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Magel2 ‐null mice are hyper‐responsive to setmelanotide, a melanocortin 4 receptor agonist
Author(s) -
Bischof Jocelyn M,
Van Der Ploeg Lex H T,
Colmers William F,
Wevrick Rachel
Publication year - 2016
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13540
Subject(s) - melanocortin , agonist , endocrinology , medicine , melanocortin 4 receptor , receptor , null allele , biology , energy homeostasis , melanocortin receptor , gene , mutant , biochemistry
Background and Purpose 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 MC 4 receptors, as they are defective in the activation of their POMC neurons and hence may fail to normally release the POMC‐derived MC 4 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. Experimental Approach We tested a dose titration of the MC 4 receptor agonist setmelanotide, in development for rare monogenic forms of obesity, in Magel2 ‐null mice. Key Results We show that Magel2 ‐null mice are hypersensitive to the appetite suppressing and metabolic effects of setmelanotide. Conclusion and Implications Setmelanotide may be a useful investigational hormone/neuropeptide replacement therapy for PWS and rare monogenic forms of obesity exhibiting impaired function of POMC neurons.