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Adipose Tissue_Appetite_and Obesity

MON-704 - Biased Signaling of Melanocortin 4 Receptor and Associations with Increased or Reduced Body Weight

Monday, June 15, 2026
9:00 AM - 2:00 PM CT
Location: ENDOExpo; Poster Floor
Disclosure(s):
Lisa Ruck: No financial relationships to disclose



Introduction: The melanocortin 4 receptor (MC4R), a G protein-coupled receptor (GPCR) primarily expressed in the hypothalamus, is a key component of the leptin-melanocortin signaling pathway, which plays a crucial role in body weight regulation. Heterozygous MC4R gene mutations have been identified as genetic risk factors for the development of obesity. In contrast, the MC4R variant V103I has been described to be associated with reduced body weight and is interpreted to be protective against the development of obesity. In recent years, several studies have highlighted the relevance of MC4R-related biased signaling in body weight regulation. However, comprehensive investigations into the signaling profiles of variants associated with either increased or decreased body weight, combined with receptor stimulation by a wide range of ligands, remain incomplete or lacking. This gap in findings presents an opportunity for the development of optimized and tailored drugs, such as peptide ligands or chaperones, aimed at modulating MC4R as a therapeutic target.

Methods:
We explored the signaling profiles of heterozygous MC4R mutations in HEK293 cells in vitro. These genetic variants were identified in a cohort of children with obesity. Using a range of in vitro assays, cell signaling profiles of Gs, Gq/11, ERK, G12/13 protein activation and -arrestin2 recruitment both in the presence and absence of various MC4R ligands (-MSH, -MSH, setmelanotide, NDP--MSH and LY2112688) have been tested. The results were combined with structural insights.

Results: We identified that the MC4R variant V103I is associated with an increased Gq activation after stimulation with -MSH. This signaling profile is altered when MC4R is stimulated by alternative ligands such as the MC4R agonist setmelanotide. Similar changes in signaling have been observed for multiple MC4R variants that are associated with an increased risk to develop obesity. Notably, in some variants with impaired signaling upon binding of the endogenous ligand -MSH, stimulation of synthetic ligands induces enhanced Gq signaling resulting in a signaling profile comparable to that observed for V103I.

Conclusion: Our findings indicate that modification of MC4R signaling profiles might be of pathogenic and therapeutic relevance. Our data further supports the previously described importance of Gq signaling for body regulation. This gathered knowledge might help to improve the development of pharmacological treatment strategies targeting MC4R.