21 improves glucose metabolism and reduces anxiety in obese prediabetic mice, this latter effect being prevented by a GPR55 antagonist . Because of the promising therapeutic effects of the phytocannabinoid cannabidiol (CBD), synthetic CBD derivatives such as abnormal CBD (Abn‐CBD; trans‐4‐[3‐methyl‐6‐(1‐methylethenyl)‐2‐cyclohexen‐1‐yl]‐5‐pentyl‐1,3‐benzenediol; Figure S1) have been synthesized .…”

“…27 We have recently demonstrated that LH-21 improves glucose metabolism and reduces anxiety in obese prediabetic mice, this latter effect being prevented by a GPR55 antagonist. 29 Because of the promising therapeutic effects of the phytocannabinoid cannabidiol (CBD), synthetic CBD derivatives such as abnormal CBD (Abn-CBD; trans-4-[3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol; Figure S1) have been synthesized. 30 Abn-CBD has vasodilator effects that were blocked by the CB1 antagonist SR141716A, but were maintained in CB1/CB2 double knockout mice, which led to the proposal that Abn-CBD acted as an agonist at a novel cannabinoid receptor.…”

Structure-Activity Relationship of the GPR55 Antagonist, CID16020046

“…CID16020046 has extended the association of GPR55 to cancer, blocking LPI-evoked angiogenesis in ovarian carcinoma and migration of breast cancer cells [24,25]. Treatment of mice with CID16020046 counteracted the anxiogenic and other behavioural effects of the cannabinoid ligand LH-21, which had previously been suggested to act via GPR55 and independently of cannabinoid CB 1 receptor [26]. Antagonists have also been used to confirm affinity for GPR55 of newly recognised lipid agonists, including LPC (lysophosphaditylcholine) and N-arachidonoylglycine [27][28][29].…”