TY - JOUR TI - The cytokine GDF15 signals through a population of brainstem cholecystokinin neurons to mediate anorectic signalling AU - Worth, Amy A AU - Shoop, Rosemary AU - Tye, Katie AU - Feetham, Claire H AU - D'Agostino, Giuseppe AU - Dodd, Garron T AU - Reimann, Frank AU - Gribble, Fiona M AU - Beebe, Emily C AU - Dunbar, James D AU - Alexander-Chacko, Jesline T AU - Sindelar, Dana K AU - Coskun, Tamer AU - Emmerson, Paul J AU - Luckman, Simon M A2 - Palmiter, Richard D A2 - Dulac, Catherine A2 - Palmiter, Richard D A2 - Dietrich, Marcelo O VL - 9 PY - 2020 DA - 2020/07/29 SP - e55164 C1 - eLife 2020;9:e55164 DO - 10.7554/eLife.55164 UR - https://doi.org/10.7554/eLife.55164 AB - 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. KW - GDF15 KW - GFRAL KW - CCK KW - food intake KW - brainstem KW - cisplatin JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -