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Updated: Nov 21, 2025
Body Composition and Metabolic Caging Analysis in High Fat Fed Mice
Published on: May 24, 2018
Pharmacological chaperone action in humanized mouse models of MC4R-linked obesity
Patricia René1, Damien Lanfray2, Denis Richard2
1Départment de Biochimie et de Médecine Moléculaire, Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Quebec, Canada.
Abstract:
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.
Insights
Pharmacological chaperones (PCs) offer a promising therapy for obesity caused by melanocortin type 4 receptor (MC4R) mutations. These PCs restore MC4R function in preclinical models, demonstrating therapeutic potential for MC4R-linked obesity.
Area of Science:
- Endocrinology
- Genetics
- Pharmacology
Background:
- Melanocortin type 4 receptor (MC4R) mutations are a primary genetic cause of obesity, often due to protein misfolding and cellular retention.
- Current treatments for MC4R-linked obesity are limited, necessitating novel therapeutic strategies.
Purpose of the Study:
- To investigate the therapeutic potential of pharmacological chaperones (PCs) for MC4R-linked obesity.
- To develop and validate preclinical models for testing PC efficacy in restoring MC4R function.
Main Methods:
- Engineered humanized MC4R (hMC4R) mouse models expressing either wild-type (WT) or a common obesity-causing mutant (R165W).
- Administered a PC to rescue cell surface expression and functional activity of the R165W-hMC4R mutant.
- Assessed the anorexigenic response to melanocortin agonists in treated and control mice.
Main Results:
- The PC successfully restored cell surface expression and function of the R165W-hMC4R mutant in vitro and in vivo.
- Treated R165W-hMC4R obese mice exhibited restored anorexigenic responses to melanocortin agonists.
- WT-hMC4R mice showed reduced sensitivity to α-MSH, resulting in a less severe obese phenotype compared to R165W-hMC4R mice.
Conclusions:
- Pharmacological chaperones represent a viable therapeutic approach for MC4R-linked obesity by correcting receptor misfolding and restoring function.
- Developed novel hMC4R mouse models that serve as valuable preclinical tools for evaluating MC4R-targeting therapies and understanding species-specific receptor differences.
