PYY

Chapter 178

PYY Louise Purtell and Herbert Herzog

ABSTRACT Peptide YY (PYY) is produced as a 36 amino acid peptide hormone within the distal gastrointestinal tract and the pancreas where it acts in a para- and endocrine fashion. It circulates in two biologically active forms, which act upon Y receptors to exert digestive, absorptive, antisecretory and satiety effects. PYY is implicated in a number of gastrointestinal diseases and has been proposed as a putative anti-obesity therapy.

DISCOVERY PYY is a 36 amino acid, straight-chain polypeptide. It shares structural similarity with pancreatic polypeptide (PP) and neuropeptide Y (NPY); all three peptides have tyrosine residues at the C-terminal which is also amidated. PYY has also a tyrosine at the N-terminus, designated in peptide nomenclature as Y, which gives PYY its name.1 PYY was first isolated from porcine small intestine by Takemoto et al in 1980, and in 1988 its protein sequence was determined in humans.28,29

STRUCTURE OF GENE The PYY gene has been cloned and sequenced from a large number of species. It comprises four exons and three introns, with each of the exons encoding a different functional domain of the mRNA7,15 (Fig. 1). The human PYY gene is located in a cluster with PP on chromosome 17q.21.1 and spans approximately 1.2 kbp. There is significant conservation of gene, sequence and protein structure between PYY, NPY, and PP, indicating that these genes arose from a common ancestor by gene duplication. In higher mammals additional gene duplication events lead to the generation of other PYY-like genes which in at least one species, bovine, lead to the production of the active peptide, seminalplasmin.8

PROCESSING OF THE PRECURSOR Transcription and translation of the PYY gene produces a 98 amino acid prepropeptide. A signal peptide is followed Handbook of Biologically Active Peptides. http://dx.doi.org/10.1016/B978-0-12-385095-9.00178-0 Copyright © 2013 Elsevier Inc. All rights reserved.

by the 36 amino acid PYY sequence and the cleavage and amidation sequence Gly-Lys-Arg, with a 31 amino acid flanking peptide at the carboxy terminal7 (Fig. 1). There are two biologically active forms of endogenous PYY: PYY1-36 and PYY3-36, which have different affinities for the Y receptors. Dipeptidyl peptidase IV (DPPIV) cleaves the tyrosine and proline residues from the N-terminal end of the full-length peptide (PYY1-36) to form the truncated peptide (PYY3-36).21,22 DPP-IV, a shortacting, abundantly-expressed cell surface enzyme, also acts to metabolize GLP-1 to its inactive form. Approximately 40% of total PYY released is converted to PYY310 36 (Fig. 1). The half-live time of the peptides in the serum is approximately 8 min17 and proteases such as kallikreins specifically remove amino acids 36 and 35 and thereby render the peptide inactive.

DISTRIBUTION IN THE GASTROINTESTINAL TRACT PYY is produced by the endocrine L-cells of the epithelial mucosa (Fig. 2). PYY is abundantly expressed in the colon, terminal ileum, and rectum, and produced to a lesser extent in the esophagus, duodenum, proximal jejunum, and stomach.18 Furthermore, in the pancreas specific PYY expressing cells surround the insulin producing cells in the islets of Langerhans (Fig. 3). PYY is colocalized in the gastrointestinal tract with proglucagon, glicentin, glucagonlike peptide 1 (GLP-1), and GLP-2 and, upon arrival of food in the duodenum, co-released from the same secretory granules.2 The level of PYY expression increases from the proximal end to the distal end of the gastrointestinal tract. PYY-expressing neurons can be found in the central nervous system and in specific gastric neurons in some species.

REGULATION OF SECRETION PYY release from the endocrine L-cells in the gut can be triggered by a number of mechanisms. Circulating levels rise within 15 min of ingestion of a meal, reaching a peak at approximately 60–120 min postprandially (Fig. 4). PYY 1307

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Chapter | 178  PYY

FIGURE 1  Transcription and translation of the PYY gene and processing of the PYY precursor protein to yield PYY1-36 and PYY3-36. UTR—untranslated region.

FIGURE 2  Nutrient-stimulated secretion of PYY from the intestinal L-cells and release through humoral and vagal channels.

plasma concentrations can remain elevated for as long as 6  h, depending on the calorie load of the meal ingested. Meal components shown to stimulate PYY secretion include glucose, bile salts, lipids, short-chain fatty acids, and amino acids. Of these, dietary lipids are the most potent stimulant of secretion.11 The sustained postprandial production of PYY is consistent with the hypothesis that the L-cells of the distal bowel and colon detect levels of these macronutrients and release PYY in response. Upon meal ingestion, plasma PYY concentrations become elevated before nutrients reach the

FIGURE 3  Pancreatic secretion of PYY from the islets of Langerhans to exert paracrine effects. See color plate 49.

distal gastrointestinal tract. This suggests that the initial postprandial PYY release may be modulated by indirect neural or humoral pathways, such as the vagus nerve.2 The presence of regulatory peptides such as cholecystokinin (CCK) and vasoactive intestinal polypeptide (VIP) may also stimulate PYY release in the absence of a meal cue.2 PYY secretion has been further shown to be stimulated by exercise, both long-term and after only a single session of high intensity exercise.16

SECTION | XIII  Handbook of Biologically Active Peptides: Gastrointestinal Peptides

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TABLE 1  Physiological Actions of Peptide YY Organ

Physiological action

Pancreas

l l l

Stomach Small intestine & colon Kidney FIGURE 4  Plasma levels of PYYTotal and PYY3-36 in response to an oral mixed meal in lean adults (n = 10). Circulating PYY is elevated postprandially with a peak at 120 minutes. (Adapted from Purtell L, Sze L, Loughnan G, Smith E, Herzog H, Sainsbury A, et al. In adults with Prader–Willi syndrome, elevated ghrelin levels are more consistemt with hyperphagia than high PYY and GLP-1 levels. Neuropeptides 2011;45:301–7.)

Appetite & food intake

Slows gastric motility Inhibits gastric acid secretion

l





l

Inhibits Cl− secretion Promotes electrolyte absorption Lengthens mouth to cecum transit time

l



l

l

Suppresses glomerular filtration rate, renin and aldosterone Promotes sodium secretion

l



l l

RECEPTORS AND SIGNALING CASCADES PYY, NPY and PP exert their physiological actions through at least five G-protein coupled receptors: Y1, Y2, Y4, Y5, and y6. These belong to the guanine nucleotide binding regulatory protein (G-protein) coupled receptors superfamily. Upon activation of the receptor, the Gialpha-subunit is released from the receptor/G-protein complex, inhibiting the production of second messenger cyclic AMP through the inhibition of adenylyl cyclase.35 In addition, the Y-receptors alter neuronal excitability and neurotransmitter release through inhibition of voltage-gated K+ channels and stimulation of Ca2+ channels.35 PYY and NPY have indistinguishable affinities for all Y-receptors with a rank order of ligand-binding affinities of Y2 > Y1 > Y5 > Y6 >> Y4; this is reversed for PP, which binds with greatest affinity to Y4 > Y6 >> Y2 > Y5 > Y1. Despite some structural and functional similarities, the Y-receptors have differential distribution profiles. In humans, the Y1 receptor is localized in the proliferative zone of the colonic epithelium and the mucosal nerves, as well as centrally where it is involved in appetite regulation and anxiety.9 The Y1 receptor has been found to have a role in regulating the proliferation of gut epithelial cells.20 The Y2 receptor has been found in the human small intestine, as well as in rat jejunum and colon mucosa. In the brain, it has been shown to be expressed in mouse hippocampus, hypothalamus and amygdale. Like the Y1 receptor, it binds PYY and NPY in preference to PP; however unlike Y1 it also shows considerable affinity for C-terminal PYY and NPY fragments such as PYY3-36. Postprandial suppression of gastric motility, and the subsequent satiety, is mediated in part through PYY’s action on the Y2 receptor. Y4 receptors are localized in both small and large intestine in

l

l

l

Vascular

Inhibits pancreatic exocrine secretion Inhibits insulin secretion (mouse, dog) Inhibits insulinotropic effects of GRP and GIP (dogs) 

Increases appetite and promotes weight gain (PYY1-36) Inhibits appetite and promotes weight loss (PYY3-36) Promotes vasoconstriction Increases systolic and diastolic blood pressure 

Growth

May facilitate GI growth and development

Bone

Inhibits osteoblast activity

humans, as well as the pancreas; they are also expressed in the brain, with the hypothalamus being the region of highest expression. Upon binding of PP to the Y4 receptor, increases in colonic muscle contraction and fecal output is triggered in mice.24 The Y5 receptor shows overlapping expression with Y1 receptors in the brain where it is also involved in appetite and energy homeostasis regulation.14 PP is thought to also act as a ligand for the y6 receptor. While functional in mouse and rabbit, this Y-receptor is truncated in the human genome.6 The truncated y6 receptor is present in a number of human tissues, including the small and large intestine; however, a specific physiological role has not yet been found for it. In mice, the expression of y6 in the suprachiasmatic nuclei of the hypothalamus suggests involvement in the circadian regulation of energy homeostasis.

BIOLOGICAL ACTIONS WITHIN GASTROINTESTINAL TRACT PYY is a key player in a number of physiological processes acting in an autocrine, paracrine, and endocrine fashion. Its main action in the gastrointestinal tract is to enhance nutrient absorption by suppressing gastric motility and inhibiting electrolyte secretion in the small intestine and colon. It also has an important role in the regulation of appetite and food intake (Table 1).

Chapter | 178  PYY

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Motor Effects When nutrients, particularly lipids, are present in the lumen of the ileum, the “ileal brake” mechanism takes effect. This acts on the upper gut to slow gastric emptying and is probably mediated by PYY. The ileal brake has been found in humans, where infusion of lipids into the ileum exerted inhibitory feedback on gastric motility.27 Studies in dogs show that ileal lipid infusions increase the interval between jejunal migrating motor complexes.33 PYY’s effects on gastrointestinal motility may act vasovagally. Witte et al compared the effects on gastric motility of PYY1-36 and PYY3-36 in humans and found the latter to be significantly more potent, both in half emptying time and gastric emptying rate.34

state. These effects were mirrored in in vitro studies: PYY dose-dependently inhibit insulin production in the presence of glucose, but not under basal conditions. Knockout mouse models also implicate PYY in pancreatic endocrine regulation and suggest that its actions are mediated by the Y1 receptors. PYY may also have indirect effects on the enteroinsular axis, as it inhibited the insuliotropic effects of gastrin releasing peptide (GRP) and gastric inhibitory peptide (GIP) in dogs. However, these insulin-inhibitory effects of PYY have not been replicated in clinical studies. Intravenous administration of PYY has not been found to influence insulin secretion in humans, either basally or under glucosedependent conditions.

Gastric Secretion

Small Intestinal and Colonic Secretion

PYY acts as a physiological enterogastrone in a number of species, including human. Gastric acid secretion in the stomach is stimulated by the parasympathetic nervous system via the vagal nerve, as well as by hormones, primarily gastrin. The presence of lipids in the lumen of the ileum causes PYY release, which in turn inhibits gastric acid secretion. In studies of dogs, PYY to inhibits pentagastrin- and histaminestimulated, but not bethanecol-stimulated gastric acid secretion.12 Further, it can abolish cephalic stage secretion, which is mediated by the vagus. This may be because of an inhibition of acetylcholine release from vagal nerve fibers.

PYY has an antisecretory action in the small intestine and colon, acting to increase fluid and electrolyte absorption. VIP modulates secretion of water and chloride ions in the small intestine through stimulation of intracellular cAMP production. PYY reduces this VIP-mediated secretion through mucosal Y1, Y2 and Y4 receptors.5,9 PYY can also exert this effect on basal or prostaglandin-stimulated cAMP production. High postprandial PYY levels ensure that electrolytes are optimally absorbed at the intestinal mucosa; in the fasted state the relative absence of this feedback allows secretory hormones to maintain fluid homeostasis.

Pancreatic Exocrine Secretion PYY inhibits pancreatic secretion. Exogenous and endogenous CCK, secretin, intraduodenal amino acids and neurotensin stimulate secretion of pancreatic juice, bicarbonate ions and pancreatic enzymes (Fig. 3). PYY acts to counter these stimulatory effects through the Y2 receptor in rats. PYY also inhibits postprandial nutrient-stimulated pancreatic secretion. Further, treatment with anti-PYY serum causes enhanced pancreatic secretion, demonstrating PYY’s importance in this feedback mechanism. As yet there is no consensus as to the mechanism by which PYY regulates pancreatic secretion. Dog studies suggest that the mechanism is independent of the vagus, and is instead mediated by adrenergic pathways. Others suggest that the feedback effects are modulated by the CCK pathway.

Pancreatic Endocrine Secretion Animal studies strongly support a role for PYY in the inhibition of pancreatic endocrine secretion, but this evidence is not borne out by clinical studies. While no effect of intravenous PYY on plasma insulin was seen in mice, it significantly reduced circulating insulin levels in dogs (Fig. 3). Both mouse and dog studies show a glucosedependent inhibition of insulin by PYY in the postprandial

Appetite and Food Intake PYY is an important modulator of appetite, feeding behavior, and body weight homeostasis. Importantly, the two circulating forms of PYY, PYY1-36 and PYY3-36, can both act through the Y2 receptor to induce satiety. Thus, the extent and rate that DPP-IV converts PYY1-36 to PYY3-36 is not critical for the satiety action of PYY. However, conversion of PYY1-36 to PYY3-36 reduces the action on the Y1 receptor, which in general has inhibitory functions in many peripheral tissues such as fat and bone.

Renal Function PYY’s influence on renal function has been studied in humans. PYY, when infused at concentrations mimicking normal postprandial levels, decreases glomerular filtration rate by 10%. Sodium secretion increased by 30%, while rennin and aldosterone is significantly suppressed. Infusion with a high dose mimicking levels in pathological conditions, shows, in addition to these changes, reduced renal plasma flow. The mechanism behind these changes is not yet clear, but, whether directly or indirectly, PYY appears to have a major role in modulating postprandial natriuresis.

SECTION | XIII  Handbook of Biologically Active Peptides: Gastrointestinal Peptides

Vascular Effects PYY plays a role in vasoconstriction, reducing blood flow to, in particular, the intestine through predominantly Y1 mediated actions.19 In humans, PYY infusion is associated with increased systolic and diastolic blood pressure.

Growth and Development PYY is one of the earliest gut peptides to be expressed in the fetal development of mice, suggesting a role in gastrointestinal growth and differentiation. In vitro studies indicate that these effects are mediated by the Y1 receptor. High levels of PYY or NPY during embryonic development is lethal because of the failure of midline formation.

PATHOPHYSIOLOGICAL IMPLICATIONS The secretion pattern of PYY is altered in, and may contribute to, a number of gastrointestinal and systemic disorders.

Anorexia Nervosa Anorexia nervosa (AN) is a condition in which patients deliberately suppress their food intake in order to reduce body weight. Whether this decreased food intake is modulated by endocrine cues has long been debated. Adolescent girls with AN have higher fasting PYY concentrations than healthy controls.23 Interestingly, another study observed that PYY levels in women with AN are strongly correlated with bone mineral density (BMD), suggesting that PYY may contribute to the bone loss often seen in this condition via over-stimulating the inhibitory Y1 receptor on bone forming cells.30

Prediabetes Low circulating PYY may not only be a function of type 2 diabetes (T2D), but also a predictor. A 2008 study investigated postprandial PYY response in healthy individuals with and without a family history of T2D. The authors found that the family history positive group have a blunted PYY secretory response, a defect that could precede insulin resistance and adiposity on the path to T2D in genetically susceptible individuals.31

Gastrointestinal Diseases Many diseases involving the gastrointestinal tract are characterized by altered patterns of PYY secretion. Malabsorptive disorders are often accompanied by elevated PYY concentrations. Celiac disease, or sprue, is an autoimmune disorder involving severe small intestinal malabsorption of nutrients because of villous atrophy. It is caused by an allergic response to the gluten protein gliadin. Tropical sprue causes

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a similar malabsorptive state, but has an unknown infectious origin. In both types of sprue, PYY concentrations are greatly elevated in both basal and postprandial states. Circulating PYY is also high in patients with other forms of gastric malabsorption, such as chronic pancreatitis, infective diarrhea, and the inflammatory bowel diseases Crohn’s disease and ulcerative colitis.3 PYY’s involvement in malabsorptive gastrointestinal disorders is consistent with its ileal brake role. Ingested nutrients are primarily absorbed in the proximal small intestine in healthy individuals. When there is a defect in intestinal absorption, such as in these conditions, unabsorbed nutrients reach the distal ileum and colon, triggering PYY release in an adaptive attempt to slow gastric emptying and thus increase mucosal contact time.

Gastrointestinal Surgery PYY concentrations increase after significant bowel resection.3 This is an adaptive response to the shortening of the gastrointestinal tract and some subsequent loss of absorptive capability. Thus PYY secretion is not elevated after resection of small bowel segments, as in this case absorptive power is not greatly altered. Significant colon resection, however, can produce the opposite effect—decreased PYY levels.3 This reflects the fact that the colonic mucosa is where a large proportion of PYY-expressing cells are localized. Removal of colon segments reduces the ability to produce and release PYY.

Bariatric Surgery The purpose of bariatric surgery is to promote weight loss through restrictive or maladaptive means. Candidates for these types of surgery are generally morbidly obese, with the low fasting and postprandial PYY levels associated with obesity. In general, bariatric surgery tends to increase circulating PYY, reflecting both decreased nutrient intake (after restrictive surgery such as vertical banded gastroplasty) and reduced nutrient absorption (malabsorption operations such as jejunoileal bypass).13 Surgery which combines both restrictive and malabsorption elements, such as Roux-en-Y gastric bypass, undoubtedly reaps the benefit of both mechanisms. Despite bariatric surgery’s stimulatory effects on PYY, post-surgery patients rarely attain levels equivalent to those of healthy individuals. This may be because many postoperative patients are still overweight, if not obese.

Pancreatitis In addition to neuroendocrine actions, a role for PYY has been found in immune function. A 2007 study found that therapeutic PYY confers significant survival benefits on mice with ethionine-induced necrotizing pancreatitis.32 The

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same group observed in vitro that these effects are mediated by a PYY-dependent suppression of amylase and cytokine secretion.

Obesity There has been much research into PYY’s role in obesity, and particular interest has been given to potential therapeutic uses. Basal PYY concentrations are lower in obese individuals than in lean, in both adults and children.25,26 An inverse linear relationship between PYY and BMI had been suggested; however, this does not hold true in the case of morbid obesity. PYY release is similarly blunted in obese individuals after mixed meal ingestion. This difference disappears, however, when the mixed meal is replaced with an oral glucose load. It may be that obese patients respond appropriately to glucose but develop resistance to fatstimulated PYY secretion. PYY has been widely proposed as a possible anti-obesity drug because of its inhibitory effects on appetite. Batterham et  al conducted a placebocontrolled study in which healthy individuals were peripherally infused with PYY3-36 to achieve postprandial concentrations. Participants reduced their ad libitum calorie intake by 36% in a meal 2 h after the infusion, and 24 h calorie intake was reduced by 33%.4 There was a comparable reduction in caloric intake when the experiment was repeated with obese participants, showing that obese and lean individuals have a similar sensitivity to peripheral PYY.

REFERENCES 1. Adrian TE, Ferri GL, Bacarese-Hamilton AJ. Human distribution and release of a putative new gut hormone, peptide YY. Gastroenterology 1985;89:1070–7. 2. Ballantyne G. Peptide YY(1-36) and Peptide YY(3-36): part I. Distribution, release and actions. Obes Surg 2006;16:651–8. 3. Ballantyne G. Peptide YY(1-36) and Peptide YY(3-36): part II. Changes after Gastrointestinal surgery and Bariatric surgery: part I. Distribution, release and actions appeared in the last issue. Obes Surg May 2006;2006(16):795–803. 4. Batterham RL, Bloom SR. The gut hormone peptide YY regulates appetite. Ann NY Acad Sci 2003;994:162–8. 5. Bilchik AJ, Hines OJ, Adrian TE, McFadden DW, Berger JJ, Zinner MJ, et al. Peptide YY is a physiological regulator of water and electrolyte absorption in the canine small bowel in vivo. Gastroenterology 1993;105:1441–8. 6. Burkhoff AM, Linemeyer DL, Salon JA. Distribution of a novel hypothalamic neuropeptide Y receptor gene and its absence in rat. Mol Brain Res 1998;53:311–6. 7. Conlon JM. The origin and evolution of peptide YY (PYY) and pancreatic polypeptide (PP). Peptides 2002;23:269–78. 8. Couzens M, Liu M, Tüchler C, Kofler B, Nessler-Menardi C, Parker RMC, et al. Peptide YY-2 (PYY2) and Pancreatic Polypeptide-2 (PPY2): species-specific evolution of novel members of the Neuropeptide Y gene family. Genomics 2000;64:318–23.

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9. Cox H M. Endogenous PYY and NPY mediate tonic Y1- and Y2-mediated absorption in human and mouse colon. Nutrition 2008;24:900– 6. 10. Cox HM. Peptide YY: a neuroendocrine neighbor of note. Peptides 2007;28:345–51. 11. Essah PA, Levy JR, Sistrun SN, Kelly SM, Nestler JE. Effect of macronutrient composition on postprandial peptide YY levels. J Clin Endocr Metab 2007;92:4052–5. 12. Guo YS, Fujimura M, Lluis F, Tsong Y, Greeley Jr GH, Thompson JC. Inhibitory action of peptide YY on gastric acid secretion. Am J Physiol 1987;253:G298–302. 13. Hanusch-Enserer U, Roden M. News in gut-brain communication: a role of peptide YY (PYY) in human obesity and following Bariatric surgery? Eur J Clin Invest 2005;35:425–30. 14. Iyengar S, Li DL, Simmons RM. Characterization of neuropeptide Y-induced feeding in mice: do Y1-Y6 receptor subtypes mediate feeding? J Pharmacol Exp Ther 1999;289:1031–40. 15. Kohri K, Nata K, Yonekura H, Nagai A, Konno K, Okamoto H. Cloning and structural determination of human peptide YY cDNA and gene. Biochim Biophys Acta 1993;1173:345–9. 16. Li JB, Asakawa A, Li Y, Cheng K, Inui A. Effects of exercise on the levels of peptide YY and Ghrelin. Exp Clin Endocr Diab 2011;119(163):6. 17. Lluis F, Fujimura M, Gómez G, Salvá J, Greeley GJ, Thompson J. Cellular localization, half-life, and secretion of peptide YY. Rev Esp Fisiol 1989;45:377–84. 18. Lundberg J, Tatemoto K, Terenius L, Hellström P, Mutt V, Hökfelt T, et al. Localization of peptide YY (PYY) in gastrointestinal endocrine cells and effects on intestinal blood flow and motility. Proc Natl Acad Sci USA 1982;79:4471–5. 19. Lundberg JM, Tatemoto K. Vascular effects of the peptides PYY and PHI: comparison with APP and VIP. Eur J Pharmacol 1982;83: 143–6. 20. Mannon PJ, Mele JM. Peptide YY Y1 receptor activates mitogenactivated protein kinase and proliferation in gut epithelial cells via the epidermal growth factor receptor. Biochem J 2000;350:655–61. 21. Medeiros MS, Turner AJ. Post-secretory processing of regulatory peptides: The pancreatic polypeptide family as a model example. Biochimie 1994;76:283–7. 22. Mentlein R, Dahms P, Grandt D, Krüger R. Proteolytic processing of neuropeptide Y and peptide YY by dipeptidyl peptidase IV. Regul Peptides 1993;49:133–44. 23. Misra M, Miller KK, Tsai P, Gallagher K, Lin A, Lee N, et al. Elevated peptide YY levels in adolescent girls with anorexia nervosa. J Clin Endocr Metab 2006;91:1027–33. 24. Moriya R, Fujikawa T, Ito J, Shirakura T, Hirose H, Suzuki J, et al. Pancreatic polypeptide enhances colonic muscle contraction and fecal output through neuropeptide Y Y4 receptor in mice. Eur J Pharmacol 2010;627:258–64. 25. Pfluger PT, Kampe J, Castaneda TR, Vahl T, D’Alessio DA, Kruthaupt T, et al. Effect of human body weight changes on circulating levels of peptide YY and peptide YY3–36. J Clin Endocr Metab 2007;92:583–8. 26. Renshaw D, Batterham RL. Peptide YY: a potential therapy for obesity. Curr Drug Targets 2005;6:171–9. 27. Spiller RC, Trotman IF, Higgins BE, Ghatei MA, Grimble GK, Lee YC, et al. The ileal brake–inhibition of jejunal motility after ileal fat perfusion in man. Gut 1984;25:365–74.

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28. Tatemoto K. Isolation and characterization of peptide YY (PYY), a candidate gut hormone that inhibits pancreatic exocrine secretion. Proc Natl Acad Sci USA 1982;79:2514–8. 29. Tatemoto K, Nakano I, Makk G, Angwin P, Mann M, Schilling J, et al. Isolation and primary structure of human peptide YY. Biochem Biophys Res Commun 1988;157:713–7. 30. Utz AL, Lawson EA, Misra M, Mickley D, Gleysteen S, Herzog DB, et al. Peptide YY (PYY) levels and bone mineral density (BMD) in women with anorexia nervosa. Bone 2008;43:135–9. 31. Viardot A, Heilbronn LK, Herzog H, Gregersen S, Campbell LV. Abnormal postprandial PYY response in insulin sensitive nondiabetic subjects with a strong family history of type 2 diabetes. Int J Obes 2008;32:943–8.

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32. Vona-Davis L, McFadden DW. PYY and the pancreas: inhibition of tumor growth and inflammation. Peptides 2007;28:334–8. 33. Wen J, Leon EL-D, Kost LJ, Sarr MG, Phillips SF. Duodenal motility in fasting dogs: humoral and neural pathways mediating the colonic brake. Am J Physiol-Gastr L 1998;274:G192–G1G5. 34. Witte AB, Grybäck P, Holst JJ, Hilsted L, Hellström PM, Jacobsson H, et al. Differential effect of PYY1-36 and PYY3-36 on gastric emptying in man. Regul Peptides 2009;158:57–62. 35. Yulyaningsih E, Zhang L, Herzog H, Sainsbury A. NPY receptors as potential targets for anti-obesity drug development. Br J Pharmacol 2011;163:1170–202.