A Setmelanotide-like Effect at MC4R Is Achieved by MC4R Dimer Separation.

Area of Science:

• Pharmacology
• Molecular Biology
• Endocrinology

Background:

• The melanocortin 4 receptor (MC4R) is crucial for energy balance and a frequent target for obesity treatment.
• MC4R mutations are the leading monogenic cause of obesity.
• MC4R forms homodimers, influencing its signaling pathways, including Gs signaling.

Purpose of the Study:

• To investigate the impact of inhibiting MC4R homodimerization on Gq/11 signaling.
• To evaluate the therapeutic potential of targeting MC4R homodimerization for obesity treatment.

Main Methods:

• Utilized MC4R/CB1R chimeras to disrupt MC4R homodimerization.
• Employed NanoBRET™ assays to confirm reduced homodimerization of chimeric receptors in HEK293 cells.
• Assessed Gq/11 signaling via luciferase-based NFAT reporter gene assays.

Main Results:

• Chimeric MC4R receptors exhibited decreased homodimerization.
• Alpha-MSH-induced NFAT signaling in chimeras reached levels comparable to setmelanotide at wild-type MC4R.
• Chimeric receptors demonstrated enhanced potency in Gq/11 signaling compared to wild-type MC4R.

Conclusions:

• Inhibiting MC4R homodimerization enhances Gq/11 signaling, producing a setmelanotide-like effect.
• MC4R chimeras show increased potency, suggesting potential for obesity therapeutics.
• Targeting MC4R homodimerization represents a promising therapeutic avenue for obesity management.