Peptide YY (3-36)

PYY is released from intestinal L-cells in proportion to calories eaten, and DPP-4 cleaves the full-length peptide to PYY(3-36), which shifts selectivity from Y1 and Y5 toward the Y2 receptor. Y2 is a presynaptic inhibitory autoreceptor on NPY/AgRP neurons in the arcuate nucleus, so PYY(3-36) suppresses the orexigenic NPY tone and disinhibits POMC neurons - a satiety signal genuinely distinct from GLP-1 and amylin. Human infusion studies reliably reduce food intake at a subsequent buffet meal by about 30%, and PYY is co-secreted with GLP-1 which is part of why bariatric surgery works so well. The problem is the therapeutic window: doses that reliably suppress appetite also reliably cause nausea, and multiple intranasal and injectable development programmes have failed on exactly that.

Targets: Y2 receptor, Y1 and Y5 receptors (weakly)

• · Research used molar infusion rates around 0.3-0.8 pmol/kg/min rather than fixed milligram doses. No validated self-administration protocol exists, and the doses circulating in grey-market protocols are not derived from any trial.

Work out your exact syringe units →

• very commonNausea— The dose-limiting effect and the reason multiple development programmes failed.
• commonVomiting
• commonNasal irritation with intranasal formulations

• Pregnancy.
• No adequate human safety database for chronic use exists.

• synergysemaglutide — Distinct receptor and physiologically co-secreted with GLP-1; the combination is a real research direction but also compounds nausea.
• synergycagrilintide — Three separate satiety pathways in theory; no human data for the combination.

• · Nausea severity.
• · Food intake and weight.

Not approved anywhere; sold as a research chemical.

• Batterham et al. 2002, gut hormone PYY(3-36) physiologically inhibits food intake, Nature (trial)
• Batterham et al. 2003, inhibition of food intake in obese subjects by peptide YY(3-36), NEJM (trial)

PYY(3-36) is released from ileal and colonic L-cells in proportion to calories ingested, and it is one of the better-characterised physiological satiety signals in humans. The receptor selectivity is the elegant part: full-length PYY(1-36) is a fairly non-selective NPY-family agonist, and DPP-4 cleavage of the N-terminal dipeptide converts it into a Y2-selective agonist. Y2 is a presynaptic autoinhibitory receptor on arcuate NPY/AgRP neurons, so PYY(3-36) works by silencing the hunger-driving neurons rather than by stimulating satiety neurons directly - inhibition of an inhibitory tone on POMC neurons, which then fire more. That is a different and arguably more elegant mechanism than anything else in this class. It is also part of the physiological explanation for why bariatric surgery works: gastric bypass and sleeve gastrectomy dramatically increase postprandial PYY and GLP-1, and blocking those signals attenuates the appetite reduction after surgery. Despite all that, every attempt to make PYY a chronic therapy has failed on nausea. The dose-response curve for food intake reduction and the dose-response curve for emesis sit almost on top of each other, and the acute infusion studies that show a 30% reduction in food intake also show that participants feel sick. There have been long-acting PYY analogues in development, and none has reached the market. Anyone buying research PYY expecting GLP-1-magnitude weight loss has misread the evidence: the acute food-intake data are solid, and there is no chronic weight-loss dataset at all.

Nausea, and a misreading of what the evidence shows. The Batterham data are about acute food intake after an infusion, and the leap from that to a peptide vial producing sustained weight loss is not supported by anything. Every attempt at chronic PYY dosing - subcutaneous, intranasal, long-acting analogues - has been defeated by the fact that the emetic dose and the anorectic dose are nearly identical. If you inject enough research-grade PYY to notice an appetite effect, you will probably feel sick, and if you do not feel sick you probably have not taken enough to do anything.

• Neuropeptide Y Y2 receptor (NPY2R) — Selective Y2 agonist; the selectivity is created by DPP-4 removing the N-terminal dipeptide

  Presynaptic inhibition of arcuate NPY/AgRP neurons, disinhibiting POMC neurons. Reduces food intake by roughly a third in acute infusion studies - and causes nausea across almost the same dose range.

• Y1 and Y5 receptors — Much reduced compared with full-length PYY(1-36)

  Minimal at the truncated form. Y1 activation would be counterproductive since it is orexigenic, which is precisely why the DPP-4 switch matters.

• PYY(3-36) infusion in obese subjects Randomised controlled human study · n=24 · 1 weeks · 2003

  Approximately 30% reduction in caloric intake at a buffet meal two hours after infusion, in both obese and lean subjects - demonstrating that obesity is not associated with PYY resistance.

Appetite suppression within 30-60 minutes of infusion, lasting a few hours. Nausea arrives on roughly the same schedule. No accumulation, no steady state.

The combination that has genuine mechanistic logic is PYY plus a GLP-1 agonist - both are released together from L-cells after a meal, they act through entirely different receptors, and co-infusion studies in humans showed additive reductions in food intake. That is real physiology. What does not exist is any chronic-dosing product that makes the combination practical, and stacking a 10-minute peptide onto a weekly drug does very little. Adding PYY to an existing GLP-1 agonist mostly adds nausea, because both act on the same emetic pathway in the area postrema even though they use different receptors to get there.

Against GLP-1 agonists: not comparable. There is no chronic PYY weight-loss dataset to compare against 15-20% figures. Against cagrilintide and the amylin analogues: amylin also signals through the area postrema and also causes nausea, but the amylin field solved the duration problem and the PYY field did not. What PYY genuinely explains is bariatric surgery - the massive postprandial PYY and GLP-1 rise after gastric bypass is a large part of why the operation works, and that is the most useful thing to take from this compound.

$60–$200/month. Research chemical pricing. The short half-life means the practical cost of any attempt at meaningful dosing is much higher than the vial price. Market observation, not verified pricing.

• ?The sequence given is the standard published human PYY(3-36) sequence and was not verified against a primary structural source.
• ?No pharmacokinetic package exists beyond the approximate half-life, because there was never a product.
• ?The 24-participant figure for the Batterham NEJM study is as commonly reported and was not individually re-verified.
• ?Whether any long-acting PYY analogue is currently in active development could not be established in this session.
• ?Cost figures are market observations, not verified pricing.

• Inhibition of food intake in obese subjects by peptide YY3-36 Batterham RL et al., N Engl J Med, 2003 · PMID 12954742

  The foundational human study. Note what it actually shows: acute food intake reduction after infusion, not chronic weight loss.

• Attenuated peptide YY release in obese subjects is associated with reduced satiety le Roux CW et al., Endocrinology, 2006 · PMID 16166213

  The finding that obese subjects release less PYY after a meal, which is the physiological argument for replacing it.

• The gut hormone peptide YY regulates appetite Batterham RL et al., Ann N Y Acad Sci, 2003 · PMID 12851312

  Review of the physiology, including the Y2 receptor mechanism.