Peptide YY

What is Peptide YY?

Peptide YY (PYY) is a 36-amino-acid peptide hormone secreted from L-cells of the distal small intestine and colon in response to nutrient ingestion. The full-length PYY 1-36 is rapidly cleaved by dipeptidyl peptidase-4 (DPP-4) to PYY 3-36 — the predominant circulating bioactive form (about 70% of circulating PYY in fed humans).

PYY 3-36 is one of the body's most important endogenous satiety signals. It is research-only as a therapeutic, but long-acting PYY analogues are in clinical development as adjuncts to GLP-1 agonists in obesity, where the complementary satiety mechanism may augment weight loss without proportionally adding GI side effects.

Structure and Family

PYY belongs to the pancreatic polypeptide family along with:

• NPY (neuropeptide Y) — central nervous system, orexigenic
• PP (pancreatic polypeptide) — pancreatic, postprandial
• PYY — gut, satiety signal

All three share a common "PP-fold" structure — a tight hairpin where N- and C-termini fold together.

The DPP-4 cleavage that produces PYY 3-36 from PYY 1-36 changes receptor selectivity dramatically:

• PYY 1-36 — binds Y1, Y2, Y5 receptors broadly
• PYY 3-36 — Y2 receptor selective (>50× selectivity over Y1, Y5)

This Y2 selectivity is the key to PYY's satiety pharmacology.

Mechanism of Action

• Y2 receptor activation — PYY 3-36 binds Y2 receptors on hypothalamic NPY/AgRP neurons in the arcuate nucleus
• Inhibition of orexigenic NPY signaling — Y2 is an autoreceptor that suppresses NPY release
• Net anorexigenic effect — reduced appetite, smaller meal sizes
• Slowed gastric emptying — additional satiety contribution
• Independent of GLP-1 — complementary to GLP-1 receptor pharmacology

The clinical hypothesis: combining Y2 satiety with GLP-1 satiety produces additive food-intake reduction with potentially less proportional nausea/GI burden.

Clinical Evidence

Original NEJM 2003 study (Batterham et al.):

• Single-dose IV PYY 3-36 in obese vs lean subjects
• 30% reduction in 24-hour food intake in obese subjects
• Established PYY 3-36 as a robust endogenous satiety signal in humans

Long-acting PYY analogue trials (2024-2025):

• PYY1875 (Novo Nordisk) and similar long-acting PYY analogues are in Phase 2
• Results so far show modest weight loss as monotherapy, with greater effects when added to GLP-1 agonists
• The additive effect with GLP-1 supports the rationale of combination therapy

Research and Clinical Investigation

PYY 3-36 is used in research as:

• A probe of Y2 receptor pharmacology
• A satiety challenge in metabolic studies (intranasal or IV administration)
• A reference for evaluating long-acting PYY analogues

Long-acting PYY analogues are in active clinical development from multiple sponsors as adjunct or combination therapy to GLP-1 agonists, rather than as standalone obesity drugs. The hypothesis is that Y2-selective satiety adds incremental weight loss to GLP-1 monotherapy in patients who plateau or have insufficient response.

Distinction from NPY

NPY and PYY are closely related (38% sequence identity, both 36 AA, same PP-fold structure) but functionally opposite:

Same family, opposite metabolic effects, driven by Y2 receptor selectivity.

Distinction from Cagrilintide

Both PYY analogues and cagrilintide are non-incretin satiety signals being developed as GLP-1 combination partners:

These represent two different "second mechanism" approaches to augmenting GLP-1 weight loss.

Place in Research

PYY remains a fundamental research peptide for satiety physiology, gut-brain communication, and obesity drug discovery. It is sold by research chemical suppliers as PYY 3-36 (the bioactive form). Long-acting analogues are advancing in clinical development.