Melanocortin-4 Receptor Signalling: Importance for Weight Regulation and Obesity Treatment

The melanocortin-4 receptor (MC4R) plays an important role in body-weight regulation. Recent proof-of-concept studies have successfully investigated MC4R agonists as a treatment option for rare monogenic forms of obesity. MC4R-related non-Gs signalling is supposed to be a key element in the regulation of satiety, which provides evidence that more MC4R mutations are functionally relevant and contribute to the development of obesity than was previously thought. The evaluation of MC4R signalling pathways is of importance, as this receptor is a promising target for antiobesity drug development. The melanocortin-4 receptor (MC4R) – embedded in the leptin–melanocortin pathway – is activated by proopiomelanocortin (POMC)-derived neuropeptides such as α- and β-melanocyte-stimulating hormone (MSH) and plays an important role in hypothalamic body-weight regulation. Accordingly, MC4R is a potential drug target to combat obesity. Previous attempts to develop MC4R agonists failed due to ineffectiveness or severe adverse events. Recently, a new generation of MC4R ligands was developed. Specifically, setmelanotide was found to be effective by inducing biased signalling of the MC4R and thereby reducing feelings of hunger and leading to substantial weight loss in patients with POMC or leptin receptor deficiency. This new potential pharmacological treatment option could be beneficial for further groups of obese patients with defects in the leptin–melanocortin signalling pathway. The melanocortin-4 receptor (MC4R) – embedded in the leptin–melanocortin pathway – is activated by proopiomelanocortin (POMC)-derived neuropeptides such as α- and β-melanocyte-stimulating hormone (MSH) and plays an important role in hypothalamic body-weight regulation. Accordingly, MC4R is a potential drug target to combat obesity. Previous attempts to develop MC4R agonists failed due to ineffectiveness or severe adverse events. Recently, a new generation of MC4R ligands was developed. Specifically, setmelanotide was found to be effective by inducing biased signalling of the MC4R and thereby reducing feelings of hunger and leading to substantial weight loss in patients with POMC or leptin receptor deficiency. This new potential pharmacological treatment option could be beneficial for further groups of obese patients with defects in the leptin–melanocortin signalling pathway. a substance that is able to activate a receptor. a neuropeptide produced in the ARC that is an endogenous antagonist and inverse agonist of MC4R. a hypothalamic nucleus where POMC is expressed. surgical intervention to treat obesity. Strategies include gastric banding, Roux-en-Y gastric bypass, and sleeve gastrectomy. also known as functional selectivity; describes the signalling properties of a ligand differing from those of the endogenous ligand of the receptor. genetic variants are localised at different positions on the paternal and the maternal allele. concentration of a substance that is needed to achieve the half-maximal effect. pharmacological term for the maximal effect of a substance (e.g., a drug). the largest family of membrane spanning receptors, with a complex structure of seven transmembrane helices that are connected by three extracellular and three intracellular loops. The N terminus is extracellular and the C terminus is intracellular. GPCRs can couple to Gs, which activates adenylyl cyclase, to Gi, which inhibits adenylyl cyclase, to Gq proteins, which activate phospholipase C-β, and to G12/13, which activates RhoA. a condition of constantly increased feelings of hunger. the most important pathway in hypothalamic weight regulation, which integrates hormonals signals from the periphery to exert a centrally mediated reaction. a compound that can bind to a receptor. a hypothalamic nucleus where MC4R is expressed. a large precursor protein that is expressed in the pituitary, skin, and hypothalamus; processing by prohormone convertases results in melanocortins (α and β), ACTH, and β-endorphin.