Version May 2024
INTRODUCTION — Originally isolated in 1968 during the preparation of insulin, pancreatic polypeptide (PP) is the founding member of the pancreatic polypeptide family [1,2]. The PP family of peptides includes peptide YY (PYY) and neuropeptide Y (NPY), which were discovered based upon their chemical structure (possessing a carboxyl-terminal tyrosine amide) [3-5]. PP, PYY, and NPY are all 36 amino acids in length, and despite structural similarities, they are found in different locations throughout the gastrointestinal tract and nervous system and possess different biological actions. PP is expressed in endocrine cells of the gut and pancreas, PYY is located in enteroendocrine cells of the ileum and colon and nerves of the enteric nervous system, and NPY is found in the central and peripheral nervous system. This wide distribution suggests that these peptides regulate many different physiological processes.
MOLECULAR FORMS — The pancreatic polypeptide (PP) peptides share a significant degree of sequence homology that produces a polyproline helix, an amphipathic alpha-helix, and an amidated carboxyl terminus, resulting in a hairpin fold known as the PP-fold (figure 1) [6]. Although unusual for small peptides, it is believed that this tertiary structure is important for the peptides' biological activities.
TISSUE DISTRIBUTION — Pancreatic polypeptide (PP) is secreted by specialized pancreatic islet cells (PP cells) that are distinct from those producing insulin, glucagon, or somatostatin [7].
Neuropeptide Y (NPY) is a principal neurotransmitter found in the central and peripheral nervous systems and is predominantly found in sympathetic neurons [8-10].
Peptide YY (PYY) has been localized to enteroendocrine cells in the mucosa of the gastrointestinal tract and is most highly concentrated in the ileum and colon [11]. PYY is produced predominantly by L cells of the ileum and colon where it is colocalized with enteroglucagon. PYY is also produced in other enteroendocrine cells throughout the intestine [12]. It has long been held that enteroendocrine cells are elongated or "flask"-shaped cells that reside in the intestinal mucosa with their apical surface open to the lumen of the intestine. In this position, enteroendocrine cells can "sense" luminal contents such as food or bacteria. Stimulation of cells causes the release of hormones from the basal surface into the paracellular space, where they are taken up by blood vessels and carried to distant sites of action. However, a new concept for enteroendocrine cell function is now apparent with the discovery that PYY cells possess neuropods that extend from their basal surface (figure 2) [13,14]. Neuropods contain many features typical of neurons, including synaptic boutons, neurofilaments, pre- and post-synaptic proteins, and small, clear synaptic vesicles. Moreover, it has been discovered that enteroendocrine cells connect directly with enteric nerves [15]. This new epithelial-neural circuit provides a pathway for the gut to connect directly to the brain. It is possible that this pathway is involved in how the brain senses gut contents.
RECEPTORS — The biologic actions of the PP/PYY/NPY family of peptides result from binding to a multitude of receptor subtypes [16]. At present, five functional receptor subtypes have been identified, all of which are typical G protein-coupled receptors that have been designated "Y" receptors (table 1) [17-21]. These receptors signal through the GTP-binding proteins Gi/Go and inhibit adenylyl cyclase. Another mechanism for signaling also involves inhibition of calcium and potassium channels that have been demonstrated in cardiac myocytes and smooth muscle cells. A sixth Y receptor has been found in some species, but its function has not been clearly established [22]. (See "Peptide hormone signal transduction and regulation".)
PEPTIDE RELEASE — The pancreatic polypeptide (PP) family of peptides functions as endocrine, paracrine, and neurocrine transmitters. Neuropeptide Y (NPY) is a true neurotransmitter, being released from nerve terminals, while peptide YY (PYY) and PP are hormones acting in both a paracrine and endocrine manner. Following a meal, PP is released into the blood from PP cells of the pancreas via vagal-cholinergic stimulation [23]. PP concentrations also fluctuate with the myoelectric activity of the gastrointestinal tract. Plasma PP levels increase in phase with the periodic contraction and secretion of the gut, an effect that is abolished with ganglionic blockade [24]. There is growing evidence that gut microbiota influence the nervous system, and it is likely that this occurs through release of hormones such as PYY or through the enteroendocrine cell-neuronal connection described above [25].
In contrast to PP, PYY levels change very slowly and not to the same degree in response to a meal. Moreover, PYY release does not depend upon intact vagal input [26]. Meal-stimulated PYY release in humans occurs largely in response to ingested fat, primarily short-chain and polyunsaturated fatty acids [27]. Gastrointestinal diseases that cause malabsorption increase blood levels of PYY. In addition, surgical conditions that increase the delivery of food to the distal ileum and colon including small bowel resection, vertical band gastroplasty, Roux-en-Y gastric bypass, and jejunoileal bypass also elevate circulating PYY levels [28]. G protein-coupled receptor 119 (GPR119) agonists have been shown to stimulate PYY release (along with glucagon-like peptide 1 and glucose-dependent insulinotropic peptide), indicating that GPR119 may be directly involved in hormone secretion [29]. PYY cells, like other enteroendocrine cells, also possess taste receptors that are linked to PYY secretion [30].
During inflammation, NPY is produced by T cells, macrophages, and dendritic cells [31].
The gut microbiota appear to modulate the release of hormones that are produced in the ileum and colon, including PYY [32]. These effects may be through direct actions of microbes themselves or microbial metabolites such as short-chain fatty acids [33,34]. As such, prebiotics or probiotics are being investigated as ways to manipulate behaviors like eating through effects on gastrointestinal hormone release
Physiological actions — PP has a number of inhibitory actions that are believed to be important for both pancreatic and gastrointestinal function. Because many of its actions are local, it has been difficult to assess the magnitude of PP's effects in the pancreas; however, it is well recognized to inhibit pancreatic exocrine secretion [35]. In addition, PP has inhibitory effects on gallbladder contraction and gut motility [36,37], and may influence food intake, energy metabolism, and the expression of gastric ghrelin and hypothalamic peptides [38]. PYY inhibits vagally stimulated gastric acid secretion and other motor and secretory functions [39-41]. PYY-producing cells of the ileum are stimulated by incompletely digested nutrients, particularly fats. PYY released into the bloodstream can inhibit several gastrointestinal processes, including gastric emptying and intestinal motility, thus delaying the delivery of additional food to the intestine. This concept is known as the "ileal brake" and is believed to be mediated largely by PYY (figure 3) [42]. Like PP, PYY also signals to the brain to reduce food intake by acting on Y2 receptors in the hypothalamus [43]. In the periphery, PYY induces lipolysis and improves glycemic control by increasing insulin sensitivity through a reduction in circulating fatty acids [44]. PYY may have a detrimental effect on bone density [45] by suppressing osteoblast activity via the Y1 receptor [46]. These findings are consistent with the observations that transgenic overexpression of PYY in mice reduced bone mass [47]. In contrast, PYY knockout mice exhibited increased bone mass.
NPY is one of the most abundant peptides in the CNS and is the most potent known stimulant of food intake [48]. In the arcuate nucleus of the hypothalamus, NPY levels increase sharply under conditions of food deprivation, which leads to an increase in food intake to restore the homeostatic condition [49]. Peripherally, NPY affects vascular and gastrointestinal smooth muscle function by binding to the Y1 receptor and through its G protein stimulates phospholipase C, resulting in the accumulation of IP3 and increased cytosolic calcium [6,36,50]. NPY also has proinflammatory effects by virtue of activating immune cells that express NPY receptors. Specifically, NPY stimulates leukocyte migration and adhesion and activates macrophages to produce inflammatory cytokines such as IL-4, IL-12, and TNF-alpha [51].
CLINICAL IMPLICATIONS OF THE PP/PYY/NPY FAMILY OF PEPTIDES — The observation that pancreatic polypeptide (PP) is secreted from the pancreas in response to vagal nerve stimulation has been used as a diagnostic test of vagal nerve function. Cephalic stimulation of the vagus nerve, such as occurs with sham feeding, stimulates release of PP that can be measured in the blood. However, following vagotomy this response is lost.
Although possessing a long evolutionary lineage, and many important effects on the gastrointestinal tract, no members of the PP family of peptides are used clinically as therapeutic agents. However, perhaps the most important possibilities pertain to regulation of food intake. An animal model overexpressing pancreatic polypeptide demonstrated reduced body weight and food intake [52] and protection against diet and genetic obesity [53]. Conversely, peptide YY (PYY) knock-out mice are predisposed to obesity and insulin resistance [54].
In addition, substantial data indicate that neuropeptide Y (NPY) and its receptor are potential targets for regulation of appetite and feeding and are involved in the pathogenesis of obesity [55,56]. Release of NPY and activation of the NPY Y2 receptor stimulate fat angiogenesis, macrophage infiltration, and the proliferation and differentiation of adipocytes, resulting in abdominal obesity and a metabolic syndrome-like condition [56]. The Y5 receptor has been proposed as an "appetite receptor," however other Y family receptors also play a role in this complex behavior. It was demonstrated in humans that aerobic exercise increased circulating PYY levels while suppressing hunger [57].
Animal models lacking various Y family receptors have been studied. Mice produced with an inactivated Y5 receptor manifested late-onset obesity, yet developed normally [58], while mice deficient in Y1 receptor expression demonstrated only mild reduction in daily food intake and NPY-stimulated feeding. However, after fasting, short-term feeding was significantly reduced in these animals [59]. Gene deletion of the Y2 receptor in mice resulted in increased food intake, body weight, and fat deposition, providing strong evidence for the importance of this receptor in regulating ingestive behavior [60]. Targeted overexpression in the dorsomedial hypothalamus increased food intake whereas ablation in this area reduced hyperphagia and obesity [61]. The ability to target specific neural pathways in the brain will be important for dissecting the location-specific functions of NPY in the regulation of energy metabolism.
Although PYY acutely inhibits insulin secretion, prolonged activation of Y1 receptors on pancreatic beta cells exerts beta cell protective effects [62]. Therefore, it has been proposed that PYY-based drugs could be used as a therapeutic strategy in the management of diabetes mellitus.
Ghrelin, originally discovered as a growth hormone receptor ligand, has been demonstrated to antagonize leptin action through activation of the NPY Y1 receptor [38,63]. Ghrelin is an acylated peptide that is produced in the stomach and hypothalamus and stimulates feeding and growth hormone release [64,65]. Intracerebroventricular injections of ghrelin stimulated feeding in rats that were deficient in growth hormone and this action was suppressed when the animals were treated with anti-ghrelin antibodies. Similarly, NPY antagonists abolished this effect. Furthermore, ghrelin treatment also enhanced NPY gene expression [64]. It appears ghrelin may be clinically useful as a growth hormone stimulant in cases of deficiency and/or as an appetite stimulant in patients with cachexia [66].
The PP family clearly has a role in feeding behavior. However, regulation of appetite is complex and involves many interacting components, including a number of signaling mechanisms [67]. Although the 36 amino acid form of PYY (PYY1-36) was the form originally isolated from intestine, a shortened form lacking the first two amino acids (PYY3-36) also exists and may play a physiological role in the regulation of food intake. In humans, PYY1-36 acts through four Y-receptor subtypes, Y1, Y2, Y4 and Y5, while PYY3-36 is a specific agonist at the Y2 receptor.
Both PYY1-36 and PYY3-36 cross the blood-brain barrier and participate in the regulation of food intake and satiety. Activation of the Y1 and Y5 receptors by PYY1-36 has been shown to increase food intake and cause weight gain, whereas activation of the Y2 receptor by PYY3-36 inhibits NPY release from cells of the arcuate nucleus, thereby decreasing food intake and resulting in weight loss [28]. A study in lean and obese humans demonstrated that infusion of PYY3-36 decreased caloric intake by approximately 30 percent compared with placebo when subjects were offered a buffet meal [68]. In addition, 24 hour caloric intake was reduced. Obese adults and children have significantly lower fasting PYY levels and levels correlate inversely with body mass index [69].These observations suggest that PYY has an important regulatory role in feeding behavior, potentially offering a target for drug development.
In a large cohort of extremely obese individuals, a genetic variant in the coding region of the PYY gene (PYY Q62P) exhibiting familial segregation has been identified [70]. Interestingly, unlike wild-type PYY, the mutated PYY protein demonstrated altered receptor binding and failed to reduce food intake when tested in vivo. These data suggest that rare mutations in PYY may influence human susceptibility to obesity.
In addition to effects on feeding, PYY has been shown to influence other behaviors such as perception, judgment, learning, and memory [71]. These effects may be through dopaminergic neural pathways in the central nervous system.
NPY has a variety effects corresponding to the wide distribution of Y receptors in various tissues. One of the most intriguing actions of NPY is the neuroprotective effects conferred through stimulation neural stem cell proliferation [72]. In this regard, it has been postulated that NPY may offer some protection in neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. Interestingly, NPY appears to be involved in emotional and affective behaviors. In preclinical studies, NPY has been shown to exert anxiolytic and stress-reducing effects through Y1 receptor specific actions and fear extinction and long-term suppression of fear through activation of the Y2 receptor [73]. In the periphery, NPY increases beta cell mass by virtue of NPY receptor expression in pancreatic islets [74].
Diseases — A PYY-producing ovarian carcinoid tumor has been associated with severe constipation which may be related to the anti-motility effects of circulating PYY [75]. Under rare conditions in which enteroendocrine cell deficiency may occur, PYY administration may improve nutrient absorption and diminish diarrhea [76].
A reduction in the abundance of PYY cells in the colon of patients with irritable bowel syndrome has been reported [77]. Interestingly, PYY cells were restored when patients were fed a low fermentable oligo-, di-, and monosaccharides and polyols (FODMAP) diet that was used to reduce their abdominal symptoms. It is not known if PYY contributes to the symptoms of irritable bowel syndrome.
SUMMARY
●The pancreatic polypeptide (PP) family of peptides includes peptide YY (PYY) and neuropeptide Y (NPY). PP, PYY, and NPY are found in different locations throughout the gastrointestinal tract and nervous system and possess different biological actions. This wide distribution suggests that these peptides regulate many different physiological processes. NPY is a true neurotransmitter, being released from nerve terminals, while PYY and PP are hormones acting in both a paracrine and endocrine manner.
●PP is secreted by specialized pancreatic islet cells (PP cells) that are distinct from those producing insulin, glucagon, or somatostatin. It inhibits pancreatic exocrine secretion. In addition, PP has inhibitory effects on gallbladder contraction and gut motility, and may influence food intake, energy metabolism, and the expression of gastric ghrelin and hypothalamic peptides. (See 'Tissue distribution' above and 'Physiological actions' above and 'Clinical implications of the PP/PYY/NPY family of peptides' above.)
●NPY is a principal neurotransmitter found in the central and peripheral nervous systems and is predominantly found in sympathetic neurons. It is the most potent known stimulant of food intake. Peripherally, NPY affects vascular and gastrointestinal smooth muscle function by binding to the Y1 receptor and through its G protein stimulates phospholipase C, resulting in the accumulation of IP3 and increased cytosolic calcium. (See 'Tissue distribution' above and 'Physiological actions' above and 'Clinical implications of the PP/PYY/NPY family of peptides' above.)
●PYY has been localized to enteroendocrine cells in the mucosa of the gastrointestinal tract and is most highly concentrated in the ileum and colon. PYY inhibits vagally stimulated gastric acid secretion and other motor and secretory functions. PYY-producing cells of the ileum are stimulated by incompletely digested nutrients, particularly fats. PYY released into the bloodstream can inhibit several gastrointestinal processes, including gastric emptying and intestinal motility, thus delaying the delivery of additional food to the intestine. (See 'Tissue distribution' above and 'Physiological actions' above and 'Clinical implications of the PP/PYY/NPY family of peptides' above.)
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