MC4R Variants Modulate α-MSH and Setmelanotide Induced Cellular Signaling at Multiple Levels
Authors' conclusion
We 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.
Study context
- Population
- 17 MC4R variants identified in adult and pediatric patients with obesity17 MC4R variants
- Comparison
- Variant vs wild-type MC4R; setmelanotide vs α-MSH
- Variant MC4Rn = 17
- Outcome
- Cell surface expression and α-MSH- or setmelanotide-induced cAMP response, β-arrestin-2 recruitment and ERK activation
Methodological detailsin vitro functional characterization
- In vitro functional characterization
Main finding
As reported in the abstract
MC4R signaling of variants
- Large heterogeneity in the function of these variants
- 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
- Variants with normal cAMP accumulation and ERK activation but decreased β-arrestin-2 recruitment, indicating disrupted desensitization and signaling mechanisms
- Setmelanotide displayed greater potency and similar efficacy vs α-MSH, and significantly increased maximal cAMP responses of several variants vs α-MSH
Further findings
- Despite the heterogeneity in functional response, no apparent difference in obesity phenotype in the patients
Original publication
MC4R Variants Modulate α-MSH and Setmelanotide Induced Cellular Signaling at Multiple Levels. J Clin Endocrinol Metab. Published 3 April 2024. doi:10.
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