Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency.

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State: Public
Version: Final published version
Serval ID
serval:BIB_857A9B9B6B6C
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency.
Journal
Molecular metabolism
Author(s)
Collet T.H., Dubern B., Mokrosinski J., Connors H., Keogh J.M., Mendes de Oliveira E., Henning E., Poitou-Bernert C., Oppert J.M., Tounian P., Marchelli F., Alili R., Le Beyec J., Pépin D., Lacorte J.M., Gottesdiener A., Bounds R., Sharma S., Folster C., Henderson B., O'Rahilly S., Stoner E., Gottesdiener K., Panaro B.L., Cone R.D., Clément K., Farooqi I.S., Van der Ploeg LHT
ISSN
2212-8778 (Electronic)
ISSN-L
2212-8778
Publication state
Published
Issued date
10/2017
Peer-reviewed
Oui
Volume
6
Number
10
Pages
1321-1329
Language
english
Notes
Publication types: Clinical Trial ; Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Pro-opiomelanocortin (POMC)-derived peptides act on neurons expressing the Melanocortin 4 receptor (MC4R) to reduce body weight. Setmelanotide is a highly potent MC4R agonist that leads to weight loss in diet-induced obese animals and in obese individuals with complete POMC deficiency. While POMC deficiency is very rare, 1-5% of severely obese individuals harbor heterozygous mutations in MC4R. We sought to assess the efficacy of Setmelanotide in human MC4R deficiency.
We studied the effects of Setmelanotide on mutant MC4Rs in cells and the weight loss response to Setmelanotide administration in rodent studies and a human clinical trial. We annotated the functional status of 369 published MC4R variants.
In cells, we showed that Setmelanotide is significantly more potent at MC4R than the endogenous ligand alpha-melanocyte stimulating hormone and can disproportionally rescue signaling by a subset of severely impaired MC4R mutants. Wild-type rodents appear more sensitive to Setmelanotide when compared to MC4R heterozygous deficient mice, while MC4R knockout mice fail to respond. In a 28-day Phase 1b clinical trial, Setmelanotide led to weight loss in obese MC4R variant carriers. Patients with POMC defects upstream of MC4R show significantly more weight loss with Setmelanotide than MC4R deficient patients or obese controls.
Setmelanotide led to weight loss in obese people with MC4R deficiency; however, further studies are justified to establish whether Setmelanotide can elicit clinically meaningful weight loss in a subset of the MC4R deficient obese population.
Keywords
Adrenal Insufficiency/drug therapy, Adrenal Insufficiency/metabolism, Adult, Amino Acid Sequence, Animals, Female, HEK293 Cells, Humans, Male, Mice, Mice, Knockout, Middle Aged, Obesity/drug therapy, Obesity/metabolism, Pro-Opiomelanocortin/deficiency, Pro-Opiomelanocortin/metabolism, Receptor, Melanocortin, Type 4/agonists, Receptor, Melanocortin, Type 4/deficiency, Receptor, Melanocortin, Type 4/genetics, Receptor, Melanocortin, Type 4/metabolism, alpha-MSH/analogs & derivatives, alpha-MSH/pharmacology, Melanocortin 4 receptor, Obesity, Setmelanotide, Stratification
Pubmed
Web of science
Open Access
Yes
Create date
26/10/2017 10:19
Last modification date
20/08/2019 15:44
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