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Excitatory transmission onto AgRP neurons is regulated by cJun NH2-terminal kinase 3 in response to metabolic stress

  1. Santiago Vernia
  2. Caroline Morel
  3. Joseph C Madara
  4. Julie Cavanagh-Kyros
  5. Tamera Barrett
  6. Kathryn Chase
  7. Norman J Kennedy
  8. Dae Young Jung
  9. Jason K Kim
  10. Neil Aronin
  11. Richard A Flavell
  12. Bradford B Lowell
  13. Roger J Davis  Is a corresponding author
  1. University of Massachusetts Medical School, United States
  2. Beth Israel Deaconess Medical Center, United States
  3. Howard Hughes Medical Institute, Yale University School of Medicine, United States
Research Article
  • Cited 18
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Cite this article as: eLife 2016;5:e10031 doi: 10.7554/eLife.10031

Abstract

The cJun NH2-terminal kinase (JNK) signaling pathway is implicated in the response to metabolic stress. Indeed, it is established that the ubiquitously expressed JNK1 and JNK2 isoforms regulate energy expenditure and insulin resistance. However, the role of the neuron-specific isoform JNK3 is unclear. Here we demonstrate that JNK3 deficiency causes hyperphagia selectively in high fat diet (HFD)-fed mice. JNK3 deficiency in neurons that express the leptin receptor LEPRb was sufficient to cause HFD-dependent hyperphagia. Studies of sub-groups of leptin-responsive neurons demonstrated that JNK3 deficiency in AgRP neurons, but not POMC neurons, was sufficient to cause the hyperphagic response. These effects of JNK3 deficiency were associated with enhanced excitatory signaling by AgRP neurons in HFD-fed mice. JNK3 therefore provides a mechanism that contributes to homeostatic regulation of energy balance in response to metabolic stress.

Article and author information

Author details

  1. Santiago Vernia

    Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    No competing interests declared.
  2. Caroline Morel

    Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    No competing interests declared.
  3. Joseph C Madara

    Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, United States
    Competing interests
    No competing interests declared.
  4. Julie Cavanagh-Kyros

    Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    No competing interests declared.
  5. Tamera Barrett

    Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    No competing interests declared.
  6. Kathryn Chase

    Department of Medicine, Division of Endocrinology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    No competing interests declared.
  7. Norman J Kennedy

    Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    No competing interests declared.
  8. Dae Young Jung

    Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    No competing interests declared.
  9. Jason K Kim

    Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    No competing interests declared.
  10. Neil Aronin

    Department of Medicine, Division of Endocrinology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    No competing interests declared.
  11. Richard A Flavell

    Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States
    Competing interests
    No competing interests declared.
  12. Bradford B Lowell

    Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, United States
    Competing interests
    No competing interests declared.
  13. Roger J Davis

    Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
    For correspondence
    roger.davis@umassmed.edu
    Competing interests
    Roger J Davis, Reviewing Editor, eLife.

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 (#A-978 and #A-1032) of the University of Massachusetts Medical School.

Reviewing Editor

  1. Richard D Palmiter, Howard Hughes Medical Institute, University of Washington, United States

Publication history

  1. Received: July 11, 2015
  2. Accepted: February 22, 2016
  3. Accepted Manuscript published: February 24, 2016 (version 1)
  4. Version of Record published: March 9, 2016 (version 2)

Copyright

© 2016, Vernia 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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