Diet‐Induced Obesity in Cannabinoid‐2 Receptor Knockout Mice and Cannabinoid Receptor 1/2 Double‐Knockout Mice

Abstract

Objective Evidence suggests that cannabinoid‐1 receptor (CB1R) activation is associated with increased food intake and body weight gain. Human epidemiological studies, however, show decreased prevalence of obesity in cannabis users. Given the overlapping and complementary functions of the cannabinoid receptors (CB1R and CB2R), mice lacking CB2R and mice lacking both CB1R and CB2R were studied. Methods A high‐fat diet was used to study metabolic changes in male mice lacking CB2R (CB2−/−) or lacking both CB1R and CB2R (double‐knockout [CB‐DKO]) compared with wild‐type mice. Results When CB2−/− mice were maintained on a high‐fat diet, their weight gain was not different from wild‐type mice (gaining 19 and 21 g, respectively), whereas CB‐DKO mice gained only 5 g. There were no significant differences in food intake or locomotor activity between the three groups. Respiratory exchange rate and heat production were elevated in CB‐DKO mice, with upregulation of adipose tissue thermogenic genes. Glucose tolerance test and insulin levels indicated increased insulin sensitivity in CB‐DKO mice, whereas CB2−/− displayed signs of impaired glucose clearance. Conclusions These results indicate that lacking both CB1R and CB2R protected mice from diet‐induced obesity, possibly through the prominent role of CB1R in obesity or through an interactive effect of both receptors.

Influence of Cannabinoid Receptor Deficiency on Parameters Involved in Blood Glucose Regulation in Mice

“…Another study reported in two-month-old male CB 2 −/− mice similar body weight values to those of normoglycaemic, age-matched, wild-type mice [18]. Increased body weight of CB 2 −/− mice was measured in other studies [19,35], which is in accordance with our data considering male CB 2 −/− mice only.…”

“…In feeding mouse models, CB 2 receptor deletion was associated with impaired glucose clearance [19], supporting our findings of elevated blood glucose and hormonal differences in CB 2 −/− . Using diet-induced obesity mice, CB 2 receptor agonists were shown to be efficacious in reducing body weight and obesity-associated metabolic parameter, e.g., insulin.…”

“…Another study on diet-induced obesity in CB 2 -knockout and CB 1/2 double-knockout mice reported that mice lacking both of the cannabinoid receptors were lean and resistant to diet-induced obesity. This phenotype was distinct from CB 2 -deficient mice which displayed signs of impaired glucose clearance [19]. Notably, in global models lacking cannabinoid receptors, other organs than pancreatic islets such as liver, skeletal muscle or adipose tissue might be directly or indirectly involved in the regulation of blood glucose levels or insulin resistance.…”

The Endocannabinoid System in Pediatric Inflammatory and Immune Diseases

“…It has been demonstrated that the EC system modulation is involved in regulating obesity [90,91], but CB1 and CB2 receptors play different roles. While CB1 activation induces increasing inflammatory processes [92], CB2 activation ameliorates the inflammatory state related to obesity [93]. Actually, there are different opinions about the role of CB2 in obesity.…”

“…Indeed, children expressing this variant show an increase in weight and high levels of pro-inflammatory cytokines (IL-6 and TNF-α). When the CB2 receptor is selectively stimulated with JWH-133, this critical condition is restored in primary cultures of adipocytes obtained from obese subjects [93,98,99]. Another polymorphism positively associated with obesity is the FAAH polymorphism rs324420 that reduces FAAH activity, leading to higher AEA levels and consequent over-activation of CB1 receptors, which, in turn, causes adipogenesis and a high obesity risk [100,101].…”