| Pancreatic polypeptide (PP) is a 36–amino acid member of the neuropeptide Y (NPY) family that is synthesized and stored in PP (F) cells of the endocrine pancreas, predominantly in the ventral head region, and released into the circulation in response to nutrient stimulation and vagal cholinergic input as a systemic regulator of digestive function and energy homeostasis. The peptide adopts the characteristic PP‑fold, a compact polyproline II helix followed by an α‑helix, which presents key side chains for high‑affinity binding to Y4 receptors and lower‑affinity engagement of Y5 and, in some species, Y6 receptors, enabling selective activation of G protein–coupled receptor signaling in the brainstem, hypothalamus, and pancreatic islets. Secretion follows a biphasic pattern after a meal, with an early vagally mediated component and a later intestinal phase driven by cholecystokinin and other gut hormones; cholinergic vagal stimulation is the dominant driver of PP release and acts as an obligatory conduit for many other secretagogues, making PP a sensitive readout of vagal tone and autonomic regulation of the endocrine pancreas. Circulating PP feeds back on the exocrine pancreas, where it inhibits secretion of fluid, bicarbonate, and digestive enzymes and counteracts cholecystokinin‑induced pancreatic secretion, and on the biliary tract and stomach, where it reduces gallbladder contraction and alters gastric emptying, thereby coordinating postprandial digestive efficiency and limiting excessive pancreatic output. At the level of central energy balance, PP acting via Y4 receptors on vagal afferents and hypothalamic nuclei, including the arcuate, ventromedial, and lateral hypothalamus, suppresses food intake, decreases orexin expression in the lateral hypothalamic “feeding center,” and increases brain‑derived neurotrophic factor expression in the ventromedial “satiety center,” resulting in a net anorexigenic effect that reduces body weight and adiposity in animal models with exogenous PP administration or PP overexpression. PP also signals directly to pancreatic islets, where Y4/Y1‑family receptors on α cells mediate an inhibitory effect on glucagon secretion, linking postprandial PP rises to modulation of hepatic glucose output and contributing to fine‑tuning of glucose homeostasis alongside insulin and somatostatin. Low PP responses are associated with vagal dysfunction and chronic pancreatitis, and markedly elevated PP levels with PP‑secreting neuroendocrine tumors, while pharmacological or supraphysiological PP infusion in humans alters satiety, gastric accommodation, and food tolerance, underscoring its potential as a tool to probe gut–brain signaling and as a candidate target for anti‑obesity and metabolic therapies. |
