Is GDF15 a peptide like the incretins?

No. It is a protein of the TGF-beta superfamily, considerably larger than a peptide hormone, and it acts on a receptor complex rather than a class B GPCR. Grouping it with GLP-1 because both reduce appetite through the hindbrain obscures how different the molecules and the receptors are.

If metformin raises GDF15, why is metformin's weight effect small?

Because the increase is modest compared with what a purpose-built agonist would produce, and because weight loss is only one of metformin's actions. The finding explains part of an effect that was previously unexplained; it does not make metformin an appetite drug.

Does the desensitisation finding rule out GDF15 agonists?

No, but it raises a specific and testable objection. The mouse data concerns an acute food-intake response after prior exposure, and the human observation is an association in an unusual population. What it establishes is that anyone developing a chronic agonist has to demonstrate durability rather than assume it.

Why would a fetus produce a hormone that makes the mother sick?

That question is not settled and the paper does not claim to answer it. The finding is that the hormone is largely fetal in origin and that maternal sensitivity determines severity. Speculating about why is a different exercise from establishing that it happens.

GLP-1 & Incretin Science

GDF15: The Same Signal, Wanted and Feared

JMWritten & reviewed by Jack Muncaster · Founder, UK PeptidesLast reviewed 2026-08-234 cited sources

GDF15 is a circulating protein of the TGF-beta superfamily that suppresses food intake by acting on GFRAL, a receptor confined to the hindbrain. The same signal drives wasting in cachexia and nausea in pregnancy, so it is being targeted in opposite directions at once.

Key facts

Full name: Growth differentiation factor 15; also MIC-1
Family: TGF-beta superfamily
Receptor: GFRAL, GDNF family receptor alpha-like
Receptor location: Neurons of the hindbrain / brainstem
Receptor identified: 2017; the field had no receptor before that
Direction of effect: Suppresses food intake
Raised in: Cancer, chronic renal failure, cardiac failure, COPD, pregnancy
Also raised by: Metformin

A hormone the field could not work on for years

GDF15 was known to affect energy balance long before anyone knew how. As a review by Mullican and Rangwala put it, the potential to target it in energy-intake disorders was an area of intense investigation but had been limited by the lack of an identified receptor, signalling mechanism and target tissue. That is an unusual position for a drug target: an effect with no known route. The situation changed in 2017, when GFRAL was identified as the neuronal brainstem receptor responsible for mediating GDF15's anorectic actions - work that four groups reported at roughly the same time, which is itself a sign of how hard the field was pushing at the question.

Why GFRAL's location is the whole story

GFRAL is not distributed broadly. It is confined to neurons of the hindbrain, in the region where the blood-brain barrier is permeable and circulating signals about the internal state of the body are read. That is the same neighbourhood as the area postrema, the structure that also mediates the aversive component of GLP-1 receptor agonism. A receptor that exists in one small brainstem population and essentially nowhere else is an unusually clean drug target in one sense - off-target tissue effects are structurally unlikely - and a difficult one in another, because that population's job is to make an animal stop eating and, if the signal is strong enough, to make it feel sick.

The metformin connection, and the knockout that proved it

One of the more surprising findings about GDF15 concerns a drug that has been in use since the 1950s. Day and colleagues showed that metformin induces expression and secretion of GDF15 from hepatocytes, working through the transcription factors ATF4 and CHOP. In wild-type mice on a high-fat diet, oral metformin raised serum GDF15 and reduced food intake, body mass, fasting insulin and glucose intolerance. In GDF15-null mice, those effects were eliminated. An increase in serum GDF15 was also associated with weight loss in patients with type 2 diabetes taking metformin. The modest weight effect of the oldest drug in diabetes may therefore run through the newest appetite pathway in obesity - and the knockout is what turns that from a correlation into a mechanism.

The same molecule, wanted from both directions

Here is the part that makes GDF15 unlike any other target in this field. Raising it suppresses appetite, which is the obesity thesis. But GDF15 is also substantially elevated in cachexia, and Tsai and colleagues note that the elevated serum levels seen in cancer, chronic renal failure, cardiac failure and chronic obstructive lung disease are similar to those required to induce the anorexia/cachexia syndrome in animals, where its brainstem action produces prolonged undernutrition and loss of both lean and fat mass. Their conclusion is that inhibiting GDF15 or GFRAL is a high-value target. So one set of programmes is trying to agonise this pathway and another is trying to block it, and both are looking at the same evidence. That is not a contradiction; it is what happens when a signal is a dial rather than a switch.

The finding that should worry anyone building a chronic agonist

The most consequential piece of GDF15 pharmacology for obesity came out of a pregnancy paper. Fejzo and colleagues reported in Nature that the great majority of GDF15 in maternal plasma derives from the feto-placental unit, and that maternal sensitivity to it is a major determinant of how sick a pregnancy makes someone. Two of their results run against intuition. Low levels of GDF15 in the non-pregnant state increase the risk of hyperemesis gravidarum. And women with beta-thalassaemia, in whom GDF15 is chronically high, report very low levels of nausea and vomiting in pregnancy. In mice, the acute food-intake response to a GDF15 bolus was influenced bi-directionally by prior circulating levels in a way the authors describe as suggesting the system is susceptible to desensitisation. A pathway that becomes less responsive the more it has been exposed is exactly the wrong property for a drug intended to be taken indefinitely.

Where this leaves the target

GDF15 has an identified receptor in a defined location, a genetic proof of concept through the metformin work, a human phenotype in both directions, and a plausible desensitisation problem. That combination makes it one of the most interesting non-incretin targets and one of the least certain. No GDF15 or GFRAL agent is licensed anywhere for any indication. Nothing described here is supplied on this site, and none of it is a treatment for anything.

Extended research context

The GLP-1 & Incretin Science deep dive

Deep dive: the two routes to a bigger effect

Every compound trying to beat GLP-1 alone has taken one of two routes. The first adds more receptors from the same hormone family — GIP in tirzepatide, GIP and glucagon in retatrutide. The second adds a non-incretin satiety hormone, which in practice means amylin: CagriSema combines cagrilintide with semaglutide, and amycretin engages both receptors from one molecule. Both routes work, because they recruit signalling pathways that do not fully overlap. Neither has escaped the constraint that binds all of them, which is that gastrointestinal tolerability worsens as effect size grows.

Deep dive: why a percentage is not a result

The most-quoted numbers in this field are the least comparable. REDEFINE 1 reported 22.7% and 20.4% for the same compound in the same trial — the first among participants who adhered to treatment, the second across everyone randomised. TRIUMPH-1 reported 28.3% in an uncomplicated obesity population while TRIUMPH-3 reported up to 22.6% in adults with established cardiovascular disease, using the same compound. Before any two figures can be compared they have to match on estimand, population, duration, comparator and whether the number is placebo-adjusted. Most published comparisons match on none of them.

Deep dive: what happens after the trial stops

Every headline figure describes weight while treatment continues. The STEP-1 extension found that a year after semaglutide was stopped, participants had given back roughly two-thirds of what they lost, moving from 17.3% mean reduction to a net 5.6% — though average weight remained below baseline and nearly half stayed at least 5% down. Meta-analysis puts regain at around 0.8 kg per month. This is why maintenance studies such as TRIUMPH-6 matter more to the field's future than another two points of peak reduction.

Research applications

▸Comparing incretin and amylin compounds on a like-for-like basis
▸Interpreting estimands, thresholds and placebo-adjusted figures in trial reports
▸Tracking the obesity pipeline across sponsors and jurisdictions
▸Understanding receptor pharmacology behind GLP-1, GIP, glucagon and amylin
▸Distinguishing licensed medicines from investigational compounds

Handling checklist

✓Identify which estimand a quoted percentage comes from before citing it
✓Check the trial population and baseline BMI against the comparison you are making
✓Confirm the duration and whether the reduction curve had plateaued
✓Read discontinuation rates alongside efficacy figures
✓Verify every NCT identifier against ClinicalTrials.gov rather than secondary reporting

Common research-handling mistakes

Learnt from thousands of researcher orders across our UK labs.

✗ Comparing headline percentages across different trials

Fix: Population, duration, estimand and comparator all differ; the numbers are not interchangeable.

✗ Quoting the larger of two figures from the same trial

Fix: Name the estimand. Efficacy and treatment-policy answer different questions.

✗ Treating peak reduction as a durable outcome

Fix: Substantial regain follows cessation across the class; peak figures describe a maintained state.

✗ Assuming an oral route means a weaker mechanism

Fix: Route and receptor count are independent. Orforglipron is weaker because it hits one receptor, not because it is a tablet.

✗ Reading investigational compounds as available treatments

Fix: Most of this pipeline holds no authorisation anywhere; mazdutide is approved only in China.

Continue researching

Peer-reviewed guides, comparators and matched reference materials.

Frequently asked questions

Is GDF15 a peptide like the incretins?: No. It is a protein of the TGF-beta superfamily, considerably larger than a peptide hormone, and it acts on a receptor complex rather than a class B GPCR. Grouping it with GLP-1 because both reduce appetite through the hindbrain obscures how different the molecules and the receptors are.
If metformin raises GDF15, why is metformin's weight effect small?: Because the increase is modest compared with what a purpose-built agonist would produce, and because weight loss is only one of metformin's actions. The finding explains part of an effect that was previously unexplained; it does not make metformin an appetite drug.
Does the desensitisation finding rule out GDF15 agonists?: No, but it raises a specific and testable objection. The mouse data concerns an acute food-intake response after prior exposure, and the human observation is an association in an unusual population. What it establishes is that anyone developing a chronic agonist has to demonstrate durability rather than assume it.
Why would a fetus produce a hormone that makes the mother sick?: That question is not settled and the paper does not claim to answer it. The finding is that the hormone is largely fetal in origin and that maternal sensitivity determines severity. Speculating about why is a different exercise from establishing that it happens.

Primary sources & clinical trials

Peer-reviewed research and registered trials from PubMed, ClinicalTrials.gov, PubChem, FDA and NIH. All links open in a new tab and point to the primary source, so every claim can be verified at origin.

Written and reviewed by

Jack Muncaster · Founder, UK Peptides

Jack founded UK Peptides in Manchester after repeatedly receiving research compounds with missing or recycled paperwork. He is responsible for supplier selection, batch release decisions and the content published in this research library. Every article here is sourced to primary literature and every product page to a signed third-party certificate.

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