{"doi":"10.1172/jci177823","title":"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.","journal":"Journal of Clinical Investigation","year":2025,"id":518227,"datarank":0.32958368660043297,"base_score":2.1972245773362196,"endowment":2.1972245773362196,"self_citation_contribution":0.32958368660043297,"citation_network_contribution":0.0,"self_endowment_contribution":0.32958368660043297,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9575,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1385664,"name":"Noah Williams","orcid":"0000-0003-1467-7170","position":1,"is_corresponding":false},{"id":872277,"name":"O Aung","orcid":"0000-0002-5257-5696","position":2,"is_corresponding":false},{"id":1386130,"name":"Melanie Alexis Ruiz","orcid":null,"position":3,"is_corresponding":false},{"id":282973,"name":"Frederick Anokye‐Danso","orcid":"0000-0002-3992-9234","position":4,"is_corresponding":false},{"id":1015437,"name":"Júnia L. de Deus","orcid":null,"position":5,"is_corresponding":false},{"id":1080930,"name":"Jiali Xiong","orcid":"0000-0003-0274-2211","position":6,"is_corresponding":false},{"id":471701,"name":"Olga Dergacheva","orcid":"0000-0003-1136-9156","position":7,"is_corresponding":false},{"id":779844,"name":"Shannon Bevans‐Fonti","orcid":null,"position":8,"is_corresponding":false},{"id":528686,"name":"Sean M. Lee","orcid":"0000-0002-9897-3315","position":9,"is_corresponding":false},{"id":456135,"name":"Jeffrey S. Berger","orcid":"0000-0002-5525-2171","position":10,"is_corresponding":false},{"id":272105,"name":"Mark N. Wu","orcid":"0000-0002-1329-0655","position":11,"is_corresponding":false},{"id":282974,"name":"Rexford S. Ahima","orcid":"0000-0002-3479-1942","position":12,"is_corresponding":false},{"id":317053,"name":"David Mendelowitz","orcid":"0000-0001-7107-1832","position":13,"is_corresponding":false},{"id":266238,"name":"Vsevolod Y. Polotsky","orcid":"0000-0002-2951-7535","position":14,"is_corresponding":false},{"id":576160,"name":"Mateus R. Amorim","orcid":"0000-0002-8490-4853","position":0,"is_corresponding":true}],"reference_count":96,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:49:09.679930Z","pmid":"40232848","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}