Peptide YY: gut hormone that tells the brain you're full
A natural hormone released by the intestine after eating that signals fullness to the brain and reduces food intake; studied as a potential obesity treatment but not yet an approved drug.
- Class
- Gut peptide / neuropeptide (species-specific form)
- Status
- Research and catalog entry; no approved therapeutic status identified
- Best-supported effect
- Sequence characterized from rabbit (Oryctolagus cuniculus) gastrointestinal tissue; no bioactivity or therapeutic effect supported by this card's source file
- Main caveat
- Compiled source provides sequence identity and species origin only; no biological assay, animal experiment, or human data attached to this card's source file
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
Peptide YY (PYY) is a gut hormone released by specialised intestinal cells called L cells after a meal. It belongs to the neuropeptide Y family alongside neuropeptide Y (NPY) and pancreatic polypeptide, and the amount secreted is roughly proportional to the caloric content of food consumed (Karra and colleagues, 2009). PYY circulates in two principal forms: the full-length PYY(1-36), which binds a broad range of NPY-family receptors, and the truncated PYY(3-36), which is generated when an enzyme called DPP-IV clips off the first two residues and selectively activates the Y2 receptor to reduce food intake. No drug based on PYY has reached regulatory approval; the peptide currently has no approved clinical use.
The 36-residue sequence stored here (YPSKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY) may represent a non-human species variant: position 3 reads Ser in this entry, whereas human PYY carries Ile at that position.
History
PYY was first described in tissues of the human gut in the mid-1980s; Adrian and colleagues (1985) documented its distribution and postprandial release, establishing it as a genuine circulating gut hormone. Interest intensified with the observation that PYY is co-localised with glucagon-like peptide-1 (GLP-1) in the L cells of the gastrointestinal mucosa (Karra and colleagues, 2009). Grandt and colleagues (1994) characterised both PYY(1-36) and PYY(3-36) and showed they differ in receptor selectivity, laying the groundwork for understanding the distinct biology of each form. The discovery that PYY(3-36) reduced feeding in both rodents and humans made it a focus of obesity research in the early 2000s; a subsequent clinical study by Gantz and colleagues (2007) explored intranasal delivery as a weight-loss strategy in obese adults.
What it does
After a meal, L cells in the distal small intestine and colon release PYY into the bloodstream in proportion to the calories consumed (Karra and colleagues, 2009). This signal travels to the brain — particularly the hypothalamus and brainstem — and signals satiety, reducing the urge to keep eating. PYY also slows gastric emptying and suppresses pancreatic and gastric secretion, actions sometimes called the "colonic brake" (Nightingale and colleagues, 1996, cited in Karra and colleagues, 2009).
The truncated form PYY(3-36) is the more potent appetite suppressor: it preferentially activates the Y2 receptor and, in doing so, inhibits both appetite-promoting (NPY) and appetite-suppressing (POMC) hypothalamic neurons, ultimately reducing food intake (Karra and colleagues, 2009). Although PYY(1-36) has a circulating half-life of approximately 10 minutes in humans, postprandial plasma levels remain elevated for up to 6 hours because of sustained L-cell release (Frontiers in Nutrition, 2015).
PYY levels are markedly elevated after Roux-en-Y gastric bypass surgery; this rise is thought to contribute to the appetite suppression and long-term weight loss that follow the procedure (Chan and colleagues, 2006, cited in Karra and colleagues, 2009).
Evidence
- Human: Gantz and colleagues (2007) conducted a clinical study of intranasal PYY(3-36) for weight reduction in obese adults, published in the Journal of Clinical Endocrinology and Metabolism; this remains one of the few published interventional studies of exogenous PYY administration in humans. A subsequent randomised study combined PYY with GLP-1 and oxyntomodulin and reported improvements in body weight and glycaemia in obese adults with prediabetes or type 2 diabetes (Frontiers in Endocrinology, 2021).
- Animal: Genetic ablation of PYY in mice produced hyperinsulinaemia and obesity, demonstrating that endogenous PYY is required for normal metabolic homeostasis (Boey and colleagues, 2006, cited in Karra and colleagues, 2009). Intermittent intravenous infusion of PYY(3-36) reduced daily food intake in rodent models.
- In vitro / mechanistic: PYY(3-36) inhibits both POMC and NPY neurons in hypothalamic preparations, demonstrating central action on the energy-balance circuitry (Karra and colleagues, 2009).
Known effects
- Appetite suppression (postprandial satiety signal) — Established physiological role; human and animal data (Karra and colleagues, 2009)
- Slowing of gastric emptying / colonic brake — Physiological; documented in human gut hormone studies
- Elevated after bariatric surgery — Observed in human cohorts; putative contributor to post-surgical satiety
- Obesity when genetically absent — Preclinical (mouse knockout model)
Safety signals
The main adverse effect observed in early human administration studies was nausea. Gantz and colleagues (2007) reported nausea as a limiting factor in the intranasal PYY(3-36) trial, a finding that has tempered enthusiasm for exogenous PYY as a standalone therapeutic. The physiological form circulates in plasma after every meal without ill effect; adverse signals are associated with pharmacological delivery at supraphysiological levels.
Regulatory status
- US: No FDA-approved drug. Not a scheduled substance. No compounding designation.
- EU: No EMA-approved product.
- WADA: No current prohibition specifically targeting PYY; its physiological nature means it is not on the prohibited list as of available records.
Mechanism
PYY(3-36) exerts its anorexigenic effect primarily through the Y2 receptor (Y2R), a Gi-coupled GPCR expressed on NPY-releasing neurons in the arcuate nucleus of the hypothalamus, on vagal afferents in the nodose ganglion, and in brainstem nuclei (Karra and colleagues, 2009). Y2R is a presynaptic autoreceptor on NPY neurons; its activation reduces NPY release and simultaneously permits POMC/CART neurons to increase their output, shifting the hypothalamic balance toward satiety. Full-length PYY(1-36) activates Y1R, Y2R, Y4R, and Y5R with less selectivity, producing a broader — and partially orexigenic, via Y1/Y5 — pharmacological profile.
The stored sequence (YPSKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY) is the unmodified linear sequence; no fatty-acid conjugation, acetyl cap, or amide terminus is present. The C-terminal -QRY motif, conserved across the NPY family, is essential for receptor recognition.
The card's primary assigned target is NPBWR1 (GPR7, the neuropeptide B/W receptor 1). NPBWR1 is structurally related to the NPY receptor family and shares some ligand-binding space (Sakurai, 2013; Wojciechowicz and colleagues, 2021), though the classical pharmacological targets of PYY are the Y1/Y2/Y4/Y5 receptors.
Open questions
- Whether a Y2R-selective PYY analog can be developed that retains anorexigenic potency without the nausea liability seen with PYY(3-36) at pharmacological doses
- Whether the elevated PYY observed after bariatric surgery is causal in sustained weight loss or epiphenomenal
- Whether the species-variant sequence stored here (Ser at position 3 rather than human Ile) is functionally equivalent to human PYY
- Oral or stable long-acting PYY formulations have not been validated in late-stage human trials
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.
Has PYY been incorrectly matched to a receptor it does not normally bind, and should it instead point to the Y2 receptor that mediates its satiety effects?
Correcting this annotation would ensure that any drug-discovery or research effort using this database is working toward the right biological target, avoiding wasted experiments chasing a false receptor interaction.
If PYY and GLP-1 target two different but cooperating hunger circuits in the brain, would using both together cause more weight loss than the simple sum of their individual effects?
A synergistic PYY plus GLP-1 combination drug could achieve greater weight loss at lower doses, potentially reducing the nausea and other side effects that currently limit GLP-1 therapy for millions of people.
Could PYY activate the same brain circuits its close relative NPY uses to buffer stress, reducing the urge to drink alcohol when under pressure?
If true, this would open an entirely new use for PYY-based molecules in treating alcohol use disorder, especially the stress-relapse subtype that is notoriously hard to manage with existing medicines.
Does swapping isoleucine (human) for serine (non-human) at position 3 of PYY weaken how strongly it activates the Y2 satiety receptor?
If this swap matters for receptor potency, it helps researchers choose the right animal model for PYY satiety studies and guides the design of PYY-based obesity drugs tuned for human receptor pharmacology.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.8776953220367432 | boltz-2 |
| ranking score | 0.8432674407958984 | boltz-2 |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 0.623 | 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{pep10717,
sequence = {YPSKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY},
target = {npbwr1},
author = {peptidemodel},
year = {2026},
status = {synthesized}
}