Leptin increases sympathetic nerve activity via induction of its own receptor in the paraventricular nucleus

Abstract

Whether leptin acts in the paraventricular nucleus (PVN) to increase sympathetic nerve activity (SNA) is unclear, since PVN leptin receptors (LepR) are sparse. We show in rats that PVN leptin slowly increases SNA to muscle and brown adipose tissue, because it induces the expression of its own receptor and synergizes with local glutamatergic neurons. PVN LepR are not expressed in astroglia and rarely in microglia; instead, glutamatergic neurons express LepR, some of which project to a key presympathetic hub, the rostral ventrolateral medulla (RVLM). In PVN slices from mice expressing GCaMP6, leptin excites glutamatergic neurons. LepR are expressed mainly in thyrotropin-releasing hormone (TRH) neurons, some of which project to the RVLM. Injections of TRH into the RVLM and dorsomedial hypothalamus increase SNA, highlighting these nuclei as likely targets. We suggest that this neuropathway becomes important in obesity, in which elevated leptin maintains the hypothalamic pituitary thyroid axis, despite leptin resistance.

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All data generated and analyzed are included in the manuscript. Source data files are provided for relevant figures.

The following data sets were generated

Article and author information

Author details

  1. Zhigang Shi

    Physiology and Pharmacology, Oregon Health & Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5828-1904
  2. Nicole E Pelletier

    Physiology and Pharmacology, Oregon Health & Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Jennifer Wong

    Physiology and Pharmacology, Oregon Health & Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Baoxin Li

    Physiology and Pharmacology, Oregon Health & Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Andrei D Sdrulla

    Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Christopher J Madden

    Neurological Surgery, Oregon Health & Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Daniel L Marks

    Pediatrics, Oregon Health & Science University, Portland, United States
    For correspondence
    marksd@ohsu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2675-7047
  8. Virginia L Brooks

    Physiology and Pharmacology, Oregon Health & Science University, Portland, United States
    For correspondence
    brooksv@ohsu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6709-6631

Funding

National Institutes of Health (HL088552)

  • Virginia L Brooks

National Institutes of Health (HL128181)

  • Virginia L Brooks

National Institutes of Health (CA217989)

  • Daniel L Marks

National Institutes of Health (NS099503)

  • Andrei D Sdrulla

National Institutes of Health (DK112198)

  • Christopher J Madden

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (TR01_IP00000151) of Oregon Health & Science University. All surgery was performed under isoflurane, alpha-chloralose, or pentobarbital anesthesia, and every effort was made to minimize suffering.

Reviewing Editor

  1. Joel K Elmquist, University of Texas Southwestern Medical Center, United States

Version history

  1. Received: January 21, 2020
  2. Accepted: June 12, 2020
  3. Accepted Manuscript published: June 15, 2020 (version 1)
  4. Version of Record published: June 25, 2020 (version 2)

Copyright

© 2020, Shi et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Zhigang Shi
  2. Nicole E Pelletier
  3. Jennifer Wong
  4. Baoxin Li
  5. Andrei D Sdrulla
  6. Christopher J Madden
  7. Daniel L Marks
  8. Virginia L Brooks
(2020)
Leptin increases sympathetic nerve activity via induction of its own receptor in the paraventricular nucleus
eLife 9:e55357.
https://doi.org/10.7554/eLife.55357

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https://doi.org/10.7554/eLife.55357

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