GDF15
Growth/differentiation factor 15
Written by Aaron CuhaReviewed Sep 2026
Also known as: GDF-15, MIC-1, Macrophage inhibitory cytokine-1
A stress cytokine that acts on the hindbrain to cause nausea, aversion and weight loss. The drug that worked in people blocks it: ponsegromab produced 1.2 to 2.8 kg of weight gain versus placebo in 187 people with cancer cachexia. A GDF15 agonist given to 126 adults with obesity produced minimal weight loss.
Overview
GDF15 is a member of the TGF-beta superfamily that circulates as a roughly 25 kDa dimer and rises in response to almost any cellular stress: mitochondrial dysfunction, tissue injury, inflammation, chemotherapy, pregnancy and metformin. Its receptor, GFRAL, was identified by several groups at once in 2017 and is expressed almost exclusively in the area postrema and nucleus of the solitary tract, the brainstem region that produces nausea and food aversion. GDF15 is best understood as an aversion signal, not a metabolic hormone, and that framing explains the whole clinical record.
GDF15 is a different molecule from GDF11. The names are adjacent, the proteins are not: GDF11 signals through activin receptors and is the subject of the contested young-blood rejuvenation literature; GDF15 signals through GFRAL and RET and is the cachexia and nausea cytokine on this page. Nothing on the GDF11 page transfers here.
The strongest human data point in the opposite direction from a weight-loss hormone. In a Pfizer-funded phase 2 trial, 187 patients with cancer cachexia and serum GDF15 of at least 1,500 pg/mL were randomised to the GDF15-neutralising antibody ponsegromab at 100, 200 or 400 mg or placebo every 4 weeks for three doses. At 12 weeks the ponsegromab groups gained more weight than placebo by a median 1.22 kg, 1.92 kg and 2.81 kg respectively, with improvements in appetite, cachexia symptoms and physical activity at 400 mg; adverse events were reported in 70 percent on ponsegromab and 80 percent on placebo. A 982-patient phase 2/3 in pancreatic cancer is recruiting. The other direction has also been tested: MBL949, a half-life extended recombinant GDF15 dimer, went through a 65-person single ascending dose study and a 126-person phase 2 in adults with obesity, dosed every other week for 14 weeks. Weight loss in the phase 2 was minimal, gastrointestinal adverse events were the most frequent, and the authors state that the robust weight loss seen in mice, rats, dogs and monkeys did not translate to humans.
Human genetics adds the mechanism. In 2024 a Nature paper showed that most GDF15 in maternal blood during pregnancy comes from the fetus and placenta, that women with genetically low GDF15 before pregnancy are at higher risk of hyperemesis gravidarum, and that women with beta-thalassaemia, who have chronically high GDF15, report very little pregnancy nausea. GDF15 is also one of the strongest protein predictors of death and multimorbidity in cohort studies: an adjusted odds ratio of 3.38 for mortality in 876 Swedish men, and positive association with 20 to 24 incident chronic diseases in 53,026 UK Biobank participants. Those are marker findings, not evidence that changing GDF15 in a healthy person changes anything. No GDF15 agonist or antagonist is approved.
Mechanism of action
Established in mice and confirmed at the receptor level in human tissue expression: GDF15 binds GFRAL, which requires the co-receptor RET to signal, in neurons of the area postrema and nucleus of the solitary tract. Activation reduces food intake and produces conditioned taste aversion; deleting GFRAL abolishes the weight loss effect of GDF15 in mice. In mice, GDF15 also drives a sympathetic lipolytic response in fat and, in a 2023 Nature paper, raises energy expenditure in muscle. The widely repeated claim that metformin works partly through GDF15 rests on a 2019 mouse study. In humans: GDF15 rises with cellular stress of almost any kind, is high in cancer cachexia, and blocking it with an antibody increases body weight, appetite and activity in patients with cachexia. Fetal GDF15 acting on the maternal brainstem is the leading explanation for nausea and vomiting of pregnancy, and prior exposure appears to desensitise the response. Giving a long-acting GDF15 agonist to people with obesity produced minimal weight loss, with gastrointestinal effects as the most common adverse event.
Human evidence
Both directions have been tested in randomised trials. Blocking GDF15 with ponsegromab increased weight, appetite and activity in 187 people with cancer cachexia. Activating the pathway with the long-acting agonist MBL949 produced minimal weight loss in 126 adults with obesity. Human genetics ties GDF15 to nausea of pregnancy, and large cohorts show it predicts death and multimorbidity.
- Ponsegromab phase 2 (NEJM 2024, NCT05546476): 187 patients, cancer cachexia, GDF15 of at least 1,500 pg/mL, 12 weeks. Median weight gain over placebo 1.22, 1.92 and 2.81 kg at 100, 200 and 400 mg. Adverse events 70 percent versus 80 percent on placebo. Pfizer funded.
- Ponsegromab phase 2/3 (NCT06989437): 982 planned patients with metastatic pancreatic cancer, recruiting, primary completion estimated January 2028. A phase 1 in lung cancer (NCT07663630, 80 planned) is not yet recruiting.
- MBL949 agonist (JCEM 2025): phase 1, 65 overweight or obese healthy volunteers, single doses to 20 mg, half-life 18 to 22 days, weight loss at higher doses. Phase 2, 126 adults with obesity, 8 biweekly doses over 14 weeks, minimal weight loss, gastrointestinal adverse events most common.
- Hyperemesis gravidarum (Nature 2024): fetal origin of maternal GDF15 by mass spectrometry; genetically low pre-pregnancy GDF15 raised risk; beta-thalassaemia with chronically high GDF15 associated with very little nausea.
- Mortality (Aging Cell 2010): 876 men, adjusted odds ratio of death 3.38 over up to 14 years, validated in 324 twins.
- Multimorbidity (Metabolism 2025): 53,026 UK Biobank participants, GDF15 associated with 20 to 24 incident diseases.
- A second anti-GDF15 antibody, visugromab, is in a 131-patient phase 2 in metastatic lung cancer with nivolumab (NCT07246863, recruiting), as an immuno-oncology strategy rather than for cachexia.
What this does not tell you: The ponsegromab result is 12 weeks in cancer cachexia with high GDF15; it says nothing about people without cancer, about survival, or about blocking GDF15 in anyone whose level is normal. The MBL949 result is one compound at one set of doses for 14 weeks, and a single negative programme does not exclude every agonist, though it is the only human test of the agonist idea published. The mortality and multimorbidity associations are markers of underlying illness and cannot show that GDF15 causes death or that lowering it would help; GDF15 rises because cells are stressed, and the stress is the problem. The metformin mechanism has not been shown in humans.
Reading the research record
The GDF15 story is a rare case where the same molecule was pursued as a drug in both directions and the human results point one way. Agonism was the obvious idea after the 2017 receptor papers: GDF15 makes mice and monkeys eat less and lose weight, so a long-acting GDF15 should be an obesity drug. The MBL949 programme tested that in 191 people across two randomised trials and found a compound with a three-week half-life, acceptable safety, gastrointestinal side effects and minimal weight loss. The 2024 pregnancy genetics explain why: GDF15 works through a brainstem aversion circuit that appears to desensitise with prior exposure, and its natural role is to make an organism stop eating when something is wrong, not to regulate fat mass. Antagonism, the less obvious idea, is the one with a positive phase 2. Pfizer funded the ponsegromab trial and is funding the 982-patient follow-on; no independent trial of GDF15 blockade has reported.
The biomarker literature runs on a different track and is easy to misread. GDF15 is among the best single protein predictors of death and of accumulating chronic disease in cohort after cohort, which has led to it being described as an ageing hormone. The cohort papers themselves attribute its level largely to kidney function, liver function, inflammation and obesity. A marker that rises when cells are damaged will predict death without causing it, and there is no human evidence that lowering GDF15 in a healthy person is beneficial; the one population in which lowering it has been tested is people with cancer who were losing weight. Finally, because searchers confuse them, GDF15 is not GDF11 and shares none of its biology or its disputes.
The evidence, charted
Fig. 1 · evidence composition
6of 10 citations (60%) are in people
Counted from the citation list on this page. The Human count is the same number shown in the badge at the top. Both understate any literature larger than the sources we cite.
Fig. 2 · evidence over time
Evidence spans 7 distinct years, 2010 to 2025, counted from the citation list on this page.
Fig. 3 · legal status at a glance
US
Not approved
UK
Approved
AU
Approved
CA
Not approved
Approved in 2 of 4, prescription route in 0, not approved in 2. A jurisdiction's classification is a regulatory fact, not a verdict on the science; see Legal status below for the full text and any notes.
Fig. 4 · dose response
No human dose response curve exists
We draw this figure where the data supports it. For this compound in humans it does not, so the panel stays empty rather than borrowing an animal curve and implying it transfers.
Key studies & citations
- Animal2017
GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates
Recombinant GDF15 induced weight loss in mice on a high-fat diet and in non-human primates with spontaneous obesity. GDF15 binds GFRAL, expressed in area postrema and nucleus of the solitary tract neurons in mice and humans; deleting GFRAL abolished the food intake and weight effects in mice. Signalling requires the co-receptor RET.
Nature Medicine - Review2021
The GDF15-GFRAL Pathway in Health and Metabolic Disease: Friend or Foe?
Field review that frames GDF15 as a stress-induced aversion signal and lays out why agonism for obesity and antagonism for cachexia were both being pursued.
Annual Review of Physiology - Human2024
Ponsegromab for the Treatment of Cancer Cachexia
187 patients with cancer cachexia and GDF15 of at least 1,500 pg/mL (40 percent non-small-cell lung, 32 percent pancreatic, 29 percent colorectal) randomised 1:1:1:1 to ponsegromab 100, 200 or 400 mg or placebo every 4 weeks for three doses. Median weight gain versus placebo at 12 weeks: 1.22 kg (95 percent credible interval 0.37 to 2.25), 1.92 kg (0.92 to 2.97) and 2.81 kg (1.55 to 4.08). Appetite, cachexia symptoms and physical activity improved at 400 mg. Adverse events in 70 percent on ponsegromab and 80 percent on placebo. Funded by Pfizer.
New England Journal of Medicine - Human2025
Ponsegromab in adults with metastatic pancreatic cancer, weight loss and fatigue (phase 2/3)
Pfizer, phase 2/3, estimated enrolment 982, recruiting, started October 2025, primary completion estimated January 2028. Status checked 11 September 2026.
ClinicalTrials.gov - Human2025
A Growth Differentiation Factor 15 Receptor Agonist in Randomized Placebo-Controlled Trials in Healthy or Obese Persons
MBL949, a half-life extended recombinant GDF15 dimer. Phase 1: 65 overweight or obese healthy volunteers, single doses 0.03 to 20 mg, terminal half-life 18 to 22 days, evidence of weight loss at higher doses. Phase 2: 126 participants with obesity, five dose regimens every other week for 8 doses over 14 weeks; weight loss was minimal. Gastrointestinal adverse events were most frequent. The authors conclude that the robust weight loss in mice, rats, dogs and monkeys did not translate to humans. Company-developed compound.
Journal of Clinical Endocrinology and Metabolism - Human2024
GDF15 linked to maternal risk of nausea and vomiting during pregnancy
Most GDF15 in maternal plasma is fetal or placental in origin, shown by mass spectrometry of a naturally labelled variant. Carriers of variants giving low pre-pregnancy GDF15 had higher risk of hyperemesis gravidarum; women with beta-thalassaemia, who have chronically high GDF15, reported very little nausea. In mice, prior GDF15 exposure blunted the food intake response, consistent with desensitisation. NIH and non-US government funded.
Nature - Human2010
Macrophage inhibitory cytokine-1 (MIC-1/GDF15): a new marker of all-cause mortality
876 Swedish men aged 35 to 80 followed up to 14 years: serum GDF15 at entry predicted all-cause mortality with an adjusted odds ratio of 3.38 (95 percent CI 1.38 to 8.26), validated in 324 same-sex twins and independent of telomere length, IL-6 and CRP. An association in a cohort, not an intervention.
Aging Cell - Human2025
Identifying proteins and pathways associated with multimorbidity in 53,026 adults
UK Biobank proteomics, 53,026 participants, 13.3 years of follow-up: GDF15 was positively associated with 20 to 24 incident chronic diseases (hazard ratios 1.21 to 3.77) and with multimorbidity, with levels largely explained by renal function, liver function, inflammation and obesity.
Metabolism - Animal2019
Metformin-induced increases in GDF15 are important for suppressing appetite and promoting weight loss
In mice, metformin raised GDF15 and the appetite and weight effects of metformin depended on it. This is the source of the claim that metformin works through GDF15; it is mouse work.
Nature Metabolism - Animal2020
Antibody-mediated inhibition of GDF15-GFRAL activity reverses cancer cachexia in mice
An antibody against GFRAL prevented cachexia in tumour-bearing mice, reversing excess lipid oxidation, and identified a sympathetic lipolytic axis by which GDF15 wastes fat and muscle independently of anorexia. The preclinical basis for blocking the pathway in people.
Nature Medicine
Frequently asked questions
Is GDF15 a weight-loss hormone?
In mice and monkeys, giving GDF15 causes weight loss through a brainstem aversion circuit. In humans, the only published test, a long-acting GDF15 agonist called MBL949 given to 126 adults with obesity for 14 weeks, produced minimal weight loss with gastrointestinal side effects. The successful GDF15 drug in people does the opposite: ponsegromab blocks GDF15 and increased weight by 1.2 to 2.8 kg over placebo in 187 patients with cancer cachexia.
Is GDF15 the same as GDF11?
No. They are different genes and different proteins. GDF11 signals through activin receptors and is the subject of the contested young-blood rejuvenation literature. GDF15 signals through GFRAL and RET in the brainstem and is a nausea and cachexia cytokine. Findings about one do not apply to the other.
Does metformin work through GDF15?
In mice, a 2019 study found metformin raises GDF15 and that its appetite and weight effects depended on it. Metformin does raise GDF15 in people, but whether that mediates any of its effects in humans has not been shown.
My GDF15 is high. Does that mean I am ageing faster?
High GDF15 predicts mortality and multimorbidity in large cohorts, with an adjusted odds ratio of death of 3.38 in one 876-man study. It rises in response to kidney and liver dysfunction, inflammation, obesity, cancer and mitochondrial disease, so it is a readout of cellular stress rather than a cause of ageing. There is no evidence that lowering it in a healthy person changes anything.
Does GDF15 cause morning sickness?
The 2024 Nature genetics study is the strongest evidence that it does: most maternal GDF15 comes from the fetus and placenta, women with genetically low GDF15 before pregnancy are more prone to hyperemesis gravidarum, and women with chronically high GDF15 from beta-thalassaemia report very little nausea. That makes GDF15 a plausible target for hyperemesis, though no such treatment has been tested.