Leptin signaling in the dorsomedial hypothalamus couples breathing and metabolism in obesity

Mismatch between CO₂ production (VCO₂) and respiration underlies the pathogenesis of obesity hypoventilation. Leptin-mediated CNS pathways stimulate both metabolism and breathing, but interactions between these functions remain elusive. We hypothesized that LEPR^b+ neurons of the dorsomedial hypothalamus (DMH) regulate metabolism and breathing in obesity. In diet-induced obese Lepr^bCre mice, chemogenetic activation of LEPR^b+ DMH neurons increases minute ventilation (VE) during sleep, the hypercapnic ventilatory response, VCO₂, and VE/VCO₂, indicating that breathing is stimulated out of proportion to metabolism. The effects of chemogenetic activation are abolished by a serotonin blocker. Optogenetic stimulation of the LEPR^b+ DMH neurons evokes excitatory postsynaptic currents in downstream serotonergic neurons of the dorsal raphe (DR). Administration of retrograde AAV harboring Cre-dependent caspase to the DR deletes LEPR^b+ DMH neurons and abolishes metabolic and respiratory responses to leptin. These findings indicate that LEPR^b+ DMH neurons match breathing to metabolism through serotonergic pathways to prevent obesity-induced hypoventilation.