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

AA Worth, R Shoop, K Tye, CH Feetham, G D'Agostino… - elife, 2020 - elifesciences.org
AA Worth, R Shoop, K Tye, CH Feetham, G D'Agostino, GT Dodd, F Reimann, FM Gribble…
elife, 2020elifesciences.org
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 …
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.
eLife