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phase 2Weight Loss & Diabetes

Peptide YY

Also known as: PYY, PYY3-36, Peptide Tyrosine-Tyrosine, PYY₃₋₃₆

Peptide YY (PYY) is a 36-amino-acid satiety hormone released from intestinal L-cells after meals, particularly in response to fat and protein. The truncated form PYY3-36 (produced by DPP-4 cleavage) is the primary circulating bioactive form, acting as a potent appetite suppressant through Y2 receptor (Y2R) activation in the hypothalamic arcuate nucleus. PYY works in concert with GLP-1 (co-released from the same L-cells) to create the postprandial satiety response. Obese individuals have blunted PYY responses to meals, making it a key target in obesity research.

3 cited references·5 researched benefits

Quick Answer

Peptide YY (PYY3-36) is a 36-amino-acid satiety hormone released from intestinal L-cells after eating, especially in response to fat and protein. It suppresses appetite by activating Y2 receptors in the hypothalamic arcuate nucleus, inhibiting orexigenic NPY neurons. PYY is co-released with GLP-1 and together they create the "ileal brake" that slows gastric emptying and signals fullness. Obese individuals have reduced postprandial PYY release, making it a therapeutic target for weight management.

Key Facts

Mechanism
PYY is co-released with GLP-1 from intestinal L-cells (predominantly in the ileum and colon) within 15 minutes of eating, with full peak at 1–2 hours. Full-length PYY1-36 is rapidly cleaved by DPP-4 to PYY3-36, which selectively binds the Y2 receptor (Y2R). In the hypothalamic arcuate nucleus, Y2R is an inhibitory presynaptic autoreceptor on NPY/AgRP neurons — PYY3-36 binding suppresses NPY/AgRP release, disinhibiting adjacent POMC/α-MSH anorexigenic neurons, thereby reducing appetite. Peripherally, PYY activates the "ileal brake" — slowing gastric emptying, reducing gastric acid secretion, and decreasing pancreatic exocrine secretion. PYY also acts on Y2R in the vagus nerve, transmitting satiety signals to the brainstem nucleus tractus solitarius. The combined central and peripheral actions create a robust postprandial satiety signal.
Research Status
phase 2
Half-Life
~15–30 minutes
Molecular Formula
C₁₇₇H₂₆₄N₄₈O₅₇S
Primary Use
Weight Loss & Diabetes
Table of Contents

Benefits

  • Potent appetite suppression — IV PYY3-36 reduces food intake by 30–36% in both lean and obese individuals over 24 hoursstrong
  • Physiological satiety signaling — essential component of the natural postprandial satiety response, working synergistically with GLP-1strong
  • Ileal brake activation — slows gastric emptying and intestinal transit, prolonging nutrient absorption and satietystrong
  • Synergistic weight loss potential — PYY combined with GLP-1 analogs or oxyntomodulin shows additive appetite suppression in early studiesmoderate
  • Post-bariatric surgery mechanism — exaggerated PYY release after Roux-en-Y gastric bypass contributes significantly to sustained weight loss and appetite reductionmoderate

Dosage Protocols

RouteDosage RangeFrequencyNotes
Intravenous infusion (research)0.5–1.0 pmol/kg/minContinuous infusion for 90–120 minutesUsed in research settings to study satiety and energy balance. Infusion rates are calibrated to achieve postprandial physiological PYY3-36 levels (~50–80 pmol/L). Higher supraphysiological doses (>1.5 pmol/kg/min) cause significant nausea.
Intranasal (investigational)100–600 mcgBefore mealsIntranasal PYY3-36 has been explored to bypass the short half-life and achieve direct CNS delivery. Early studies showed modest appetite reduction but bioavailability and dose optimization remain challenges.

Medical disclaimer

Dosage information is provided for educational reference only. Always follow your prescriber's instructions and consult a qualified healthcare provider before starting any peptide protocol.

Side Effects

  • Nausea — the most common side effect in clinical infusion studies, particularly at higher dosescommon
  • Abdominal discomfort — cramping and bloating from slowed GI transitcommon
  • Dizziness — transient lightheadedness reported during IV infusion studiescommon
  • Constipation — reduced colonic motility at higher doses from the ileal brake effectcommon

Frequently Asked Questions

Why do obese individuals have lower PYY levels?
Studies consistently show that obese individuals have lower fasting PYY levels and a blunted postprandial PYY response compared to lean controls. The meal-stimulated PYY rise is 30–50% lower in obese subjects. This creates a deficiency in the satiety signal, potentially contributing to overeating. Importantly, when PYY3-36 is infused exogenously, obese individuals show a normal appetite-suppressing response — they are not resistant to PYY, they simply produce less of it. This makes PYY a particularly attractive therapeutic target because the downstream signaling machinery remains intact.
How does PYY contribute to weight loss after bariatric surgery?
After Roux-en-Y gastric bypass (RYGB), PYY levels increase dramatically — postprandial PYY is 2–5× higher than pre-surgery levels. This occurs because nutrients reach the distal ileum and colon (where L-cells are densest) much faster after bypass, causing exaggerated PYY and GLP-1 release. This "hindgut hypothesis" explains much of the appetite suppression and metabolic improvement seen after RYGB. Patients who achieve the greatest PYY increases tend to lose the most weight and maintain it long-term. Sleeve gastrectomy also increases PYY, though typically less than RYGB.
What is the relationship between PYY and GLP-1?
PYY and GLP-1 are co-released from the same intestinal L-cells after meals, and they work synergistically to suppress appetite. GLP-1 acts primarily through vagal afferents and brainstem circuits, while PYY3-36 acts primarily through hypothalamic Y2 receptors — different but complementary pathways. Combined infusion of PYY3-36 and GLP-1 produces greater appetite suppression than either hormone alone (additive effect). This synergy is being exploited therapeutically: several drug development programs are combining GLP-1 analogs with PYY analogs for enhanced weight loss beyond what GLP-1 RAs alone achieve.
How does PYY differ from NPY (Neuropeptide Y)?
Despite the similar names and membership in the same PP-fold peptide family, PYY and NPY have opposite effects on appetite. NPY (Neuropeptide Y) is produced in the hypothalamic arcuate nucleus and is the most potent known appetite stimulant — it drives hunger. PYY (Peptide YY) is produced in the gut and suppresses appetite. The trick is receptor selectivity: full-length PYY1-36 activates all Y receptors (including the orexigenic Y1/Y5 receptors, which would increase appetite), but the biologically active form PYY3-36 selectively binds Y2 receptors, which are inhibitory autoreceptors on NPY neurons. So PYY3-36 actually shuts down NPY signaling, creating its anorexigenic effect.

References

  1. 1
    Peripheral PYY3-36 reduces food intake and body weight in normal-weight and obese humans(2003)PubMed ↗
  2. 2
    Gut hormone PYY3-36 physiologically inhibits food intake in obesity and after gastric bypass(2006)PubMed ↗
  3. 3
    PYY and GLP-1 as targets for anti-obesity drug development: synergistic action and clinical potential(2007)PubMed ↗

Latest Research

Last updated: 2026-02-19