The cytokine GDF15 signals through a population of brainstem cholecystokinin neurons to mediate anorectic signalling
- University of Manchester, United Kingdom
- University of Melbourne, Australia
- University of Cambridge, United Kingdom
- Eli Lilly and Company, United States
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
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.
Reviewing Editor
- Richard D Palmiter, Howard Hughes Medical Institute, University of Washington, United States
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.
Version history
- Received: January 14, 2020
- Accepted: July 26, 2020
- Accepted Manuscript published: July 29, 2020 (version 1)
- 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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The cytokine GDF15 signals through a population of brainstem cholecystokinin neurons to mediate anorectic signalling
eLife 9:e55164.
https://doi.org/10.7554/eLife.55164
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