Targeting melanocortin 4 receptor to treat sleep-disordered breathing in mice.

Summary

In obese mice, the MC4R agonist setmelanotide increased minute ventilation, enhanced the hypercapnic ventilatory response, and abolished sleep apneas. Mechanistically, parafacial MC4R+ neurons (but not NTS MC4R+ neurons) mediated these effects; their chemogenetic activation augmented HCVR, and their ablation eliminated setmelanotide’s impact.

Key Findings

• Setmelanotide increased minute ventilation across sleep/wake states and enhanced the hypercapnic ventilatory response in obese mice.
• Sleep apneas were abolished by setmelanotide treatment.
• Parafacial (but not NTS) MC4R+ neurons mediated the effect; chemogenetic activation augmented HCVR, and caspase ablation eliminated the drug effect.
• Parafacial MC4R+ neurons projected to respiratory premotor neurons at C3–C4.

Clinical Implications

MC4R agonists (e.g., setmelanotide) could be repurposed to treat sleep-disordered breathing, particularly in obesity, by enhancing CO2 chemoreflex drive. This offers a pharmacologic alternative or adjunct to CPAP for selected patients pending human trials.

Limitations

• Preclinical mouse study; human translatability and dosing/safety remain unknown
• Focused on setmelanotide; class effects and long-term outcomes not assessed

Future Directions

Conduct early-phase clinical trials testing MC4R agonists in obesity-related SDB/OSA, with physiologic endpoints (HCVR, apnea–hypopnea index) and safety; map homologous parafacial circuits in humans.