PYY: gut hormone that tells your brain you're full
A natural hormone released from the gut after eating that signals fullness to the brain and reduces appetite; studied as a potential treatment for obesity but not yet an approved drug.
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A chemistry service or a researcher ordered the sequence, it was manufactured, and mass spectrometry confirmed the right molecule was produced.
A binding or activity measurement confirmed that it actually does what the computer predicted — or didn't.
What this is
Peptide YY (PYY) is a 36-amino-acid gut hormone produced by enteroendocrine L-cells in the distal small intestine and colon. It is co-released with GLP-1 after meals, with secretion proportional to caloric load and driven especially by protein and long-chain fatty acids. PYY circulates in two forms: the full-length PYY(1-36) and the shorter active fragment PYY(3-36), generated when the enzyme DPP-4 cleaves the two amino acids at the N-terminus. PYY(3-36) is the satiety-active form — it is Y2-receptor-selective and is the fragment studied in all therapeutic development to date. The C-terminal tyrosine residue of the full-length peptide carries an amide group; this modification, along with the tyrosine residues at both termini, is the basis of the "YY" name. The stored 36-residue sequence represents the full-length PYY(1-36) backbone; PYY(3-36), the biologically active satiety fragment, begins at the third position after DPP-4 cleavage.
As an endogenous hormone, PYY's satiety physiology is well established and important for understanding both obesity and the durable appetite suppression seen after bariatric surgery. As a drug target, it has proven difficult: nausea and vomiting dose-limit the satiety effect, and no exogenous PYY product has reached regulatory approval in any jurisdiction.
History
PYY was isolated in 1982 by Kazuhiko Tatemoto, Mats Carlquist, and Viktor Mutt at the Karolinska Institute in Stockholm. Working from porcine upper intestinal tissue, they used a chemical detection method for C-terminally amidated peptides to identify two new hormones: PYY and, from brain tissue, neuropeptide Y (NPY). PYY was placed in the pancreatic polypeptide family and initially characterized for its effects on pancreatic exocrine secretion and gastrointestinal motility (Tatemoto and colleagues, 1982).
The peptide's role in central satiety regulation took two more decades to establish. The pivotal paper came in August 2002, when Batterham and colleagues at Imperial College London published in Nature that peripheral infusion of PYY(3-36) at physiologic postprandial concentrations reduced ad libitum caloric intake by approximately 33% over 24 hours in healthy human volunteers (Batterham and colleagues, 2002). A follow-up study published in the New England Journal of Medicine in 2003 extended the finding to obese subjects, showing approximately 30% suppression of caloric intake in both lean and obese individuals — and that obese subjects had lower endogenous postprandial PYY levels (Batterham and colleagues, 2003).
These findings triggered therapeutic development. Nastech Pharmaceutical (later MDRNA) developed an intranasal PYY(3-36) spray and took it into a Phase 2 obesity trial that failed its primary efficacy endpoint, with high rates of dropout from nausea and vomiting in the higher-dose arm (Gantz and colleagues, Journal of Clinical Endocrinology & Metabolism, 2007). Novo Nordisk subsequently developed a long-acting PYY(3-36) analogue (NNC0165-1875) designed for once-weekly subcutaneous dosing as an add-on to semaglutide; the Phase 2 read-out reported only modest incremental weight loss and was tolerability-limited, and the program was discontinued (Wulff and colleagues, Obesity, 2025).
In parallel, observational and mechanistic work established that Roux-en-Y gastric bypass surgery produces an exaggerated postprandial PYY surge sustained for years — now widely regarded as one of the central mechanisms underlying bariatric surgery's durable satiety and weight-loss effects (Karra and colleagues, Journal of Physiology, 2009).
What it does
PYY acts as a brake on appetite. After a meal, L-cells in the intestine release PYY alongside GLP-1, and the resulting rise in circulating PYY(3-36) signals to appetite-regulating centers in the brain that food has been consumed — reducing hunger and cutting caloric intake in the hours that follow. The size of the PYY signal scales with the size of the meal, and protein and fat are stronger triggers than carbohydrates.
PYY also slows the passage of food through the gut and reduces pancreatic secretion, effects that help calibrate the pace of digestion but that also contribute to the nausea burden that has made exogenous PYY difficult to use therapeutically. The roughly tenfold postprandial PYY elevation observed after Roux-en-Y gastric bypass is considered a major contributor to why bariatric surgery produces sustained fullness in a way that simple caloric restriction does not.
Evidence
- Human: Controlled infusion studies by Batterham and colleagues (2002, Nature; 2003, NEJM) established that IV PYY(3-36) at physiologic postprandial concentrations reduced ad libitum caloric intake by approximately 30–33% in both lean and obese volunteers. Obese subjects showed blunted endogenous postprandial PYY alongside comparable acute caloric suppression with exogenous infusion. A Phase 2 RCT of intranasal PYY(3-36) (Gantz and colleagues, 2007, Journal of Clinical Endocrinology & Metabolism) failed its primary efficacy endpoint, with the higher-dose arm limited by nausea and vomiting. A Phase 2 program evaluating long-acting analogue NNC0165-1875 as an add-on to semaglutide showed only modest incremental weight loss and was tolerability-limited; the program was subsequently discontinued (Wulff and colleagues, Obesity, 2025). Observational human data consistently document substantially elevated postprandial PYY after Roux-en-Y gastric bypass, sustained over years (Karra and colleagues, 2009).
- Animal: Peripheral PYY(3-36) consistently reduces food intake and attenuates weight gain in rodent models; the effect is abolished in Y2-receptor knockout animals, confirming receptor specificity (Karra and colleagues, 2009; Lafferty and colleagues, 2021).
- Mechanistic: Y2-receptor-mediated suppression of orexigenic NPY/AgRP neurons in the arcuate nucleus is one of the best-characterized central satiety circuits. DPP-4-mediated generation of PYY(3-36) from PYY(1-36), co-secretion with GLP-1, and post-bariatric PYY hypersecretion are well documented (Chaudhri and colleagues, Philosophical Transactions of the Royal Society B, 2006; Karra and colleagues, 2009).
- Antimicrobial biology: A 2023 paper published in Science (Pierre and colleagues) identified a distinct, non-endocrine role for PYY(1-36): expression by gut Paneth cells as an antimicrobial peptide retained in surface mucus, where it maintains Candida commensal balance — a function separate from the endocrine satiety axis.
Known effects
- Acute appetite suppression — Human controlled infusion (Batterham and colleagues, 2002, 2003); approximately 30–33% reduction in 24-hour caloric intake observed
- Endogenous postprandial satiety signaling — Strong; one of the best-characterized gut-hormone satiety axes alongside GLP-1 (Chaudhri and colleagues, 2006)
- Contribution to post-bariatric satiety — Moderate; postprandial PYY elevation after Roux-en-Y gastric bypass is documented and widely considered mechanistically significant (Karra and colleagues, 2009)
- Reduction of food intake in animal models — Moderate; consistent across rodent studies; Y2-receptor-dependent
- Gut antimicrobial activity (Paneth cell PYY) — Emerging; distinct from the endocrine satiety function; identified in Science 2023 (Pierre and colleagues)
- Weight loss as a standalone pharmaceutical — Not established; all exogenous PYY(3-36) programs attempted have failed on tolerability or missed efficacy endpoints
Safety signals
Nausea is the primary dose-limiting effect of exogenous PYY(3-36) and has been the consistent obstacle across all development programs. The Phase 2 intranasal trial (Gantz and colleagues, 2007) reported high rates of dropout from nausea and vomiting at the higher-dose arm. The Novo Nordisk combination program with semaglutide observed additive GI tolerability burden, contributing to program discontinuation. Abdominal discomfort has also been reported in the context of exogenous PYY administration. Headache has been noted specifically with intranasal formulations, though the degree to which this reflects the route versus the compound has not been separated in the available literature.
Long-term cardiovascular, pancreatic, and bone effects of sustained Y2 receptor agonism are uncharacterized: no PYY analogue has reached chronic licensed use. The interaction between DPP-4 inhibitors and endogenous PYY(3-36) half-life is pharmacologically noted in the literature; clinical significance is described as modest. GLP-1 receptor agonists share overlapping pharmacology, and additive GI burden was observed in the Novo Nordisk Phase 2 combination program. CYP-based drug-drug interactions are not expected given PYY's peptide clearance mechanism.
No FDA-approved PYY product exists against which compounded supply can be validated; available literature explicitly states that compounded PYY(3-36) from research-chemical channels lacks the purity, potency, and sterility controls of sponsor-manufactured trial product.
Regulatory status
- US (FDA): No approved product. No FDA-approved PYY or PYY(3-36) product for any indication as of early 2026. PYY is not a controlled substance. Research use under IND is possible.
- EU (EMA) / UK (MHRA) / Canada / Australia / Japan: No approved product in any major jurisdiction per available sources.
- WADA: PYY is not specifically named on the WADA Prohibited List. However, WADA's S2 category (peptide hormones, growth factors, related substances and mimetics) is broadly written; peptides with effects on appetite, metabolism, or body composition may fall under its catch-all language. Current list status was not independently refreshed in this card.
Mechanism
PYY is synthesized and secreted by enteroendocrine L-cells in the distal small intestine and colon, co-released with GLP-1 after nutrient ingestion. Secretion is proportional to caloric load and is driven especially by protein and long-chain fatty acids. The full-length PYY(1-36) is cleaved at its N-terminus by DPP-4 to yield PYY(3-36), the Y2-receptor-selective active fragment. Full-length PYY(1-36) acts at Y1 and Y5 receptors in addition to Y2; therapeutic interest has focused on the selective Y2 activity of the (3-36) form.
PYY(3-36) crosses the blood–brain barrier and acts on Y2 autoreceptors on orexigenic NPY/AgRP neurons in the arcuate nucleus of the hypothalamus, suppressing their firing and thereby disinhibiting downstream anorexigenic POMC neurons. Additional documented sites of action include the vagus nerve and brainstem (area postrema, nucleus tractus solitarius), as well as reward-processing regions in the cortex and limbic system. Functional MRI studies cited in the literature show PYY(3-36) infusion shifts hypothalamic, brainstem, and corticolimbic appetite circuit activity toward a fed-state pattern (Karra and colleagues, 2009).
Peripheral effects of PYY include slowed gastric emptying and inhibition of pancreatic exocrine secretion. These reinforce the central satiety signal but also contribute to the nausea and GI tolerability burden that has dose-limited exogenous PYY programs. The plasma half-life of endogenous PYY(3-36) is approximately 8–12 minutes, which explains the focus of drug development on longer-acting analogues and alternative delivery routes.
The distribution and function of the related neuropeptides B and W signaling system — with which PYY shares some receptor-family context — has been reviewed separately (Chottova Dvorakova, Frontiers in Physiology, 2018).
Open questions
- Drug tolerability gap: Why exogenous PYY(3-36) has repeatedly failed the tolerability-efficacy tradeoff that GLP-1 agonism has navigated — whether this reflects an intrinsically narrow Y2 therapeutic window, molecule-engineering limitations, or receptor-site adverse signaling — is not settled.
- Next-generation analogue potential: Whether a long-acting PYY(3-36) analogue with an improved tolerability profile could add clinically meaningful weight loss on top of GLP-1 or GLP-1/GIP agonists remains open following the discontinuation of NNC0165-1875.
- Causal obesity relationship: Whether blunted postprandial PYY in obese individuals drives obesity or results from altered meal patterns, gut microbiota, or adiposity is not causally established.
- Long-term safety: Chronic cardiovascular, pancreatic, and bone effects of sustained Y2 receptor agonism are uncharacterized — no PYY analogue has reached chronic licensed use.
- Bariatric surgery PYY contribution: The relative causal contribution of post-bariatric PYY hypersecretion versus GLP-1 and other gut-hormone changes to durable satiety has not been causally dissected.
- Receptor selectivity and tolerability: Whether selective Y2 agonism can separate the satiety signal from adverse GI effects, or whether Y1/Y5 receptor balance is relevant to the nausea burden, is not established.
- Dietary modulation: Whether dietary strategies that maximize endogenous PYY release (high-protein meals, fiber, long-chain fatty acids) translate into meaningful long-term weight or appetite outcomes is not established.
Related peptides
- GLP-1, semaglutide, tirzepatide, liraglutide — co-secreted with PYY from intestinal L-cells; GLP-1 receptor agonism is the comparator class that PYY drug development has repeatedly fallen short against.
- Cagrilintide — amylin analog used with semaglutide in CagriSema; part of the same gut-hormone combination obesity-pharmacology landscape that motivated the PYY add-on programs.
- Neuropeptide Y (NPY) — sister peptide isolated by the Tatemoto group shortly after PYY; shares the pancreatic polypeptide family fold and the Y1/Y2/Y5 receptor system, but acts as a central orexigenic signal, opposite to PYY's anorectic effect.
- Oxyntomodulin — another L-cell co-secreted gut peptide investigated for appetite suppression and weight management.
Research directions for this peptide, selected from the current sources — hypotheses you can explore and model. None of it is proven yet; tap any one to see the full thinking.
Does the body control whether PYY stimulates or suppresses appetite simply by choosing which enzyme-trimmed version of the hormone it releases into circulation?
If PYY(1-36) hits appetite-promoting receptors while PYY(3-36) hits appetite-suppressing ones, then any drug designed around PYY would need to target the right form or it could backfire. This would explain why past PYY-based drugs caused unexpected side effects.
Do DPP-4 inhibitor drugs (taken by millions for diabetes) change which brain receptor the fullness hormone PYY talks to?
Millions of people take DPP-4 inhibitors daily. If this shift in PYY signalling is real, it could partly explain why some patients on these drugs report changes in appetite, and might suggest new combinations with weight-loss therapies.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.9179519414901733 | boltz-2 |
| ranking score | 0.861882209777832 | boltz-2 |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 0.522 | global PDE — lower = better |
| disorder | NaN | fraction disordered |
▸3-letter notation
▸recipeboltz-2 1.0
| parameter | value |
|---|---|
| model | boltz-2 1.0 |
| weights | — |
| hardware | nvidia_nim_api |
| mlx version | — |
| python | — |
| random seed | — |
| msa strategy | none |
| diffusion samples | 1 |
| runtime | — |
| predicted by | mlx@peptide |
| predicted at | 2026-04-24 |
▸citationbibtex
@peptide{pep10713,
sequence = {YPIKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY},
target = {npbwr1},
author = {peptidemodel},
year = {2026},
status = {synthesized}
}