1. Neuroscience
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The cytokine GDF15 signals through a population of brainstem cholecystokinin neurons to mediate anorectic signalling

  1. Amy A Worth
  2. Rosemary Shoop
  3. Katie Tye
  4. Claire H Feetham
  5. Giuseppe D'Agostino
  6. Garron T Dodd
  7. Frank Reimann
  8. Fiona M Gribble
  9. Emily C Beebe
  10. James D Dunbar
  11. Jesline T Alexander-Chacko
  12. Dana K Sindelar
  13. Tamer Coskun
  14. Paul J Emmerson
  15. Simon M Luckman  Is a corresponding author
  1. University of Manchester, United Kingdom
  2. University of Melbourne, Australia
  3. University of Cambridge, United Kingdom
  4. Eli Lilly and Company, United States
Research Article
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Cite this article as: eLife 2020;9:e55164 doi: 10.7554/eLife.55164

Abstract

The cytokine, GDF15, is produced in pathological states which cause cellular stress, including cancer. When over expressed, it causes dramatic weight reduction, suggesting a role in disease-related anorexia. Here we demonstrate that the GDF15 receptor, GFRAL, is located in a subset of cholecystokinin neurons which span the area postrema and the nucleus of the tractus solitarius of the mouse. GDF15 activates GFRALAP/NTS neurons and supports conditioned taste and place aversions, while the anorexia it causes can be blocked by a monoclonal antibody directed at GFRAL or by disrupting CCK neuronal signalling. The cancer-therapeutic drug, cisplatin, induces the release of GDF15 and activates GFRALAP/NTS neurons, as well as causing significant reductions in food intake and body weight in mice. These metabolic effects of cisplatin are abolished by pre-treatment with the GFRAL monoclonal antibody. Our results suggest that GFRAL neutralising antibodies or antagonists may provide a co-treatment opportunity for patients undergoing chemotherapy.

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. Amy A Worth

    Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
    Competing interests
    No competing interests declared.

  2. Rosemary Shoop

    Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3617-4358

  3. Katie Tye

    Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
    Competing interests
    No competing interests declared.

  4. Claire H Feetham

    Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
    Competing interests
    No competing interests declared.

  5. Giuseppe D'Agostino

    Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
    Competing interests
    No competing interests declared.

  6. Garron T Dodd

    Department of Physiology, University of Melbourne, Melbourne, Australia
    Competing interests
    No competing interests declared.

  7. Frank Reimann

    Wellcome Trust MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.

  8. Fiona M Gribble

    Wellcome Trust MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.

  9. Emily C Beebe

    Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, United States
    Competing interests
    Emily C Beebe, Paid employee of Eli Lilly..

  10. James D Dunbar

    Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, United States
    Competing interests
    James D Dunbar, Paid employee of Eli Lilly..

  11. Jesline T Alexander-Chacko

    Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, United States
    Competing interests
    Jesline T Alexander-Chacko, Paid employee of Eli Lilly..

  12. Dana K Sindelar

    Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, United States
    Competing interests
    Dana K Sindelar, Paid employee of Eli Lilly..

  13. Tamer Coskun

    Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, United States
    Competing interests
    Tamer Coskun, Paid employee of Eli Lilly..

  14. Paul J Emmerson

    Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, United States
    Competing interests
    Paul J Emmerson, Paid employee of Eli Lilly..

  15. Simon M Luckman

    Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
    For correspondence
    simon.luckman@manchester.ac.uk
    Competing interests
    Simon M Luckman, BB/S008098/1 is a BBSRC Industrial Partnership Award between SML and Eli Lilly.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5318-5473

Funding

Biotechnology and Biological Sciences Research Council (BB/M001067/1)

  • Simon M Luckman

Biotechnology and Biological Sciences Research Council (BB/L021129/1)

  • Simon M Luckman

Medical Research Council (MR/R002991/1)

  • Simon M Luckman

Medical Research Council (MR/P009824/2)

  • Giuseppe D'Agostino

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

Ethics

Animal experimentation: All procedures were conducted in accordance with either: the United Kingdom Animals (Scientific Procedures) Act, 1986 (ASPA) and approved by the local animal welfare ethical review body (AWERB); the Eli Lilly Institutional Animal Care and Use Committee (IACUC) in accordance with the National Institutes of Health Guide for Care and Use of Laboratory Animals; or the University of Melbourne Animal Ethics Committee (1914919) and conformed to National Health & 8 Medical Research Council (Australia) guidelines regarding the care and use of experimental animals. Additional guidance from the UK National Centre for 3R's (NC3Rs) was followed where applicable.

Reviewing Editor

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

Publication history

  1. Received: January 14, 2020
  2. Accepted: July 26, 2020
  3. Accepted Manuscript published: July 29, 2020 (version 1)
  4. Version of Record published: August 6, 2020 (version 2)

Copyright

© 2020, Worth 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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