Targeting melanocortin 4 receptor to treat sleep-disordered breathing in mice
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
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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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 5

Set treatment for 2 weeks augments the HCVR.

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Set treatment for 2 weeks augments the HCVR. (A–E) Set decreased food in...
(A–E) Set decreased food intake (A), induced mild weight loss (*P < 0.05, Set vs. Veh, †P < 0.05, Set vs. pair-fed [PF] using fitted linear mixed models and Tukey’s multiple comparison) (B), increased RR (C) but not VT (D), and increased VE in room air (E). (F and G) Set increased VE at 8% CO2 (F) and HCVR (G) in DIO male C57BL/6J mice in comparison with Veh and PF (*P ≤ 0.05, **P < 0.01, ***P < 0.001, using 1-way ANOVA and Tukey’s multiple-comparison test). (H–J) Set decreased apnea index during NREM (H), REM (I), and total (J) sleep (*P < 0.05 using fitted robust linear models). n = 9 in the Set group; n = 8 in the Veh group; n = 9 in PF group.