Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom.
Rowett Institute, University of Aberdeen, Aberdeen, United Kingdom.
Elife. 2020 Jul 29;9:e55164. doi: 10.7554/eLife.55164.
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 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 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.
细胞因子 GDF15 在引起细胞应激的病理状态下产生，包括癌症。当过度表达时，它会导致体重明显减轻，提示其在与疾病相关的厌食症中发挥作用。在这里，我们证明 GDF15 受体 GFRAL 位于跨越小鼠的后区和孤束核的胆囊收缩素神经元的一个亚群中。GDF15 激活 GFRAL 神经元并支持条件性味觉和位置厌恶，而它引起的厌食可以通过针对 GFRAL 的单克隆抗体或破坏 CCK 神经元信号来阻断。癌症治疗药物顺铂诱导 GDF15 的释放并激活 GFRAL 神经元，同时导致小鼠的食物摄入量和体重显著减少。顺铂的这些代谢作用通过用 GFRAL 单克隆抗体预处理而被消除。我们的结果表明，GFRAL 中和抗体或拮抗剂可能为接受化疗的患者提供联合治疗机会。
