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The gut hormone peptide YY (PYY) belongs to the pancreatic polypeptide (PP) family along with PP and neuropeptide Y (NPY). These peptides mediate their effects through the NPY receptors of which there are several subtypes (Y1, Y2, Y4, and Y5). The L cells of the gastrointestinal tract are the major source of PYY, which exists in two endogenous forms: PYY(1-36) and PYY(3-36). The latter is produced by the action of the enzyme dipeptidyl peptidase-IV (DPP-IV). PYY(1-36) binds to and activates at least three Y receptor subtypes (Y1, Y2, and Y5), whereas PYY(3-36) is more selective for Y2 receptor (Y2R). The hypothalamic arcuate nucleus, a key brain area regulating appetite, has access to nutrients and hormones within the peripheral circulation. NPY neurons within the arcuate nucleus express the Y2R. In response to food ingestion plasma PYY(3-36) concentrations rise within 15 min and plateau by approximately 90 min. The peak PYY(3-36) level achieved is proportional to the calories ingested, suggesting that PYY(3-36) may signal food ingestion from the gut to appetite-regulating circuits within the brain. We found that peripheral administration of PYY(3-36) inhibited food intake in rodents and increased C-Fos immunoreactivity in the arcuate nucleus. Moreover, direct intra-arcuate administration of PYY(3-36) inhibited food intake. We have shown that Y2R null mice are resistant to the anorectic effects of peripherally administered PYY(3-36), suggesting that PYY(3-36) inhibits food intake through the Y2R. In humans, peripheral infusion of PYY(3-36), at a dose which produced normal postprandial concentrations, significantly decreased appetite and reduced food intake by 33% over 24 h. These findings suggest that PYY(3-36) released in response to a meal acts via the Y2R in the arcuate nucleus to physiologically regulate food intake.