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

Research output: Contribution to journalArticlepeer-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 languageEnglish (US)
Article number108358
JournalCell reports
Volume33
Issue number6
DOIs
StatePublished - 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

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