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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.