0040 Leptin Signaling in the Dorsomedial Hypothalamus Couples Metabolism and Breathing in Obesity

Abstract Introduction Individuals with obesity hypoventilation syndrome (OHS) are unable to increase ventilation match increased CO2 production (VCO2). Obstructive sleep apnea (OSA), defined by the closure of upper airway during sleep, is present in 90% OHS patients. Leptin, an adipocyte-produced hormone, acts leptin receptor (LEPRb) positive neurons and was implicated pathophysiology OSA OHS. Diet-induced obese (DIO) C57BL/6J mice shows features OSA. Leptin-mediated neural pathways may link metabolism breathing obesity. We hypothesized that LEPRb-positive dorsomedial hypothalamus (DMH) necessary sufficient control VCO2 stimulation these relieves DIO mice. Methods expressed designer receptors exclusively activated drugs (DREADDs) DMH Leprb-Cre measured hypercapnic ventilatory response (HCVR), VCO2, O2 consumption (VO2). Results Activation inspiratory flow minute REM without affecting architecture. The effect pronounced limitation, suggeting obstruction relieved. HCVR this blunted a serotonin antagonist, methysergide. augmented VO2, VE/VCO2, suggesting stimulated out proportion increases metabolism. In vitro experiments revealed project 5-HT dorsal raphe (DR) optogenetic evoked excitatory postsynaptic currents DR. Administration retrograde Cre-dependent AAV harboring caspase DR deleted abolished respiratory metabolic effects chemogenetic stimulation. Apoptosis projecting also prevented induced intranasal leptin. Conclusion Leptin HCVR, improves patency acting on conclude couple Support (if any) NIH (R01 HL128970, R01 HL133100, HL138932), AHA (#915167).