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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 C Beebe | James D Dunbar | Jesline T Alexander-Chacko | Dana K Sindelar | Tamer Coskun | Paul J Emmerson | Simon M Luckman
eLife | 2020

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.

Pubmed ID: 32723474

Associated grants

  • Agency: Medical Research Council, United Kingdom
    Id: MR/R002991/1
  • Agency: Biotechnology and Biological Sciences Research Council, United Kingdom
    Id: BB/S008098/1
  • Agency: Medical Research Council, United Kingdom
    Id: MR/P009824/2
  • Agency: Medical Research Council, United Kingdom
    Id: MR/P009824/1
  • Agency: Medical Research Council, United Kingdom
    Id: MR/T032669/1
  • Agency: Medical Research Council, United Kingdom
    Id: MC_UU_12012/5
  • Agency: Medical Research Council, United Kingdom
    Id: MC_UU_12012/3
  • Agency: Medical Research Council, United Kingdom
    Id: MC_UU_00014/3
  • Agency: Biotechnology and Biological Sciences Research Council, United Kingdom
    Id: BB/M001067/1
  • Agency: Biotechnology and Biological Sciences Research Council, United Kingdom
    Id: BB/H007172/1
  • Agency: Biotechnology and Biological Sciences Research Council, United Kingdom
    Id: BB/L021129/1
  • Agency: Medical Research Council, United Kingdom
    Id: MR/L021129/1

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