Distribution of pancreatic polypeptide and peptide YY

The cellular distribution of PP and PYY in mammals is reviewed. Expression of PP is restricted to endocrine cells mainly present in the pancreas predominantly in the duodenal portion (head) but also found in small numbers in the gastro-intestinal tract. PYY has a dual expression in both endocrine cells and neurons. PYY expressing endocrine cells occur all along the gastrointestinal tract and are frequent in the distal portion. Islet cells expressing PYY are found in many species. In rodents they predominate in the splenic portion (tail) of the pancreas. A limited expression of PYY is found also in endocrine cells in the adrenal gland, respiratory tract and pituitary. Peripheral, particularly enteric, neurons also express PYY as does a restricted set of central neurons.     

Feedback regulation of pancreatic secretion by peptide YY

The present status of our understanding of the feedback regulation of pancreatic secretion by peptide YY (PYY) released from the distal intestine is reviewed. Exocrine pancreatic secretion is primarily controlled by the cephalic (the vagus nerve), gastric (acid and pepsin secretion, and nutrients delivered into the duodenum by gastric emptying), and intestinal (secretin and CCK) mechanisms. PYY acts on the multiple sites in the brain and gut, and inhibits pancreatic secretion by regulating these primary control mechanisms. The involvement of Y(1) and Y(2) receptors has been suggested in the regulation of pancreatic secretion. However, it remains to be studied which site of action or receptor subtype is physiologically most important for this regulation.     

Ontogeny and the effect of aging on pancreatic polypeptide and peptide YY

Pancreatic polypeptide (PP) and peptide YY (PYY) are related neuroendocrine peptides that are expressed in specialized cells. PP is found around the time of birth in different species. PYY in mice and rats has been extensively studied. PYY is the first peptide hormone to appear in both the pancreas and the colon and is initially expressed together with all other pancreatic islet and gut hormones. This suggests that there is a PYY-producing endocrine progenitor cell, at least in rodents. Whether the same is true for other species is unknown. In chickens, however, pancreatic insulin and glucagon cells appear before PYY. After birth, PYY levels in rats and humans reflect adaptation to enteral feeding. Whereas PYY cells increase with age in rodents, no such changes have been found in humans.     

Spinal and peripheral modulation of gastric acid secretion and arterial pressure by neuropeptide Y, peptide YY, and pancreatic polypeptide in rats

Spinal and peripheral modulation of pentagastrin-stimulated gastric acid secretion by the pancreatic polypeptide-fold (PP-fold) peptides, neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP), in urethane-anesthetized rats was evaluated. Neuropeptide Y, PYY, and PP (400 pmol) were administered via intravenous (IV) and intrathecal (IT) injections. The ₂ antagonist, yohimbine, was used to evaluate the role of the ₂ adrenergic receptors in the modulation of pentagastrin-stimulated gastric acid secretion by NPY, PYY, and PP. Peptide YY and PP (IV) rapidly increased pentagastrin-stimulated gastric acid secretion. Peptide YY and PP (IT) increased pentagastrin-stimulated gastric acid secretion following administration into the thoracic (T8–T10) region of the spinal cord. The ₂ adrenergic receptor antagonist, yohimbine, did not modify the increases in pentagastrin-stimulated gastric acid secretion following PYY and PP (IV or IT) administration. Neuropeptide Y (IT) decreased pentagastrin-stimulated gastric acid secretion. However, in the presence of ₂ adrenergic receptor blockade, pentagastrin-stimulated gastric acid secretion was potentiated by NPY (IT) administration. Therefore, the inhibitory effect of NPY (IT) on pentagastrin-stimulated gastric acid secretion required the activation of ₂ adrenergic receptors in the spinal cord of rats. Mean arterial blood pressure (MAP) was increased immediately following NPY and PYY (IV) administration. During the same time period, PP (IV) decreased MAP in anesthetized rats. Mean arterial blood pressure was rapidly increased by NPY and PYY (IT) in anesthetized rats. The increase in MAP following PYY (IT) was partially attenuated in the presence of yohimbine. The modulation of MAP and gastric acid secretion by the PP-fold peptides occurred by independent mechanisms at spinal and peripheral sites in the rat. The modulation of pentagastrin-stimulated gastric acid secretion by PYY and PP in rats differed from that of the third member of the PP-fold family, NPY, following spinal and peripheral administration.     

Gastrointestinal satiety signals III. Glucagon-like peptide 1, oxyntomodulin, peptide YY, and pancreatic polypeptide

Many peptides are synthesized and released from the gastrointestinal tract and pancreas, including pancreatic polypeptide (PP) and the products of the gastrointestinal L cells, glucagon-like peptide 1 (GLP-1), oxyntomodulin, and peptide YY (PYY). Whereas their roles in regulation of gastrointestinal function have been known for some time, it is now evident that they also influence eating behavior. This review considers the anorectic peptides PYY, PP, GLP-1, and oxyntomodulin, which decrease appetite and promote satiety in both animal models and humans.     

Analogs of pancreatic polypeptide and peptide YY with a locked PP-fold structure are biologically active

Pancreatic polypeptide (PP), peptide YY (PYY) and neuropeptide Y (NPY), members of the PP-fold family share a high degree of sequence homology. Nuclear magnetic resonance (NMR) and X-ray crystallography studies have shown these peptides can adopt a tightly organized tertiary structure called the PP-fold, which has long been assumed to be the active structure of this family of peptides. To date, however, no studies have been completed with PYY and PP which confirm if the PP-fold structure is important for their physiological actions. The aim of the study was to test if PYY and PP locked into the PP-fold maintained biological activity. Therefore, we designed and produced analogs of PP and PYY in a cyclic conformation with two cysteine amino acid substitutions at the N-terminus and at position 27. These were oxidized to form a cysteine disulfide bond locking the peptides into the PP-fold structure. Studies demonstrate that the cyclic analogs have both similar in vivo activity to their parent molecules, and affinity for the Y2 and Y4 receptors. Results suggest that the proposed PP and PYY-fold is likely to be their biologically active conformation.     

The origin and evolution of peptide YY (PYY) and pancreatic polypeptide (PP)

It is generally accepted that the neuropeptide Y (NPY) family of homologous peptides arose as a result of a series of gene duplication events. Recent advances in comparative genomics allow to formulate a hypothesis that explains, at least in part, the complexity of the family. Chromosome mapping studies reveal that the gene encoding PYY may have arisen from a common ancestral gene (termed NYY) in an ancient chromosomal duplication event that also involved the hox gene clusters. A tandem duplication of the PYY gene concomitant with or just before the emergence of tetrapods generated the PPY gene encoding PP. In the primate and ungulate lineages, the PYY-PPY gene cluster has undergone a more recent gene duplication event to create a PYY2-PPY2 gene cluster on the same chromosome. In the human and baboon, this cluster probably does not encode functional NPY family peptides but expression of the bovine PYY2 gene generates seminalplasmin, a major biologically active component of bull semen. An independent duplication of the PYY gene in the lineage of teleost fish has generated peptides of the PY family that are synthesized in the pancreatic islets of Acanthomorpha. The structural organization of the biosynthetic precursors of PYY and PP (preproPYY and preproPP) has been quite well preserved during the evolution of vertebrates but conservative pressure on individual domains in the proteins has not been uniform. The duplication of the PYY gene that generated the PPY gene appears to have resulted in a relaxation of conservative pressure on the functional domain with the result that the amino acid sequences of tetrapod PYYs are more variable than the PYYs of jawed fish. Although the primary structure of PP has been quite strongly conserved in mammals, with the exception of the rodents, the extreme variability in the sequences of amphibian and reptilian PPs means that the peptide is a useful molecular marker to study the branching order in early tetrapod evolution     

Growth hormone, ghrelin and peptide YY secretion after oral glucose administration in healthy and obese women

The mechanism of the altered GH secretion in obesity is unclear. There is evidence that oral glucose (OG) administration initially decreases and subsequently stimulates GH secretion. Ghrelin is a peptide that displays strong growth hormone-releasing activity. Its physiological importance on GH regulation is unclear. Our aim was to study fasting GH concentrations and their response to OG administration in relation with ghrelin secretion in obese and healthy women, in order to elucidate the hypothetical participation of ghrelin on post-oral glucose GH secretion. 36 women were included in the study. After an overnight fast, 75?g of oral glucose was administered; glucose, insulin, ghrelin, and PYY (1-36) were obtained at baseline and during 300?min. The area under the curve between 0 and 300?min (AUC) of GH μ/l·min) was lower in obese patients than in controls; 262.5±57.5 vs. 534.9±95.6, p=0.01, for obese and controls respectively. GH peak (μg/l) was lower in obese patients than in controls; 3.7±0.7 vs. 7.1±1.0, p=0.012, for obese and controls, respectively. The AUC of total ghrelin (pg/ml·min) was lower in obese patients than in controls; 233,032±12,641 vs. 333,697±29,877, p=0.004, for the obese patients and controls respectively. PYY (1-36) was similar in obese and healthy women after OG. There were significant correlations between the different indices of post-oral glucose GH and ghrelin secretion. These data suggest that ghrelin is a physiological regulator of GH in the post-oral glucose state, and the decreased ghrelin secretion could be one of the mechanisms responsible for the altered GH secretion in obesity.     

Central and peripheral regulation of gastric acid secretion by peptide YY

Peptide YY (PYY) released postprandially from the ileum and colon displays a potent inhibition of cephalic and gastric phases of gastric acid secretion through both central and peripheral mechanisms. To modulate vagal regulation of gastric functions, circulating PYY enters the brain through the area postrema and the nucleus of the solitary tract, where it exerts a stimulatory action through PYY-preferring Y1-like receptors, and an inhibitory action through Y2 receptors. In the gastric mucosa, PYY binds to Y1 receptors in the enterochromaffin-like cells to inhibit gastrin-stimulated histamine release and calcium signaling via a pertussis toxin-sensitive pathway.     

Lack of CCK-like pancreatic stimulation by intraduodenal amino acids in the anesthetized cat

We have attempted to demonstrate a pancreatic secretory response to intraduodenal amino acids in the anesthetized cat. In four cats stimulated with supramaximal doses of secretin, protein concentrations in pancreatic juice were measured after intraduodenal bolus injection of various amino acids, IV CCK, or electrical stimulation of the vagus nerve. In addition, the duodenum was perfused with phenylalanine (50 mM) for 30 min in two cats, and the vagus nerve stimulated electrically for 15 min in one. In no case did amino acids produce pancreatic protein secretion, whereas CCK and vagal stimulation always did so. We conclude that this insensitivity to amino acids in the cat is a species difference from the dog and man.     

Inhibition of gastric acid secretion by peptide YY is independent of gastric somatostatin release in the rat

The purpose of this study was to determine whether the inhibitory action of peptide YY (PYY) on gastric acid secretion is attributable to the release of gastric somatostatin in rats. Two groups of rats (six rats/group) were anesthetized with urethane and prepared with gastric fistulas and jugular catheters. Pentagastrin (18 micrograms/kg-h) was given intravenously for 150 min to stimulate gastric acid secretion. Intravenous PYY (130 micrograms/kg-h) inhibited pentagastrin-stimulated gastric acid secretion significantly (P less than 0.05). Administration of iv PYY resulted in a 41% reduction (P less than 0.05) in pentagastrin-stimulated gastric acid secretion. In another group of anesthetized rats, administration of PYY (10(-7), 10(-8) M) failed to stimulate a release of somatostatin from the isolated-perfused rat stomach. Our findings indicate that PYY can inhibit gastric acid secretion independently of release of gastric somatostatin in the rat.     

Identification of a novel 65-kDa cell surface receptor common to pancreatic polypeptide, neuropeptide Y and peptide YY

By affinity cross-linking and sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis, we identified a novel cell surface receptor on intact rat cells, which bound, with similar dissociation constants, pancreatic polypeptide (PP), neuropeptide Y (NPY) and peptide YY (PYY), the members of the PP family. The receptor was detected on pancreatic islet and acinar cells, hepatocytes and epithelial cells of the stomach, duodenum and small intestine. Its molecular weight was estimated to be 65,000, and the cross-linking of [125I] labeled ligands was inhibited by an excess of unlabeled PP, NPY or PYY. The results suggest that the 65-kDa molecule is a common receptor for PP family peptides.     

Cellular localization, half-life, and secretion of peptide YY

Tissue and plasma concentration of peptide YY (PYY) were measured by means of a radioimmunoassay (RIA) developed in our laboratory, using a specific PYY antiserum generated in New Zealand white rabbits against synthetic PYY, and dextran-coated charcoal to terminate the assay. Cellular localization of PYY was studied immunohistochemically using the peroxidase-antiperoxidase (PAP) technique. The highest tissue concentration of PYY was found in the mucosa of the terminal ileum and colon. PYY-containing secretory granules were primarily found in the basal pole of open-type endocrine cells. Basal plasma concentration of PYY was 70 +/- 9 pg/ml and rose to 357 +/- 30 pg/ml during the IV administration of PYY at 400 pmol/kg-h. A significant correlation was found (r = 0.94, p less than 0.05) between dose of PYY (12.5, 25, 50, 100, 200, 400 pmol/kg-h, IV) and plasma concentration of PYY. The calculated half-life of PYY in plasma was 8.3 +/- 1.9 minutes. Plasma concentration of PYY during the intraduodenal administration of sodium oleate (150 +/- 20 pg/ml) or long-chain triglyceride (187 +/- 37 pg/ml) was similar to plasma concentration of PYY obtained during the IV administration of PYY at 100 pmol/kg-h. Plasma concentration of PYY raised (126 +/- 10 pg/ml) after the administration of bombesin (400 pmol/kg-h, IV). Bile enhanced release of PYY. The present study suggests a hormonal role for PYY.     

Evidence for dopaminergic modulation of pancreatic polypeptide secretion in man

This study examines the role of dopaminergic mechanisms in the regulation of human pancreatic polypeptide (hPP) secretion in 11 normal male volunteers. Administration of domperidone (20 mg iv), an extracerebral inhibitor of dopamine receptors, resulted in a hPP rise (p<0.05) within 10 min and a peak response (p<0.01) at 15 min after drug administration. Administration of the dopaminergic agonist, bromocriptine, 2.5 mg tid for 4 days eliminated hPP responses to isometric handgrip exercise in these 11 volunteers. These results suggest that dopaminergic mechanisms may exert a tonic inhibitory effect on hPP secretion in normal subjects.     

Effect of intraduodenal sodium bicarbonate in rat and rabbit exocrine pancreatic secretion.

The effect of intraduodenal sodium bicarbonate, 0.1 M, on exocrine pancreatic secretion and the release of two peptides, secretin and VIP, was studied in anesthetized rats and rabbits, two species largely used in the gastroenterology laboratories. In the rabbit, intraduodenal sodium bicarbonate perfusion had no effect either on exocrine pancreatic secretion or on portal plasma levels of secretin and VIP. By contrast, in the rat, intraduodenal sodium bicarbonate perfusion significantly increased hydroelectrolyte exocrine pancreatic secretion and portal plasma secretin levels. A clear interspecific difference reflecting the different gastrointestinal physiology of both species is observed.     

Tobacco NtLTP1, a glandular-specific lipid transfer protein, is required for lipid secretion from glandular trichomes

Glandular trichomes are the phytochemical factories of plants, and they secrete a wide range of commercially important natural products such as lipids, terpenes and flavonoids. Herein, we report that the Nicotiana tabacum LTP1 (NtLTP1) gene, which is specifically expressed in long glandular trichomes, plays a role in lipid secretion from trichome heads. NtLTP1 mRNA is abundantly transcribed in trichomes, but NtLTP3, NtLTP4 and NtLTP5 are not. In situ hybridization revealed that NtLTP1 mRNAs accumulate specifically in long trichomes and not in short trichomes or epidermal cells. X-gluc staining of leaves from a transgenic plant expressing the NtLTP1 promoter fused to a GUS gene revealed that NtLTP1 protein accumulated preferentially on the tops of long glandular trichomes. GFP fluorescence from transgenic tobacco plants expressing an NtLTP1-GFP fusion protein was localized at the periphery of cells and in the excreted liquid droplets from the glandular trichome heads. In vitro assays using a fluorescent 2-p-toluidinonaphthalene-6-sulfonate probe indicated that recombinant NtLTP1 had lipid-binding activity. The overexpression of NtLTP1 in transgenic tobacco plants resulted in the increased secretion of trichome exudates, including epicuticular wax. In transgenic NtLTP1-RNAi lines, liquid secretion from trichomes was strongly reduced, but epicuticular wax secretion was not altered. Moreover, transgenic tobacco plants overexpressing NtLTP1 showed increased protection against aphids. Taken together, these data suggest that NtLTP1 is abundantly expressed in long glandular trichomes, and may play a role in lipid secretion from long glandular trichomes.     

Neuropeptide Y, peptide YY, and pancreatic polypeptide modulate duodenal and colonic motility at a thoracic spinal site in rats.

Neuropeptide Y, PYY, and PP (200 pmol) alter intraluminal pressure in the duodenum and colon of rats following their administration into the thoracic (T8-T10) region of the spinal cord. Neuropeptide Y decreases the tone of the duodenum and the colon following intrathecal (T8-T10) administration prior to an increase in tone to baseline or greater. There is no effect on intraluminal pressure of either the duodenum or the colon following intrathecal administration of NPY or PP into the lumbar (L4-L5) region of the spinal cord. Following intrathecal (T8-T10) administration of PYY and PP, increases in intraduodenal pressures are observed (+2.1 and +3.0 mmHg from saline baseline). Phasic contractions of the duodenum are increased following intrathecal administration of PYY into the thoracic spinal cord of rats. Neuropeptide Y, PYY, and PP increase intracolonic pressure +2.2, +3.3, and +3.7 mmHg from saline baseline, respectively. Phasic contractions of the colon are increased following PP intrathecal thoracic administration. Responsiveness of the duodenum or colon to the different ligands of the PP-fold peptide family in the absence of alpha-adrenergic blockade did not vary. The increases in intraluminal pressure of the duodenum and colon following intrathecal administration of the PP-fold peptides are attenuated by both alpha-1 adrenergic (prazosin) and alpha-2 adrenergic (yohimbine) blockade. There is a difference in responsiveness of the colon between the ligands of the PP-fold family in the presence of the alpha-2 adrenergic blockade. The findings of this study indicate that duodenal and colonic motility are modulated by the PP-fold peptides at thoracic spinal sites via alteration of sympathetic outflow.     

Immunohistochemical study on the ontogenetic development of the regional distribution of peptide YY, pancreatic polypeptide, and glucagon-like peptide 1 endocrine cells in bovine gastrointestinal tract

The regional distribution and relative frequency of peptide YY (PYY)-, pancreatic polypeptide (PP)-, and glucagon-like peptide 1 (GLP-1)-immunoreactive (IR) cells were determined immunohistochemically in the gastrointestinal tract at seven ontogenetic stages in pre- and postnatal cattle. Different frequencies of PYY-, PP-, and GLP-1-IR cells were found in the intestines at all stages; they were not found in the esophagus and stomach. The frequencies varied depending on the intestinal segment and the developmental stage. The frequencies of PYY- and PP-IR cells were lower in the small intestine and increased from ileum to rectum, whereas GLP-1-IR cells were more numerous in duodenum and jejunum, decreased in ileum and cecum, and increased again in colon and rectum. The frequencies also varied according to pre- and postnatal stages. All three cell types were most numerous in fetus, and decreased in calf and adult groups, indicating that the frequencies of these three types of endocrine cells decrease with postnatal development. The results suggest that these changes vary depending on feeding habits and adaptation of growth, secretion, and motility of intestine at different ontogenetic stages of cattle.     

BRCA2 is required for neurogenesis and suppression of medulloblastoma

Defective DNA damage responses in the nervous system can result in neurodegeneration or tumorigenesis. Despite the importance of DNA damage signalling, the neural function of many critical DNA repair factors is unclear. BRCA2 is necessary for homologous recombination repair of DNA and the prevention of diseases including Fanconi Anemia and cancer. We determined the role of BRCA2 during brain development by inactivating murine Brca2 throughout neural tissues. In striking contrast to early embryonic lethality after germ-line inactivation, Brca2(LoxP/LoxP);Nestin-cre mice were viable. However, Brca2 loss profoundly affected neurogenesis, particularly during embryonic and postnatal neural development. These neurological defects arose from DNA damage as Brca2(LoxP/LoxP);Nestin-cre mice showed extensive gammaH2AX in neural tissue and p53 deficiency restored brain histology but lead to rapid formation of medulloblastoma brain tumors. In contrast, loss of the Atm kinase did not markedly attenuate apoptosis after Brca2 loss, but did partially restore cerebellar morphology, supporting a genomic surveillance function for ATM during neurogenesis. These data illustrate the importance of Brca2 during nervous system development and underscore the tissue-specific requirements for DNA repair factors.