GDF15

GDF15 is a stress-induced cytokine and divergent member of the transforming growth factor-β (TGF-β) superfamily that functions as a multifunctional signaling molecule. PMID 33172749PMID 34836750 It is also known by alternative names including macrophage inhibitory cytokine-1 (MIC-1) and non-steroidal anti-inflammatory drug-activated gene (NAG-1). PMID 34836750PMID 31663791

GDF15 is normally expressed at low levels in most tissues under physiological conditions, with the notable exception of the placenta where it is abundant. PMID 32508832 However, it is prominently induced in response to cellular stress, tissue injury, inflammation, mitochondrial dysfunction, oxidative stress, hypoxia, and telomere erosion. PMID 33172749PMID 40825163PMID 28062617 The GDF15 gene promoter contains two binding sites for the p53 transcription factor, which mediates its upregulation in response to various cellular stressors. PMID 32466889

GDF15 signals through the GFRAL (glial-derived neurotrophic factor family receptor α-like) receptor, which is selectively expressed in hindbrain neurons, particularly in the area postrema and nucleus tractus solitarius. PMID 33172749PMID 34849709 This receptor signals through the coreceptor RET to mediate GDF15's effects. PMID 33172749

The primary established physiological functions of GDF15 include:

• Appetite regulation and energy homeostasis: GDF15 acts as a potent anorectic signal, reducing food intake and body weight through GFRAL-mediated signaling in the brainstem. This pathway is linked to increased sympathetic outflow and possible activation of the hypothalamic-pituitary-adrenal (HPA) stress axis. PMID 32936319PMID 34849709PMID 34831213
• Metabolic regulation: GDF15 controls adipose tissue metabolism, insulin sensitivity, and body growth. It influences energy balance during obesity and diabetes. PMID 34836750PMID 33317942PMID 36542831
• Cardioprotection: In cardiac tissue, GDF15 exhibits autocrine/paracrine properties with antioxidative, anti-inflammatory, and antiapoptotic effects. It is highly induced in cardiomyocytes after ischemia/reperfusion and myocardial infarction. PMID 34445593
• Immunomodulation: GDF15 can suppress type 1 inflammatory responses while promoting type 2 responses. It plays a role in immune tolerance and has been proposed as an immune checkpoint molecule. PMID 36542831PMID 32508832
• Cellular stress response: GDF15 serves as a universal defense mechanism against damaging environmental pressures associated with biological aging and disease. PMID 32466889

The effects of GDF15 can be beneficial or detrimental depending on timing, magnitude, and duration of signaling. PMID 40825163 While it appears protective in acute stress and tissue injury, chronically elevated levels are associated with poor outcomes in cancer, cardiovascular disease, and metabolic disorders. PMID 40825163PMID 28062617

The classification of GDF15 as a functional exerkine remains controversial, with current evidence suggesting it may be a "coincidental bystander" rather than an essential mediator of exercise benefits. PMID 34849709

• Exercise-induced secretion: Prolonged endurance exercise increases circulating GDF15 to levels comparable to those seen in pathological states and with metformin treatment. GDF15 expression and secretion from skeletal muscle can be induced by intense exercise. PMID 34849709PMID 34831213
• Myokine characteristics: GDF15 is considered a myokine and myomitokine because it can be produced and secreted by skeletal muscle, particularly under stress conditions. In muscle, GDF15 expression is linked to mitochondrial stress. PMID 34831213

Evidence against functional exerkine role:

Lack of causal relationship: Studies using GDF15-deficient mice demonstrate that while GDF15 is associated with exercise-induced increases in corticosterone and indices of lipid utilization (NEFA, beta-hydroxybutyrate), these metabolic changes occur normally in GDF15-/- mice, indicating the associations are not causal. PMID 39480267

Uncertain physiological significance: The jury remains out on whether exercise-induced GDF15 has functional implications for appetite and metabolism or whether it simply reflects cellular stress without mediating beneficial adaptations. PMID 34849709

Context-dependent effects: GDF15 production in muscle can be induced both by beneficial exercise and by pathological states such as sarcopenia and mitochondrial myopathy, suggesting it may be a general stress marker rather than a specific exercise mediator. PMID 34831213

Current consensus suggests that while GDF15 increases with exercise and associates with metabolic changes, definitive evidence for its role as a functional exerkine mediating exercise benefits is lacking. PMID 34849709PMID 39480267PMID 39472228

, GDF-15 shows promise as a therapeutic target due to its ability to suppress appetite and reduce body weight through binding to GFRAL (glial cell-derived neurotrophic factor family receptor $alpha$-like) in the hindbrain. PMID 34381196 This mechanism is largely independent of other appetite-regulating hormones like leptin or GLP-1, making it an appealing candidate for treating obesity, type 2 diabetes, and non-alcoholic fatty liver disease. PMID 34381196 Several GDF-15 analogs/mimetics are currently under development. PMID 39000420

In cardiovascular disease, GDF-15 demonstrates cardioprotective properties through its autocrine/paracrine effects, which are antioxidative, anti-inflammatory, and antiapoptotic. PMID 34445593 GDF-15 expression is highly induced in cardiomyocytes after ischemia/reperfusion and myocardial infarction, suggesting a protective role in cardiac injury. PMID 34445593PMID 33317942 Studies support its potential use by modulating metabolic activity and promoting adaptive angiogenesis and cardiac regenerative processes. PMID 34445593

In cancer, the therapeutic potential is more complex and context-dependent. While GDF-15 may have protective effects in early disease stages, it appears to promote tumor growth in later stages of malignant cancer. PMID 32936319PMID 34836750 This has led to development of GDF-15-targeting monoclonal antibodies as potential cancer therapeutics. PMID 39000420

In neurologic disease, emerging evidence suggests GDF-15 may have neuroprotective roles against neurodegeneration, though its role as a therapeutic target in neurologic disorders is yet to be established. PMID 40825163

The anti-inflammatory and immunomodulatory properties of GDF-15 have also positioned it as a potential immune checkpoint target for cancer immunotherapy. PMID 32508832