ArticleJCI insight2021
Pharmacological chaperone action in humanized mouse models of MC4R-linked obesity.
Article in JCI insight, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers, 1 of them a synthesis that pooled it.
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Who cites it
12 citing papers in PubMed, 1 synthesis or guideline pooled it, 18 citations in OpenAlex.
- A Systematic Review of Proteomics in Obesity: Unpacking the Molecular Puzzle.Current obesity reports · 2024Pooled it
- Recent developments in GPCR signalling in appetite regulation.Bioscience reports · 2026Review
- The role of accessory proteins and co-factors in regulation of melanocortin-4 receptor signalling: An update.Journal of neuroendocrinology · 2026Review
- Functional rescue and AI analysis of a human inactivating GPCR mutation using a small molecule.EMBO molecular medicine · 2026Article
- Assessing the limitations of paraformaldehyde fixation for accurate cell surface receptor measurement.Frontiers in pharmacology · 2026Article
- A small molecule stabilizer rescues the surface expression of nearly all missense variants in a GPCR.Nature structural & molecular biology · 2025Article
- Navigating the Strengths and Constraints of Mouse Models in Obesity Research.Endocrinology · 2025Review
- MC4R Variants Modulate α-MSH and Setmelanotide Induced Cellular Signaling at Multiple Levels.The Journal of clinical endocrinology and metabolism · 2024Article
- Segregation of nascent GPCRs in the ER-to-Golgi transport by CCHCR1 via direct interaction.Journal of cell science · 2024Article
- Ligands for Melanocortin Receptors: Beyond Melanocyte-Stimulating Hormones and Adrenocorticotropin.Biomolecules · 2022Review
- Targeting trafficking as a therapeutic avenue for misfolded GPCRs leading to endocrine diseases.Frontiers in endocrinology · 2022Review
- Hypothalamic GPCR Signaling Pathways in Cardiometabolic Control.Frontiers in physiology · 2021Review
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.