Weight loss medications are emerging candidates for pharmacotherapy of sleep-disordered breathing (SDB). A melanocortin 4 receptor (MC4R) agonist, setmelanotide (Set), is used to treat obesity caused by abnormal melanocortin and leptin signaling. We hypothesized that Set can treat SDB in mice with diet-induced obesity. We performed a proof-of-concept randomized crossover trial of a single dose of Set versus vehicle and a 2-week daily Set versus vehicle trial, examined colocalization of Mc4r mRNAs with the markers of CO2-sensing neurons Phox2b and neuromedin B in the brainstem, and expressed Cre-dependent designer receptors exclusively activated by designer drugs (DREADDs) 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 premotor neurons retrogradely labeled from C3–C4. In conclusion, MC4R agonists enhance the HCVR and treat SDB by acting on the parafacial MC4R+ neurons.
Mateus R. Amorim, Noah R. Williams, O. Aung, Melanie Alexis Ruiz, Frederick Anokye-Danso, Junia L. de Deus, Jiali Xiong, Olga Dergacheva, Shannon Bevans-Fonti, Sean M. Lee, Jeffrey S. Berger, Mark N. Wu, Rexford S. Ahima, David Mendelowitz, Vsevolod Y. Polotsky
Usage data is cumulative from April 2025 through July 2025.
Usage | JCI | PMC |
---|---|---|
Text version | 1,974 | 33 |
568 | 9 | |
Figure | 329 | 0 |
Table | 34 | 0 |
Supplemental data | 134 | 2 |
Citation downloads | 69 | 0 |
Totals | 3,108 | 44 |
Total Views | 3,152 |
Usage information is collected from two different sources: this site (JCI) and Pubmed Central (PMC). JCI information (compiled daily) shows human readership based on methods we employ to screen out robotic usage. PMC information (aggregated monthly) is also similarly screened of robotic usage.
Various methods are used to distinguish robotic usage. For example, Google automatically scans articles to add to its search index and identifies itself as robotic; other services might not clearly identify themselves as robotic, or they are new or unknown as robotic. Because this activity can be misinterpreted as human readership, data may be re-processed periodically to reflect an improved understanding of robotic activity. Because of these factors, readers should consider usage information illustrative but subject to change.