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

Cell Reports (Dec 2023)

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

Journal volume & issue: Vol. 42, no. 12
p. 113512

Abstract

Read online

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.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

About the journal

Abstract

Keywords