Melanocortin 4 receptor signalling in sleep-disordered breathing

The melanocortin 4 receptor (MC4R) is a key component of the leptin-melanocortin system. Recent studies have started to expand our understanding of the role of MC4R beyond energy balance and sexual behaviour, exploring its potential influence on respiratory function, particularly in the context of obesity hypoventilation syndrome and obstructive sleep apnoea. The MC4R pathway is implicated in respiratory control. MC4R is expressed on the CO₂-sensing neurons of the retrotrapezoid nucleus, and activation of the MC4R⁺ neurons in the retrotrapezoid nucleus augments the hypercapnic ventilatory response. MC4R is present at other sites of the neural respiratory network, where this receptor might also be involved in ventilatory control. The US Food and Drug Administration approved the MC4R agonist setmelanotide, which has been used effectively for the treatment of obesity involving the leptin-melanocortin pathway. Setmelanotide is also a promising treatment option for obesity hypoventilation syndrome and obstructive sleep apnoea, particularly in people with obesity caused by specific genetic disorders, including POMC, LEPR^b, MC4R and other associated gene mutations.