GDF-15: The Stress Hormone That Decides When We Eat, Burn, and Waste Away

Deep in the brainstem, a single molecular switch helps decide whether we feel hungry, nauseated, or full — and scientists are now mapping how that switch, a hormone called growth differentiation factor 15 (GDF-15), shapes everything from obesity to cancer cachexia. A comprehensive review published in the British Journal of Biomedical Science synthesizes basic research, clinical data, and translational evidence to argue that GDF-15 is far more than a simple appetite signal: it is a pleiotropic stress cytokine that integrates energy status, inflammation, muscle metabolism, and iron homeostasis into a single readable biomarker with genuine therapeutic potential.

GDF-15 belongs to the transforming growth factor-beta (TGF-beta) superfamily and was originally identified as macrophage inhibitory cytokine-1, a factor secreted by activated immune cells. The gene sits on chromosome 19 at locus 19p13.11, and the protein circulates in several molecular forms, including a pro-GDF-15 monomer, a pro-GDF-15 dimer, an N-terminal pro-fragment, and the mature dimer that carries biological activity. Expression is widespread but uneven: the placenta is the dominant site, followed by the prostate, adipose tissue, liver, skeletal muscle, and heart. Inflammation, tumors, ionizing radiation, and certain drugs all modulate its production, which is one reason circulating levels rise so reliably under physiological and pathological stress alike.

For years, the mechanism behind GDF-15’s appetite-suppressing effects remained elusive. That changed in 2017, when independent teams identified glial cell-derived neurotrophic factor family receptor alpha-like protein (GFRAL) as the specific receptor mediating GDF-15’s control of appetite and body weight. GFRAL, a distant homolog of the glial cell-derived neurotrophic factor family, is expressed almost exclusively in the area postrema and nucleus of the solitary tract — hindbrain regions that govern nausea, vomiting, and satiety. Under healthy conditions, median circulating GDF-15 hovers around 0.4 to 0.5 ng/mL, but levels climb with exercise, aging, and pregnancy, and surge dramatically in diseases ranging from cancer to cardiovascular dysfunction.

The review’s authors, led by Binbin Peng and Wei Zhao of Tianjin Medical University General Hospital alongside colleagues at Capital Medical University and Xi’an Medical University, emphasize that GDF-15’s physiological portfolio extends well beyond appetite. It protects tissues during acute injury by dampening macrophage-driven inflammatory bursts and reinforcing protective molecules such as renal Klotho protein. It participates in embryonic development through its high placental expression. It modulates iron metabolism by regulating hepcidin, the master hormone of iron homeostasis, thereby influencing erythropoiesis. And it shapes energy balance centrally, reducing food intake in models of both obesity and cachexia through the GDF-15/GFRAL/rearranged during transfection (RET) signaling axis.

In obesity, the picture is paradoxical. Circulating GDF-15 is generally elevated in people with obesity, yet recombinant GDF-15 administration reliably suppresses appetite and reduces body weight in animal models. The review interprets this as a compensatory stress response: the hormone rises to counteract obesity-related metabolic derangement, including insulin resistance, but prolonged metabolic insult may eventually overwhelm that compensation. Mechanistically, activation of GFRAL in hindbrain neurons triggers phosphorylation of ERK1/2, STAT3, AMPK, and PI3K/Akt pathways, inhibiting orexigenic neuropeptide Y neurons while stimulating anorexigenic proopiomelanocortin neurons in the hypothalamus. Intriguingly, GDF-15 can also improve insulin sensitivity in obese rodents through beta-adrenergic receptor-mediated mechanisms independent of GFRAL and independent of weight loss itself, acting on liver and adipose tissue while reshaping macrophage polarization within fat depots.

The clinical data reinforce GDF-15’s sensitivity to energy flux. Acute complete starvation raises levels in proportion to triglyceride-rich lipoproteins, a trend especially pronounced in athletes with Relative Energy Deficiency in Sport. Intermittent fasting increases GDF-15 by roughly 5 percent more than caloric restriction in obese women, yet without a corresponding drop in food intake — hinting at GFRAL-independent regulatory pathways. Bariatric surgery, particularly sleeve gastrectomy, markedly elevates GDF-15 in circulation and gastrointestinal tissue, partially explaining postoperative weight loss. Moderate-intensity exercise raises GDF-15 in obese individuals alongside appetite suppression, and notably without subsequent energy compensation, helping create the negative energy balance needed for sustained weight reduction.

In anorexia nervosa, GDF-15 tells a different story. Serum levels run approximately 15 percent higher in acutely ill patients than in healthy controls and fall significantly with refeeding and nutritional recovery, suggesting the hormone tracks metabolic stress rather than a fixed psychiatric trait. High GDF-15 correlates with ghrelin and jointly predicts body mass index reduction, while levels above 0.8 ng/mL associate with fibroblast growth factor 21 changes and mitochondrial dysfunction, painting anorexia as a state of prolonged energy deficiency. Exercise, hyperinsulinemia, and metformin all induce GDF-15 expression in these patients through insulin- and glucagon-coordinated regulation, underscoring the hormone’s exquisite responsiveness to metabolic perturbation.

In cancer cachexia, the hormone’s role turns darker. Elevated GDF-15 above 3.4 ng/mL in pancreatic and non-small cell lung cancer correlates with continuous weight loss, deteriorating physical condition, and heavy tumor burden. In advanced heart failure, levels above 1.2 ng/mL flag higher cachexia incidence and adverse outcomes, and blocking the GDF-15 pathway in heart-failure mice delays cachexia progression. Anorexic cancer patients show median levels of 1.2 ng/mL versus 0.8 ng/mL in non-anorexic patients and 0.6 ng/mL in healthy controls, with levels correlating positively with anorexia severity. Chemotherapy with platinum agents induces GDF-15 secretion that no current antiemetic fully prevents, and tumor-bearing mice overexpressing GDF-15 lose 28 percent of body weight through anorexia-driven fat and muscle depletion.

Muscle metabolism reveals the hormone’s most context-dependent behavior. Acute exercise transiently raises circulating GDF-15 — peaking at 120 minutes post-exercise at 2.3 ng/mL in trained individuals before returning toward baseline within 48 hours — and may protect against exercise stress while promoting slow oxidative fiber formation via Akt/mTOR signaling. Yet chronically elevated GDF-15 above 1.2 ng/mL associates with sarcopenia, frailty, reduced handgrip strength, and poor prognosis, particularly in older hospitalized patients and those with chronic obstructive pulmonary disease. The review proposes that GDF-15 drives muscle wasting through multiple routes: central appetite suppression via GFRAL/RET, hypothalamic-pituitary-adrenal axis activation that elevates glucocorticoids and upregulates the E3 ubiquitin ligases MuRF-1 and atrogin-1, direct peripheral activation of TAK-1/NF-kappaB signaling that suppresses muscle microRNAs, GFRAL-RET-mediated suppression of lipogenic genes in adipose tissue, and hepcidin inhibition that promotes iron overload and independent muscle degeneration.

Therapeutically, the field is moving fast but cautiously. Ponsegromab, a monoclonal antibody against GDF-15, completed a phase II trial in 187 patients with cancer cachexia, producing weight gain, improved activity levels, and reduced cachexia symptoms. Visugromab (CTL-002) combined with the checkpoint inhibitor nivolumab is being tested in advanced solid tumors, where neutralizing GDF-15 can overcome resistance to immune checkpoint blockade. On the obesity side, GDF-15 analogues and GFRAL agonists such as MBL949 and LY3463251 have struggled to translate robust preclinical weight loss into human efficacy, partly because natural GDF-15’s short half-life of roughly three hours and its tendency to aggregate limit delivery — problems that recombinant Fc-fusion modifications partially solve. The review’s authors argue that GDF-15 agonists and antagonists will ultimately need to be deployed in opposite clinical directions, with agonists for obesity and antagonists for cachexia, calibrated precisely to each patient’s metabolic state. They call for sex-stratified cohorts, tissue-specific knockout models, organoid co-culture systems, and wearable biosensors for real-time monitoring to close the gap between biomarker discovery and precision intervention. What emerges is a molecule that refuses to be categorized as simply good or bad: GDF-15 is, in the authors’ framing, a context-dependent integrator of metabolic stress whose clinical value depends entirely on where, when, and how much of it is circulating.

Subject of Research: The pleiotropic role of the cytokine GDF-15 in regulating nutritional status, energy metabolism, and nutrition-related disorders

Article Title: Pleiotropic effects of GDF-15 to regulate nutritional status: perspectives from body composition to nutrition-related disorders

Article References: Pleiotropic effects of GDF-15 to regulate nutritional status: perspectives from body composition to nutrition-related disorders. (n.d.). https://doi.org/10.3389/bjbs.2026.16085

Image Credits: AI Generated

DOI: 10.3389/bjbs.2026.16085

Keywords: GDF-15, GFRAL, appetite regulation, cachexia, obesity, metabolic syndrome, sarcopenia, anorexia nervosa, cancer cachexia, insulin resistance, biomarker, TGF-beta superfamily