The mechanisms in the nervous system that control appetite and satiation are complex. And the dysfunctions in those mechanisms that lead to hyperphagia and obesity in people with PWS are likewise complex and unclear. Yet, several hypothalamic appetite regulators have been identified. Among them, the endocannabinoid (eCB) system appears to be critically involved in the regulation of appetite, body weight, and metabolism.
In a recent scientific publication titled Targeting the Endocannabinoid/CB1 Receptor System for Treating Obesity in Prader-Willi Syndrome, published in the journal Molecular Metabolism (1), Tam and collaborators used both human clinical data and animal models for PWS to identify a role for the eCB system in the development of obesity and altered metabolism in PWS. These findings are paving the way for the development and clinical testing of drugs acting on the cannabinoid system to combat obesity and its devastating consequences in PWS.
Cannabis And Appetite
Cannabis sativa L. (marijuana) preparations have been used in medicine for millenia to treat nausea, pain, epilepsy, hypertension, anxiety, cachexia, etc. The stimulant properties of cannabis on appetite have been recorded as early as 300 ad. Although investigations into the chemistry of cannabis began in the mid-19th century, it was not until 1964 that ∆9-tetrahydrocannabinol (THC), the major psychoactive component of cannabis, was isolated and its structure elucidated. Cannabis has more than 80 chemical constituents, known as “cannabinoids,” which alter the release of neurotransmitters from the brain. (Neurotransmitters are chemical messengers that are released in the brain to allow transmission of information between brain cells.) Two of the most active and studied constituents of cannabis are THC and cannabidiol (CBD).
CBD is a non-psychoactive component that acts on many of the same receptors as THC, but without the psychoactive side effects. In the 1930s and 1940s, concern about the dangers of abuse led to the banning of marijuana and its constituents for medicinal use in the United States and many other countries. It took decades until cannabinoids came to be reconsidered compounds of therapeutic value. The discovery in the 1990s of cannabinoid receptors (CB1R and CB2R) that are expressed in the brain and peripherally and their endogenous ligands, named endocannabinoids (eCBs), which mimic the behavioral actions of THC, has triggered the exponential growth of studies exploring the eCB system in health and disease.
Cannabinoid Studies On Obesity and PWS
The first-in-class CB1R antagonist rimonabant was tested for 1 year in overweight individuals and was shown to be effective in reducing weight, waist circumference, and several cardiovascular and metabolic risk factors. In 2007, rimonabant was also tested in obese adults with PWS in a small double-blind, placebo-controlled clinical trial. Despite a trend towards weight loss and lower body fat mass in the rimonabant group, the trial was terminated early due to psychiatric adverse events, and rimonabant has since been removed from the EU market.
In 2012, Tam and collaborators developed a new compound (JD5037) acting peripherally to block CB1R, which robustly reduced food intake, body weight, and adiposity in mouse models of obesity. Interestingly, they showed that in contrast to rimonabant, which binds to CB1R present in the brain and in the periphery, JD5037’s action was restricted to CB1R in the periphery. In addition, JD5037 had no effect on behaviors and did not induce anxiety in mice. These results published in Cell Metabolism in 2012 suggested that a peripheral action of eCBs on CB1R rather than a central action mediates eCB hypophagic effects without causing behavioral effects that are associated with blocking the receptor in the brain.
Testing In a PWS Mouse Model
The next step consisted of testing JD5037 in a PWS mouse model. Thanks to an FPWR grant, Tam and collaborators used Magel2 knockout mice to show that the chronic blockade of CB1R in the periphery was as effective as globally acting CB1R antagonism in reversing obesity and its metabolic abnormalities. These results suggest that the disrupted body composition and energy balance in Magel2-null mice are associated with increased eCB “tone.”
To examine further whether increased eCB tone also occurs in individuals with PWS, Tam and colleagues measured plasma levels of circulating eCBs (AEA, 2-AG, and their endogenous precursor and breakdown ligand) in two independent cohorts of patients with PWS in Israel and the US. They found that circulating levels of eCBs were indeed markedly elevated in PWS and appeared to be correlated with several metabolic parameters.
Taken together, the results of this new study suggest that dysregulation of the eCB/CB1R system may contribute to hyperphagia and obesity in Magel2-null mice and in individuals with PWS. The development of peripherally restricted CB1R antagonists may be an effective therapeutic strategy to manage severe obesity in PWS and avoid the psychiatric side effects likely due to central eCB/CB1R effects.
(1) Knani I, Earley BJ, Udi S, Nemirovski A, Hadar R, Gammal A, Cinar R, Hirsch HJ, Pollak Y, Gross I, Eldar-Geva T, Reyes-Capo DP, Han JC, Haqq AM, Gross-Tsur V, Wevrick R, Tam J. 2016. Targeting the endocannabinoid/CB1 receptor system for treating obesity in Prader-Willi syndrome. Mol Metab 5:1187–1199.