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

Authors

• 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.

APA Citation

Amorim, Mateus R.; Wang, Xin; Aung, O; Bevans-Fonti, Shannon; Anokye-Danso, Frederick; Ribeiro, Caitlin; Escobar, Joan; Freire, Carla; Pho, Huy; Dergacheva, Olga; Branco, Luiz G.; Ahima, Rexford S.; Mendelowitz, David; and Polotsky, Vsevolod Y., "Leptin signaling in the dorsomedial hypothalamus couples breathing and metabolism in obesity" (2023). GW Authored Works. Paper 3717.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/3717

Department

Anesthesiology and Critical Care Medicine