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Pharmacological chaperone action in humanized mouse models of MC4R-linked obesity

MC4R mutations represent the largest monogenic cause of obesity, resulting mainly from receptor misfolding and intracellular retention by the cellular quality control system. The present study aimed at determining whether pharmacological chaperones (PCs) that restore folding and plasma membrane traf...

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Autores principales: René, Patricia, Lanfray, Damien, Richard, Denis, Bouvier, Michel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934941/
https://www.ncbi.nlm.nih.gov/pubmed/33434184
http://dx.doi.org/10.1172/jci.insight.132778
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author René, Patricia
Lanfray, Damien
Richard, Denis
Bouvier, Michel
author_facet René, Patricia
Lanfray, Damien
Richard, Denis
Bouvier, Michel
author_sort René, Patricia
collection PubMed
description MC4R mutations represent the largest monogenic cause of obesity, resulting mainly from receptor misfolding and intracellular retention by the cellular quality control system. The present study aimed at determining whether pharmacological chaperones (PCs) that restore folding and plasma membrane trafficking by stabilizing near native protein conformation may represent valid therapeutic avenues for the treatment of melanocortin type 4 receptor–linked (MC4R-linked) obesity. To test the therapeutic PC potential, we engineered humanized MC4R (hMC4R) mouse models expressing either the WT human MC4R or a prevalent obesity-causing mutant (R165W). Administration of a PC able to rescue cell surface expression and functional activity of R165W-hMC4R in cells restored the anorexigenic response of the R165W-hMC4R obese mice to melanocortin agonist, providing a proof of principle for the therapeutic potential of MC4R-targeting PCs in vivo. Interestingly, the expression of the WT-hMC4R in mice revealed lower sensitivity of the human receptor to α–melanocyte-stimulating hormone (α-MSH) but not β-MSH or melanotan II, resulting in a lower penetrance obese phenotype in the WT-hMC4R versus R165W-hMC4R mice. In conclusion, we created 2 new obesity models, a hypomorphic highlighting species differences and an amorphic providing a preclinical model to test the therapeutic potential of PCs to treat MC4R-linked obesity.
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spelling pubmed-79349412021-03-09 Pharmacological chaperone action in humanized mouse models of MC4R-linked obesity René, Patricia Lanfray, Damien Richard, Denis Bouvier, Michel JCI Insight Technical Advance MC4R mutations represent the largest monogenic cause of obesity, resulting mainly from receptor misfolding and intracellular retention by the cellular quality control system. The present study aimed at determining whether pharmacological chaperones (PCs) that restore folding and plasma membrane trafficking by stabilizing near native protein conformation may represent valid therapeutic avenues for the treatment of melanocortin type 4 receptor–linked (MC4R-linked) obesity. To test the therapeutic PC potential, we engineered humanized MC4R (hMC4R) mouse models expressing either the WT human MC4R or a prevalent obesity-causing mutant (R165W). Administration of a PC able to rescue cell surface expression and functional activity of R165W-hMC4R in cells restored the anorexigenic response of the R165W-hMC4R obese mice to melanocortin agonist, providing a proof of principle for the therapeutic potential of MC4R-targeting PCs in vivo. Interestingly, the expression of the WT-hMC4R in mice revealed lower sensitivity of the human receptor to α–melanocyte-stimulating hormone (α-MSH) but not β-MSH or melanotan II, resulting in a lower penetrance obese phenotype in the WT-hMC4R versus R165W-hMC4R mice. In conclusion, we created 2 new obesity models, a hypomorphic highlighting species differences and an amorphic providing a preclinical model to test the therapeutic potential of PCs to treat MC4R-linked obesity. American Society for Clinical Investigation 2021-02-22 /pmc/articles/PMC7934941/ /pubmed/33434184 http://dx.doi.org/10.1172/jci.insight.132778 Text en © 2021 René et al. http://creativecommons.org/licenses/by/4.0/ This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Technical Advance
René, Patricia
Lanfray, Damien
Richard, Denis
Bouvier, Michel
Pharmacological chaperone action in humanized mouse models of MC4R-linked obesity
title Pharmacological chaperone action in humanized mouse models of MC4R-linked obesity
title_full Pharmacological chaperone action in humanized mouse models of MC4R-linked obesity
title_fullStr Pharmacological chaperone action in humanized mouse models of MC4R-linked obesity
title_full_unstemmed Pharmacological chaperone action in humanized mouse models of MC4R-linked obesity
title_short Pharmacological chaperone action in humanized mouse models of MC4R-linked obesity
title_sort pharmacological chaperone action in humanized mouse models of mc4r-linked obesity
topic Technical Advance
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934941/
https://www.ncbi.nlm.nih.gov/pubmed/33434184
http://dx.doi.org/10.1172/jci.insight.132778
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