Peptide YY

PYY, peptide tyrosine tyrosine, PYY1-36 (full length), PYY3-36 (the main circulating active form), NN9748 / NNC0165-1875 (a Novo Nordisk long-acting PYY analogue, investigational)

Metabolic & weight

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Summary

Class: Naturally occurring 36-amino-acid gut hormone of the NPY family (with neuropeptide Y and pancreatic polypeptide); PYY3-36 is the 34-residue fragment left after DPP-4 removes the first two amino acids
Mechanism: Released from L cells of the lower gut after eating, in proportion to calories; PYY3-36 acts on Y2 receptors in the hypothalamus, brainstem and vagal nerves to reduce appetite and slow gut transit
Routes studied: Intravenous infusion (human physiology studies); subcutaneous and intranasal (small trials of PYY3-36 and analogues); long-acting analogues subcutaneous weekly (Phase 1–2)
Half-life: Short — PYY3-36 is cleared within minutes to tens of minutes; analogues are engineered for once-weekly dosing
Storage: Research reagent only; not supplied as a medicine
Regulatory status: Not approved anywhere; investigational analogues in or recently out of Phase 2

Doses are as reported in studies or by the community — never recommendations.

1What it is

PYY was isolated from pig intestine in 1980 by Tatemoto and Mutt and named for the tyrosine (Y) residues at both ends. It is made by the same L cells that produce GLP-1 and oxyntomodulin, mostly in the ileum, colon and rectum, and is released in proportion to the calories in a meal, staying raised for several hours. The enzyme DPP-4 — the same one that destroys GLP-1 — clips two amino acids off, and the resulting PYY3-36 is the form that acts on appetite.

PYY3-36 became a headline molecule in 2002 when a London group reported that a 90-minute infusion cut food intake at a buffet meal by a third. Interest in it as an obesity drug has waxed and waned since: the effect is real but narrow, nausea appears at doses only slightly above the effective ones, and early attempts at an intranasal product failed. The current scientific interest is as one component of multi-hormone combinations (with GLP-1 ) and as part of the explanation for why bariatric surgery suppresses appetite — PYY levels rise sharply after gastric bypass. Community/self-directed use: essentially none documented; it is a research reagent, not a marketplace peptide.

2How it's thought to work

Y2 receptor agonism. PYY3-36 selectively activates Y2 receptors, which are inhibitory autoreceptors on NPY/AgRP neurons in the arcuate nucleus. Switching off these hunger neurons reduces food intake. Y2 receptors on vagal afferents and in the brainstem also contribute.

"Ileal brake". PYY slows gastric emptying and intestinal transit, prolonging the sense of fullness, and reduces pancreatic and gastric secretion.

Full-length PYY1-36. acts on Y1 and Y5 receptors too, which can increase feeding; the balance between forms matters, which is one reason results with mixed preparations were inconsistent.

Reward. fMRI work suggests PYY3-36 shifts brain activity from hypothalamic (homeostatic) to orbitofrontal (hedonic) control of eating (Batterham 2007, Nature).

PYY(3-36) released by L cells in the gut after a meal, acting at the Y2 receptor in the hypothalamus. Appetite falls over the hours that follow — the same family as neuropeptide Y, but at a receptor that turns intake down rather than up.Schematic — not to scale

3What the research shows

Acute reduction of food intake

Batterham 2002 (Nature) infused PYY3-36 into 12 lean volunteers and reported a ~33% reduction in buffet intake and lower hunger for 12 hours. Batterham 2003 (NEJM) showed obese people responded equally well and had lower endogenous PYY — unlike leptin, there was no resistance. Several groups replicated an intake reduction (Degen 2005, Gastroenterology; Sloth 2007, Am J Physiol), though the size of the effect varied and a group of rodent labs reported difficulty reproducing the animal data (Tschöp 2004, Nature correspondence). The consensus is that the effect is genuine but dose-sensitive, with nausea appearing at infusion rates above physiological levels. [2][3][5]

Graded B (largely negative so far)

Weight loss with chronic dosing

An intranasal PYY3-36 product (Nastech) produced no significant weight loss over 12 weeks and caused nausea and vomiting at higher doses (Gantz 2007, J Clin Endocrinol Metab). Novo Nordisk ran Phase 1–2 studies of a long-acting PYY analogue (NNC0165-1875) alone and combined with semaglutide (NCT04969939, completed ~2023); the combination appeared to add modest weight loss over semaglutide alone, and the company subsequently deprioritised the PYY programme in its public pipeline †. No PYY-based medicine has reached Phase 3. [6]

Combination with GLP-1

Co-infusion of PYY3-36 with GLP-1 (or oxyntomodulin) reduces food intake more than either alone in healthy volunteers (Neary 2005, Endocrinology; Tan 2017, Diabetes — the "GOP" triple infusion mimicking post-bypass hormone levels in people with obesity and diabetes, producing ~4 kg weight loss over 4 weeks). [8]

Bariatric surgery physiology

PYY and GLP-1 responses to meals rise markedly after Roux-en-Y gastric bypass and sleeve gastrectomy; blocking them with octreotide restores appetite (le Roux 2006 and 2007, Ann Surg / Endocrinology). This is strong indirect evidence that endogenous PYY matters for human appetite. [7]

Graded C/D

Animal and mechanistic

Y2 knockout mice are resistant to PYY3-36's anorectic effect; PYY-null mice are mildly obese. Rodent studies also report effects on bone (PYY appears to lower bone mass, a possible contributor to post-bypass bone loss).

4Reported side effects and interactions

Literature-reported

nausea is the dose-limiting effect and appears at infusion rates not far above those that reduce intake; vomiting, abdominal discomfort, cold sweats and reduced gastric emptying are reported. Analogue trials reported GI effects similar to GLP-1 . No serious safety signal, but exposure has been short.

Community-reported

none documented.

Theoretical. chronic Y2 agonism may affect bone density (rodent and bariatric data); effects on blood pressure and mood via NPY-family receptors are plausible but unstudied in humans beyond acute infusions.

Interactions. additive appetite suppression with GLP-1 agonists; DPP-4 inhibitors would in theory reduce conversion of PYY1-36 to PYY3-36, with uncertain net effect.

Markers researchers commonly monitor

No clinical monitoring exists because there is no clinical use. In research settings:

Marker	Why it's watched
Fasting and post-meal plasma PYY	the physiological readout; lower post-meal responses are reported in obesity and higher ones after bariatric surgery.
Gastric emptying (breath test or scintigraphy)	PYY slows it.
Bone density (DEXA) and bone turnover markers	because of the rodent and post-bypass bone signal.
Nausea scores and food intake at a test meal	the primary pharmacodynamic measures in trials.
CBC and CMP	general baseline in any experimental infusion study.

Free for everyone. Safety information is never behind a paywall.

5Reconstitution and handling

PYY3-36 exists only as a research-grade peptide for laboratory and clinical-study use; there is no pharmaceutical presentation, validated storage guidance or self-administered dose. The site calculator is not applicable.

6Commonly studied alongside

GLP-1 and its analogues (semaglutide), oxyntomodulin (the "GOP" combination), amylin and cagrilintide (fellow satiety hormones in multi-agonist research), cholecystokinin / sincalide, ghrelin (its functional opposite).

Informational cross-links. Not stack recommendations.

7Regulatory status by region

Region	Status (checked —)
United States	Not approved; investigational analogues only
European Union	Not authorised
United Kingdom	Not licensed
Australia	Not approved
South Africa	Not registered
Sport	Not specifically listed by WADA; a non-approved substance would fall under S0 †

8Open questions

Can a long-acting PYY analogue separate appetite suppression from nausea well enough to add value on top of GLP-1 ?
How much of the post-bariatric-surgery appetite change is attributable to PYY versus GLP-1 and other factors?
Does Y2 agonism carry a bone-loss liability in humans?

9References

1Tatemoto K, Mutt V (1980). Isolation of two novel candidate hormones using a chemical method for finding naturally occurring polypeptides. Nature. PubMed · DOI
2Batterham RL et al. (2002). Gut hormone PYY3-36 physiologically inhibits food intake. Nature. PubMed · DOI
3Batterham RL et al. (2003). Inhibition of food intake in obese subjects by peptide YY3-36. NEJM. PubMed · DOI
4Batterham RL et al. (2007). PYY modulation of cortical and hypothalamic brain areas predicts feeding behaviour in humans. Nature. PubMed · DOI
5Sloth B et al. (2007). 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. PubMed · DOI
6Gantz I et al. (2007). Efficacy and safety of intranasal peptide YY3-36 for weight reduction in obese adults. J Clin Endocrinol Metab. PubMed · DOI
7le Roux CW et al. (2007). Gut hormones as mediators of appetite and weight loss after Roux-en-Y gastric bypass. Ann Surg. DOI
8Tan T et al. (2017). The effect of a subcutaneous infusion of GLP-1, OXM, and PYY on energy intake and expenditure in obese volunteers. J Clin Endocrinol Metab. PubMed · DOI
9Novo Nordisk. A research study to investigate how well NNC0165-1875 in combination with semaglutide works in people with obesity (NCT04969939), ClinicalTrials.gov record. PubMed

References are being resolved to PubMed/DOI identifiers; links search PubMed for the citation until then.

† Being confirmed by our reviewers against current sources.

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11Page history

30 Oct 2026Profile published — awaiting medical review

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