PYY (3-36)
From PeptidePlaza, the free peptide reference · Entry #037 · Metabolic · Hand-curated entry · Editorial standards
PYY (3-36) (also known as Peptide YY, PYY3-36, Peptide tyrosine tyrosine) is a metabolic research peptide. The gut's post-meal "stop eating" signal, released from L-cells in proportion to calories consumed. Rises sharply after gastric bypass — one reason the surgery works.
Peptide YY (3-36) is the physiologically active, DPP-4-cleaved form of the 36-amino-acid gut hormone PYY, secreted from intestinal L-cells (the same cells that release GLP-1) in proportion to caloric load after a meal. Cleavage of the N-terminal Tyr-Pro by DPP-4 shifts receptor selectivity from broad NPY-family activity to relative selectivity for the Y2 receptor, an inhibitory presynaptic autoreceptor. Acting on Y2 receptors in the arcuate nucleus, PYY(3-36) inhibits NPY/AgRP orexigenic neurons and disinhibits POMC neurons, reducing food intake. Infusion studies in humans have shown roughly 30% reduction in caloric intake at a subsequent meal. PYY(3-36) levels rise markedly after Roux-en-Y gastric bypass and sleeve gastrectomy, and are considered part of the hormonal explanation for surgical weight loss durability. Development as a standalone drug has repeatedly failed on tolerability — nausea is dose-limiting and the therapeutic window is narrow — but PYY analogues with improved half-life are in active development, including as combination partners for GLP-1 agonists.
1 Mechanism of action
Selective agonist at the Y2 receptor, a Gi-coupled presynaptic autoreceptor. In the hypothalamic arcuate nucleus, Y2 activation inhibits NPY/AgRP neurons and secondarily disinhibits anorexigenic POMC/CART neurons, reducing appetite. Also slows gastric emptying and intestinal transit (the "ileal brake").
Primary targets: Y2 receptor (primary) · Y1/Y5 (weak)
2 Reported effects
Effects below are those reported in the published literature cited on this page. They are not claims of clinical benefit and not medical advice.
2.1 Reported benefits
- Physiological satiety signal — reduced caloric intake ~30% in human infusion studies
- Mechanism entirely independent of GLP-1 receptor signalling
- Slows gastric emptying and intestinal transit (ileal brake)
- Central to understanding why bariatric surgery produces durable weight loss
- Attractive combination partner for incretin therapies
2.2 Side effects
- Nausea — dose-limiting and the primary reason development has stalled
- Vomiting at supraphysiological doses
- Reduced blood pressure with rapid infusion
- Injection site reactions
- Very short duration of action requiring impractical dosing frequency
3 Chemical and physical properties
| CAS number | 123583-37-9 |
|---|---|
| Molar mass | 4049.5 g/mol |
| Purity (typical) | >98% |
| Half-life | ~8–10 minutes (IV); very short |
| Storage | −20 °C, lyophilised powder, desiccated |
| Solubility | Sterile water / bacteriostatic water |
| Receptors / targets | Y2 receptor (primary), Y1/Y5 (weak) |
3.1 Amino acid sequence
Ile-Lys-Pro-Glu-Ala-Pro-Gly-Glu-Asp-Ala-Ser-Pro-Glu-Glu-Leu-Asn-Arg-Tyr-Tyr-Ala-Ser-Leu-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2
4 Research dosages
Human infusion studies used 0.3–0.8 pmol/kg/min IV over 90 minutes; subcutaneous research protocols vary widely with no validated standard.
5 Research studies (7)
- Gut Hormone PYY(3-36) Physiologically Inhibits Food Intake
Nature (2002) · RCT · N=12 (human arm)Landmark study demonstrating that peripheral PYY(3-36) infusion reduces food intake in rodents and humans.Key finding: Infusion reduced caloric intake at a subsequent buffet meal by approximately 33% in humans, without nausea at physiological doses. - Gut hormones and appetite regulation.
Current opinion in endocrinology, diabetes, and obesity (2024) · ReviewVarious gut hormones interact with the brain through delicate communication, thereby influencing appetite and subsequent changes in body weight. - GLP-1 Analog Modulates Appetite, Taste Preference, Gut Hormones, and Regional Body Fat Stores in Adults with Obesity.
The Journal of clinical endocrinology and metabolism (2020) · RCTLiraglutide 3 mg SQ modulates appetite, taste preference, gut hormones, and regional body fat stores in adults with obesity without reduction in lean body mass. - Peptide YY: more than just an appetite regulator.
Diabetologia (2014) · ReviewReplenishment of beta cell mass is a key aim of novel therapeutic interventions for diabetes, and the implementation of new strategies will be aided by understanding the mechanisms employed to regulate beta... - Obesity and appetite control.
Experimental diabetes research (2012) · ReviewObesity is one of the major challenges to human health worldwide; however, there are currently no effective pharmacological interventions for obesity. - The role of peptide YY in appetite regulation and obesity.
The Journal of physiology (2009) · PreclinicalThe last decade has witnessed a marked increase in our understanding of the importance of gut hormones in the regulation of energy homeostasis. - Gastrointestinal satiety signals.
International journal of obesity (2005) (2008) · ReviewObesity constitutes a major global healthcare challenge.
6 Safety and risk profile
6.1 Regulatory status
PYY (3-36) is currently classified as Investigational. It has no approved human indication in the United States; availability elsewhere does not imply demonstrated safety or efficacy.
Safety score: 62/100 — moderate concern. Derived from clinical data volume, known risks and regulatory status.
6.2 Contraindications
Conditions and populations in which use is contraindicated:
- Pregnancy or lactation
- Eating disorders
- Severe gastrointestinal motility disorder
- Hypotension (rapid infusion lowers blood pressure)
6.3 Drug interactions
| Drug or class | Interaction | Risk |
|---|---|---|
| GLP-1 receptor agonists | Additive satiety and additive nausea; investigated as a combination strategy but tolerability is the constraint. | Moderate |
| DPP-4 inhibitors | Alter the PYY(1-36)/PYY(3-36) balance and therefore receptor selectivity within the NPY family. | Moderate |
| Antihypertensives | Additive blood pressure reduction during infusion. | Low |
6.4 Long-term risks
- No chronic human exposure data
- Unknown consequences of sustained Y2 receptor agonism
- Potential for conditioned taste aversion with repeated nausea
6.5 Research best practices
- Store lyophilised at −20 °C, desiccated and protected from light
- Reconstitute immediately before use — degradation in solution is rapid
- Use low-binding tubes and syringes; the peptide adsorbs readily to plastic and glass
- Control for DPP-4 activity in any protocol using the full-length PYY(1-36)
7 Frequently asked questions
- Why has PYY never become a drug?
- Its therapeutic window is narrow: doses that reliably suppress appetite tend to cause nausea, and its native half-life of minutes demands either continuous infusion or heavy engineering. Long-acting analogues and combinations with GLP-1 agonists are the current approach.
- What does PYY have to do with bariatric surgery?
- Post-prandial PYY(3-36) levels rise sharply after gastric bypass and sleeve gastrectomy because nutrients reach distal L-cells faster. This exaggerated satiety signalling is one of the leading explanations for why surgical weight loss is more durable than dieting.
- Is intranasal PYY effective?
- An intranasal formulation was developed and abandoned — phase 2 work failed to demonstrate adequate efficacy at tolerable doses, with nausea again the limiting factor.
8 References
- Gut hormones and appetite regulation. PubMed (2024). Hong SH, et al.. View source
- GLP-1 Analog Modulates Appetite, Taste Preference, Gut Hormones, and Regional Body Fat Stores in Adults with Obesity. PubMed (2020). Kadouh H, et al.. View source
- Peptide YY: more than just an appetite regulator. PubMed (2014). Persaud SJ, et al.. View source
- Obesity and appetite control. PubMed (2012). Suzuki K, et al.. View source
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