Format

Send to

Choose Destination
Br J Pharmacol. 2016 Sep;173(17):2614-21. doi: 10.1111/bph.13540. Epub 2016 Jul 27.

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

Author information

1
Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada.
2
Rhythm Pharmaceuticals, Boston, MA, USA.
3
Department of Pharmacology, University of Alberta, Edmonton, AB, Canada.

Abstract

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 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.

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.

PMID:
27339818
PMCID:
PMC4978157
DOI:
10.1111/bph.13540
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center