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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number113512
JournalCell Reports
Volume42
Issue number12
DOIs
StatePublished - Dec 26 2023

Keywords

  • CP: Metabolism
  • CP: Neuroscience
  • designer receptor exclusively activated by designer drugs
  • dorsal raphe nucleus
  • hypercapnic ventilatory response
  • inspiratory flow limitation
  • intranasal administration
  • leptin receptor
  • obesity hypoventilation
  • obstructive sleep apnea
  • serotonin
  • sleep disordered breathing

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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