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

Alejandra V Rodríguez Rondón1,2, Mila S Welling1,2,3, Erica L T van den Akker1,3

  • 1Obesity Center CGG and Expertise Center Genetic Obesity, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands.

The Journal of Clinical Endocrinology and Metabolism
|April 3, 2024
PubMed
Abstract

Insights

Pathogenic melanocortin-4 receptor (MC4R) variants cause obesity through diverse signaling defects. Setmelanotide, an MC4R agonist, shows varied effects, highlighting the need for personalized obesity treatment strategies.

Area of Science:

  • Endocrinology and Metabolism
  • Molecular Biology
  • Genetics

Background:

  • The melanocortin-4 receptor (MC4R) is crucial for regulating body weight.
  • Mutations in MC4R are the primary genetic cause of monogenic obesity.

Purpose of the Study:

  • To functionally characterize 17 MC4R variants identified in obese patients.
  • To assess the impact of setmelanotide, a potent MC4R agonist, on these variants.

Main Methods:

  • Assessed cell surface expression, cAMP response, β-arrestin-2 recruitment, and ERK activation for wild-type and variant MC4R.
  • Utilized α-melanocyte stimulating hormone (α-MSH) and setmelanotide as agonists.

Main Results:

  • Observed significant heterogeneity in MC4R variant function, affecting signaling pathways differently.
  • Setmelanotide demonstrated higher potency than α-MSH, enhancing cAMP responses in several variants.
  • Despite functional diversity, no clear correlation was found between variant function and obesity phenotype severity.

Conclusions:

  • Obesity-associated MC4R variants exhibit varied effects on MC4R signaling pathways.
  • Comprehensive functional analysis is vital for understanding MC4R variant-associated obesity.
  • These findings support personalized treatment approaches for obesity based on MC4R genotype and signaling characteristics.
Keywords:
G-protein-coupled receptorsgenetic variationmelanocortin-4 receptorobesitysetmelanotideα-MSHβ-arrestins

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