Mc4r, or melanocortin receptor-4, is a G protein-coupled receptor that plays a crucial role in regulating food intake and energy metabolism [1,2]. It is involved in the leptin-melanocortin pathway and is essential for body weight regulation [4]. Disruptions in Mc4r are a significant genetic cause of severe and early-onset obesity and hyperphagia disorders [1].

In functional 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 that Mc4r is necessary for the weight-loss response to this agonist [3]. Additionally, most Mc4r variants identified in human studies cause loss of function, leading to obesity. However, a subset of gain-of-function variants is associated with lower body mass index (BMI) and reduced odds of obesity, type 2 diabetes, and coronary artery disease [2].

In conclusion, Mc4r is vital for energy homeostasis, with its disruption being a key factor in obesity. Studies using gene knockout mouse models have revealed its role in the body's response to agonists like Setmelanotide, highlighting its potential as a therapeutic target for obesity and related cardiometabolic diseases [2,3].