The GDF15-GFRAL Pathway in Health and Metabolic Disease: Friend or Foe?
GDF15 is a cell activation and stress response cytokine of the glial cell line-derived neurotrophic factor family within the TGF-β superfamily. It acts through a recently identified orphan member of the GFRα family called GFRAL and signals through the Ret coreceptor. Cell stress and disease lead to elevated GDF15 serum levels, causing anorexia, weight loss, and alterations to metabolism, largely by actions on regions of the hindbrain. These changes restore homeostasis and, in the case of obesity, cause a reduction in adiposity. In some diseases, such as advanced cancer, serum GDF15 levels can rise by as much as 10-100-fold, leading to an anorexia-cachexia syndrome, which is often fatal. This review discusses how GDF15 regulates appetite and metabolism, the role it plays in resistance to obesity, and how this impacts diseases such as diabetes, nonalcoholic fatty liver disease, and anorexia-cachexia syndrome. It also discusses potential therapeutic applications of targeting the GDF15-GFRAL pathway and lastly suggests some potential unifying hypotheses for its biological role.
['Breit|Samuel N|SN|', 'Brown|David A|DA|', 'Tsai|Vicky Wang-Wei|VW|']
D000818:Animals D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors D055436:Growth Differentiation Factor 15 D006801:Humans D008659:Metabolic Diseases D015398:Signal Transduction
metabolism GDF15 TGF-β superfamily GFRα GFRAL Ret obesity anorexia-cachexia appetite GDNF MIC-1 area postrema nucleus of the solitary tract