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Study · In vitro (cells) · 2024

3 results

MC4R Variants Modulate α-MSH and Setmelanotide Induced Cellular Signaling at Multiple Levels.

Rodríguez Rondón AV, Welling MS, van den Akker ELT, van Rossum EFC, Boon EMJ, van Haelst MM, Delhanty PJD, Visser JA

The Journal of clinical endocrinology and metabolism1 Sept 2024Cited by 13 (Europe PMC)

PMID38567654 (opens in a new tab)PMCIDPMC11403317 (opens in a new tab)DOI10.1210/clinem/dgae210 (opens in a new tab)PepBankPUB-38567654
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Summary

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

Results from this study3

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

  1. 01LabIn vitro (cells)Activity measurement

    In cells expressing MC4R, setmelanotide showed greater potency than α-MSH.

    In plain wordsIn cells expressing MC4R, setmelanotide was more potent than α-MSH.

    Peptide
    Setmelanotide
    Outcome
    IncreasePotency
    Study

    n: not reported in source

    Cells expressing wild-type or variant MC4R
    Comparator
    α-MSH
    Outcome group
    Receptor activity and mechanism · Pharmacology
    Studied dose
    Dose not stated

    Source sentences

    Summary
    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.
    1 context sentence
    Summary · context
    Cell 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.
  2. 02LabIn vitro (cells)Activity measurement

    In cells expressing MC4R, setmelanotide showed similar efficacy to α-MSH.

    In plain wordsIn cells expressing MC4R, setmelanotide produced a similar maximum effect to α-MSH.

    Peptide
    Setmelanotide
    Outcome
    No significant changeEfficacy
    Study

    n: not reported in source

    Cells expressing wild-type or variant MC4R
    Comparator
    α-MSH
    Outcome group
    Receptor activity and mechanism · Pharmacology
    Studied dose
    Dose not stated

    Source sentences

    Summary
    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.
    1 context sentence
    Summary · context
    Cell 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.
  3. 03LabIn vitro (cells)Activity measurement

    In cells expressing several MC4R variants, setmelanotide induced significantly greater maximal cAMP responses than α-MSH.

    In plain wordsIn cells expressing several MC4R variants, setmelanotide produced greater maximum cAMP responses than α-MSH.

    Peptide
    Setmelanotide
    Outcome
    IncreaseMaximal cAMP response
    Study

    n: not reported in source

    Cells expressing wild-type or variant MC4R
    Comparator
    α-MSH
    Outcome group
    Receptor activity and mechanism · Pharmacology
    Studied dose
    Dose not stated

    Source sentences

    Summary
    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.
    1 context sentence
    Summary · context
    Cell 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.

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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

    28 Oct 2026, 02:03 UTC

    Study results updated

  2. Version 1

    27 Oct 2026, 16:36 UTC

    First added · source update from Europe PMC

Subjects

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