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

Mismatch between CO2 production (VCO2) and respiration underlies the pathogenesis of obesity hypoventila-tion. Leptin-mediated CNS pathways stimulate both metabolism and breathing, but interactions between these functions remain elusive. We hypothesized that LEPRb+ neurons of the dorsomedial hypothalamus (DMH) regu-late metabolism and breathing in obesity. In diet-induced obese LeprbCre mice, chemogenetic activation of LEPRb+ 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 chemo-genetic activation are abolished by a serotonin blocker. Optogenetic stimulation of the LEPRb+ DMH neurons evokes excitatory postsynaptic currents in downstream serotonergic neurons of the dorsal raphe (DR). Admin-istration of retrograde AAV harboring Cre-dependent caspase to the DR deletes LEPRb+ DMH neurons and abolishes metabolic and respiratory responses to leptin. These findings indicate that LEPRb+ DMH neurons match breathing to metabolism through serotonergic pathways to prevent obesity-induced hypoventilation.