Peptide YY (PYY 3-36)
PYY 3-36, PYY(3-36), peptide tyrosine tyrosine, PYY, pancreatic peptide YY
Peptide YY is released from L-cells of the ileum and colon after eating, in proportion to the calories consumed. The enzyme DPP-4 trims the full 36-residue peptide to PYY 3-36, which is selective for the Y2 receptor and is the form responsible for reducing appetite. It reliably reduces food intake at a single meal in humans, but a randomised trial of intranasal PYY 3-36 for weight loss failed, and it has never become a medicine on its own.
Mechanism
PYY belongs to the pancreatic polypeptide family alongside neuropeptide Y and pancreatic polypeptide, sharing the characteristic PP-fold structure and a C-terminal amidated tyrosine. It is co-secreted with GLP-1 and oxyntomodulin from intestinal L-cells within 15 to 30 minutes of eating, in proportion to caloric load, with fat the most potent stimulus. Dipeptidyl peptidase-4 removes the N-terminal Tyr-Pro dipeptide to yield PYY 3-36, and this cleavage is the entire pharmacological point: full-length PYY(1-36) activates Y1, Y2 and Y5 receptors more or less indiscriminately, whereas PYY 3-36 loses affinity for Y1 and Y5 and becomes essentially Y2-selective.
Y2 receptors are presynaptic inhibitory autoreceptors. The dominant proposed mechanism is that circulating PYY 3-36 reaches the arcuate nucleus of the hypothalamus, where the blood-brain barrier is incomplete at the median eminence, and inhibits orexigenic NPY/AgRP neurons through Y2 autoreceptors. Disinhibition of adjacent anorexigenic POMC neurons follows, and appetite falls. Vagal afferent Y2 receptors and direct brainstem action also contribute, and the relative weight of these routes remains debated. Beyond appetite, PYY 3-36 slows gastric emptying and small bowel transit (the so-called ileal brake) and reduces gastric acid and pancreatic exocrine secretion. Postprandial PYY rises markedly after Roux-en-Y gastric bypass and sleeve gastrectomy, and is one of the leading candidate explanations for the appetite suppression those operations produce.
What the research shows
Batterham and colleagues reported in Nature in 2002 that peripheral PYY 3-36 inhibited food intake in rodents and, in healthy human volunteers, significantly decreased appetite and reduced food intake by 33 per cent over 24 hours, identifying the hypothalamic Y2 receptor as the mechanism. A follow-up in the New England Journal of Medicine in 2003 showed that infusion reduced caloric intake by around 30 per cent at lunch in both obese and lean subjects, and that fasting and postprandial PYY concentrations were significantly lower in obesity, suggesting PYY deficiency rather than resistance, an appealing therapeutic framing.
The field then became contentious. A large multi-laboratory replication effort published in Nature in 2004, involving dozens of investigators across several groups, reported that PYY 3-36 did not reproducibly reduce food intake in rodents, raising the possibility that stress from handling and injection contributed to the original effect. The human acute effect has generally held up better than the rodent one. But the therapeutic test failed: Gantz and colleagues randomised obese adults to 12 weeks of intranasal PYY 3-36 or placebo after a 2-week placebo run-in, and concluded that intranasal PYY 3-36 at those doses and preprandial timing is not efficacious in inducing weight loss. Fifty-nine per cent of the highest-dose group discontinued because of nausea and vomiting, and weight loss with the lower active dose did not differ significantly from placebo.
The honest summary is that PYY 3-36 is an authentic postprandial satiety signal whose acute effect on a single meal is well documented, whose contribution to bariatric surgery outcomes is plausible and actively researched, and which failed to convert into weight loss in the one published randomised therapeutic trial. Interest has shifted to long-acting Y2-selective analogues used alongside GLP-1 receptor agonism rather than to native PYY 3-36.
Evidence assessment
Mixed evidence
Acute reduction in food intake after intravenous PYY 3-36 has been demonstrated in randomised crossover human studies including in obese subjects, and the physiology is supported by the post-bariatric-surgery literature. But a prominent multi-laboratory rodent replication attempt published in Nature failed, and the one published randomised controlled trial of PYY 3-36 as a weight-loss therapy (12 weeks of intranasal dosing) was negative, with 59 per cent of the highest-dose group discontinuing for nausea and vomiting. Human trials exist but are small, short and conflicting on the outcome that matters.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
Gut hormone PYY(3-36) physiologically inhibits food intake Preclinical only
Peripheral PYY 3-36 significantly decreased appetite and reduced food intake by 33 per cent over 24 hours in humans and inhibited food intake in rodents, attributed to Y2 receptor action on hypothalamic NPY neurons. The landmark paper for the field.
Inhibition of food intake in obese subjects by peptide YY3-36 Preclinical only
PYY 3-36 infusion reduced caloric intake by approximately 30 per cent at lunch, similarly in obese and lean subjects; endogenous fasting and postprandial PYY were significantly lower in obesity, suggesting deficiency rather than resistance.
Physiology: does gut hormone PYY3-36 decrease food intake in rodents? Preclinical only
Independent groups were unable to reproduce a reliable reduction in food intake with PYY 3-36 in rodents, raising the possibility that handling stress contributed to the original effect. A prominent and instructive replication failure.
Efficacy and safety of intranasal peptide YY3-36 for weight reduction in obese adults Preclinical only
NEGATIVE. The authors concluded intranasal PYY 3-36 at these doses and preprandial timing is not efficacious in inducing weight loss after 12 weeks. Fifty-nine per cent of the highest-dose group discontinued for nausea and vomiting, and the lower dose did not differ significantly from placebo. The only published randomised therapeutic trial of PYY 3-36.
Safety
Nausea and vomiting are the dose-limiting adverse effects and are consistently reported in human studies, becoming pronounced at doses above the physiological range. In the intranasal trial they caused 59 per cent of the highest-dose group to discontinue. Because PYY 3-36 slows gastric emptying, it can cause early satiety, bloating and abdominal discomfort. The observation that much of the acute food-intake reduction in early studies may have been mediated by nausea rather than by physiological satiety is a legitimate and unresolved criticism of the literature. There is no long-term human safety dataset. The trials were short and the drug was never licensed, so nothing is known about effects over months or years. PYY 3-36 sold as a research chemical has no pharmacopoeial identity or purity assurance and no clinical evidence of sustained weight benefit; the only published randomised trial of it as a weight-loss agent was negative, which is the single most relevant fact for anyone considering it.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | No UK marketing authorisation and no licensed product. PYY 3-36 offered for sale to consumers is an unlicensed research chemical. It should not be confused with the licensed GLP-1 receptor agonists used for weight management, which have an entirely different evidence base. |
| United States | Not an approved medicine. PYY 3-36 has no FDA-approved indication and no marketed product. Development of Y2 receptor agonists continues, including long-acting analogues studied in combination with GLP-1 receptor agonists, but nothing is licensed. |
| WADA (sport) | Not listed on the WADA Prohibited List. PYY 3-36 acts at Y2 receptors, is not a growth hormone secretagogue, and has no performance-enhancing rationale. Its documented effects are reduced appetite and nausea. |
Questions
Because the cleavage changes what the peptide does. Full-length PYY(1-36) activates Y1, Y2 and Y5 receptors; removing the first two amino acids by DPP-4 leaves PYY 3-36, which is essentially Y2-selective. Y2 receptor action on hypothalamic NPY neurons is what reduces appetite. Y1 activation, by contrast, is associated with vasoconstriction.
It reduces intake at a single meal. That is well documented in humans. Sustained weight loss is a different question and the answer from the one published randomised therapeutic trial is no: 12 weeks of intranasal PYY 3-36 in obese adults did not induce weight loss, and nausea and vomiting caused 59 per cent of the top-dose group to drop out.
It is one of the leading candidates, but not the whole story. Postprandial PYY and GLP-1 both rise markedly after Roux-en-Y gastric bypass and sleeve gastrectomy, and blocking these signals attenuates the appetite suppression. But bile acid changes, microbiome shifts and altered nutrient delivery all contribute, and no single hormone accounts for the effect.
Only in that both are gut hormones co-released from the same L-cells after a meal. They act on completely different receptors and have completely different evidence bases: GLP-1 receptor agonists have large, replicated phase 3 trials and marketing authorisations, whereas PYY 3-36 has short acute infusion studies and a failed randomised weight-loss trial. Current interest lies in long-acting Y2 agonists used alongside GLP-1 agonists, not in PYY 3-36 alone.