Distribution of pancreatic polypeptide and peptide YY

Peptides 23 (2002) 251–261

Distribution of pancreatic polypeptide and peptide YY Eva Ekblad*, Frank Sundler Department of Physiological Sciences, Section for Neuroendocrine Cell Biology, Lund University, Lund, Sweden Received 7 May 2001; accepted 14 September 2001

Abstract 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. © 2002 Elsevier Science Inc. All rights reserved. Keywords: Pancreatic polypeptide; PP; Peptide YY; PYY; Endocrine cells; Enteric nervous system; Gastro-intestinal tract; Pancreas; Adrenal gland; Airways; Peripheral nervous system; Central nervous system

1. The peptides Pancreatic polypeptide (PP) and peptide YY (PYY) belong to the neuropeptide Y (NPY) family of peptides and both have 36 amino acids. PP was first isolated from side fractions in the purification of chicken insulin [37,39] while PYY was first isolated from porcine gut by virtue of its C-terminal amidation [75]. PP, PYY and NPY contain several tyrosine residues, display high sequence homology, are C-terminally amidated and their precursors have a similar construction. They share a common tertiary structure, the so-called PP-fold, i.e. they are U-shaped with an extended polyproline helix and ␣ helix connected by ␤ turn. NPY molecule is the most highly conserved and is therefore considered the phylogenetic oldest one. The genes for NPY and PYY have been suggested to arise from a common ancestor gene. PP gene probably evolved by duplication of PYY gene (for references see [28,40]). Both PP and PYY activate receptors designated Y receptors. Five Y receptors have so far been cloned, Y1, Y2, Y4, Y5 and y6, and found to belong to the huge family of heptahelical G protein-coupled receptors. In addition, a Y3 receptor and some non-mammalian receptors have been identified pharmacologically. PYY is as potent as NPY in

activating Y1, Y2 and Y5 receptors. PYY also activates Y3 receptors, however, less potently than NPY. Both PYY and NPY have a low affinity for the Y4 receptor. PP is the preferred ligand for the Y4 receptor. The order of potency for the peptides of NPY family in binding to the y6 receptor is controversial, as is the physiological significance of this receptor (for references see [51]).

2. Distribution of PP and PYY On the whole PP expression is restricted to endocrine cells, PYY is expressed in both neurons and endocrine cells, while NPY is preferentially expressed in neurons. The fact that these peptides exhibit significant structural similarities has rendered studies on their distribution difficult. Antibody cross-reactivity is one of the main obstacles. However, refinements of the various immun methods, the development of new and selective antibodies and the use of in situ hybridization have been fruitful and by now we have a consistent and detailed knowledge about the distribution of each member of the NPY family. 2.1. Gastro-intestinal tract

* Corresponding author. Tel.: ⫹46-46-222-06-88; fax: ⫹46-46-22232-32. E-mail address: [email protected] (E. Ekblad).

In the gastrointestinal tract, PYY is widely expressed in endocrine cells while PP-immunoreactive endocrine cells

0196-9781/02/$ – see front matter © 2002 Elsevier Science Inc. All rights reserved. PII: S 0 1 9 6 - 9 7 8 1 ( 0 1 ) 0 0 6 0 1 - 5

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are scarce. In addition PYY is, at least in some species, expressed in a discrete system of enteric neurons. In the stomach of adult mammals, PP-immunoreactive cells have only been described in opossum, cat and dog [21,42,72]. Such cells are few and, as demonstrated in dog antrum, they seem to represent a subpopulation of the gastrin cells [68]. In rat [19,74] and man [77] a few PP cells appear in the gastric mucosa for a short postnatal period

only. In man these gastric PP-immunoreactive cells are identical with the glicentin/glucagon-immunoreactive cells and found to be present in both oxyntic and antral mucosa while in the rat the PP immunoreactive cells are confined to the antral mucosa. Intestinal PP-immunoreactive cells seem to be lacking, or are only occasionally seen in many animal species [42]. A sparse number of PP-immunoreactive cells have been

Fig. 1. Rat oxyntic (A and B) and pyloric (C and D) and cat pyloric (E and F) mucosa double immunostained for PYY and somatostatin or gastrin. In rat oxyntic mucosa PYY cells constitute a subpopulation of somatostatin cells. In pyloric mucosa of both rat and cat most of the PYY cells contain in addition gastrin. The gastrin cells outnumber the PYY cells in both species. Magnification ⫻200 (A-D), ⫻175 (E and F).

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Fig. 2. Human small (A) and large (B and C) intestine immunostained for PYY. A moderate number of PYY cells is found in the small intestine while they are numerous in the large intestine. A transversely cut crypt is shown in C. Magnification ⫻110.

reported to occur in the human colon and rectum [13,67] and these cells are distinct from PYY-immunoreactive cells [18] indicating there identity as “true” PP cells. In dog intestine PP cells seem to be restricted to the duodenum [21,72]. In rat colon PP is transiently expressed in endocrine cells for a short period postnatally [19]. PYY expressing cells are found in both the upper and the lower gastrointestinal tract. However, the most abundant source of PYY is the distal gut as evidenced by the large number of PYY-immunoreactive endocrine cells and by a high concentration of PYY. Radioimmunoassay (RIA) data show that in rat [48], sheep [60] and human [1] gut PYY concentrations are low in duodenum and jejunum while they are high in ileum and colon. The highest concentration of PYY is found in the rectum [1]. In the gastric oxyntic mucosa PYY-immunoreactive endocrine cells are few in mammals (Fig. 1A; [19,48,61,71]). In mice, rats and guinea pigs the majority of these PYY cells are identical with a subpopulation of somatostatin-containing cells (Fig. 1A and B; 71). In the antral mucosa a higher number of PYY cells can be detected and these cells constitute a subpopulation of the gastrin-immunoreactive cells (Fig. 1C-F; 19, 61, 71). A minor population of PYY-immunoreactive antral cells contain also somatostatin. Antral PYY cells are in rodents localized within the basal part in the glands (Fig 1C) while in carnivores and man they reside in the mid-portion (Fig. 1E) i.e. the preferred sites of the gastrin cells [71]. In the upper small intestine PYY-immunoreactive cells are few but consistently present as shown in man (Fig. 2A), pig, cat, guinea pig and rat [11,48] and in the Brunner’s glands of man [7]. The PYY-immunoreactive cells increase markedly in number in distal small intestine and large intestine (Figs. 2 and 3; [11,45,48,56]). The vast majority of intestinal PYY-immunoreactive cells contain also glicentin (also referred to as gut glucagon) and the glucagon-like peptides I and II (GLP I and II), all deriving from proglucagon [9,11,31,57]. PYY has also been reported to occur together with serotonin in endocrine cells of the human rectum [46]. A high number of PYY-immunoreactive cells are found throughout the rectum but they decrease markedly in number at the anal transitional zone [31]. During rat fetal development PYY-immunoreactive en-

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docrine cells are present in the stomach, particularly within the antral mucosa, and in the duodenum already on embryonic day 19 [61]. PYY cells are regularly seen also in the intestinal tract at this stage (Fig. 4A and B). Thereafter the number of PYY cells increases gradually in number in both the stomach and duodenum until approximately one week postnatally; subsequently they decrease in number [61]. The possibility that the PYY cells in rat gastrointestinal tract occur even earlier than at embryonic day 19 was not studied by Onolfo et al. but may be suggested in the light of the findings by Upchurch et al. [79]. Upchurch et al. showed, in rat colon, that PYY cells appeared already at embryonic day 15.5 followed by other hormones such as glucagon, serotonin, neurotensin and somatostatin at embryonic day 16.5– 18.5. In fact, the onset of PYY mRNA expression is already at embryonic age 11 in the foregut of the rat [35]. Thus, PYY seems to be the earliest hormone produced by colonic endocrine cells and other hormones are subsequently coexpressed in the same cells as PYY. In human fetuses PYY-immunoreactive endocrine cells are detected in both stomach and intestine from the first trimester (8 –10 weeks; the earliest time point studied) [20]. The number of PYY cells increases with gestational age and an adult pattern is established at 22 weeks of gestation. Throughout this developmental period PYY is co-expressed with glicentin and the glucagon-like peptides I and II [20]. Interestingly, PYY has been reported to occur not only in intestinal endocrine cells but also in enteric neurons. PYYcontaining neurons are found in myenteric ganglia in the gastrointestinal tract of mice, rats, cats, ferrets, pigs [10,32, 50,71]. The nerve fibers mainly innervate the smooth muscle and are found in highest number in the stomach and duodenum (Fig 5). In mouse, rat and pig a remarkable arrangement of serosal ganglia with numerous PYY-immunoreactive cell bodies has been described [10,71]. These serosal ganglia are located at the esophagogastric junction and some of the PYY-immunoreactive neurons also store vasoactive intestinal peptide (VIP) and gastrin releasing peptide (GRP) [71]. The enteric nerves containing PYY are distinct from those containing NPY [18] and the presence of authentic PYY in enteric nerves was further strengthened by the identification of PYY in extracts of enteric ganglia with a RIA not recognizing NPY [10]. The dual localization of PYY in both endocrine cells and intestinal nerves suggests that it is implicated in several gut functions, including motility and secretion. The early, and sometimes transient, expression of PYY during fetal development indicates that it may serve functions other than short-term regulatory such as promoting development and maturation of the digestive tract. 2.2. Pancreas PP cells are often referred to as the fourth cell type in the endocrine pancreas, the three other being insulin (beta), glucagon (alpha) and somatostatin (delta) cells. That they

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Fig. 3. Human colon. Double immunostaining for PYY (A) and glicentin (B) reveals that the PYY cells are identical with those storing glicentin. Immunogold staining for PYY (C) and glicentin (D) on consecutive ultrathin sections demonstrating gold particles distributed over virtually all secretory granules in both sections indicating co-existence of PYY and glicentin in the same secretory granules. The typical morphology, a broad base harboring the secretory granules and a slender apical extension, of the so-called open type of endocrine cells to which the PYY cells belong is clearly demonstrated. Magnification ⫻160 (A and B), ⫻17 000 (C and D).

are the fourth cell type reflects that the PP cell is the most recently discovered of the four main islet cell types with a known hormone content [41– 43,62]. It also infers that PP cells constitute the fourth islet cell with respect to population size (usually less than 10% of all islet cells). Furthermore, PP cells are the fourth endocrine cell type to appear during ontogeny; in rodents PP is histochemically demonstrable not until around birth [34,54,74]. PP cells often take up a peripheral position in the islets (Fig. 6A and B) admixed with glucagon and somatostatin cells. The early insight that the PP cell is distinct from the three other major

islet cell populations stimulated studies on the characterization of the PP cell with respect to size and morphology of the secretory granules. In the rat, the PP cells have small, round, electron-dense granules whereas in, e.g. the cat and dog, PP cell granules are much larger and less electron dense [42]. It was then realized that the PP cells in these latter species were identical to cells previously designated F cells [22,26,42]. It may be mentioned in this context that the human pancreas seems to harbor two ultrastructurally distinguishable types of PP cells, one having fairly small electron-dense granules (as in e.g. the rat) and the other having

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Fig. 4. Fetal rat (E19) small (A) and large (B) intestine and pancreas (C and D) demonstrating the early appearance of both PYY as shown by immunocytochemistry (A-C) and autoradiographically labeled (in situ hybridization) PYY mRNA (D). Magnification ⫻170 (A-C), ⫻200 (D).

larger, more electron-lucent granules (as in e.g. the cat and dog) [69]. Several circumstances have contributed to the problems that have been encountered in the identification of the PP cells by immunocytochemistry and in the estimation of their numbers. Firstly, the distribution of the PP cells is in many species not restricted to the islets, but single or clustered cells occur scattered in the exocrine parenchyma (12, 41, for further references see 71). In fact, in birds the vast majority of pancreatic PP cells have an extra-islet localization (Fig 7; [43]). Secondly, PP cells are not homogenously distributed throughout the pancreas. As studied in detail in mouse and rat, PP cells are much more frequent in the duodenal portion, arising from the ventral primordium, than in the rest of the pancreas, that arises from the dorsal primordium (Fig. 6A and B; [42,62], reviewed in [6] and [71]).

Thirdly, PP is not the only member of the PP-fold peptide family expressed in the pancreas. As studied in detail in mouse and rat, PYY and its mRNA are also expressed in islet cells, mostly glucagon cells, from early embryonic stages throughout life (Figs. 4C and D and 6C and D; [3,12,34,53,54,79]). In other mammals, e.g. cat, dog and pig, the PP cells contain PYY [12]. To complicate the demonstration of the various PP-fold peptides further, also NPY and its mRNA are, as studied in some detail in the rat, expressed in islet cells (insulin cells) during late fetal life, only to gradually disappear during the first two postnatal weeks; thereafter islet NPY is restricted to neuronal elements [54]. However, in the adult golden hamster islet NPY and NPY mRNA expression remains in the somatostatin cells [55]. The very early expression of PYY gene in islet cell precursors of the mouse and rat pancreas (Fig. 4C and D) during embryonic development is intriguing. Thus, PYY is

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Fig. 5. PYY immunoreactive enteric neurons are found particularly in the upper digestive tract. (A) Shows a high number of PYY immunoreactive fibers in a smooth muscle bundle lining the minor side of the rat stomach close to the esophagogastric junction (the esophagus is indicated by an asterix). (B) Shows numerous PYY fibers in a whole mount preparation of the smooth muscle from mouse stomach (curvatura minor). The smooth muscle and myenteric ganglia from rat fundic (C) and pyloric (D) portion of the stomach contain numerous PYY-immunoreactive nerve fibers. PYY-immunoreactive myenteric nerve cell bodies can also be seen (arrows). In the cat myenteric PYY-immunoreactive neurons are found in esophagus (E), fundic (F) and pyloric (G) portion of the stomach and, in small number, in the small intestine (H). Magnification ⫻120 (A), ⫻180 (B), ⫻150 (C and D), ⫻170 (E-H).

expressed already in the islet progenitor cells when they first can be recognized. At this stage they co-express insulin and glucagon, and PYY expression then continues in the lineage specified to become glucagon cells. The early appearance of PYY has fostered speculations that it could be involved in the process of islet cell differentiation, specification, and/or growth [80]. This resembles the early ontogenetic appearance of PYY described in developing gastrointestinal endo-

crine cells, notably the antral gastrin cells and the intestinal proglucagon/GLP-I-expressing cells [61,73,79]. It has been reported that PP transcripts can be identified very early in the embryonic mouse pancreas with PCR technique [25,27]. However, available data indicate that immunohistochemically demonstrable levels of PP in mice and rats are not reached until the perinatal period, as indicated above (for references see [54,80]). Notably, PP cells

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Fig. 6. Rat pancreas immunostained for PP (A and B) and PYY (C and D). The duodenal portion of the pancreas contains a high number of PP cells (A) but a small number of PYY cells (C) whereas the tail of the pancreas contains a low number of PP cells (B) and a high number of PYY cells (D). The cells are confined to the periphery of the islets. Magnification ⫻180.

seem to make a much earlier debut in larger mammals— including primates and man—, being present already in the pancreas premordium during embryonic development [4,5, 83]. 2.3. Adrenal gland and peripheral nervous system All three members of the NPY-family of peptides are reported to be present in the adrenal gland [49,57]. Of the three peptides the expression of NPY in adrenal medullary cells is well documented in a number of species by several investigators ([65,82], for a review see [64]). Also PYY appears to be present in medullary cells, at least in some species (e.g. the cat) as shown by immunocytochemistry (Fig. 8; own unpublished). This finding is supported by the demonstration that PYY is released from cat adrenals during splanchnic artery occlusion shock [24]. RIA data also indicate the presence of PYY in the human adrenal glands [70]. Rat adrenal medulla seems, however, to be devoid of immunoreactive PYY (own unpublished) as well as PYY mRNA [63]. The expression of PP in the adrenal medulla is

controversial. PP-immunoreactive cells in rat adrenal medulla has been reported [49,81], however, the identity of the PP-immunoreactive material is unclear. Studies utilizing well-defined antibodies in both immunocytochemistry (own unpublished) and RIA [52] have failed to reveal any expression of PP in adrenal medullary cells of the rat. The physiological relevance of the expression of PP-fold peptides in the adrenal medulla has been suggested to be that these peptides modulate adrenocortical secretory activity; the main binding sites to both PYY and NPY have been localized to the inner adrenocortical zones [58]. PYY- (like NPY-; [14]) containing nerve fibers have, in addition, been reported to occur in high numbers in the adrenal capsule [30]. The PYY fibers were reported to belong to the sympathetic nervous system. In the rat sympathetic PYY-immunoreactive nerve fibers were also described in other peripheral organs i.e. auricles and atria of the heart, carotid body and submandibular salivary gland and PYY was found to co-exist with NPY in rat superior cervical ganglia [30]. The presence of PYY in sympathetic neurons as well as in the adrenal gland has, however, been questioned and the

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Fig. 7. Chicken pancreas with PP-immunoreactive endocrine cells scattered throughout the exocrine parenchyma. Magnification ⫻120.

immunostaining suggested to be due to cross reactivity of the PYY antibodies with NPY [63]. The objections were based on studies using in situ hybridization in which no hybridization to PYY mRNA could be detected in sympathetic ganglia or adrenals from the rat. In the sensory nervous system expression of PYY appears transiently at embryonic day 16 in dorsal root ganglia of the rat and at embryonic day 14 in trigeminal ganglia [35]. These findings may suggest a role for PYY in the development and maturation of sensory neurons. 2.4. Central nervous system Neurons expressing PP-like material were early reported to occur also in the central nervous system (CNS) [23,29,

44,47,59]. The isolation of NPY [76] and the subsequent findings of a large number of NPY-immunoreactive neurons in CNS [2] and a high content of NPY in brain [16] lead to the view that NPY represented all the PP-like material in the CNS (cf. [15]). Since then it has, however, been revealed that PYY-immunoreactive neurons, distinct from the NPYimmunoreactive ones, exist in some areas of the rat brain. PYY-immunoreactive nerve cell bodies are found in the medulla oblongata, nucleus reticularis and in the dorsal medulla including nucleus of the solitary tract of the rat. Nerve terminals containing PYY are localized in the hypothalamus, pons, medulla and spinal cord [8,17]. HPLC analysis showed that the PYY-immunoreactive material is indistinguishable from synthetic porcine PYY [17]. Data from in situ hybridization further strengthen the authenticity of neuronal PYY in the brain by showing the presence of PYY mRNA expression in neurons in rostral and lateral caudal medulla [63]. Also PP has, on the basis of radioimmunoassays on extracts from pig brain, been suggested to exist in the hypothalamus, pineal body, hippocampus, substantia nigra and pituitary gland [33]. However, no PP mRNA expression could be detected in rat CNS [63]. If the PP-immunoreactive material represents cross-reactivity with other peptides of the NPY-family or if species differences account for the discrepancies in results has yet to be resolved. The system of central PYY neurons is comparatively small and its regional distribution suggests that the peptide could be involved in food intake and pituitary secretion. 2.5. Airways In the syrian golden hamster PYY immunoreactivity has been described in solitary endocrine cells and in cells within the neuroepithelial bodies located at the entrance to the alveolar ducts and within the alveolar ducts and sacs [36]. The presence of PYY in lung tissue was verified by RIA in the same study, and by the use of HPLC the PYY-immunoreactive material was found to show high hydrophobic variability. The reason for this complexity of the extracted PYY material is unknown but may be due to the presence of extended forms of PYY, other yet unidentified related peptide(s) or to species variations in the peptide sequence; hamster PYY has not yet been sequenced. By RIA PYYimmunoreactive material is also measurable, although in low quantities, in rat lung [38]. The localization of PYY in hamster lung does not overlap with that of NPY, which is restricted to nerve terminals [36,66,78], and may suggest a local action within the lung.

3. Conclusion Fig. 8. Cat adrenal medulla harbours a moderate number of PYY-immunoreactive cells. Magnification ⫻160.

PP is predominantly expressed in the endocrine pancreas and PYY in gut endocrine cells and, to some extent, also in

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enteric nerves. In addition, PYY seems to be of importance during the embryonic development of the gastro-enteropancreatic endocrine system, since it is expressed very early here.

Acknowledgments Grant support from the Swedish MRC (project no 04X4499 and 04X-13406 01A), Swedish Diabetes Association, and the Påhlsson, Nanna Svartz, B. Ihre, Crafoord, Bergvall, and Novo Nordic Foundations.

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