Targeting melanocortin 4 receptor to treat sleep-disordered breathing in mice
Mateus R. Amorim, … , David Mendelowitz, Vsevolod Y. Polotsky
Mateus R. Amorim, … , David Mendelowitz, Vsevolod Y. Polotsky
Published April 15, 2025
Citation Information: J Clin Invest. 2025;135(12):e177823. https://doi.org/10.1172/JCI177823.
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Research Article Neuroscience Pulmonology

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

Abstract

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.

Authors

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

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Figure 8

Chemogenetic stimulation of MC4R+ neurons in the RTN (ventral to the facial motor nucleus) increases VE and the HCVR, but not metabolism.

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Chemogenetic stimulation of MC4R+ neurons in the RTN (ventral to the fac...
(A) Cre-dependent DREADDs AAV8-hSyn-DIO-hM3D(Gq)-mCherry was deployed in the RTN of Mc4r-Cre DIO mice. (B–G) In situ hybridization images. (B) Lower-power image of the brainstem containing RTN. (C) High-power image of the ventral surface of the brainstem containing Mc4r/Nmb/mCherry/DAPI. The outlined area is enlarged in D–F. The arrowheads point to Nmb and mCherry (E) and Mc4r and mCherry (F) colocalizations. (G) Histology in the presence of Cre-dependent caspase (AAV5-flex-taCasp3-TEVp) (Casp). Note a significant reduction in Mc4r and Nmb. (H–J) Individual in situ hybridization images showing DAPI in blue (H), Mc4r in green (I), and mCherry in red (J). (K–M) Upon stimulation with the DREADDs ligand J60, mice showed increases in VT and VE (K) and HCVR (L) without any effect on oxygen consumption (VO2), CO2 production (VCO2), or the respiratory exchange ratio (RER) (M) in comparison with saline (Sal). n = 5–7. *P ≤ 0.05, using the Wilcoxon’s matched-pairs, signed-rank test. (N) Percentage of colocalized cells. (O) Number of Nmb+ among Mc4r+ cells. **P < 0.01, using the Mann-Whitney U test (n = 5 – 6). 7N, facial motor nucleus. Sp5, spinal trigeminal nucleus. Scale bars: 500 μm (B); 100 μm (C); 50 μm (D–F); 30 μm (G); 100 μm (H–J).