The cytokine GDF15 signals through a population of brainstem cholecystokinin neurons to mediate anorectic signalling.
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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.
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2050-084X
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Medical Research Council (MC_UU_12012/3)
Medical Research Council (MC_UU_12012/5)
Wellcome Trust (106262/Z/14/Z)
MRC (MC_UU_00014/3)
MRC (via University of Manchester) (MR/R002991/1)
Medical Research Council (MR/L021129/1)
Medical Research Council (MC_PC_12012)