ArticleThe Journal of clinical endocrinology and metabolism2024
MC4R Variants Modulate α-MSH and Setmelanotide Induced Cellular Signaling at Multiple Levels.
Article in The Journal of clinical endocrinology and metabolism, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 15 citations in OpenAlex.
- Rationale of renewed efforts in developing MC4R modulators to treat metabolic disorders.Acta pharmaceutica Sinica. B · 2026Review
- Recent developments in GPCR signalling in appetite regulation.Bioscience reports · 2026Review
- Mice lacking β-arrestin-2 in melanocortin 4 receptor-expressing neurons show marked metabolic deficits.JCI insight · 2026Article
- Functional characterisation of obesity-associated MRAP2 variants on MC4R and GHSR signalling.Human molecular genetics · 2026Article
- Pathogenic variation in insulin resistance genes is common in polycystic ovary syndrome (PCOS): a strategy for causal gene discovery using whole-exome sequencing (WES) in complex traits.medRxiv : the preprint server for health sciences · 2025Article
- Loss-of-Function GHSR Variants Are Associated With Short Stature and Low IGF-I.The Journal of clinical endocrinology and metabolism · 2025Article
- Article
- MC4R Variants Modulate α-MSH and Setmelanotide Induced Cellular Signaling at Multiple Levels.The Journal of clinical endocrinology and metabolism · 2024Article
- Exploring the therapeutic potential of precision medicine in rare genetic obesity disorders: a scientific perspective.Frontiers in nutrition · 2024Review
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
contextThe melanocortin-4 receptor (MC4R) plays an important role in body weight regulation. Pathogenic MC4R variants are the most common cause of monogenic obesity.
objectiveWe have identified 17 MC4R variants in adult and pediatric patients with obesity. Here we aimed to functionally characterize these variants by analyzing 4 different aspects of MC4R signaling. In addition, we aimed to analyze the effect of setmelanotide, a potent MC4R agonist, on these MC4R variants. MATERIALS AND
methodsCell surface expression and α-melanocyte stimulating hormone (α-MSH)- or setmelanotide-induced cAMP response, β-arrestin-2 recruitment, and ERK activation were measured in cells expressing either wild type or variant MC4R.
resultsWe found a large heterogeneity in the function of these variants. We identified variants with a loss of response for all studied MC4R signaling, variants with no cAMP accumulation or ERK activation but normal β-arrestin-2 recruitment, and variants with normal cAMP accumulation and ERK activation but decreased β-arrestin-2 recruitment, indicating disrupted desensitization and signaling mechanisms. Setmelanotide displayed a greater potency and similar efficacy as α-MSH and induced significantly increased maximal cAMP responses of several variants compared to α-MSH. Despite the heterogeneity in functional response, there was no apparent difference in the obesity phenotype in our patients.
conclusionWe show that these obesity-associated MC4R variants affect MC4R signaling differently yet lead to a comparable clinical phenotype. Our results demonstrate the clinical importance of assessing the effect of MC4R variants on a range of molecular signaling mechanisms to determine their association with obesity, which may aid in improving personalized treatment.
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