Targeting melanocortin 4 receptor to treat sleep disordered breathing in mice

Weight loss medications are emerging candidates for pharmacotherapy of sleep disordered breathing (SDB). A melanocortin receptor 4 (MC4R) agonist, setmelanotide (SET), is used to treat obesity caused by abnormal melanocortin and leptin signaling. We hypothesized that SET can treat SDB in diet induced obese mice. We performed a proof-of-concept randomized crossover trial of a single dose of SET vs vehicle and a two-week daily SET vs vehicle trial, examined co-localization of Mc4r mRNAs with markers of CO2 sensing neurons Phox2b and neuromedin-B in the brainstem, and expressed Cre-dependent designer receptors exclusively activated by designer drugs or caspase in obese Mc4r-Cre mice. SET increased minute ventilation across sleep/wake states, enhanced the hypercapnic ventilatory response (HCVR) and abolished apneas during sleep. Phox2b+ neurons in the nucleus of the solitary tract (NTS) and the parafacial region expressed Mc4r. Chemogenetic stimulation of the MC4R+ neurons in the parafacial region, but not in the NTS, augmented HCVR without any changes in metabolism. Caspase elimination of the parafacial MC4R+ neurons abolished effects of SET on HCVR. Parafacial MC4R+ neurons projected to the respiratory pre-motor neurons retrogradely labeled from C3-C4. In conclusion, MC4R agonists enhance the HCVR and treat SDB by acting on the parafacial MC4R+ neurons.