Respiratory effects of the melanocortin 4 receptor in the lateral parabrachial nucleus

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. We have shown that diet-induced obese (DIO) mice emulate all features of human OHS, including awake hypercapnia, upper airway obstruction during sleep, and sleep hypoventilation. Our parent grant identified the melanocortin 4 receptor (MC4R) as a pathway regulating the hypercapnic ventilatory response (HCVR). 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. 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. The lateral parabrachial nucleus (LPBN) of the pons, the area of the brain implicated in the control of respiratory rate, shows very high level of expression of MC4R. The hypothesis of this supplement is that setmelanotide acts in the LPBN to increase respiratory rate and minute ventilation. The supplement will examine if the respiratory effects of MC4R activation by setmelanotide can be mimicked by chemogenetic activation and attenuated by chemogenetic inhibition of MC4R+ neurons in the LPBN neurons. We hypothesize that, in DIO Mc4r-Cre mice, chemogenetic activation of Cre-dependent excitatory hM3D(Gq) designer receptor exclusively activated by designer drugs (DREADD) selectively expressed in MC4R+ LBPN neurons will increase minute ventilation and treat OHS without affecting metabolism (Aim 1); and that chemogenetic activation of Cre- dependent inhibitory hM4D(Gi) DREADD selectively expressed in MC4R+ LBPN neurons will exacerbate OHS and block stimulatory effects of systemic setmelanotide on ventilation, but not on metabolism (Aim 2). The research delineated in the supplement is not an expansion (change in scope) of the parent grant requiring peer review.