Setmelanotide, a melanocortin-4-receptor agonist, increases the hypercapnic ventilatory response and relieves hypoventilation in obese mice

肥胖低通气综合征 医学 高碳酸血症 内分泌学 内科学 瘦素 通气不足 黑素皮质素 麻醉 肥胖 呼吸系统 受体
作者
O Aung,Mateus R. Amorim,Frederick Anokye‐Danso,Vsevolod Y. Polotsky
出处
期刊:Physiology [American Physiological Society]
卷期号:38 (S1) 被引量:1
标识
DOI:10.1152/physiol.2023.38.s1.5731024
摘要

Introduction: Obesity leads to high cardiorespiratory morbidity and mortality. Obese individuals can develop obesity hypoventilation syndrome (OHS) characterized by daytime hypercapnia in the absence of alternative underlying causes. OHS leads to daytime sleepiness, cardiovascular complications, and cyanosis. There is no effective pharmacotherapy for OHS. Leptin, an adipose-produced hormone, improves breathing in OHS, but obese individuals and rodents are resistant to the beneficial effects of leptin. The melanocortin axis is a downstream target of leptin but effects of this axis on control of breathing are poorly studied. Setmelanotide is an FDA-approved drug for weight loss that specifically binds to the melanocortin 4 receptor (MC4R). We have previously demonstrated that C57BL/6J mice with diet induced obesity (DIO) hypoventilate during sleep and exhibit all features of OHS. We hypothesized that the activation of MC4R by setmelanotide augments the control of breathing during sleep in DIO mice. Methods: We performed a proof-of-concept single dose randomized trial of intraperitoneal setmelanotide (1.0 mg/kg) vs vehicle in DIO C57BL/6J mice using a cross-over design. The injections were followed by sleep studies, and measurements of the hypercapnic ventilatory response, oxygen consumption (VO 2 ), and carbon dioxide production (VCO 2 ). Results: Activation of MC4R by setmelanotide increased inspiratory flow, respiratory rate, and minute ventilation during NREM and REM sleep compared to vehicle. Activation of MC4R by setmelanotide increased the hypercapnic ventilatory response. Setmelanotide also increased VCO 2 , and VO 2 , but the ventilation was increased out of proportion to the upregulation of metabolism, which was evident from increases in the VE/VO 2 and VE/VCO 2 ratios. Conclusion: Activation of MC4R by setmelanotide relieved hypoventilation during sleep and increased the hypercapnic ventilatory response in obese mice. Our study identified MC4 as a promising therapeutic target in OHS. NIH (R01 HL128970, R01 HL133100, and R01 HL138932), AHA (#915167). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

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