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