The Discovery of Peptide YY

Category	Research
Also known as	PYY history, peptide tyrosine tyrosine, PYY 3-36
Last updated	2026-04-14
Reading time	3 min read
Tags	historypyygut-peptidessatietyL-cells

Overview

Peptide YY (PYY) is a 36-amino-acid peptide secreted by L-cells of the distal small intestine and colon in response to nutrient ingestion. It was identified in 1980 by Kazuhiko Tatemoto and Viktor Mutt at the Karolinska Institute in Stockholm, as part of Mutt's long-running systematic search for novel gut peptides. The name "PYY" reflects the peptide's N- and C-terminal tyrosine residues ("Y" in single-letter amino acid code).

PYY is closely related in sequence to two other peptides: neuropeptide Y (NPY), a widespread neuropeptide, and pancreatic polypeptide (PP), a pancreatic islet hormone. Together they form the NPY family, all of which share structural features and a set of related G protein-coupled receptors (Y1, Y2, Y4, Y5).

PYY circulates primarily as PYY-(1-36) and PYY-(3-36), the latter produced by cleavage at the amino-terminus by dipeptidyl peptidase-4 (DPP-4). PYY-(3-36) is a selective Y2 receptor agonist and is considered the major bioactive form for anorexigenic effects. Rising postprandial PYY levels contribute to the sense of fullness at the end of a meal, and this has made PYY a target of interest for obesity therapy.

Key People

Viktor Mutt (1923–1998): Leader of the Karolinska peptide-discovery program.
Kazuhiko Tatemoto: First author of the PYY discovery paper; isolated NPY and PYY in the same time frame.
Stephen R. Bloom and Rachel L. Batterham: British endocrinologists who performed influential human PYY satiety studies.
Karolina Skibicka and others: Neuroscientists studying PYY effects in the central nervous system.

Timeline

1980: Tatemoto and Mutt isolate PYY from porcine intestine.
1982: NPY is also isolated, revealing the PYY/NPY/PP family.
1990s: Y receptors (Y1–Y5) are cloned.
2002: Batterham and colleagues report that PYY-(3-36) reduces food intake in humans.
2010s: Roux-en-Y gastric bypass shown to dramatically elevate PYY and GLP-1, implicating these peptides in post-surgical weight loss.
2020s: PYY analogs and PYY/GLP-1 combinations studied as obesity therapies.

Background

PYY is part of a coordinated gut endocrine response to food. L-cells co-secrete PYY and GLP-1 in response to nutrients, particularly lipids and proteins, reaching the distal small intestine. These peptides slow gastric emptying (the "ileal brake"), enhance insulin secretion, and signal satiety through both peripheral and central pathways. PYY-(3-36) acts on Y2 receptors in the arcuate nucleus of the hypothalamus to inhibit NPY/AgRP neurons and thereby reduce appetite.

Bariatric surgery provided a natural experiment in PYY biology. Roux-en-Y gastric bypass and sleeve gastrectomy produce exaggerated postprandial PYY and GLP-1 responses, far larger than those seen in typical diet-induced weight loss. This hormonal shift is thought to contribute to the sustained appetite suppression and weight loss seen after these procedures.

Modern Relevance

PYY has attracted pharmaceutical interest as a potential anti-obesity target. Native PYY-(3-36) is limited by short half-life, nausea, and receptor desensitization at higher doses, but stabilized analogs and long-acting formulations are in clinical development. Several programs are testing PYY analogs in combination with GLP-1 receptor agonists, aiming to recapitulate the PYY + GLP-1 surge seen after bariatric surgery without the procedure.

Beyond obesity, PYY is studied in gastrointestinal motility disorders, short bowel syndrome, and inflammatory bowel disease. Y-receptor-selective compounds offer a way to dissect the many roles of the NPY/PYY/PP family. For broader context, see neuropeptide-y-history and glp-1-discovery.