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 Escobar,
Carla Freire,
Huy Pho,
Olga Dergacheva,
Luiz G.S. Branco,
Rexford S. Ahima,
David Mendelowitz,
Vsevolod Y. Polotsky
Affiliations
Mateus R. Amorim
Department of Medicine, Johns Hopkins University, Baltimore, MD 21224, USA; Department of Anesthesiology and Critical Care Medicine, George Washington University, Washington, DC 20037, USA; Corresponding author
Xin Wang
Department of Pharmacology and Physiology, George Washington University, Washington, DC 20037, USA
O. Aung
Department of Medicine, Johns Hopkins University, Baltimore, MD 21224, USA
Shannon Bevans-Fonti
Department of Medicine, Johns Hopkins University, Baltimore, MD 21224, USA; Department of Anesthesiology and Critical Care Medicine, George Washington University, Washington, DC 20037, USA
Frederick Anokye-Danso
Department of Medicine, Johns Hopkins University, Baltimore, MD 21224, USA
Caitlin Ribeiro
Department of Pharmacology and Physiology, George Washington University, Washington, DC 20037, USA
Joan Escobar
Department of Pharmacology and Physiology, George Washington University, Washington, DC 20037, USA
Carla Freire
Department of Medicine, Johns Hopkins University, Baltimore, MD 21224, USA
Huy Pho
Department of Medicine, Johns Hopkins University, Baltimore, MD 21224, USA
Olga Dergacheva
Department of Pharmacology and Physiology, George Washington University, Washington, DC 20037, USA
Luiz G.S. Branco
University of São Paulo, Ribeirão Preto, São Paulo 14040-904, Brazil
Rexford S. Ahima
Department of Medicine, Johns Hopkins University, Baltimore, MD 21224, USA
David Mendelowitz
Department of Pharmacology and Physiology, George Washington University, Washington, DC 20037, USA
Vsevolod Y. Polotsky
Department of Medicine, Johns Hopkins University, Baltimore, MD 21224, USA; Department of Anesthesiology and Critical Care Medicine, George Washington University, Washington, DC 20037, USA; Department of Pharmacology and Physiology, George Washington University, Washington, DC 20037, USA; Corresponding author
Summary: 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 LEPRb+ neurons of the dorsomedial hypothalamus (DMH) regulate 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 chemogenetic 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). Administration 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.
