Peptide YY

Overview

Peptide YY (PYY) is a 36-amino acid peptide hormone named for its N-terminal and C-terminal tyrosine residues (the single-letter code for tyrosine is Y, hence "peptide YY"). It was isolated in 1980 by Kazuhiko Tatemoto and colleagues at the Karolinska Institute using a novel C-terminal amide detection method that identified multiple previously unknown bioactive peptides.

PYY is secreted by enteroendocrine L-cells of the distal small intestine and colon in response to nutrient entry into the gut, with a post-prandial rise proportional to caloric intake. Once released, PYY acts through the Y-family of GPCRs (Y1, Y2, Y4, Y5) — receptors that it shares with neuropeptide Y (NPY) and pancreatic polypeptide, the three members of the pancreatic polypeptide family.

A critical distinction in PYY biology is the existence of two mature circulating forms: PYY 1-36 (full-length peptide) and PYY 3-36 (generated by dipeptidyl peptidase-4 [DPP-4] cleavage of the N-terminal Tyr-Pro dipeptide). PYY 1-36 binds all Y receptor subtypes with similar affinity, while PYY 3-36 is a Y2-receptor selective agonist. This DPP-4-mediated conversion effectively changes the receptor-selective profile of circulating PYY after meals, making PYY 3-36 the dominant bioactive form at Y2 receptors in arcuate nucleus NPY/AgRP neurons, where it suppresses appetite.

PYY has become a prominent model peptide for post-prandial satiety signaling, alongside GLP-1, oxyntomodulin, and cholecystokinin. Its prominence was reinforced by findings that PYY plasma levels rise dramatically after bariatric surgery (Roux-en-Y gastric bypass), contributing to post-surgical appetite reduction, and that obese individuals have blunted postprandial PYY responses.

Structure/Sequence

Human PYY 1-36: YPIKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY-NH₂

Human PYY 3-36: IKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY-NH₂

• Length (PYY 1-36): 36 amino acids
• Length (PYY 3-36): 34 amino acids
• Molecular weight: ~4,300 g/mol (PYY 1-36)
• Gene: PYY (chromosome 17q21.1)
• C-terminal amidation: Essential for receptor binding
• N-terminal Tyr-Pro dipeptide: Cleaved by DPP-4 to generate PYY 3-36

PP-Fold Structure

PYY, NPY, and PP share a characteristic "PP-fold" tertiary structure:

• N-terminal polyproline II helix (residues 1-8)
• Hairpin turn
• C-terminal α-helix (residues 15-32)
• Hydrophobic interior packing between the helical segments

This compact hairpin structure is stabilized by hydrophobic interactions and is essential for high-affinity receptor binding. The C-terminal pentapeptide (TRQRY-NH₂) is the critical "message" for Y receptor activation.

Relationship to NPY and PP

PYY shares the PP-fold with neuropeptide Y (70% identity) and pancreatic polypeptide (~50% identity). The three peptides have distinct Y-receptor selectivity profiles that distinguish their physiology.

Mechanism of Action

Y-Receptor Family

PYY binds Y-family GPCRs (Gi/o-coupled, inhibit adenylyl cyclase):

• Y1R: Broadly distributed; mediates vasoconstrictor and anti-anxiety effects of NPY; PYY 1-36 binds well, PYY 3-36 poorly
• Y2R: Key receptor for PYY 3-36 satiety effects; located on NPY/AgRP neurons in arcuate nucleus as autoreceptor
• Y4R: Primarily a PP receptor; moderate PYY activity
• Y5R: Implicated in feeding and anxiety; both PYY forms bind

DPP-4 Conversion

Dipeptidyl peptidase-4 (DPP-4) cleaves the Tyr-Pro N-terminal dipeptide of PYY 1-36 to yield PYY 3-36. This conversion:

• Produces a Y2-selective agonist from a pan-Y receptor agonist
• Shifts pharmacology toward appetite suppression
• Occurs in circulation and on cell surfaces (DPP-4/CD26 is membrane-bound and soluble)

Postprandial Release

• L-cells release PYY in response to luminal nutrients
• Release is proportional to caloric load, with fat and protein particularly stimulatory
• Peak plasma concentrations occur 1-2 hours after meals
• PYY 3-36 generation occurs post-release through DPP-4 activity

Appetite Suppression

• Y2 autoreceptors on NPY/AgRP neurons in arcuate nucleus
• PYY 3-36 binding inhibits these orexigenic neurons via Gi-mediated hyperpolarization
• Reduces NPY release
• Indirectly disinhibits POMC neurons
• Net effect: reduced food intake

Gastrointestinal Effects

• Delays gastric emptying
• Reduces intestinal motility
• Inhibits gastric acid and pancreatic exocrine secretion
• Part of the "ileal brake" mechanism limiting intestinal transit
• Enhances sodium and water absorption

Bariatric Surgery Effects

• Plasma PYY rises dramatically after Roux-en-Y gastric bypass
• Contributes to post-surgical appetite reduction
• Blunted PYY response in obesity is partially restored after surgery

Research Summary

Common Discussion Topics

1. PYY 3-36 and Y2 selectivity — The conversion of pan-Y agonist PYY 1-36 to Y2-selective PYY 3-36 by DPP-4 is an elegant example of post-release peptide modification that changes receptor selectivity. This shifts the physiological profile of PYY over time after release.

2. Ileal brake physiology — PYY is a canonical "ileal brake" hormone, released when nutrients reach the distal small intestine and signaling back to slow proximal GI motility. This feedback helps coordinate the pace of digestion with absorptive capacity.

3. Bariatric surgery mechanism — The post-bariatric rise in PYY (and GLP-1) is a major contributor to the sustained appetite reduction after gastric bypass. This has made PYY a compelling target for "medical bariatrics" — pharmacological mimicry of surgical metabolic benefits.

4. PP-fold family — PYY, NPY, and PP form a structural family with shared PP-fold and partially overlapping Y-receptor pharmacology. Studying their comparative pharmacology has been informative for designing receptor-selective tools.

5. Therapeutic development challenges — Despite decades of interest, PYY-based therapeutics have progressed slowly. Nasal and injectable PYY 3-36 formulations have been studied; the Y2 agonist obicagonalutide and similar agents represent current development.

Related Compounds

• Pancreatic Polypeptide — related PP-fold family member
• Neuropeptide Y — closest structural relative with opposite CNS effects
• GLP-2 — co-secreted L-cell peptide
• Oxyntomodulin — co-released satiety peptide