The role of the melanocortin 4 receptor in control of breathing

This application is submitted in response to the PA-23-189 Research Supplements to Promote Diversity in Health-Related Research (Admin Supp - Clinical Trial Not Allowed). The parent grant is ‘Melanocortin 4 receptor agonists to treat sleep disordered breathing in obesity’, R01HL174409-01, 07/01/2024 – 06/30/2028 with contact PI Vsevolod Y Polotsky, MD, PhD. Obesity hypoventilation syndrome (OHS) is a severe form of sleep disordered breathing (SDB) characterized by daytime hypercapnia and hypoventilation during sleep. There is no effective pharmacotherapy for OHS. Our parent grant is focused on respiratory effects of the melanocortin 4 receptor (MC4R). MC4R agonists increase energy expenditure and suppress food intake in obese rodents and humans. The MC4R agonist setmelanotide has been approved for treatment of genetic forms of obesity linked to mutations in the POMC/MC4R/leptin pathways. Our data shows that (1) setmelanotide (SET) robustly augments the hypercapnic ventilatory response (HCVR) and treats SDB in DIO mice and that (2) chemogenetic activation of MC4R (+) neurons in the parafacial region (and specifically in the retrotrapezoid nucleus, RTN) of the rostral ventrolateral medulla (RVLM) increases baseline ventilation and HCVR without any effect on metabolism. The overarching hypothesis of the parent award is that MC4R agonists treat OHS by augmenting hypercapnic sensitivity in MC4R+ neurons of the parafacial region, which is a major center of CO2 sensitivity. However, one important question remains unaddressed: Is MC4R just a marker of CO2 sensing neurons in the parafacial region or it mediates respiratory sensitivity? This question will be addressed in our supplement providing a logical extension of the current award. We will use diet induced obese (DIO) male and female mice, which possess loxP sites flanking the entire coding region of the melanocortin 4 receptor (Mc4r) gene (Mc4rflox mice). MC4R deficiency in the parafacial region will be induced by stereotactic transfection of adeno-associated virus (AAV) carrying Cre-recombinase. Specific Aim 1 will determine if MC4R in the parafacial neurons is necessary for normal breathing during sleep and for the hypercapnic ventilatory response (HCVR) during sleep and wakefulness. We propose that MC4R deficiency in neurons of the parafacial region will (A) induce SDB and (B) attenuate the HCVR during sleep and wakefulness without any change in metabolism. Specific Aim 2 will determine how MC4R deficiency in the parafacial neurons impacts on respiratory and metabolic effects of SET. We propose that MC4R deficiency in neurons of the parafacial region will abolish beneficial effects of SET on (A) SDB and (B) the HCVR during sleep and wakefulness without any change in metabolism. The research delineated in the supplement is not an expansion (change in scope) of the parent grant requiring peer review.