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

Elife. 2020 Jul 29:9:e55164. doi: 10.7554/eLife.55164.

Abstract

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.

Keywords: CCK; GDF15; GFRAL; brainstem; cisplatin; food intake; mouse; neuroscience; rat.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anorexia / genetics*
  • Brain Stem / physiology*
  • Cholecystokinin / metabolism
  • Growth Differentiation Factor 15 / administration & dosage
  • Growth Differentiation Factor 15 / genetics*
  • Growth Differentiation Factor 15 / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neurons / physiology*
  • Pica / genetics*
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley
  • Recombinant Proteins / administration & dosage
  • Signal Transduction*

Substances

  • GDF15 protein, human
  • Gdf15 protein, mouse
  • Growth Differentiation Factor 15
  • Recombinant Proteins
  • Cholecystokinin