Magel2-null mice are hyper-responsive to setmelanotide, a melanocortin 4 receptor agonist

作者：Bischof Jocelyn M; Van Der Ploeg Lex H T; Colmers William F; Wevrick Rachel

来源：British Journal of Pharmacology, 2016, 173(17): 2614-2621.

DOI：10.1111/bph.13540

BACKGROUND AND PURPOSE
alpha- and beta-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 a-and beta-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 MC4 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.

• 出版日期2016-9