Peptide YY

Overview

Peptide YY (PYY) is a 36-amino acid member of the pancreatic polypeptide (PP) family, first isolated from porcine intestine by Tatemoto in 1982. Named for its N-terminal tyrosine (Y) and C-terminal tyrosine residues, PYY is secreted by enteroendocrine L cells concentrated in the distal ileum, colon, and rectum. Circulating PYY levels rise postprandially, contributing to satiation and the ileal brake mechanism that slows proximal GI motility.

Structure and Biosynthesis

PYY is produced as a 96-amino acid prepropeptide that undergoes proteolytic processing to yield the mature 36-residue hormone. Two bioactive forms exist: PYY(1-36) and the truncated PYY(3-36), generated by dipeptidyl peptidase IV (DPP-IV) cleavage of the N-terminal Tyr-Pro residues. PYY(3-36) is the predominant circulating form and exhibits selectivity for the Y2 receptor. The peptide adopts a hairpin-like structure stabilized by a PP-fold motif, which is conserved across the PP family.

Receptor Pharmacology

PYY acts through Y receptors (Y1, Y2, Y4, and Y5), which are G-protein-coupled receptors coupled to Gi/Go, inhibiting adenylyl cyclase. PYY(1-36) binds all Y receptor subtypes with varying affinity, while PYY(3-36) preferentially activates Y2. In the hypothalamus, PYY(3-36) inhibits NPY neurons in the arcuate nucleus, reducing orexigenic signaling. Y2 receptors on vagal afferents relay satiety signals to the brainstem nucleus tractus solitarius.

Physiological Actions

PYY delays gastric emptying and reduces small intestinal and colonic motility (the ileal brake). This mechanism optimizes nutrient absorption by slowing transit through the gut. In the hypothalamus, PYY suppresses food intake in a dose-dependent manner. Plasma PYY is reduced in obesity and increased after bariatric surgery, suggesting a role in long-term energy balance. PYY also modulates intestinal secretion and may have anti-inflammatory effects in the GI tract.

Clinical Implications

Recombinant PYY(3-36) has been investigated as an anti-obesity agent, producing transient reductions in food intake in human trials. PYY agonists targeting Y2 receptors represent potential therapies for hyperphagia syndromes. Elevated PYY levels are observed in inflammatory bowel disease and post-vagotomy dumping syndrome. PYY’s role in the gut-brain axis continues to be explored for metabolic and neuropsychiatric applications.