PYY (Peptide YY)

Appetite / GI

Also known as: Peptide YY, PYY3-36, Peptide Tyrosine Tyrosine, PYY1-36

Neuropeptide Y FamilyResearch phase: Endogenous hormone (well characterized)Regulatory: Endogenous peptide. PYY analogs have been explored as anti-obesity therapeutics but none are approved.

Mechanism

PYY is the "fullness hormone" — a 36-amino-acid peptide released from intestinal L cells after eating. Its active form PYY(3-36) acts on the brain's appetite centers (hypothalamus) to reduce hunger and food intake. It works as a natural counterbalance to ghrelin (the hunger hormone). PYY levels increase proportionally to calories consumed, particularly with protein and fat.

Technical detail

PYY is a 36-amino-acid peptide of the neuropeptide Y family, released from intestinal L cells postprandially. PYY(1-36) is converted to PYY(3-36) by DPP-4, switching receptor selectivity from non-selective NPY receptor activation to preferential Y2 receptor (Y2R) agonism. Y2R is a Gi-coupled GPCR; activation on arcuate nucleus NPY/AgRP neurons causes presynaptic inhibition of orexigenic NPY release (reducing appetite). Peripheral effects include slowed gastric emptying ("ileal brake"), reduced intestinal secretion, and increased water/electrolyte absorption. PYY is reduced in obesity and elevated after gastric bypass surgery.

Evidence

Long-acting PYY3-36 analogue with semaglutide for obesity: from preclinical assessment through randomized clinical studies
Wulff BS et al. (2025) — Obesity (Silver Spring) — PMID: 40629530
Phase 1/2 studies found long-acting PYY1875 was tolerated in phase 1 and produced only modest add-on efficacy with semaglutide in phase 2, with frequent GI adverse events at higher doses.
moderate
Safety and efficacy of an extended-release peptide YY analogue for obesity: A randomized, placebo-controlled, phase 1 trial
Tan TMM et al. (2021) — Diabetes Obes Metab — PMID: 33606914
Phase 1 randomized trial of extended-release PYY analogue Y14 in overweight/obese volunteers showed 2.9 to 3.6 kg weight loss over 31 days and 38% to 55% reductions in food intake, with mostly mild GI or injection-site adverse events.
moderate
Effects of PYY1-36 and PYY3-36 on appetite, energy intake, energy expenditure, glucose and fat metabolism in obese and lean subjects
Sloth B et al. (2007) — Am J Physiol Endocrinol Metab — PMID: 17148749
Randomized crossover infusion study in lean and obese men showed high-dose PYY3-36 reduced energy intake but frequently caused nausea, limiting tolerability.
moderate
Efficacy and safety of intranasal peptide YY3-36 for weight reduction in obese adults
Gantz I et al. (2007) — J Clin Endocrinol Metab — PMID: 17341568
12-week placebo-controlled obesity trial in 133 adults found intranasal PYY3-36 was not meaningfully efficacious for weight loss, and the higher dose had substantial nausea/vomiting-related discontinuation.
moderate
Effect of peptide YY3-36 on food intake in humans
Degen L et al. (2005) — Gastroenterology — PMID: 16285944
Synthetic human PYY3-36 infusion in healthy male volunteers reduced food intake dose-dependently, with maximal inhibition around 35%, but nausea and fullness increased at the highest dose.
moderate

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