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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article numbere55164
Pages (from-to)1-19
Number of pages19
JournaleLife
Volume9
DOIs
Publication statusPublished - 29 Jul 2020

Research Beacons, Institutes and Platforms

  • Lydia Becker Institute

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