| Texto completo | |
| Autor(es): Mostrar menos - |
Amorim, Mateus R.
;
Williams, Noah R.
;
Aung, O.
;
Ruiz, Melanie Alexis
;
Anokye-Danso, Frederick
;
de Deus, Junia L.
;
Xiong, Jiali
;
Dergacheva, Olga
;
Bevans-Fonti, Shannon
;
Lee, Sean M.
;
Berger, Jeffrey S.
;
Wu, Mark N.
;
Ahima, Rexford S.
;
Mendelowitz, David
;
Polotsky, Vsevolod Y.
Número total de Autores: 15
|
| Tipo de documento: | Artigo Científico |
| Fonte: | Journal of Clinical Investigation; v. 135, n. 12, p. 16-pg., 2025-06-16. |
| Resumo | |
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. (AU) | |
| Processo FAPESP: | 19/13249-3 - O papel da sinalização da leptina no hipotálamo dorsomedial na permeabilidade das vias aéreas superiores durante o sono |
| Beneficiário: | Mateus Ramos Amorim |
| Modalidade de apoio: | Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado |