Targeting melanocortin 4 receptor to treat sleep disordered breathing in mice

Mateus R. Amorim, Department of Anesthesiology and Critical Care Medicine, George Washington University, Washington, United States of America.
Noah R. Williams, Department of Anesthesiology and Critical Care Medicine, George Washington University, Washington, United States of America.
O Aung, Department of Medicine, Medical College of Wisconsin, Milwaukee, United States of America.
Melanie Alexis Ruiz, Department of Anesthesiology and Critical Care Medicine, George Washington University, Washington, United States of America.
Frederick Anokye-Danso, Department of Medicine, Johns Hopkins University, Baltimore, United States of America.
Junia Lara de Deus, Department of Anesthesiology and Critical Care Medicine, George Washington University, Washington, Washington, United States of America.
Jiali Xiong, Biochemistry, Cellular, and Molecular Biology Graduate Program, Johns Hopkins University School of Medicine, Washington, United States of America.
Olga Dergacheva, Department of Pharmacology and Physiology, George Washington University, Washington, United States of America.
Shannon Bevans-Fonti, Department of Anesthesiology and Critical Care Medicine, George Washington University, Washington, United States of America.
Sean M. Lee, Office of Clinical Research, George Washington University, Washington, United States of America.
Jeffrey S. Berger, Department of Anesthesiology and Critical Care Medicine, George Washington University, Washington, United States of America.
Mark N. Wu, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States of America.
Rexford S. Ahima, Department of Medicine, Johns Hopkins University, Baltimore, United States of America.
David Mendelowitz, Department of Pharmacology and Physiology, George Washington University, Washington, United States of America.
Vsevolod Y. Polotsky, Department of Anesthesiology and Critical Care Medicine, George Washington University, Washington, United States of America.

Document Type

Journal Article

Publication Date

4-15-2025

Journal

The Journal of clinical investigation

DOI

10.1172/JCI177823

Keywords

Mouse models; Neuroscience; Obesity; Pharmacology; Pulmonology

Abstract

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.

Department

Anesthesiology and Critical Care Medicine

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