GFRAL (GDNF Family Receptor Alpha-Like) is the sole known receptor for GDF15. GFRAL is expressed exclusively in the hindbrain (area postrema and nucleus tractus solitarius). Upon GDF15 binding, GFRAL recruits the co-receptor RET (a receptor tyrosine kinase), forming a GDF15–GFRAL–RET ternary complex that activates ERK, AKT, and PLCγ signaling to suppress appetite and regulate energy balance. GDF15 does not bind canonical TGF-β receptors.

GDF15 has opposite therapeutic utility in different contexts. In obesity, GDF15 agonists or long-acting GDF15-Fc fusion proteins are being developed to suppress appetite and reduce body weight. In cancer cachexia, tumor-derived GDF15 contributes to muscle wasting and anorexia — anti-GDF15 neutralizing antibodies (e.g., Ponsegromab) aim to block this pathological signaling and restore appetite and lean mass. The choice depends on whether excessive or insufficient GDF15 signaling is the therapeutic target.

Normal fasting serum GDF15 is approximately 0.2–1.2 ng/mL in healthy adults, increasing with age. Levels >2 ng/mL suggest pathological stress. Highly elevated GDF15 (>5-10 ng/mL) is seen in advanced cancers with cachexia, mitochondrial myopathies, and severe heart failure. In pregnancy, GDF15 rises dramatically during the first trimester (peaking ~10-50 ng/mL) and is strongly associated with hyperemesis gravidarum (severe nausea/vomiting).

Since GFRAL expression is restricted to the hindbrain, there are no naturally GFRAL-expressing cell lines. The standard approach uses GFRAL/RET co-transfected HEK293 or CHO reporter cells. Readouts include: (1) RET phosphorylation (pY1062) by Western blot or ELISA after GDF15 stimulation, (2) ERK1/2 phosphorylation downstream of RET, or (3) luciferase reporter assays with GFRAL/RET-SRE-Luc cells. Bioactive GDF15 should show dose-dependent RET phosphorylation with an EC₅₀ in the low nanomolar range.

These are all names for the same protein, reflecting its independent discovery by different groups. GDF15 (Growth Differentiation Factor 15) is the official gene name. MIC-1 (Macrophage Inhibitory Cytokine 1) was its original name when cloned from activated macrophages. NAG-1 (NSAID-Activated Gene 1) was identified in NSAID-treated cells. PTGFB (Placental TGF-beta) reflects its high expression in placental tissue. Use "GDF15" for consistency in publications and database searches.