Targeting the endocannabinoid/CB1 receptor system for treating obesity in Prader–Willi syndrome

Abstract

ObjectiveExtreme obesity is a core phenotypic feature of Prader–Willi syndrome (PWS). Among numerous metabolic regulators, the endocannabinoid (eCB) system is critically involved in controlling feeding, body weight, and energy metabolism, and a globally acting cannabinoid-1 receptor (CB1R) blockade reverses obesity both in animals and humans. The first-in-class CB1R antagonist rimonabant proved effective in inducing weight loss in adults with PWS. However, it is no longer available for clinical use because of its centrally mediated, neuropsychiatric, adverse effects.MethodsWe studied eCB ‘tone’ in individuals with PWS and in the Magel2-null mouse model that recapitulates the major metabolic phenotypes of PWS and determined the efficacy of a peripherally restricted CB1R antagonist, JD5037 in treating obesity in these mice.ResultsIndividuals with PWS had elevated circulating levels of 2-arachidonoylglycerol and its endogenous precursor and breakdown ligand, arachidonic acid. Increased hypothalamic eCB ‘tone’, manifested by increased eCBs and upregulated CB1R, was associated with increased fat mass, reduced energy expenditure, and decreased voluntary activity in Magel2-null mice. Daily chronic treatment of obese Magel2-null mice and their littermate wild-type controls with JD5037 (3 mg/kg/d for 28 days) reduced body weight, reversed hyperphagia, and improved metabolic parameters related to their obese phenotype.ConclusionsDysregulation of the eCB/CB1R system may contribute to hyperphagia and obesity in Magel2-null mice and in individuals with PWS. Our results demonstrate that treatment with peripherally restricted CB1R antagonists may be an effective strategy for the management of severe obesity in PWS.

Metabolic Profiling of CB1 Neutral Antagonists

“…Liver tissue was extracted as described previously (Knani et al, 2016) and its triglyceride content determined using EnzyChrom ™ Triglyceride Assay Kit (BioAssay Systems, CA).…”

Current and emerging therapies for managing hyperphagia and obesity in Prader‐Willi syndrome: A narrative review

“…This leptin resensitization was shown to be significantly correlated with the reductions in food intake and body weight, suggesting that JD5037 might exert its hypophagic and weight‐lowering effects via the reversal of leptin resistance. A similar study showed consistent anti‐obesity effects of JD5037 in a PWS mouse model, in which mice receiving 28‐day treatment with JD5037 displayed improvements in body weight, hyperphagia, and obesity‐associated metabolic parameters . The same study reported that there were increased concentrations of eCBs and CB1R in the hypothalamus of mice with PWS.…”

“…These elevations were associated with increased fat mass, reduced energy expenditure, and decreased voluntary activity observed in mouse models of PWS. The dysregulated eCB system identified in mouse models of PWS was further confirmed in humans; there were upregulated levels of 2‐arachidonoylglycerol and arachidonic acid in plasma of patients with PWS . Thus, eCB system dysregulation may be responsible, at least in part, for the hyperphagia and obesity of PWS.…”

Dysfunctional oleoylethanolamide signaling in a mouse model of Prader-Willi syndrome

“…The identity of these hypothetical factors is unknown, however. It is notable that a recent study found an abnormal increase in 2-arachidonoylglycerol (2-AG) system, which may contribute to hyperphagia and obesity in Magel2 -null mice [41]. Interestingly, the changes in OEA production found in Magel2 -null mice are markedly different from those seen in mice that are made obese either by exposure to a high-fat diet or by genetic deletion of leptin ( ob / ob mice).…”