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

Vicky W W Tsai; Yasmin Husaini; Amanda Sainsbury; David A Brown; Samuel N Breit

doi:10.1016/j.cmet.2018.07.018

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.

Authors

Vicky W W Tsai¹, Yasmin Husaini¹, Amanda Sainsbury², David A Brown¹, Samuel N Breit³

Affiliations

¹ St Vincent's Centre for Applied Medical Research, St Vincent's Hospital, Sydney, NSW 2010, Australia; Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia.
² The University of Sydney, The Boden Institute of Obesity, Nutrition, Exercise & Eating Disorders, Sydney Medical School, Charles Perkins Centre, Sydney, NSW 2006, Australia.
³ St Vincent's Centre for Applied Medical Research, St Vincent's Hospital, Sydney, NSW 2010, Australia; Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia. Electronic address: s.breit@amr.org.au.

PMID: 30184485
DOI: 10.1016/j.cmet.2018.07.018

Abstract

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

Substances

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