Leptin signaling in the dorsomedial hypothalamus couples breathing and metabolism in obesity
Mateus R. Amorim, Xin Wang, O Aung, Shannon Bevans‐Fonti, Frederick Anokye‐Danso, Caitlin Ribeiro, Joan B. Escobar, Carla Freire, Huy Pho, Olga Dergacheva, Luiz G.S. Branco, Rexford S. Ahima, David Mendelowitz, Vsevolod Y. Polotsky
Abstract
Mismatch between CO 2 production (Vco 2 ) 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 b Cre mice, chemogenetic activation of LEPR b + DMH neurons increases minute ventilation (Ve) during sleep, the hypercapnic ventilatory response, Vco 2 , and Ve/Vco 2 , 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.