MC4R, or melanocortin receptor-4, is a G protein-coupled receptor. It is involved in regulating food intake and energy metabolism through various signaling pathways, and is a key genetic factor in severe and early-onset obesity and hyperphagia disorders [1]. MC4R is part of the leptin-melanocortin pathway, which is crucial for bodyweight regulation [4].

In rodent studies, wild-type rodents are more sensitive to the MC4R agonist Setmelanotide compared to MC4R heterozygous deficient mice, while MC4R knockout mice fail to respond, indicating the role of MC4R in weight loss response to the agonist [3]. Also, in a Phase 1b clinical trial, Setmelanotide led to weight loss in obese MC4R variant carriers [3].

In conclusion, MC4R plays a vital role in energy metabolism and bodyweight regulation. Studies using rodent models, especially knockout models, have been instrumental in understanding its function. These findings have implications for developing treatments for obesity and related cardiometabolic diseases, as targeting MC4R-related pathways may offer effective strategies for weight loss and disease management [2,3].

References:

1. Wei, Ran, Li, Danjie, Jia, Sheng, Chen, Yuhong, Wang, Jiqiu. 2023. MC4R in Central and Peripheral Systems. In Advanced biology, 7, e2300035. doi:10.1002/adbi.202300035. https://pubmed.ncbi.nlm.nih.gov/37043700/

2. Lotta, Luca A, Mokrosiński, Jacek, Mendes de Oliveira, Edson, Wareham, Nicholas J, Farooqi, I Sadaf. . Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity. In Cell, 177, 597-607.e9. doi:10.1016/j.cell.2019.03.044. https://pubmed.ncbi.nlm.nih.gov/31002796/

3. Collet, Tinh-Hai, Dubern, Béatrice, Mokrosinski, Jacek, Farooqi, I Sadaf, Van der Ploeg, Lex H T. 2017. Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency. In Molecular metabolism, 6, 1321-1329. doi:10.1016/j.molmet.2017.06.015. https://pubmed.ncbi.nlm.nih.gov/29031731/

4. Clément, Karine, van den Akker, Erica, Argente, Jesús, Wabitsch, Martin, Kühnen, Peter. 2020. Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials. In The lancet. Diabetes & endocrinology, 8, 960-970. doi:10.1016/S2213-8587(20)30364-8. https://pubmed.ncbi.nlm.nih.gov/33137293/