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
Department of Anesthesiology and Critical Care Medicine, George Washington University, Washington, DC, USA.
Department of Physiology, Medical School of Ribeirão Preto, Sao Paulo, Brazil.
J Clin Invest. 2025 Apr 15;135(12). doi: 10.1172/JCI177823. eCollection 2025 Jun 16.
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.
减肥药物正成为治疗睡眠呼吸障碍（SDB）药物治疗的潜在选择。一种黑皮质素4受体（MC4R）激动剂——setmelanotide（Set），用于治疗由异常黑皮质素和瘦素信号传导引起的肥胖症。我们假设Set可以治疗饮食诱导肥胖小鼠的SDB。我们进行了一项单剂量Set与赋形剂的概念验证随机交叉试验以及一项为期2周的每日Set与赋形剂试验，检测了脑干中Mc4r mRNA与二氧化碳传感神经元Phox2b和神经降压素B标记物的共定位，并在肥胖的Mc4r-Cre小鼠中表达了仅由设计药物（DREADDs）或半胱天冬酶激活的Cre依赖性设计受体。Set增加了睡眠/清醒状态下的分钟通气量，增强了高碳酸血症通气反应（HCVR），并消除了睡眠期间的呼吸暂停。孤束核（NTS）和面部旁区域的Phox2b+神经元表达Mc4r。对面部旁区域而非NTS中的MC4R+神经元进行化学遗传刺激，可增强HCVR，而代谢无任何变化。消除面部旁MC4R+神经元中的半胱天冬酶可消除Set对HCVR的作用。面部旁MC4R+神经元投射到从C3-C4逆行标记的呼吸前运动神经元。总之，MC4R激动剂通过作用于面部旁MC4R+神经元来增强HCVR并治疗SDB。
