A Leptin-Mediated Neural Mechanism Linking Breathing to Metabolism

Jeehaeh Do; Zheng Chang; Gabriella Sekerková; Donald R. McCrimmon; Marco Martina

doi:10.1016/j.celrep.2020.108358

A Leptin-Mediated Neural Mechanism Linking Breathing to Metabolism

Jeehaeh Do, Zheng Chang, Gabriella Sekerková, Donald R. McCrimmon^*, Marco Martina^*

^*Corresponding author for this work

Neuroscience

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

Abstract

Breathing is coupled to metabolism. Leptin, a peptide mainly secreted in proportion to adipose tissue mass, increases energy expenditure with a parallel increase in breathing. We demonstrate that optogenetic activation of LepRb neurons in the nucleus of the solitary tract (NTS) mimics the respiratory stimulation after systemic leptin administration. We show that leptin activates the sodium leak channel (NALCN), thereby depolarizing a subset of glutamatergic (VGluT2) LepRb NTS neurons expressing galanin. Mice with selective deletion of NALCN in LepRb neurons have increased breathing irregularity and central apneas. On a high-fat diet, these mice gain weight with an associated depression of minute ventilation and tidal volume, which are not detected in control littermates. Anatomical mapping reveals LepRb NTS-originating glutamatergic axon terminals in a brainstem inspiratory premotor region (rVRG) and dorsomedial hypothalamus. These findings directly link a defined subset of NTS LepRb cells to the matching of ventilation to energy balance.

Original language	English (US)
Article number	108358
Journal	Cell reports
Volume	33
Issue number	6
DOIs	https://doi.org/10.1016/j.celrep.2020.108358
State	Published - Nov 10 2020

Funding

This work was supported by National Institutes of Health ( NIH ) grants HL122921 (D.R.M.) and NS 090346 (M.M.). J.D. was also supported by the General Motor Control Mechanisms and Disease Training Program (T32NS041234) . In addition, this work was supported by the Comprehensive Metabolic Core at Northwestern University and the Northwestern University Sequencing Core (NUSeq). We thank Dr. Tony Kowal and Mr. Mahmoud Farhan for their help in maintaining and genotyping the various transgenic mouse colonies.

Keywords

NALCN
chemosensitivity
galanin
high-fat diet
in situ hybridization histochemistry
leptin
minute ventilation
nucleus of the solitary tract
obesity hypoventilation syndrome
tidal volume

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2020.108358

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title = "A Leptin-Mediated Neural Mechanism Linking Breathing to Metabolism",

abstract = "Breathing is coupled to metabolism. Leptin, a peptide mainly secreted in proportion to adipose tissue mass, increases energy expenditure with a parallel increase in breathing. We demonstrate that optogenetic activation of LepRb neurons in the nucleus of the solitary tract (NTS) mimics the respiratory stimulation after systemic leptin administration. We show that leptin activates the sodium leak channel (NALCN), thereby depolarizing a subset of glutamatergic (VGluT2) LepRb NTS neurons expressing galanin. Mice with selective deletion of NALCN in LepRb neurons have increased breathing irregularity and central apneas. On a high-fat diet, these mice gain weight with an associated depression of minute ventilation and tidal volume, which are not detected in control littermates. Anatomical mapping reveals LepRb NTS-originating glutamatergic axon terminals in a brainstem inspiratory premotor region (rVRG) and dorsomedial hypothalamus. These findings directly link a defined subset of NTS LepRb cells to the matching of ventilation to energy balance.",

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KW - tidal volume

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A Leptin-Mediated Neural Mechanism Linking Breathing to Metabolism

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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