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 Beebe, James D. Dunbar, Jesline Alexander-Chacko, Dana K. Sindelar, Tamer Coşkun, Paul J. Emmerson, Simon M. Luckman
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 GFRAL AP/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 GFRAL AP/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.