Knowledge, attitudes, and practice in breast cancer early detection: evidence from a nationally stratified study of healthcare providers in Jordan.

Growth differentiation factor 15 (GDF-15) is a member of the transforming growth factor-β (TGF-β) superfamily and has been initially identified as a factor secreted by activated macrophages (i.e., macrophage inhibitory cytokine-1), with the gene located at chromosomal locus 19p13.11 []. GDF-15 is represented in multiple forms, including the pro-GDF-15 monomer, pro-GDF-15 dimer, N-terminal pro-fragment of the peptide, and the mature GDF-15 dimer []. GDF-15 is widely distributed across a spectrum of organs and tissues with certain tissue predominance: the placenta is the main expression site, followed by the prostate, adipose tissue, liver, skeletal muscle and heart in that order []. Its expression is regulated by various factors, such as inflammation, tumors, ionizing radiation, and drugs []. More recently, the concept that GDF-15 may induce appetite suppression and weight loss has been well established, although the exact mechanism remains elusive []. Until 2017, multiple studies successfully identified glial cell-derived neurotrophic factor family receptor α-like protein (GFRAL) as a specific receptor for GDF-15 to regulate appetite and weight [–], exclusively representing the defined receptor for GDF-15. GFRAL, a distant homologue of the glial cell-derived neurotrophic factor family, is expressed in the area postrema (AP) of the hindbrain, a key region involved in regulating nausea, vomiting, and appetite []. It plays important roles in neuroprotection, brain development, and energy metabolism. Under physiological conditions, the median level of GDF-15 in human blood fluctuates between 0.4–0.5 ng/mL (as reported by Kralisch S et al.) [, ]. Under specific physiological conditions, such as exercise [, ], aging [], and pregnancy [], its circulating levels increase, but remain lower than those in pathological entities []. Across multiple disease conditions like cancer cachexia, cardiovascular diseases, and muscle-fat-bone metabolic disorders, its expression level is reported to be significantly upregulated; meanwhile, it is partially suggestive of the magnitude and prognosis of various diseases [] (; ). From a physiological perspective, GDF-15 exhibits pleiotropic effects. Its core functions cover: (1) Regulation of energy metabolism: GDF-15 reduces food intake through the central appetite-suppressing pathway and affects energy balance in the models of obesity and cachexia []; (2) Tissue protection: In patients with acute injuries, GDF-15 promotes tissue homeostasis by impeding the inflammatory burst (e.g., macrophage activation) and strengthening protective molecules (e.g., renal Klotho protein) []; (3) Embryonic development: GDF-15’s high expression in the placenta implicates its involvement in the developmental embryonic process []; (4) Modulation of iron metabolism: GDF-15 affects erythropoiesis and iron homeostasis by regulating hepcidin [, , ]. Dual roles and controversies of GDF-15 in body composition and nutrition-related disorders. The dual roles of GDF-15 under physiological and pathological conditions. This infographic illustrates the multifaceted implications of growth differentiation factor 15 (GDF-15) in human health. On the left, under physiological conditions, GDF-15 mediates adaptive responses, including metabolic adjustments during exercise, maternal physiological adaptations in pregnancy, metabolic stress responses (e.g., energy homeostasis regulation), and age-related physiological changes. On the right, pathological conditions are characterized by dysregulated GDF-15 signaling, which is linked to adverse outcomes as follows: (1) Undernutrition-related disorders: muscle atrophy, cancer cachexia, anorexia nervosa, wasting syndrome, and frailty; (2) Overnutrition-related disorders: MetS, IR, type 2 diabetes, and obesity; (3) Nutritional deficiency states: iron-deficiency anemia and osteoporosis. This contrast underscores GDF-15’s role as a biomarker that bridges physiological adaptation and pathological dysregulation in nutritional and metabolic health.