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Study · Animal study (in vivo) · mouse · 2021

1 result

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

René P, Lanfray D, Richard D, Bouvier M

JCI insight22 Feb 2021Cited by 15 (Europe PMC)

PMID33434184 (opens in a new tab)PMCIDPMC7934941 (opens in a new tab)DOI10.1172/jci.insight.132778 (opens in a new tab)PepBankPUB-33434184
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Summary

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.
CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study1

1 result from studies that gave the peptide. No result from this study comes from people.

  1. 01AnimalAnimal study (in vivo)Mechanism

    In mice expressing wild-type human MC4R, the human receptor showed lower sensitivity to alpha-MSH but not to melanotan II.

    In plain wordsIn mice carrying the human MC4R receptor, the receptor was less sensitive to alpha-MSH but not less sensitive to melanotan II.

    Peptide
    Melanotan II
    Outcome
    No significant changeSensitivity of wild-type human MC4R to melanotan II
    Study

    mousen: not reported in source

    Humanized MC4R (WT-hMC4R) mice
    Outcome group
    Receptor activity and mechanism · Metabolic and weight
    Studied dose
    Dose not stated

    Source sentences

    Summary
    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.
    1 context sentence
    Summary · context
    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).

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Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

  1. Version 2Current

    10 Oct 2026, 09:43 UTC

    Study results updated

  2. Version 1

    9 Oct 2026, 03:04 UTC

    First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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