What Is PYY? The Gut Hormone That Kept Failing as a Drug

Guides · Gut and appetite hormones

PYY, or peptide YY, is a 36-amino-acid hormone released by cells in the lower intestine after a meal, and it is one of the clearest satiety signals the gut sends to the brain. It is also one of the most instructive failures in modern obesity pharmacology. A single 2002 paper suggested PYY could be turned into an appetite drug; more than two decades later, after a public replication fight, a failed nasal spray and a large pharmaceutical programme that was quietly shelved, no PYY-based product is approved anywhere in the world.

What is PYY?

PYY is encoded by the PYY gene on chromosome 17q21.31, immediately next to PPY, the gene for pancreatic polypeptide. The two genes are close neighbours because one arose from a duplication of the other. The protein starts life as a 97-residue preproprotein (UniProt P10082) and is trimmed down to the mature 36-residue hormone, which carries a C-terminal tyrosine amide.

The name is a small piece of chemists’ shorthand: there is a tyrosine at the beginning of the chain and another, amidated, at the end. Tyrosine’s one-letter code is Y, so the peptide with a Y at each end became peptide YY.

PYY belongs to a three-member family often called the PP-fold or NPY family: neuropeptide Y, PYY and pancreatic polypeptide. All three are 36 residues long, all three are amidated at the C-terminus, and all three fold into the same characteristic U-shaped hairpin. The differences between them are in what they do and where they act, not in their basic architecture.

The two residues that change everything

The most elegant thing about PYY is what happens to it in the bloodstream. The enzyme DPP-4, also known as CD26, snips the N-terminal tyrosine-proline dipeptide off the front of the molecule, leaving PYY(3-36). The Guide to Pharmacology is explicit that these shortened forms are not simply degradation products but are actively generated by DPP-4, and that point matters: the enzyme is not disposing of PYY, it is editing it.

The edit changes which receptors PYY talks to. The full-length hormone binds the Y receptor family fairly broadly. PYY(3-36) prefers Y2. That is a preference and not an absolute; the same source notes these C-terminal fragments also activate Y5 at similar concentrations, so describing PYY(3-36) as Y2-selective overstates the case.

The Y receptor family itself is worth knowing. Four receptors are functional in humans, Y1, Y2, Y4 and Y5. A fifth, y6, is truncated and non-functional in primates. There is no Y3; the slot was named before anything was cloned to fill it. All of them are class A G-protein-coupled receptors that couple to pertussis-toxin-sensitive Gi/Go proteins and lower cyclic AMP.

Where this becomes interesting is the arcuate nucleus of the hypothalamus, a region that sits close enough to the circulation to sample blood-borne signals. Y2 is heavily expressed there on NPY neurons, positioned presynaptically. In the 2002 study that started all of this, PYY(3-36) inhibited the electrical activity of NPY nerve terminals, which in turn allowed neighbouring POMC neurons to fire. In short: a peptide made in the lower gut turns down the brain’s main hunger circuit.

Where PYY comes from and when it rises

PYY is made by enteroendocrine L-cells in the distal ileum, colon and rectum. Those same cells also carry the proglucagon gene, which is why PYY and GLP-1 are released together. Any account of what happens to appetite after a meal that mentions one of them and not the other is telling half the story.

The time course is fast for a hormone made so far down the gut. Plasma PYY begins rising within about 15 minutes of eating, peaks somewhere around 60 to 90 minutes, and can stay elevated for several hours. Since food has not reached the ileum in 15 minutes, something upstream must be triggering release; cholecystokinin, released from the upper small intestine, is one candidate that has been shown to stimulate PYY secretion. If you want the upstream half of that story, see our explainers on cholecystokinin and gastrin.

The size of the response tracks the size of the meal closely. In one human study the rise in plasma PYY scaled with meal calories with an R-squared of 0.96, and participants with obesity produced a smaller PYY response at every meal size tested. Fat and protein are stronger stimuli for PYY release than carbohydrate.

The ileal brake

Appetite is the headline, but PYY’s day job is broader. It slows gastric emptying, inhibits gastric acid secretion, damps pancreatic exocrine secretion and slows intestinal transit. Physiologists group these effects under the name “ileal brake”: nutrients arriving in the distal gut send a signal back up the tract telling everything upstream to slow down. Because PYY inhibits acid secretion it also gets called an enterogastrone, and because it is strongly antisecretory in the intestine it has been described as an endogenous brake on diarrhoea.

One detail is a useful check on over-simplified accounts. The pancreatic effect does not appear to run through the same receptor logic as the appetite effect: PYY(1-36), PYY(3-36) and PYY(4-36) are reported to be about equally potent at reducing pancreatic secretion. The DPP-4 edit that matters so much for appetite does not matter equally everywhere.

The replication fight

In 2002 a group led by Rachel Batterham reported in Nature that peripheral PYY(3-36) reduced food intake in rats, reduced it in mice but not in mice lacking the Y2 receptor, and cut human food intake by about a third over 24 hours. The following year the same group published a human study in the New England Journal of Medicine: intake at a buffet lunch two hours after infusion fell by 30 percent in participants with obesity and 31 percent in lean participants, and fasting PYY correlated negatively with body-mass index.

That NEJM paper is frequently mis-cited, so it is worth stating precisely. The 30 and 31 percent figures describe the buffet lunch. Over the full 24 hours the reductions were smaller, and intake in the 12-to-24-hour window was not affected at all.

Then in 2004 Nature published a Brief Communication Arising signed by 42 authors from 15 institutions, several of them pharmaceutical companies, reporting that they had been unable to replicate the rodent findings and questioning whether an anti-obesity approach built on PYY was worth pursuing. The Batterham group replied with a table of seven independent rodent studies that had reproduced the effect. Both sides had declared financial interests. It was, by the standards of physiology journals, a public brawl.

The most useful contribution came two years later and was not from either camp. Abbott and colleagues showed that the anorectic response to peripheral PYY(3-36) in rats appeared in animals that had been extensively handled before the experiment, but not in unhandled animals or animals housed with environmental enrichment. In other words the effect was real but conditional, and highly sensitive to how stressed the animals were.

From landmark result to failed drug

The pharmaceutical history of PYY is short and consistent, and the obstacle has always been the same: nausea.

The first serious attempt was an intranasal PYY(3-36) spray developed by Nastech and licensed to Merck. In a 12-week trial in 133 adults with obesity, 27 of 46 participants on the highest dose stopped treatment because of nausea and vomiting, and the trial found no weight loss advantage over placebo. The published conclusion was blunt: at those doses and that timing, intranasal PYY(3-36) is not efficacious for weight reduction.

The most recent serious attempt was Novo Nordisk’s long-acting analogue, NNC0165-1875, tested as an add-on to semaglutide. The Phase 2 trial randomised 120 participants after a 32-week semaglutide run-in. The add-on produced about 2.15 percentage points more weight loss than placebo, which cleared statistical significance at p=0.0437. It also produced gastrointestinal adverse events in roughly two thirds of participants versus under a third on placebo, and twice the discontinuation rate. The authors’ own summary described modest efficacy and poor tolerability, and the escalation to the highest planned dose was abandoned after nearly every participant who tried it discontinued.

PYY is not finished as a target. As of August 2026 two Phase 2 programmes are recruiting: a Y2 receptor agonist from Eli Lilly and a triple GLP-1 / GIP / Y2 agonist from Boehringer Ingelheim. Both are being tested as add-ons to existing incretin therapy rather than as stand-alone appetite drugs, which is a reasonable read of the last twenty years of evidence. Neither is approved, and no PYY-based product is approved anywhere.

PYY and bariatric surgery

PYY turns up constantly in discussions of why gastric bypass works, and the evidence there is genuinely interesting but weaker than it is usually made to sound.

The observational signal is strong. Patients after Roux-en-Y gastric bypass show markedly higher post-meal PYY and GLP-1, and critically, patients who lost the same amount of weight through gastric banding did not. That comparison is the useful one: it separates “the surgery rearranged the gut” from “the patient lost weight.”

The causal evidence is more modest. In a randomised human study, blocking the GLP-1 receptor alone did nothing to food intake, and lowering PYY(3-36) alone did nothing either; only doing both together raised intake, by roughly 20 percent. Each hormone appears able to cover for the other. Rodent work pointed the same way, with a selective Y2 antagonist producing no effect on the weight trajectory after bypass.

And PYY does not predict who succeeds. A 2026 meta-analysis found no association between post-operative PYY levels and how much weight an individual lost, concluding that the variability is driven by something other than PYY secretion. The fairest summary in the literature is that PYY has functional relevance but not predictive capacity.

Frequently asked questions

Is PYY the same thing as neuropeptide Y?

No. They are relatives, not synonyms, and their effects on appetite run in opposite directions. Both are 36 residues long and share the same fold, but neuropeptide Y is a brain neurotransmitter that drives eating, while PYY is a gut hormone associated with stopping. Confusingly, DPP-4 edits both of them and shifts both toward Y2. See our neuropeptide Y explainer for the other half of the family.

Is PYY available as a drug or a supplement?

No. There is no approved PYY product in any country, and no FDA-cleared PYY assay. Every PYY analogue described above is or was investigational. PYY is also a peptide, so it would be digested rather than absorbed if swallowed, which rules out the oral route that supplements would need.

Why did GLP-1 drugs succeed where PYY drugs failed?

Both signals cause nausea at high exposure. The difference is that GLP-1 analogues were engineered with a workable gap between the dose that produces weight loss and the dose that makes people feel unwell, and they could be titrated slowly into that gap. PYY analogues have so far not shown that separation: in the trials above the tolerability ceiling arrived before meaningful efficacy did.

Does a higher-protein meal raise PYY more?

Fat and protein are stronger stimuli for PYY release than carbohydrate, and the total PYY response scales closely with the calorie content of the meal. That is a description of measured physiology, not a dietary recommendation, and a larger PYY response has not been shown to translate into weight change on its own.

Informational only – not medical advice · 21+. VialHelp does not sell peptides and does not recommend any product, brand or protocol. Nothing on this page describes a treatment, and no PYY product is approved for human use in any country.