GFRAL, also known as GDNF Family Receptor Alpha-Like, is an orphan member of the GFR-α family. GFRAL is a brainstem-restricted receptor for Growth differentiation factor 15 (GDF15), which regulates food intake, energy expenditure and body weight in response to metabolic and toxin-induced stresses. Upon interaction with its ligand GDF15, GFRAL interacts with RET and induces cellular signaling through activation of MAPK- and AKT- signaling pathways.

GFRAL regulates body weight and the receptor mediating the metabolic effects of GDF15, enabling potential pharmacotherapies for the treatment of obesity. GFRAL is expressed in neurons of the area postrema and the nucleus of the solitary tract in mice and humans, and genetic deletion of the receptor abrogates the ability of GDF15 to decrease food intake and body weight in mice. Moreover, diet-induced obesity and insulin resistance are exacerbated in GFRAL-deficient mice, suggesting a homeostatic role for this receptor in metabolism¹.

GDF15, a distant member of the transforming growth factor (TGF)-β family, is a secreted protein that circulates in plasma as a 25-kDa homodimer. In humans, elevated GDF15 correlates with weight loss, and the administration of GDF15 to mice with obesity reduces body weight, at least in part, by decreasing food intake.
GDF15 has been implicated in various biological functions, including cancer cachexia, renal and heart failure, atherosclerosis, and metabolism. A connection between GDF15 and body-weight regulation was initially suggested based on an observation that increasing GDF15 levels in serum correlated with weight loss in individuals with advanced prostate cancer. GFRAL-/- mice were refractory to the effects of recombinant human GDF15 on body weight, food intake and glucose parameters. Blocking the interaction between GDF15 and GFRAL with a monoclonal antibody prevented the metabolic effects of GDF15 in rats. GFRAL mRNA is highly expressed in the area postrema of mouse, rat and monkey models, in accordance with previous reports implicating this region of the brain in the metabolic actions of GDF15².

The GDNF family includes glial cell line-derived neurotrophic factor (GDNF), artemin (ARTN), Neurturin (NRTN) and persephin (PSPN)³. These factors are heavily involved in the development and function of the nervous system (both central and peripheral). GDNF serves an important role outside the nervous system, where it plays a role in kidney morphogenesis⁴.

In general, GFLs all signal through the receptor tyrosine kinase RET. Their specificity is implemented by different GDNF family receptors a (GFRα), which act as co-receptors. These extracellular proteins are bound to the plasma membrane via a glycosyl phosphatidyl inositol (GPI) anchor. GFRα1-4 are responsible for the binding of GDNF, NRTN, ARTN, and PSPN respectively and the subsequent activation of RET. Soluble forms of the receptor, produced by the cleavage of a yet unknown phospholipase or protease, can be detected. Alternative spliced forms of the protein can also lead to the production of soluble forms of GFRα receptors⁵.