1. Neuroscience
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Insulin regulates POMC neuronal plasticity to control glucose metabolism

  1. Garron T Dodd
  2. Natalie J Michael
  3. Robert S Lee-Young
  4. Salvatore P Mangiafico
  5. Jack T Pryor
  6. Astrid C Munder
  7. Stephanie E Simonds
  8. Jens Claus Brüning
  9. Zhong-Yin Zhang
  10. Michael A Cowley
  11. Sofianos Andrikopoulos
  12. Tamas L Horvath
  13. David Spanswick  Is a corresponding author
  14. Tony Tiganis  Is a corresponding author
  1. Monash University, Australia
  2. University of Melbourne, Australia
  3. Max Plank Institute for Metabolism Research, Germany
  4. Purdue University, United States
  5. Yale University School of Medicine, United States
Research Article
  • Cited 43
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Cite this article as: eLife 2018;7:e38704 doi: 10.7554/eLife.38704

Abstract

Hypothalamic neurons respond to nutritional cues by altering gene expression and neuronal excitability. The mechanisms that control such adaptive processes remain unclear. Here we define populations of POMC neurons in mice that are activated or inhibited by insulin and thereby repress or inhibit hepatic glucose production (HGP). The proportion of POMC neurons activated by insulin was dependent on the regulation of insulin receptor signaling by the phosphatase TCPTP, which is increased by fasting, degraded after feeding and elevated in diet-induced obesity. TCPTP-deficiency enhanced insulin signaling and the proportion of POMC neurons activated by insulin to repress HGP. Elevated TCPTP in POMC neurons in obesity and/or after fasting repressed insulin signaling, the activation of POMC neurons by insulin and the insulin-induced and POMC-mediated repression of HGP. Our findings define a molecular mechanism for integrating POMC neural responses with feeding to control glucose metabolism.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Garron T Dodd

    Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  2. Natalie J Michael

    Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9032-0862
  3. Robert S Lee-Young

    Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  4. Salvatore P Mangiafico

    Department of Medicine, University of Melbourne, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  5. Jack T Pryor

    Department of Physiology, Monash University, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  6. Astrid C Munder

    Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  7. Stephanie E Simonds

    Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  8. Jens Claus Brüning

    Department of Neuronal Control of Metabolism, Max Plank Institute for Metabolism Research, Cologne, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Zhong-Yin Zhang

    Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Michael A Cowley

    Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  11. Sofianos Andrikopoulos

    Department of Medicine, University of Melbourne, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  12. Tamas L Horvath

    Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7522-4602
  13. David Spanswick

    Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia
    For correspondence
    David.Spanswick@monash.edu
    Competing interests
    The authors declare that no competing interests exist.
  14. Tony Tiganis

    Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia
    For correspondence
    Tony.Tiganis@monash.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8065-9942

Funding

National Health and Medical Research Council

  • David Spanswick
  • Tony Tiganis

National Health and Medical Research Council

  • Michael A Cowley

National Institutes of Health

  • Tamas L Horvath

National Institutes of Health

  • Zhong-Yin Zhang

National Health and Medical Research Council

  • Sofianos Andrikopoulos

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

Ethics

Animal experimentation: Experiments were approved by the Monash University School of Biomedical Sciences Animal EthicsCommittee (MARP2013/137).

Reviewing Editor

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

Publication history

  1. Received: May 27, 2018
  2. Accepted: September 14, 2018
  3. Accepted Manuscript published: September 19, 2018 (version 1)
  4. Version of Record published: October 3, 2018 (version 2)

Copyright

© 2018, Dodd 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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