Obesity-associated MRAP2 variants impair multiple MC4R-mediated signaling pathways

Area of Science:

• Endocrinology
• Molecular Biology
• Genetics

Background:

• Melanocortin-4 receptor (MC4R) is crucial for regulating appetite and energy homeostasis.
• Mutations in MC4R are a leading cause of monogenic obesity.
• Melanocortin-2 receptor accessory protein 2 (MRAP2) modulates MC4R signaling, and its variants are implicated in obesity.

Purpose of the Study:

• To functionally characterize previously reported human MRAP2 variants identified in overweight and obese individuals.
• To investigate the impact of MRAP2 variants on multiple MC4R signaling pathways, including cAMP and IP3 signaling.
• To determine the pathogenicity of MRAP2 variants by assessing their effects on MC4R function.

Main Methods:

• Expression of twelve MRAP2 variants with MC4R in cellular models.
• Measurement of MC4R-mediated cAMP and IP3 signaling.
• Assessment of protein expression, cell surface localization, and internalization.
• Structural modeling to predict MRAP2-MC4R interaction sites.

Main Results:

• All MRAP2 variants identified in obese individuals impaired MC4R function.
• Seven variants reduced cAMP signaling, and nine variants reduced IP3 signaling.
• Mutations in MRAP2 C-terminus affected receptor internalization; structural modeling identified key interaction sites.

Conclusions:

• Human MRAP2 variants associated with obesity disrupt multiple MC4R signaling pathways.
• Both Gs-cAMP and Gq-IP3 signaling pathways must be evaluated to assess MRAP2 variant pathogenicity.
• This study provides a comprehensive functional analysis of MRAP2 variants in the context of obesity.