O-1918 is a synthetic compound structurally similar to the plant constituent cannabidiol, and is an antagonist for GPR55 and GPR18. While the role of GPR18 in obesity is unknown, GPR55 knockout mice have increased adiposity and insulin resistance. In humans, the expression of GPR55 is increased in visceral fat and positively correlated with obesity and T2D. Both receptors are classified as putative cannabinoid receptors. The endocannabinoid system is involved in regulating energy homeostasis. Therefore modulation of these receptors may be a useful obesity target.
To determine the role that O-1918 has on the regulation of body weight and circulating hormones and cytokines.
Male Sprague Dawley rats were fed a high fat diet (41% energy from fat) for 9 weeks to induce obesity, then treated with 1mg/kg of O-1918 or vehicle for a further 6 weeks. Weight and food intake were monitored daily. Body composition using EchoMRI was measured at baseline, during week-3 and week-6 of treatment. Following treatment, rats were anaesthetised, blood was collected via cardiac puncture and fat pads collected and weighed immediately post-mortem. Plasma concentrations of hormones and cytokines were determined using commercially available Bioplex Diabetes and Cytokine kits.
In obese rats, O-1918 treatment did not change food intake, body weight, body composition or fat pad weight compared to obese control. Despite no alteration in food intake or body weight, O-1918 reduced plasma leptin and ghrelin compared to obese control. O-1918 also increased pro-inflammatory cytokines including IL-1a, IL2, IL17a, IL18 and RANTES, some of which are linked with insulin resistance and T2D.
These results demonstrate that GPR55/GPR18 antagonist, O-1918 did not alter food intake, body weight or adiposity suggesting it is not an effective anti-obesity therapeutic. The changes observed in the circulating hormones and cytokines require further investigation into any tissue-specific effects.