title: Magel2-null mice are hyper-responsive to setmelanotide, a melanocortin 4 receptor agonist.
abstract: α- and β-melanocyte-stimulating hormones (MSH) are derived from pro-opiomelanocortin (POMC) and are the natural agonist ligands of the melanocortin 4 receptor, a key regulator of energy homeostasis. Recent rodent and human data have implicated the MAGEL2 gene, which may regulate activation of POMC neurons, as a significant contributor to the metabolic symptoms observed in Prader-Willi Syndrome (PWS). Firstly, patients with protein truncating mutations in MAGEL2 exhibit numerous clinical characteristics of PWS. Secondly, Magel2-null mice may not normally activate MC4 receptors, as they are defective in the activation of their POMC neurons and hence may fail to normally release the POMC-derived MC4 receptor agonist ligands α- and β-MSH. Magel2-null mice represent a tractable animal model for the metabolic and appetitive imbalance seen in patients with PWS.
  
  
  
  We tested a dose titration of the MC4 receptor agonist setmelanotide, in development for rare monogenic forms of obesity, in Magel2-null mice.
  
  
  
  We show that Magel2-null mice are hypersensitive to the appetite suppressing and metabolic effects of setmelanotide.
  
  
  
  Setmelanotide may be a useful investigational hormone/neuropeptide replacement therapy for PWS and rare monogenic forms of obesity exhibiting impaired function of POMC neurons.
authors.affiliation: Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada.
authors.forename: Jocelyn M
authors.initials: JM
authors.lastname: Bischof
authors.affiliation: Rhythm Pharmaceuticals, Boston, MA, USA.
authors.forename: Lex H T
authors.initials: LH
authors.lastname: Van Der Ploeg
authors.affiliation: Department of Pharmacology, University of Alberta, Edmonton, AB, Canada.
authors.forename: William F
authors.initials: WF
authors.lastname: Colmers
authors.affiliation: Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada.
authors.forename: Rachel
authors.identifier: 0000-0002-3343-5794
authors.initials: R
authors.lastname: Wevrick
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism; D001069:Appetite Regulation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007274:Injections, Intraperitoneal; D008297:Male; D008660:Metabolism / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011218:Prader-Willi Syndrome / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists*; D013329:Structure-Activity Relationship; D000521:alpha-MSH / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D064267:Intrinsically Disordered Proteins
chemical_list: D000951:Antigens, Neoplasm; D011333:Pro-Opiomelanocortin; D011506:Proteins; D044105:Receptor, Melanocortin, Type 4; D000521:alpha-MSH; C403091:Magel2 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D064267:Intrinsically Disordered Proteins; C579663:setmelanotide