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 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. Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

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. Leptin signaling in the dorsomedial hypothalamus couples breathing and metabolism in obesity. Cell reports. 2023 Dec 26;42(12):113512

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PMID: 38039129

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