The cytokine GDF15 signals through a population of brainstem cholecystokinin neurons to mediate anorectic signalling
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 cholecystokin...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2020-07-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/55164 |
| _version_ | 1811252896757448704 |
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| author | Amy A Worth Rosemary Shoop Katie Tye Claire H Feetham Giuseppe D'Agostino Garron T Dodd Frank Reimann Fiona M Gribble Emily C Beebe James D Dunbar Jesline T Alexander-Chacko Dana K Sindelar Tamer Coskun Paul J Emmerson Simon M Luckman |
| author_facet | Amy A Worth Rosemary Shoop Katie Tye Claire H Feetham Giuseppe D'Agostino Garron T Dodd Frank Reimann Fiona M Gribble Emily C Beebe James D Dunbar Jesline T Alexander-Chacko Dana K Sindelar Tamer Coskun Paul J Emmerson Simon M Luckman |
| author_sort | Amy A Worth |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T16:42:24Z |
| format | Article |
| id | doaj.art-825a4f2bc81540a88d659e35ab6f5327 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:42:24Z |
| publishDate | 2020-07-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-825a4f2bc81540a88d659e35ab6f53272022-12-22T03:24:44ZengeLife Sciences Publications LtdeLife2050-084X2020-07-01910.7554/eLife.55164The cytokine GDF15 signals through a population of brainstem cholecystokinin neurons to mediate anorectic signallingAmy A Worth0https://orcid.org/0000-0003-2573-7140Rosemary Shoop1https://orcid.org/0000-0002-3617-4358Katie Tye2Claire H Feetham3Giuseppe D'Agostino4Garron T Dodd5Frank Reimann6Fiona M Gribble7Emily C Beebe8James D Dunbar9Jesline T Alexander-Chacko10Dana K Sindelar11Tamer Coskun12Paul J Emmerson13Simon M Luckman14https://orcid.org/0000-0001-5318-5473Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United KingdomFaculty of Biology, Medicine and Health, The University of Manchester, Manchester, United KingdomFaculty of Biology, Medicine and Health, The University of Manchester, Manchester, United KingdomFaculty of Biology, Medicine and Health, The University of Manchester, Manchester, United KingdomFaculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom; Rowett Institute, University of Aberdeen, Aberdeen, United KingdomSchool of Biomedical Sciences, The University of Melbourne, Victoria, AustraliaInstitute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, United KingdomInstitute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, United KingdomLilly Research Laboratories, Eli Lilly & Company, Indianapolis, United StatesLilly Research Laboratories, Eli Lilly & Company, Indianapolis, United StatesLilly Research Laboratories, Eli Lilly & Company, Indianapolis, United StatesLilly Research Laboratories, Eli Lilly & Company, Indianapolis, United StatesLilly Research Laboratories, Eli Lilly & Company, Indianapolis, United StatesLilly Research Laboratories, Eli Lilly & Company, Indianapolis, United StatesFaculty of Biology, Medicine and Health, The University of Manchester, Manchester, United KingdomThe 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.https://elifesciences.org/articles/55164GDF15GFRALCCKfood intakebrainstemcisplatin |
| spellingShingle | Amy A Worth Rosemary Shoop Katie Tye Claire H Feetham Giuseppe D'Agostino Garron T Dodd Frank Reimann Fiona M Gribble Emily C Beebe James D Dunbar Jesline T Alexander-Chacko Dana K Sindelar Tamer Coskun Paul J Emmerson Simon M Luckman The cytokine GDF15 signals through a population of brainstem cholecystokinin neurons to mediate anorectic signalling eLife GDF15 GFRAL CCK food intake brainstem cisplatin |
| title | The cytokine GDF15 signals through a population of brainstem cholecystokinin neurons to mediate anorectic signalling |
| title_full | The cytokine GDF15 signals through a population of brainstem cholecystokinin neurons to mediate anorectic signalling |
| title_fullStr | The cytokine GDF15 signals through a population of brainstem cholecystokinin neurons to mediate anorectic signalling |
| title_full_unstemmed | The cytokine GDF15 signals through a population of brainstem cholecystokinin neurons to mediate anorectic signalling |
| title_short | The cytokine GDF15 signals through a population of brainstem cholecystokinin neurons to mediate anorectic signalling |
| title_sort | cytokine gdf15 signals through a population of brainstem cholecystokinin neurons to mediate anorectic signalling |
| topic | GDF15 GFRAL CCK food intake brainstem cisplatin |
| url | https://elifesciences.org/articles/55164 |
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