Peptide YY: gut fullness hormone (canine/mouse/pig/rat forms)
A natural gut hormone released after eating that tells the brain you're full; studied in animals to understand appetite and stress; not a 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
Peptide YY (PYY) is a gut hormone released after eating that tells the brain to stop eating — one of the body's primary "fullness" signals. It is produced mainly by specialized cells (L-cells) in the lower small intestine and colon, and it is released in proportion to the calorie content of a meal. The name comes from the presence of tyrosine (one-letter code: Y) at both the N- and C-termini of the 36-amino-acid chain. PYY was first isolated from porcine intestinal tissue by Tatemoto (1982) and is highly conserved across mammals; the stored sequence here represents the canonical 36-residue backbone shared across canine, mouse, porcine, and rat species. The active molecule carries a C-terminal tyrosine amide (–NH₂) that is not visible in the standard one-letter sequence but is required for full receptor binding activity (Tatemoto 1982).
History
Kazuhiko Tatemoto isolated PYY from extracts of porcine upper intestinal tissue in 1982, using a novel chemical assay that detected the unusual C-terminal amide structure (Tatemoto 1982, PNAS). He noted the sequence's homology to pancreatic polypeptide (PP) and proposed that PYY and PP together form a new peptide family — what is now called the PP-fold (or NPY) family. That family also includes neuropeptide Y (NPY), and all three share a characteristic hairpin-loop tertiary structure. The initial report identified PYY as a candidate gut hormone that inhibits pancreatic exocrine secretion. Over the following decades, research expanded PYY's known roles to appetite regulation, gastrointestinal motility, and energy homeostasis (Chaudhri and colleagues 2006; Vincent and colleagues 2008). In 2002, Batterham and colleagues demonstrated in Nature that the circulating fragment PYY(3–36) acts via the hypothalamic arcuate nucleus to reduce food intake by 33% in human volunteers — establishing PYY as a major target for obesity research.
What it does
After a meal, PYY is secreted from L-cells into the bloodstream and acts to slow digestion and suppress appetite. It inhibits gastric acid secretion, slows gastric emptying and intestinal transit (the "ileal brake" effect), and reduces pancreatic enzyme and bicarbonate secretion — actions that collectively help pace nutrient absorption (Chey and colleagues 2001; Chaudhri and colleagues 2006). Simultaneously, circulating PYY signals the hypothalamus to dampen appetite. The predominant circulating form, PYY(3–36), is generated when the enzyme DPP-IV cleaves the N-terminal Tyr-Pro dipeptide from the full-length PYY(1–36); this truncation shifts receptor selectivity heavily toward the Y2 subtype and is the form responsible for the central appetite-suppressing effect (Vincent and colleagues 2008; Silva and colleagues 2012). Fasting and postprandial PYY levels are consistently lower in obese individuals than in lean controls, pointing to a blunted satiety signal as a possible contributor to excess food intake (Vincent and colleagues 2008).
Evidence
- Human: Intravenous infusion of postprandial concentrations of PYY(3–36) significantly decreased appetite and reduced 24-hour food intake by 33% in lean and obese volunteers (Batterham and colleagues 2002, cited in Vincent and colleagues 2008 and Silva and colleagues 2012). A Phase II randomized placebo-controlled trial of intranasal PYY(3–36) in obese adults by Gantz and colleagues (2007, JCEM) found no statistically significant weight loss versus placebo after 12 weeks at the 200 µg dose; the 600 µg dose arm was largely discontinued due to nausea and vomiting. No PYY-based therapy is currently approved.
- Animal: Peripheral injection of PYY(3–36) inhibits food intake in rodents through Y2 receptor-dependent mechanisms; the effect is absent in Y2-receptor-null mice (cited in Vincent and colleagues 2008). Postprandial PYY levels rise markedly after Roux-en-Y gastric bypass in animal models, paralleling the appetite reduction seen after surgery.
- In vitro: PYY(1–36) and PYY(3–36) show distinct receptor-subtype binding profiles across the Y-receptor family; PYY(1–36) binds Y1, Y2, and Y5 subtypes, while the truncated PYY(3–36) preferentially targets Y2 (Silva and colleagues 2012).
Known effects
- Appetite suppression — Emerging/Preclinical-to-Phase II; mediated by Y2 receptor signaling in the arcuate nucleus
- Inhibition of pancreatic exocrine secretion — Mechanistic/Preclinical; blocks secretin- and CCK-stimulated enzyme and bicarbonate output (Tatemoto 1982; Chey and colleagues 2001)
- Gastric emptying delay / ileal brake — Mechanistic; reduces gastric motility and intestinal transit rate (Chaudhri and colleagues 2006)
- Reduced postprandial food intake — Phase II (human infusion studies); 33% reduction in 24-hour caloric intake in human infusion studies (cited in Vincent and colleagues 2008)
- Elevated post-bariatric surgery levels — Observational; circulating PYY rises substantially after Roux-en-Y gastric bypass, potentially contributing to post-surgical satiety (Silva and colleagues 2012)
Safety signals
The clinical safety record for exogenous PYY is limited. In the Gantz and colleagues (2007) Phase II intranasal trial, nausea and vomiting were the primary adverse effects; 59% of participants in the highest-dose arm (600 µg three times daily) discontinued due to these effects. The 200 µg arm was better tolerated but inefficacious. No long-term safety data from approved human use exists, as no PYY-based drug has cleared regulatory review. The dose-dependent emetic profile has been a key obstacle for intranasal and subcutaneous development programmes.
Regulatory status
- US: Not approved. Investigational only. No PYY-based drug has completed Phase III trials or received FDA review.
- EU: Not approved. Not on the EMA product database.
- WADA: Not listed on the prohibited list as of 2026. Endogenous peptide hormones occupy a regulatory grey zone; classification may change if efficacious formulations reach development.
Related peptides
PYY belongs to the PP-fold family alongside neuropeptide Y and pancreatic polypeptide, which share the hairpin tertiary structure and act through overlapping Y-receptor subtypes. For gut-derived satiety hormones co-released from L-cells, see also GLP-1 receptor agonists such as semaglutide and liraglutide, which act through a distinct receptor but are co-secreted with PYY postprandially and have reached regulatory approval for obesity and type-2 diabetes (Silva and colleagues 2012; Chaudhri and colleagues 2006).
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 PYY only activate the NPBWR1 stress-linked receptor when it carries the amide chemical tag on its tail, while the satiety Y2 receptor accepts either form?
If true, defects in the enzyme that adds this amide tag could quietly shift PYY's function, potentially contributing to eating disorders or chronic stress conditions in a way that would be missed by studies that only measure total PYY levels.
Does PYY reduce damaging enzyme secretion from the pancreas through both its known receptor and the NPBWR1 receptor, making it more effective than single-receptor approaches?
If true, PYY or a stable version of it could be developed as a treatment for pancreatitis, a painful and potentially life-threatening condition with few good medical therapies available today.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.8840794563293457 | boltz-2 |
| ranking score | 0.8378406763076782 | boltz-2 |
▸3-letter notation
▸recipeboltz-2 2.2.1
| parameter | value |
|---|---|
| model | boltz-2 2.2.1 |
| weights | — |
| hardware | vast_v100_32gb |
| mlx version | — |
| python | — |
| random seed | 1 |
| msa strategy | colabfold_local |
| runtime | — |
| predicted by | — |
| predicted at | 2026-05-22 |
▸citationbibtex
@peptide{pep10712,
sequence = {YPAKPEAPGEDASPEELSRYYASLRHYLNLVTRQRY},
target = {npbwr1},
author = {peptidemodel},
year = {2026},
status = {synthesized}
}