title: Targeting the endocannabinoid/CB1 receptor system for treating obesity in Prader-Willi syndrome.
abstract: 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 theMagel2-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 inMagel2-null mice. Daily chronic treatment of obeseMagel2-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 inMagel2-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.
authors.affiliation: Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Knani
authors.affiliation: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Earley
authors.affiliation: Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Shiran
authors.initials: S
authors.lastname: Udi
authors.affiliation: Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Alina
authors.initials: A
authors.lastname: Nemirovski
authors.affiliation: Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Rivka
authors.initials: R
authors.lastname: Hadar
authors.affiliation: Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Asaad
authors.initials: A
authors.lastname: Gammal
authors.affiliation: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.
authors.forename: Resat
authors.initials: R
authors.lastname: Cinar
authors.affiliation: Neuropediatric Unit, Department of Pediatrics, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: Harry J
authors.initials: HJ
authors.lastname: Hirsch
authors.affiliation: Neuropediatric Unit, Department of Pediatrics, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: Yehuda
authors.initials: Y
authors.lastname: Pollak
authors.affiliation: Neuropediatric Unit, Department of Pediatrics, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: Itai
authors.initials: I
authors.lastname: Gross
authors.affiliation: Reproductive Endocrinology and Genetics Unit, Department of Obstetrics and Gynecology, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: Talia
authors.initials: T
authors.lastname: Eldar-Geva
authors.affiliation: Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA.
authors.forename: Daniela P
authors.initials: DP
authors.lastname: Reyes-Capo
authors.affiliation: 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.
authors.forename: Joan C
authors.initials: JC
authors.lastname: Han
authors.affiliation: Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Haqq
authors.affiliation: Neuropediatric Unit, Department of Pediatrics, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: Varda
authors.initials: V
authors.lastname: Gross-Tsur
authors.affiliation: Department of Medical Genetics, University of Alberta, Edmonton, AB Canada.
authors.forename: Rachel
authors.initials: R
authors.lastname: Wevrick
authors.affiliation: Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel. Electronic address: yossit@ekmd.huji.ac.il.
authors.forename: Joseph
authors.initials: J
authors.lastname: Tam
mesh_terms: D000328:Adult; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D001095:Arachidonic Acids / Q000097:blood; D001835:Body Weight / Q000187:drug effects; D016022:Case-Control Studies; D004195:Disease Models, Animal; D063388:Endocannabinoids / Q000097:blood / Q000378:metabolism; D005260:Female; D005989:Glycerides / Q000097:blood; D006801:Humans; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011218:Prader-Willi Syndrome / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D015431:Weight Loss / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins; D064267:Intrinsically Disordered Proteins
chemical_list: D000951:Antigens, Neoplasm; D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; D011506:Proteins; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D013449:Sulfonamides; C403091:Magel2 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D064267:Intrinsically Disordered Proteins; C094503:glyceryl 2-arachidonate; C577200:JD5037
keywords: Endocannabinoids; Magel2; Metabolic syndrome; PWS; Peripheral CB1 blockade