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Melanocortin 4 receptor signalling in sleep-disordered breathing
Md Tarikul Islam1, Mateus R Amorim1,2, Vsevolod Y Polotsky1,3,4
1Department of Anesthesiology and Critical Care Medicine, George Washington University, Washington, DC, USA.
The Journal of Physiology
|April 9, 2026
Summary
Targeting the melanocortin 4 receptor (MC4R) shows promise for treating sleep-disordered breathing. MC4R agonists like setmelanotide improve ventilation and reduce apneas, offering new hope for obesity hypoventilation syndrome patients.
Area of Science:
- Neuroscience
- Respiratory Medicine
- Pharmacology
Background:
- The melanocortin 4 receptor (MC4R) is integral to the leptin-melanocortin system.
- Emerging research highlights MC4R's role in respiratory control beyond energy balance.
- MC4R is expressed in key respiratory control centers like the retrotrapezoid nucleus.
Purpose of the Study:
- To investigate the potential of MC4R targeting for sleep-disordered breathing.
- To evaluate the effects of MC4R agonists on respiratory function.
- To explore therapeutic applications for obesity hypoventilation syndrome (OHS) and obstructive sleep apnea (OSA).
Main Methods:
- Review of recent findings on MC4R's role in respiratory control.
- Analysis of setmelanotide's effects on ventilation and apneas.
- Examination of implications for genetic obesity-related OHS and OSA.
Main Results:
- MC4R activation augments hypercapnic ventilatory response.
- The MC4R agonist setmelanotide increases minute ventilation during sleep and wakefulness.
- Setmelanotide reduces sleep apneas and enhances hypercapnic ventilatory response in preclinical models.
Conclusions:
- Targeting MC4R presents a novel therapeutic strategy for sleep-disordered breathing.
- Setmelanotide demonstrates potential for treating OHS and OSA, especially in genetically predisposed individuals.
- MC4R modulation offers a promising avenue for managing respiratory dysfunction associated with obesity.
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