Leptin signaling in the dorsomedial hypothalamus couples breathing and metabolism in obesity

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. Electronic address: amorimmr@hotmail.com.
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. 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. Electronic address: vsevolod.polotsky@gwu.edu.

Document Type

Journal Article

Publication Date

12-26-2023

Journal

Cell reports

Volume

42

Issue

12

DOI

10.1016/j.celrep.2023.113512

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

Abstract

Mismatch between CO production (Vco) 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+ neurons of the dorsomedial hypothalamus (DMH) regulate metabolism and breathing in obesity. In diet-induced obese LeprCre mice, chemogenetic activation of LEPR+ DMH neurons increases minute ventilation (Ve) during sleep, the hypercapnic ventilatory response, Vco, and Ve/Vco, 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+ 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+ DMH neurons and abolishes metabolic and respiratory responses to leptin. These findings indicate that LEPR+ DMH neurons match breathing to metabolism through serotonergic pathways to prevent obesity-induced hypoventilation.

Department

Anesthesiology and Critical Care Medicine

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