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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2021
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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. |
format | Online Article Text |
id | pubmed-7934941 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
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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