Peptide YY (PYY) is a 36-amino-acid peptide hormone produced primarily in the enteroendocrine L cells of the intestinal epithelium, which inhibits gastric acid secretion, pancreatic exocrine secretion, and food intake. It is a member of the PP-fold family of peptides and is released in response to dietary fat.
AI generated definition based on: Handbook of Biologically Active Peptides, 2006
Peptide YY (PYY) is a 36-amino-acid gut hormone primarily secreted by enteroendocrine L cells located in the distal small intestine and colon in response to food intake. It plays a crucial role in appetite regulation, energy homeostasis, and gastrointestinal functions. PYY exists in two main molecular forms: the full-length PYY1-36 and the truncated PYY3-36, which is generated by cleavage via the enzyme dipeptidyl peptidase IV (DPP-IV) and represents the predominant postprandial circulating form. PYY3-36 displays selective affinity for the Y2 receptor subtype, while PYY1-36 has affinity for Y1 and Y2 receptors.
Following food ingestion, circulating PYY levels begin to rise within 15 minutes, peak at 1–2 hours, and remain elevated for several hours postprandially. The release of PYY is proportional to caloric intake and influenced by the macronutrient composition of the meal. PYY3-36 crosses the blood-brain barrier and interacts with central nervous system pathways, including hypothalamic arcuate neurons, to modulate appetite and satiety. Alterations in PYY release and sensitivity have been documented in physiological and pathological states such as obesity and eating disorders, with lower postprandial PYY levels observed in obese individuals and dysregulated PYY responses reported in conditions like bulimia nervosa and anorexia nervosa.
Peptide YY belongs to the pancreatic polypeptide-fold (PP-fold) family, sharing structural homology and a hairpin-like tertiary structure with neuropeptide Y (NPY) and pancreatic polypeptide (PP). It contains tyrosine residues at both the amino and carboxy terminals; the carboxy-terminal tyrosine amidation is essential for its biological activity. The full-length isoform, PYY1-36, is produced by enteroendocrine L cells in the distal gut and released into circulation in response to nutrient intake. PYY1-36 is rapidly cleaved by DPP-IV, which removes the N-terminal Tyr-Pro dipeptide to generate PYY3-36, the predominant circulating form postprandially.
PYY1-36 binds with high affinity to Y1, Y2, and Y5 receptor subtypes, but has lower affinity for Y4; PYY3-36 is a selective high-affinity agonist at the Y2 receptor, with markedly reduced affinity for Y1 and Y4 receptors. The Y receptor family consists of G-protein-coupled receptors (GPCRs) with five subtypes cloned in mammals: Y1, Y2, Y4, Y5, and Y6; however, Y6 is nonfunctional in humans. These receptors are distributed in both the central and peripheral nervous systems, including the hypothalamic arcuate nucleus, brainstem regions such as the area postrema and nucleus tractus solitarius, and on vagal afferents.
Upon ligand binding, Y receptors couple to inhibitory G proteins, resulting in inhibition of adenylate cyclase and reduction of cyclic adenosine monophosphate (cAMP) accumulation; they also modulate intracellular calcium channels and can mediate presynaptic inhibition of neurotransmitter release. Activation of Y2 receptors by PYY3-36 in the hypothalamus and brainstem leads to suppression of appetite.
PYY3-36 is released from endocrine L cells in the distal ileum and colon in response to food intake and acts as a satiety signal by binding with high affinity to presynaptic Y2 receptors on neuropeptide Y/agouti-related peptide (NPY/AgRP) neurons in the arcuate nucleus (ARC) of the hypothalamus, inhibiting their orexigenic activity. PYY3-36 can access the brain via circumventricular organs such as the area postrema and subfornical organ, and may permeate the blood–brain barrier to a certain extent. Direct injection of PYY3-36 into the ARC reduces food intake, while injection into the paraventricular nucleus does not, confirming anatomical specificity. Peripheral administration of PYY3-36 increases c-Fos expression in the ARC and other metabolic regulation and reward regions, including the nucleus of the solitary tract (NTS), central amygdala, and nucleus accumbens (NAc). PYY3-36 also increases c-Fos expression in the ARC, NTS, area postrema, amygdala, and thalamus.
Vagal afferent pathways convey PYY3-36 signals from the periphery to the brainstem. The anorectic effects of PYY3-36 are abolished by vagotomy, indicating the importance of the vagus nerve in mediating these effects. Animal and human studies demonstrate that peripheral infusion of PYY3-36 reduces food intake in a dose-dependent manner, decreases meal size and duration, and increases satiety, with effects lasting up to 12 hours after administration. These effects are observed in both lean and obese subjects and are abolished in Y2 receptor-null mice or by Y2 receptor antagonists.
PYY3-36 also modulates dopaminergic reward pathways, increasing dopamine release in the striatum and activating reward-related brain regions such as the orbitofrontal cortex (OFC), ventral tegmental area (VTA), ventral striatum, and insula. Functional neuroimaging studies show that PYY3-36 infusion alters neuronal activity in homeostatic and reward regions, with changes in OFC activation predicting food intake and attenuating neural responses to food cues. PYY3-36-induced enhancement of striatal dopamine activity is associated with modulation of salience attribution and behavioral responses. The physiological role of endogenous PYY in feeding regulation remains to be fully established. Environmental stressors can influence the expression of PYY3-36’s anorectic effects.
PYY is secreted by enteroendocrine L cells in the distal ileum and colon in response to nutrient stimuli, particularly fats and proteins. It is a key neurohumoral component of the ileal brake mechanism, which inhibits gastric emptying and slows the delivery of nutrients to the small intestine, thereby modulating intestinal transit and contributing to satiety. The inhibitory effects of PYY on gastric acid secretion and pancreatic exocrine function are mediated via Y1 and Y2 receptors located on enteric neurons and epithelial cells.
Neural reflexes involving vagal afferents and central nuclei, such as the dorsal vagal complex, mediate the actions of PYY on digestion and energy balance, with PYY able to access these brainstem regions through fenestrated capillaries. PYY’s effects on satiety and energy homeostasis are further modulated by interactions with other gut hormones, including glucagon-like peptide-1 (GLP-1), which can have additive effects on energy intake. The release of PYY is influenced by hormonal factors and modulation by gut microbiota-derived short-chain fatty acids.
Evidence suggests that PYY3-36 modulates central dopamine systems and impacts behavioral domains such as salience learning and working memory. The secretion and function of PYY are also subject to modulation by gut microbiota, which can alter enteroendocrine cell activity and PYY levels.
