2. Academic Validation
  3. Targeting the endocannabinoid/CB1 receptor system for treating obesity in Prader-Willi syndrome

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

  • Mol Metab. 2016 Oct 22;5(12):1187-1199. doi: 10.1016/j.molmet.2016.10.004.
Ibrahim Knani 1,  Brian J Earley 2,  Shiran Udi 1,  Alina Nemirovski 1,  Rivka Hadar 1,  Asaad Gammal 1,  Resat Cinar 2,  Harry J Hirsch 3,  Yehuda Pollak 3,  Itai Gross 3,  Talia Eldar-Geva 4,  Daniela P Reyes-Capo 5,  Joan C Han 6,  Andrea M Haqq 7,  Varda Gross-Tsur 3,  Rachel Wevrick 8,  Joseph Tam 9
Affiliations

Affiliations

  • 1 Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
  • 2 Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.
  • 3 Neuropediatric Unit, Department of Pediatrics, Shaare Zedek Medical Center, Jerusalem, Israel.
  • 4 Reproductive Endocrinology and Genetics Unit, Department of Obstetrics and Gynecology, Shaare Zedek Medical Center, Jerusalem, Israel.
  • 5 Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA.
  • 6 Unit 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.
  • 7 Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.
  • 8 Department of Medical Genetics, University of Alberta, Edmonton, AB Canada.
  • 9 Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel. Electronic address: [email protected].
PMID: 27900261 DOI: 10.1016/j.molmet.2016.10.004
Abstract

Objective: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords

Endocannabinoids; Magel2; Metabolic syndrome; PWS; Peripheral CB1 blockade.

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