The MIC-1/GDF15-GFRAL Pathway in Energy Homeostasis: Implications for Obesity, Cachexia, and Other Associated Diseases

Cell Metab. 2018 Sep 4;28(3):353-368. doi: 10.1016/j.cmet.2018.07.018.


MIC-1/GDF15 is a stress response cytokine and a distant member of the transforming growth factor beta (TGFb) superfamily, with no close relatives. It acts via a recently identified receptor called glial-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL), which is a distant orphan member of the GDNF receptor family that signals through the tyrosine kinase receptor Ret. MIC-1/GDF15 expression and serum levels rise in response to many stimuli that initiate cell stress and as part of a wide variety of disease processes, most prominently cancer and cardiovascular disease. The best documented actions of MIC-1/GDF15 are on regulation of energy homeostasis. When MIC-1/GDF15 serum levels are substantially elevated in diseases like cancer, it subverts a physiological pathway of appetite regulation to induce an anorexia/cachexia syndrome initiated by its actions on hindbrain neurons. These effects make it a potential target for the treatment of both obesity and anorexia/cachexia syndromes, disorders lacking any highly effective, readily accessible therapies.

Keywords: GDNF; GFRAL; MIC-1/GDF15; TGFb; area postrema; cachexia; cancer; inflammation; nucleus of the solitary tract; obesity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Anorexia / metabolism
  • Cachexia / metabolism*
  • Cardiovascular Diseases / metabolism
  • Diabetes Mellitus / metabolism
  • Energy Metabolism / physiology*
  • Glial Cell Line-Derived Neurotrophic Factor Receptors / metabolism*
  • Growth Differentiation Factor 15 / metabolism*
  • Homeostasis
  • Humans
  • Inflammation / metabolism
  • Mice
  • Mitochondrial Diseases / metabolism
  • Neoplasms / metabolism
  • Obesity / metabolism*
  • Rats


  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Growth Differentiation Factor 15