PYY(3-36): natural fullness hormone released after eating
A gut hormone the body makes after a meal to tell the brain you're full; studied as a possible treatment for obesity, but not yet an approved drug.
A researcher, an agent, or an algorithm wrote down the sequence and picked a target to hit.
An AI model like OpenFold3 or AlphaFold built a 3D structure and scored how well it fits the binding site.
A second contributor repeated the computation on their own hardware and the scores matched.
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
PYY(3-36) — also written as peptide YY(3-36) or PYY3-36 — is a 34-amino-acid gut hormone fragment that the body naturally produces after eating. It is released by specialized cells lining the lower small intestine and colon, travels through the bloodstream to the brain, and signals that a meal has been consumed. The active fragment is generated from the full 36-amino-acid peptide YY by the enzyme DPP-4, which trims two residues from the N-terminus; the resulting PYY(3-36) is the form that drives satiety signaling (Karra et al. 2009; Ballantyne 2006). Unlike some gut peptides that have been turned into approved drugs, no PYY(3-36) product has reached the market — but its central role in the body's own appetite-regulation circuitry makes it a consistent reference point in obesity research and in understanding why bariatric surgery produces lasting weight loss.
History
Peptide YY was isolated in 1982 by Kazuhiko Tatemoto, Mats Carlquist, and Viktor Mutt working from porcine upper intestinal tissue at the Karolinska Institute. Their method targeted peptides with C-terminal tyrosine amides, which led simultaneously to PYY and neuropeptide Y (NPY) from brain tissue; the name referenced the tyrosine (Y) residues at both termini of the 36-amino-acid sequence (Tatemoto and colleagues 1982). For roughly two decades PYY was studied mainly as a regulator of pancreatic secretion and gastrointestinal motility. Its standing as a genuine satiety hormone changed in 2002 when Batterham and colleagues at Imperial College London reported in Nature that peripheral infusion of PYY(3-36) at physiologic postprandial concentrations reduced ad libitum caloric intake by roughly 33% over 24 hours in healthy volunteers (Batterham et al. 2002, Nature; summarized in Karra et al. 2009). A follow-up study published in the New England Journal of Medicine in 2003 extended the finding to obese subjects and showed that postprandial PYY levels were blunted in obesity, suggesting a possible contribution to impaired satiety (Batterham et al. 2003, NEJM; le Roux et al. 2006). These results triggered drug-development programs. An intranasal PYY(3-36) spray developed by Nastech Pharmaceutical (later MDRNA) failed its Phase 2 efficacy endpoint in 2007, with dropout driven by nausea and vomiting at higher doses (peptidelist catalog). Novo Nordisk's long-acting analogue NNC0165-1875, designed for once-weekly dosing as an add-on to semaglutide, reported only modest incremental weight loss in Phase 2 and was discontinued (peptidelist catalog). In parallel, observational and mechanistic work established that Roux-en-Y gastric bypass surgery produces exaggerated postprandial PYY release, sustained for years — a finding cited as one mechanism underlying the durable satiety effects of bariatric surgery (Silva et al. 2012).
What it does
After a meal, intestinal L-cells release PYY(3-36) in proportion to the caloric load — protein and fat are the strongest stimuli. The peptide reaches the brain via the bloodstream and dampens the drive to eat: in infusion studies it consistently reduced how much people ate at a subsequent meal and lowered total caloric intake across the following 24 hours (Karra et al. 2009; le Roux et al. 2006). Beyond appetite suppression, PYY(3-36) slows gastric emptying and inhibits pancreatic exocrine secretion, reinforcing the satiety state from multiple angles (Ballantyne 2006; Vincent et al. 2008). In people with obesity, the postprandial rise in PYY is blunted compared with lean individuals, and this blunting correlates with reduced subjective satiety — the proposed mechanism linking PYY deficiency to impaired appetite control in obesity (le Roux et al. 2006). A separate line of research has found that PYY(1-36) — the full-length form, not PYY(3-36) — is also secreted by Paneth cells in the gut epithelium and functions as an antimicrobial peptide maintaining fungal commensalism; this Paneth-cell role is specific to the full-length form and is not shared by PYY(3-36) (Pierre et al. 2023).
Evidence
- Human: Physiologic IV infusion of PYY(3-36) at postprandial concentrations reduced food intake in healthy lean and obese volunteers in controlled studies (Karra et al. 2009). Obese subjects show blunted postprandial PYY release associated with reduced satiety (le Roux et al. 2006). An intranasal PYY(3-36) Phase 2 trial (Nastech) failed its weight-loss efficacy endpoint; a long-acting analogue (NNC0165-1875) showed only modest incremental benefit over semaglutide in Phase 2 and was discontinued (peptidelist catalog).
- Animal: Rodent studies consistently show reduced food intake and body weight gain with peripheral PYY(3-36) administration; Y2 receptor knockout abolishes the effect (summarized in Karra et al. 2009). Primate data in rhesus macaques showed PYY(3-36) inhibited morning but not evening food intake, with associated body-weight reduction (Koegler and colleagues 2005, Diabetes).
- In vitro / mechanistic: Y2-receptor-mediated inhibition of orexigenic NPY/AgRP neurons in the arcuate nucleus has been characterized as the central anorectic mechanism; functional MRI studies in humans showed PYY(3-36) infusion shifts hypothalamic activity toward a fed-state pattern (Karra et al. 2009). Co-secretion with GLP-1 from L-cells and additive appetite suppression in co-infusion studies provide the mechanistic rationale for combination gut-hormone approaches (Silva et al. 2012).
Known effects
- Reduced food intake / appetite suppression — Human infusion studies (physiologic doses); effect size roughly 30% caloric intake reduction; Moderate evidence (Karra et al. 2009)
- Blunted postprandial release in obesity — Observed in human studies; correlates with reduced satiety; the causal direction (driver vs. consequence of obesity) is not settled (le Roux et al. 2006)
- Slowed gastric emptying — Peripheral effect documented; reinforces satiety signaling (Ballantyne 2006)
- Inhibition of pancreatic exocrine secretion — Documented peripheral effect (Ballantyne 2006)
- Elevated levels after bariatric surgery — Exaggerated postprandial PYY release after Roux-en-Y gastric bypass is well-documented and cited as a contributor to durable post-surgical satiety (Silva et al. 2012)
- Antimicrobial activity (full-length PYY1-36 only) — Paneth-cell PYY1-36 acts as an antimicrobial peptide; this property is absent in PYY(3-36) (Pierre et al. 2023)
Safety signals
Safety data on exogenous PYY(3-36) comes from short-duration infusion studies and the discontinued clinical programs rather than from chronic licensed use. The consistent dose-limiting toxicity across programs has been nausea and vomiting, which narrowed the therapeutic window and contributed to the Nastech Phase 2 dropout and to tolerability constraints in the NNC0165-1875 Phase 2 add-on trial (peptidelist catalog; Karra et al. 2009). Long-term safety, cardiovascular outcomes, and effects of chronic Y2-receptor agonism on bone, pancreatic function, or other organ systems have not been characterized at the level of evidence available for GLP-1 agonists, because no PYY analogue has progressed to chronic licensed use (peptidelist catalog). No FDA-approved or EMA-approved PYY product exists.
Regulatory status
- US: No FDA-approved PYY or PYY(3-36) product for any indication. Research use under investigational (IND) pathways.
- EU: No EMA-approved PYY product.
- WADA: PYY(3-36) is not specifically named on the WADA Prohibited List. WADA category S2 (peptide hormones, growth factors, related substances and mimetics) is written broadly; athletes should seek guidance from their national anti-doping organization before any use (peptidelist catalog).
Mechanism
PYY(3-36) is produced by enteroendocrine L-cells in the distal small intestine and colon, co-secreted with GLP-1 in response to nutrient ingestion. DPP-4 cleaves two residues from the N-terminus of the full-length PYY(1-36), yielding the Y2-receptor-selective active fragment PYY(3-36) (Karra et al. 2009; Ballantyne 2006). In the arcuate nucleus of the hypothalamus, PYY(3-36) acts on Y2 autoreceptors on orexigenic NPY/AgRP neurons, suppressing their activity and thereby disinhibiting downstream anorexigenic POMC neurons — a mechanism that has been characterized as central to the anorectic effect (Karra et al. 2009). Additional sites of action include the vagus nerve and brainstem nuclei (area postrema, nucleus tractus solitarius), consistent with a distributed appetite-suppression circuit (Karra et al. 2009; Vincent et al. 2008). Effects on food intake appear additive with GLP-1 in co-infusion studies, which is the pharmacological basis for interest in combination gut-hormone therapeutics targeting both the GLP-1 receptor and the Y2 receptor (Silva et al. 2012). The stored sequence for this card is the 34-residue PYY(3-36) fragment (positions 3–36 of the full PYY sequence); the native peptide is a linear sequence with no reported lipid conjugation, PEGylation, or cyclization. Endogenous PYY(3-36) has a short plasma half-life, which is why therapeutic development has focused on longer-acting analogues (Karra et al. 2009).
Open questions
- Why PYY(3-36) drug development has repeatedly failed the tolerability-efficacy tradeoff while GLP-1 agonism succeeded — whether this reflects a fundamentally narrow therapeutic window at Y2, delivery and half-life challenges, or molecule-engineering limitations is not settled (Karra et al. 2009; peptidelist catalog).
- Whether a next-generation long-acting PYY(3-36) analogue with improved tolerability could add clinically meaningful benefit on top of GLP-1 or dual GLP-1/GIP agonism.
- Whether blunted postprandial PYY in obesity is a driver of impaired satiety or a consequence of adiposity, altered meal composition, or gut microbiota changes — the causal direction remains unresolved (le Roux et al. 2006).
- The relative contribution of PYY versus GLP-1 versus other gut-hormone changes to the satiety and weight-loss effects of bariatric surgery — observational correlations are strong, but causal dissection is harder (Silva et al. 2012).
- Long-term cardiovascular, pancreatic, and bone effects of chronic Y2 receptor agonism — not characterized because no PYY analogue has reached chronic licensed use.
Related peptides
- Peptide YY (PYY, full-length) — the 36-residue precursor from which PYY(3-36) is generated by DPP-4 cleavage; the full-length PYY(1-36) has antimicrobial activity in Paneth cells that PYY(3-36) lacks
- GLP-1(7-36) amide — the biologically active form of GLP-1, co-secreted from the same intestinal L-cells as PYY(3-36); both peptides contribute additively to postprandial satiety, and GLP-1 receptor agonists are the pharmacological success story that PYY-based drug development has not yet replicated
- Neuropeptide Y (sheep form) — the orexigenic neuropeptide whose NPY/AgRP neurons in the arcuate nucleus are the primary synaptic target that PYY(3-36) inhibits to produce satiety
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 low levels of a natural fullness hormone after meals, in obese people, cause hunger signals in the brain to stay switched on in a way that cannot be fixed by other hormones?
If true, it would identify a specific gap in the brain's appetite control that standard obesity hormones cannot fill, potentially pointing to a treatment that works for people who do not respond to other appetite therapies.
Could a capsule that releases PYY(3-36) in the lower gut, the place where the body naturally makes it, reduce appetite without the nausea seen when the hormone is given through the nose?
If this delivery method works, it could offer a non-injection weight-loss treatment that avoids the nausea that derailed earlier versions of this drug, making it more tolerable than current options for people who struggle with daily injections.
Could giving PYY(3-36) before meals protect people who have had gastric bypass surgery from the dangerous blood-sugar crashes that can happen after eating?
Post-bypass low blood sugar affects up to 30% of gastric bypass patients and has no approved drug treatment. If this approach works, it could help a large group of patients who currently have very few options for managing this serious complication.
Does this natural fullness hormone reduce the pleasure-driven urge to eat, through a different brain pathway than the one that controls basic hunger, and can those two effects be separated?
If the two effects are separable, it could open the door to treatments aimed specifically at compulsive or reward-driven eating, such as binge eating disorder, rather than just calorie-based appetite suppression.
Are the receptors currently listed as the main targets for PYY(3-36) actually wrong, the result of a data mix-up, with the real target being a different receptor entirely?
If the listed targets are corrected, researchers and anyone building tools on top of this data would avoid being misled down the wrong drug design or combination-therapy paths, saving time and resources.
Does a particular coiled section in the middle of the PYY(3-36) molecule make direct contact with its target receptor, and would breaking that coil destroy the hormone's ability to bind?
If this structural detail is confirmed, it could guide scientists to design smaller, more stable versions of the hormone that keep the appetite-suppressing effect but are easier to manufacture and less prone to breakdown in the body.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.9421985149383545 | boltz-2 |
| ranking score | 0.7633717060089111 | boltz-2 |
▸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 | colabfold_nvidia |
| diffusion samples | 1 |
| runtime | — |
| predicted by | mlx@peptide |
| predicted at | 2026-04-25 |
▸citationbibtex
@peptide{pep10604,
sequence = {IKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY},
target = {npy2r},
author = {peptidemodel},
year = {2026},
status = {synthesized}
}