|Mol Metab. 2016 Oct 22;5(12):1187-1199. eCollection 2016.|
Targeting the endocannabinoid/CB1 receptor system for treating obesity in Prader-Willi syndrome.
Knani I1, Earley BJ2, Udi S1, Nemirovski A1, Hadar R1, Gammal A1, Cinar R2, Hirsch HJ3, Pollak Y3, Gross I3, Eldar-Geva T4, Reyes-Capo DP5, Han JC6, Haqq AM7, Gross-Tsur V3, Wevrick R8, Tam J1.
1Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
2Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.
3Neuropediatric Unit, Department of Pediatrics, Shaare Zedek Medical Center, Jerusalem, Israel.
4Reproductive Endocrinology and Genetics Unit, Department of Obstetrics and Gynecology, Shaare Zedek Medical Center, Jerusalem, Israel.
5Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA.
6Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA; Department of Pediatrics, University of Tennessee Health Science Center, Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, TN, USA; Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, USA.
7Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.
8Department of Medical Genetics, University of Alberta, Edmonton, AB Canada.
Extreme 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.
We 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.
Individuals 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.
Dysregulation 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.