PYY 3-36 Research

PYY 3-36 research holds a real human record on appetite alongside a published dispute over whether the original animal results reproduce. That dispute is not settled. The compound is the fragment of the gut hormone peptide YY that circulates after a meal. It reached clinical trials as a candidate obesity treatment and stopped there. This article describes what the literature investigated, not any outcome a reader should expect.

What PYY 3-36 is

PYY 3-36 is a 34-amino-acid, C-terminally amidated fragment of peptide YY. It arises when the enzyme DPP-4 removes the first two residues from the 36-residue parent hormone, which gut endocrine cells release after eating. The product specification lists CAS 123583-37-9 and a molecular weight of 4,049.52 g/mol, and that CAS resolves on PubChem to CID 59404585. Vendors commonly supply this peptide as the trifluoroacetate salt, which is not the same physical substance as the free base that CAS names.

Naming is a real hazard here: the PubChem synonym list for full-length peptide YY, CAS 106388-42-5 at CID 56841989, also carries the string "PYY (3-36)". The two molecules differ in mass by roughly 260 daltons and in receptor behavior, and the PubChem CIDs separate them where the synonym string does not. The full-length parent also holds a second record, CAS 118997-30-1 at CID 126455957, which is the better-characterized of the two. PYY 3-36 is the 34-residue fragment.

The original findings and the proposed mechanism

PYY 3-36 is a preferential agonist at the NPY Y2 receptor, and the 2002 Nature paper reported that peripheral injection inhibited food intake and reduced weight gain in rats.^[1] The same paper found an anorectic effect in wild-type mice but not in mice lacking the Y2 receptor.^[1] Human infusion at postprandial concentrations reduced food intake by 33% over 24 hours.^[1] The mechanism proposed there was hypothalamic: peptide acting on arcuate Y2 receptors, suppressing NPY neurons and so activating adjacent melanocortin neurons.^[1]

A double-blind, placebo-controlled human crossover trial followed in 2003, in twelve obese and twelve lean subjects. Buffet lunch intake fell 30% in the obese group and 31% in the lean group, both significant.^[2] Obese subjects were not resistant to PYY 3-36, unlike the pattern reported for leptin. That paper also found lower fasting peptide YY in obese subjects, and suggested a PYY deficiency might contribute to obesity.^[2]

The proposed mechanism did not survive independent testing. In mice, the anorectic effect did not require the melanocortin-4 receptor.^[3] A later mouse study found the anorectic effect independent of the vagus nerve, with neuronal activation in the area postrema and nucleus tractus solitarius instead.^[4] A 2005 critical review rejected the melanocortin account too, along with the suggestion that PYY deficiency exists in human obesity.^[5]

The replication dispute

In 2004, 42 authors published a Brief Communications Arising in Nature. They stated they had been unable to replicate the rodent results, and argued this called the anti-obesity approach into question.^[6] The original authors replied in the same issue, with twelve authors.^[7]

A 2005 review then tallied the attempts, and reported that 33 of 41 rodent studies across 16 laboratories, or 83%, could not reproduce the effect.^[5] Some obtained no change and some obtained increased food intake. The review stated the same adaptation protocols, routes, doses, strains, diets, vendors, light cycles and room temperatures were used.^[5]

Two qualifications belong with that 83%. It is a review's tally rather than an independent audit. It is also not a second, independent voice: most of the review's authors are also authors of the 2004 critique, as the two published author lists show.^[5][6]

The defense turns on animal handling, and a 2004 mouse study reported the satiety effect was absent in mice not thoroughly acclimated to handling and injection.^[3] That study came from a laboratory outside the originating group. One of its authors also co-signed the original authors' reply, so that laboratory sits on both sides of the dispute.^[3][7] A 2006 rat study from the originating group found that moving a rat to a clean cage abolished the response entirely.^[8] A melanocortin agonist tested in the same rats was unaffected by the cage change.^[8]

These positions contradict each other on facts, not interpretation. The review says matched protocols still failed, while the handling studies say conditions decide the result. Nothing in the record resolves the conflict.

The disagreement is scientific rather than a misconduct story, and no retraction or expression of concern attaches to any of these papers. The critique carries a published corrigendum whose content was not accessible for this article. Nothing in the record makes it a retraction or a climbdown.

Independent animal work in both directions

Several laboratories outside the originating group did reproduce the acute effect. The mouse study that broke the melanocortin mechanism was one of them, and its effect ran three to four hours with no change in 12-hour intake.^[3] Intravenous infusion in rats inhibited food intake dose-dependently, reaching maximal inhibition of 47%.^[9] In rhesus monkeys, intramuscular administration acutely reduced 6-hour food intake.^[10] The lead author of that primate study also signed the 42-author failed-replication letter, so the record was never a clean two-camps split.^[6][10] A further laboratory found that a single injection inhibited intake in mice but not in rats.^[11] That same laboratory reported reduced body weight and improved glycemic control over 28 days in glucose-intolerant obese rats.^[11]

Whether the effect is partly malaise is unsettled. Peripheral administration produced conditioned taste aversion in mice.^[4] In rats, higher infusion rates produced both feeding inhibition and taste aversion, while the lowest rates suppressed intake without measurable aversion.^[12] A separate rat study found no conditioned taste aversion at either level it tested.^[11]

Human research on appetite and tolerability

Independent human replication does exist: a 2005 double-blind, placebo-controlled study gave graded intravenous infusions to healthy male volunteers. Food intake fell dose-dependently there.^[13] The authors qualified their own result. They reported the inhibition was significant only at pharmacologic plasma concentrations, and concluded a physiologic role in human satiety remained to be defined.^[13] Nausea and fullness were the most common side effects, and were worst at the highest exposure.^[13]

Tolerability constrained more than one human infusion study. A blinded, randomized crossover infusion study enrolled 12 lean and 12 obese men, 24 in total. Only 4 of those 24 completed the PYY 3-36 infusions, because of nausea.^[14] The protocol was then revised downward, and that study also reported lower ratings of well-being and increased heart rate with PYY 3-36.^[14] The paper carries a published erratum.^[14]

Raising exposure above physiological levels bought no further appetite suppression in one human study, and it caused nausea in 5 of 6 volunteers.^[15] Satiety rose and food intake fell, but no more than at physiological levels.^[15]

One subcutaneous study gave a different result, and administration to 24 obese males raised plasma PYY and improved satiety and hunger ratings.^[16] It produced no effect at all on ad libitum energy intake, so subjective appetite and measured eating came apart there.^[16]

Clinical development and how it ended

Two Phase 2 obesity trials appear in the record. The published one missed its primary endpoint. The larger one was never published, and what is known of its outcome comes from a company announcement rather than from the literature.

Merck Research Laboratories tested intranasal PYY 3-36 against placebo for 12 weeks in 133 obese adults, alongside a hypocaloric diet and exercise.^[17] At the lower of two exposure levels, the least-squares mean difference against placebo was -0.9 kg, with a 95% confidence interval of -2.6 to 0.7 and P = 0.251.^[17] A 2.11 kg difference had been sought.^[17] Intranasal delivery got the peptide in during that trial, and it still produced no significant weight loss beyond placebo.^[17] In the higher-exposure arm, 27 of 46 patients, or 59%, discontinued because of nausea and vomiting, and only 12 of 46 completed.^[17] That arm's mean weight change was -1.4 kg against -2.8 kg on placebo, and the authors state no meaningful inference can be drawn from it.^[17] Sponsor staff published this negative result themselves.^[17]

A larger trial followed, and it exists in the public record only as a registry entry and a company announcement. Nastech Pharmaceutical Company ran a 24-week randomized trial of nasal PYY 3-36 in 551 obese patients, with an active comparator arm.^[18] The registry record shows completion in 2008 and carries no posted results.^[18] The sponsor's successor announced in August 2008 that the trial missed both its primary and secondary efficacy endpoints. That outcome is a company announcement rather than peer-reviewed evidence. Two registered Phase 1 studies also finished with no posted results and no published report.^[18] A further registered study has sat at status unknown since its 2022 estimated dates, and it also has no posted results.^[18]

PYY 3-36 has no FDA approval, and FDA's public approval, labeling and product listing records hold no entry for it under any name form or under its UNII. That is a never-filed status rather than a withdrawal or a refusal. This describes the United States only, and says nothing about regulators elsewhere.

Where PYY 3-36 research stands now

Recent work has moved toward combination rather than monotherapy. In diet-induced obese rats over four weeks, PYY 3-36 plus liraglutide produced weight loss similar to Roux-en-Y gastric bypass, and was superior to either agent alone.^[19] PYY 3-36 alone was significantly inferior to the combination.^[19]

Three animal findings argue against durability. In rhesus monkeys, the suppression of food intake was not sustained across successive daily administrations.^[10] In mice, the acute anorectic effect was followed by a delayed orexigenic effect, which three other anorectic agents did not produce.^[20] In diet-induced obese mice, chronic infusion reduced food intake only at the highest exposure tested and only over the first three days.^[11] Weight gain in those mice did fall dose-dependently.^[11] The 2005 review reached the same conclusion on durability, holding that the data spoke against sustained reductions in food intake, body fat or weight gain.^[5]

Authorship cuts across both sides of this dispute. The originating group at Imperial College London published the reply, the cage-change study, the supraphysiological ceiling finding and the rebound finding.^{[7][8][15][20]} That group produced both its own strongest defense and two of the least flattering results. The 83% tally and the 2004 critique share most of their authors, so they are not independent of each other.^[5][6]

Conclusion

PYY 3-36 research produced a short-term effect on human food intake, and a group outside the originating laboratory reproduced it. That group reported the inhibition was significant only at pharmacologic plasma concentrations.^[13] No durable weight-loss result was demonstrated in humans. The rodent record is genuinely contested, and it is unresolved on the published evidence. Nausea limited exposure in more than one human infusion study and in the published Phase 2 trial. No marketing application appears ever to have been filed with FDA. PYY 3-36 from Purepeptides is a research compound.

Frequently Asked Questions

Is there human evidence that PYY 3-36 reduces food intake?

Yes, from short-term studies. Human infusion reduced food intake in the 2002 report, and a 2003 crossover trial in 12 obese and 12 lean subjects found significant reductions in both groups.^[1][2] An independent group replicated a dose-dependent reduction in healthy male volunteers, but reported it was significant only at pharmacologic plasma concentrations.^[13] The published 12-week Phase 2 trial did not produce significant weight loss against placebo.^[17]

How does PYY 3-36 differ from full-length peptide YY?

PYY 3-36 is the 34-residue fragment, produced when DPP-4 removes two residues from the 36-residue parent, and the two differ in mass and in receptor behavior. One of PubChem's full-length parent records carries the string "PYY (3-36)" in its own synonym list, and the CIDs separate the molecules where that string does not.

Has the original rodent finding been independently replicated?

The record is split, and it is not settled. A 42-author group reported failure to replicate, and a review sharing most of those authors tallied 33 of 41 rodent studies across 16 laboratories as failures.^[5][6] Other laboratories outside the originating group did reproduce the acute anorectic effect, in rats and in rhesus monkeys.^[9][10] The melanocortin mechanism proposed in the original paper did not survive testing in mice.^[3]

References

1. 1

   Batterham RL, Cowley MA, Small CJ, et al. Gut hormone PYY(3-36) physiologically inhibits food intake. *Nature*. 2002;418(6898):650-4. PMID 12167864. DOI: 10.1038/nature00887
2. 2

   Batterham RL, Cohen MA, Ellis SM, et al. Inhibition of food intake in obese subjects by peptide YY3-36. *N Engl J Med*. 2003;349(10):941-8. PMID 12954742. DOI: 10.1056/NEJMoa030204
3. 3

   Halatchev IG, Ellacott KL, Fan W, Cone RD. Peptide YY3-36 inhibits food intake in mice through a melanocortin-4 receptor-independent mechanism. *Endocrinology*. 2004;145(6):2585-90. PMID 15016721. DOI: 10.1210/en.2003-1754
4. 4

   Halatchev IG, Cone RD. Peripheral administration of PYY(3-36) produces conditioned taste aversion in mice. *Cell Metab*. 2005;1(3):159-68. PMID 16054059. DOI: 10.1016/j.cmet.2005.02.003
5. 5

   Boggiano MM, Chandler PC, Oswald KD, et al. PYY3-36 as an anti-obesity drug target. *Obes Rev*. 2005;6(4):307-22. PMID 16246216. DOI: 10.1111/j.1467-789X.2005.00218.x
6. 6

   Tschöp M, Castañeda TR, Joost HG, et al. Physiology: does gut hormone PYY3-36 decrease food intake in rodents? *Nature*. 2004;430(6996):1 p following 165. PMID 15243972. DOI: 10.1038/nature02665. Erratum in *Nature*. 2004;431(7007); PubMed gives the erratum page as 1038 and Crossref DOI 10.1038/nature03019 gives 414, and that discrepancy is unresolved.
7. 7

   Batterham RL, Cowley MA, Small CJ, et al. Does gut hormone PYY3-36 decrease food intake in rodents? (reply). *Nature*. 2004;430(6996):3-4. DOI: 10.1038/nature02666. No PubMed ID; indexed only as the discussion half of PMID 15243972.
8. 8

   Abbott CR, Small CJ, Sajedi A, et al. The importance of acclimatisation and habituation to experimental conditions when investigating the anorectic effects of gastrointestinal hormones in the rat. *Int J Obes (Lond)*. 2006;30(2):288-92. PMID 16231018. DOI: 10.1038/sj.ijo.0803137
9. 9

   Chelikani PK, Haver AC, Reidelberger RD. Intravenous infusion of peptide YY(3-36) potently inhibits food intake in rats. *Endocrinology*. 2005;146(2):879-88. PMID 15539554. DOI: 10.1210/en.2004-1138
10. 10

    Moran TH, Smedh U, Kinzig KP, et al. Peptide YY(3-36) inhibits gastric emptying and produces acute reductions in food intake in rhesus monkeys. *Am J Physiol Regul Integr Comp Physiol*. 2005;288(2):R384-8. PMID 15388494. DOI: 10.1152/ajpregu.00535.2004
11. 11

    Vrang N, Madsen AN, Tang-Christensen M, Hansen G, Larsen PJ. PYY(3-36) reduces food intake and body weight and improves insulin sensitivity in rodent models of diet-induced obesity. *Am J Physiol Regul Integr Comp Physiol*. 2006;291(2):R367-75. PMID 16914421. DOI: 10.1152/ajpregu.00726.2005
12. 12

    Chelikani PK, Haver AC, Reidelberger RD. Dose-dependent effects of peptide YY(3-36) on conditioned taste aversion in rats. *Peptides*. 2006;27(12):3193-201. PMID 16962209. DOI: 10.1016/j.peptides.2006.08.001
13. 13

    Degen L, Oesch S, Casanova M, et al. Effect of peptide YY3-36 on food intake in humans. *Gastroenterology*. 2005;129(5):1430-6. PMID 16285944. DOI: 10.1053/j.gastro.2005.09.001
14. 14

    Sloth B, Holst JJ, Flint A, Gregersen NT, Astrup A. Effects of PYY1-36 and PYY3-36 on appetite, energy intake, energy expenditure, glucose and fat metabolism in obese and lean subjects. *Am J Physiol Endocrinol Metab*. 2007;292(4):E1062-8. PMID 17148749. DOI: 10.1152/ajpendo.00450.2006. Erratum in *Am J Physiol Endocrinol Metab*. 2007;293(6):E1847.
15. 15

    le Roux CW, Borg CM, Murphy KG, Vincent RP, Ghatei MA, Bloom SR. Supraphysiological doses of intravenous PYY3-36 cause nausea, but no additional reduction in food intake. *Ann Clin Biochem*. 2008;45(Pt 1):93-5. PMID 18275682. DOI: 10.1258/acb.2007.007068
16. 16

    Sloth B, Davidsen L, Holst JJ, Flint A, Astrup A. Effect of subcutaneous injections of PYY1-36 and PYY3-36 on appetite, ad libitum energy intake, and plasma free fatty acid concentration in obese males. *Am J Physiol Endocrinol Metab*. 2007;293(2):E604-9. PMID 17566112. DOI: 10.1152/ajpendo.00153.2007
17. 17

    Gantz I, Erondu N, Mallick M, et al. Efficacy and safety of intranasal peptide YY3-36 for weight reduction in obese adults. *J Clin Endocrinol Metab*. 2007;92(5):1754-7. PMID 17341568. DOI: 10.1210/jc.2006-1806
18. 18

    ClinicalTrials.gov registry records NCT00537420 (Nastech Pharmaceutical Company, Phase 2, 551 enrolled, completed 2008), NCT00331175 (Pfizer, Phase 1, 31 enrolled), NCT03490786 (Gila Therapeutics, Phase 1, 12 enrolled) and NCT05110664 (University College London, status unknown). None carries a results section.
19. 19

    Dischinger U, Hasinger J, Königsrainer M, et al. Toward a medical gastric bypass: chronic feeding studies with liraglutide + PYY(3-36) combination therapy in diet-induced obese rats. *Front Endocrinol (Lausanne)*. 2020;11:598843. PMID 33551994. DOI: 10.3389/fendo.2020.598843
20. 20

    Parkinson JR, Dhillo WS, Small CJ, et al. PYY3-36 injection in mice produces an acute anorexigenic effect followed by a delayed orexigenic effect not observed with other anorexigenic gut hormones. *Am J Physiol Endocrinol Metab*. 2008;294(4):E698-708. PMID 18285527. DOI: 10.1152/ajpendo.00405.2007