GDF15

GDF15 is a stress-inducible secreted member of the transforming growth factor-β superfamily, originally described as macrophage inhibitory cytokine-1 and later characterized as a liver-injury–induced growth differentiation factor^[1][2]. In metabolic and inflammatory stress, GDF15 functions as an endocrine signal that links peripheral tissue injury, nutrient stress, and systemic adaptation rather than acting as a conventional intracellular signaling enzyme^[3][4]. Mechanistically, circulating GDF15 engages the hindbrain GFRAL–RET pathway, which controls food intake, body weight, and energy balance, making the GDF15–GFRAL axis a central experimental model for anorexia, cachexia, nausea, and obesity research^[4][5]. In disease models, GDF15 supports tissue tolerance during infection and inflammatory injury, while human pregnancy studies link fetal and maternal GDF15 biology to nausea and hyperemesis gravidarum risk^[3][6]. Compared with related GDF/TGF-β family ligands, the selected literature distinguishes GDF15 by its divergent sequence identity, stress-responsive expression, and GFRAL-dependent endocrine biology rather than by functionally validated GDF15 isoforms^[1][2][4]. For experimental applications, recombinant GDF15 or metformin-induced GDF15 elevation can model pathway activation, whereas anti-GDF15 antibody blockade, including ponsegromab, tests causal involvement in cancer cachexia and appetite-loss phenotypes^[5][7].