Pancreatic polypeptide: more than just another gut hormone?

Abstract

The demonstration by Asakawa et al.1Asakawa A. Inui A. Yuzuriha H. Ueno N. Katsuura G. Fujimiya M. Fujino M.A. Niijima A. Meguid M.M. Kasuga M. Characterization of the effects of pancreatic poypeptide in the regulation of energy balance.Gastroenterology. 2003; 124: 1325-1336Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar that pancreatic polypeptide (PP) inhibits food intake and stimulates energy expenditure following its peripheral administration adds yet another putative peptide signaling molecule to the list of those that are involved in overall energy balance. Since the identification of leptin as the protein product of the ob gene in 1995,2Zhang Y. Proenca R. Maffei M. Barone M. Leopold L. Friedman J.M. Positional cloning of the mouse obese gene and its human homologue.Nature. 1994; 372: 425-432Crossref PubMed Scopus (11622) Google Scholar multiple neuropeptides whose expression is modified by leptin and that affect food intake and/or energy expenditure following their exogenous administration have been uncovered and our understanding of how these signaling pathways interact to result in the regulation of food intake and body weight continues to evolve. While Asakawa et al.1Asakawa A. Inui A. Yuzuriha H. Ueno N. Katsuura G. Fujimiya M. Fujino M.A. Niijima A. Meguid M.M. Kasuga M. Characterization of the effects of pancreatic poypeptide in the regulation of energy balance.Gastroenterology. 2003; 124: 1325-1336Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar do not identify a new peptide, they do provide evidence for a new role for a gut hormone with known actions in gastrointestinal motility and secretion. Thus, PP may be added to the list of gut peptides with actions that affect overall energy balance.PP is a member of the peptide family that also includes neuropeptide Y (NPY) and peptide YY (PYY). The 3 peptides have different patterns of expression and distribution with PP and PYY localized to the pancreas and gastrointestinal tract respectively and NPY found in both brain and peripheral neurons.3Ekblad E. Sunbdler F. Distribution of pancreatic polypeptide and peptide YY.Peptides. 2002; 23: 251-261Crossref PubMed Scopus (200) Google Scholar Multiple receptor subtypes with different affinities for the endogenous peptides have been identified. NPY and PYY have high affinity for the Y1, Y2, and Y5 receptors while PP is the endogenous ligand for the Y4 site.4Michel M.C. Beck-Stickinger A. Cox H. Doods H.N. Herzog H. Larhammar D. Quiron R. Schwartz T. Westfall T. XV1 International Union of Pharmacology recommendations for the nomenclature of Neuropeptide Y, peptide YY and pancreatic polypeptide receptors.Pharmacol Rev. 1998; 50: 143-150PubMed Google Scholar An alternate endogenous form of PYY, PYY(3-36), demonstrates increased affinity for the Y2 site that is thought to be a primarily a presynaptic receptor found on NPY expressing neurons.4Michel M.C. Beck-Stickinger A. Cox H. Doods H.N. Herzog H. Larhammar D. Quiron R. Schwartz T. Westfall T. XV1 International Union of Pharmacology recommendations for the nomenclature of Neuropeptide Y, peptide YY and pancreatic polypeptide receptors.Pharmacol Rev. 1998; 50: 143-150PubMed Google ScholarMultiple actions for these peptides in food intake have now been described. High concentrations of NPY are found in hypothalamic nuclei implicated in energy balance. NPY is an orexigenic peptide in that it stimulates eating when injected into the brain. NPY expressing cells in the hypothalamic arcuate nucleus coexpress leptin receptors and NPY is one of the downstream mediators of leptin’s actions in overall energy balance.5Woods S.C. Seeley R.J. Ports Jr, D. Scxhwartz M.W. Signals that regulate food intake and energy homeostasis.Science. 1998; 280: 1378-1383Crossref PubMed Scopus (975) Google Scholar When leptin levels are low as in periods of food deprivation, NPY expression is elevated. When leptin levels are high, or following exogenous leptin administration, NPY expression decreases. Based on data from experiments using selective pharmacological tools and antisense oligonucleotides, the orexigenic actions of NPY are thought to be mediated through interactions with Y1 and Y5 receptors.4Michel M.C. Beck-Stickinger A. Cox H. Doods H.N. Herzog H. Larhammar D. Quiron R. Schwartz T. Westfall T. XV1 International Union of Pharmacology recommendations for the nomenclature of Neuropeptide Y, peptide YY and pancreatic polypeptide receptors.Pharmacol Rev. 1998; 50: 143-150PubMed Google Scholar Centrally administered PYY and PP also elevate food intake, mimicking the actions of NPY.6Morley J.E. Levine A.S. Grace M. Kneip L. Peptide YY (PYY) a potent orexigenic agent.Brain Res. 1985; 341: 200-203Crossref PubMed Scopus (118) Google Scholar, 7Campbell R.E. Smith M.S. Allen S.E. Grayson B.E. French-Mullen J.M.H. Grave K.L. Orexin neurons express a functional pancreatic poypetide Y4 receptor.J Neurosci. 2003; 23: 1487-1497PubMed Google ScholarRecent data from Batterham et al.8Batterham R.L. Cowley M.A.S. Small C.J. Herzog H. Cohen M.A. Dakin C.L. Wren A.M. Brynes A.E. Low M.L. Ghatel M.A. Cone R.D. Bloom S.B. Gut hormone PYY(3-36) physiologically inhibits food intake.Nature. 2002; 418: 650-654Crossref PubMed Scopus (1822) Google Scholar have demonstrated an anorexigenic action for PYY(3-36). This alternate form of PYY is released into circulation from the distal intestine in response to meal ingestion, reaching peak levels 60-90 minutes after meal initiation. Peripherally administered PYY(3-36) at doses that produced plasma levels similar to those found postprandially exerted prolonged inhibitory effects on food intake. The authors suggested a brain site for this feeding inhibitory action of PYY(3-36) mediated through an interaction with arcuate nucleus Y2 receptors. The arcuate site of action was supported by data demonstrating that direct arcuate nucleus injections of PYY(3-36) in doses as low as 100 fmol inhibited food intake. Mediation through a Y2 site was supported by findings indicating that the actions of PYY(3-36) were mimicked by administration of a specific Y2 agonist and data showing that PYY(3-36) did not affect food intake in Y2 null mice. This pattern of results suggests that postprandially released PYY(3-36) may directly access hypothalamic sites, bind to presynaptic Y2 receptors to inhibit the release of NPY and in that way suppress subsequent food intake. Importantly, infusions of PYY(3-36) in humans that resulted in normal postprandial plasma levels, reduced ratings of appetite and significantly decreased test meal intake.Although the data from Asakawa et al.1Asakawa A. Inui A. Yuzuriha H. Ueno N. Katsuura G. Fujimiya M. Fujino M.A. Niijima A. Meguid M.M. Kasuga M. Characterization of the effects of pancreatic poypeptide in the regulation of energy balance.Gastroenterology. 2003; 124: 1325-1336Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar demonstrate that PP has a similar inhibitory effect on food intake following its exogenous peripheral administration, the mode of action for PP and the underlying mechanisms for affecting food intake seem to be different from that proposed for PYY(3-36). Following its exogenous administration PP resulted in reductions in both deprivation-induced and dark-cycle food intake. The reductions had a rapid onset in that feeding was reduced within 20 minutes and a long duration of action resulting in significant decreases over a full 24 hours. Rather than directly accessing brain sites, PP appears to have a peripheral site of action. Data demonstrating that PP inhibits hepatic vagal afferent activity and vagotomy blocks the feeding inhibitory actions of PP, suggest that PP directly interacts with peripheral vagal afferent terminals and PP-related signals are then transmitted to the brain over afferent vagal axons. Given that the dorsal vagal complex, the central site of vagal afferent terminations, contains a dense population of PP (Y4) binding sites,9Whitcomb D.C. Puccio A.M. Vigna S.R. Taylor H. Hoffman G.E. Distribution of pancreatic polypeptide receptors in the rat brain.Brain Res. 1997; 760: 137-149Crossref PubMed Scopus (62) Google Scholar a vagally dependent action suggests that possibility that peripheral PP is directly interacting with vagal PP receptor sites. Also consistent with a peripheral site of action for PP’s feeding inhibition, Campbell et al. have recently identified Y4 receptor sites on lateral hypothalamic orexin neurons and demonstrated that PP injected at this central site activates these neurons and results in a stimulation rather than an inhibition of food intake.7Campbell R.E. Smith M.S. Allen S.E. Grayson B.E. French-Mullen J.M.H. Grave K.L. Orexin neurons express a functional pancreatic poypetide Y4 receptor.J Neurosci. 2003; 23: 1487-1497PubMed Google ScholarAlthough peripheral PP may not directly access hypothalamic sites, the feeding inhibitory action appears to depend on alterations in the expression of a number of central and peripheral peptides involved in feeding control. Thus, Asakawa et al.1Asakawa A. Inui A. Yuzuriha H. Ueno N. Katsuura G. Fujimiya M. Fujino M.A. Niijima A. Meguid M.M. Kasuga M. Characterization of the effects of pancreatic poypeptide in the regulation of energy balance.Gastroenterology. 2003; 124: 1325-1336Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar demonstrate that peripherally administered PP reduces deprivation induced mRNA expression for the hypothalamic orexigenic peptides NPY and orexin and of ghrelin within the stomach. PP also enhanced mRNA expression of the anorexigenic peptide urocortin. These data suggest that modulation of a vagal afferent pathway can have long-term effects on gene expression in brain and gut systems involved in food intake control. Together with the extended duration of action, these findings are different from those obtained with cholecystokinin (CCK), another gut peptide that inhibits food intake through vagal mechanisms. CCK is involved in terminating individual meals and has not been shown to result in longer-term alterations in hypothalamic gene expression.10Moran T.H. Cholecystokinin and satiety current perspectives.Nutrition. 2000; 16: 858-865Abstract Full Text Full Text PDF PubMed Scopus (209) Google ScholarPP not only reduces food intake but also enhances energy expenditure as demonstrated by increased activity in sympathetic nerves innervating adipose tissue and increased oxygen consumption. Data such as these suggest that the overall effect of PP on body weight could be significant. Consistent with its effects on both food intake and energy expenditure, repeated PP administration resulted in significantly reduced body weight gain and fat pad weight in ob/ob mice.Although Asakawa et al. did not assess the potential for PP to affect food intake in human subjects, previous work has shown that PP administration will diminish the hyperphagia in patients with Prader-Willi syndrome.11Bernston G.G. Zipf W.B. O’Dorsio T.M. Hoffman J.A. Chance R.E. Pancreatic polypeptide infusions reduce food intake in Prader-Willi syndrome.Peptides. 1993; 14: 497-503Crossref PubMed Scopus (114) Google Scholar Prader-Willi syndrome is associated with low baseline and meal stimulated serum PP levels and high circulating ghrelin levels.12Cummings D.E. Clement K. Purnell J.Q. Vaisse C. Foster K.E. Frayo R.S. Schwartz M.W. Basdevant A. Weigle D.S. Elevated plasma ghrelin levels in Prader-Willi syndrome.Nature Medicine. 2002; 8: 643-644Crossref PubMed Scopus (513) Google Scholar Since exogenous PP down-regulates ghrelin expression, the effect of PP on food intake in Prader-Willi patients may depend in part on its ability to affect levels of circulating ghrelin.The identification of a role for PP in energy balance provides both potential insights into an etiology for obesity and an additional target for antiobesity drug development. Data from the most resent National Health and Nutrition Survey (NHANES) estimates that 64% of adults in the United States are either overweight or obese. This represents a significant increase in prevalence over results from previous surveys. Although we have made great strides in identifying brain and peripheral systems involved in the regulation of energy balance, we have yet to uncover how specific dysregulations in these systems may contribute to the growing obesity epidemic. As new signaling pathways that contribute to both food intake and energy expenditure are identified, the possibility of uncovering polymorphisms that may be associated with aspects of obesity phenotypes continues to grow. Finally, PP acting through peripheral Y4 receptors is an attractive target system for drug development. Since this appears to be a peripheral signaling pathway, there is the potential advantage of developing agents that would have little CNS involvement. At present, there are only 2 drugs available with FDA approval for long-term obesity treatment, olistat and sibutramine. Additional pharmacotherapies are clearly needed. The demonstration by Asakawa et al.1Asakawa A. Inui A. Yuzuriha H. Ueno N. Katsuura G. Fujimiya M. Fujino M.A. Niijima A. Meguid M.M. Kasuga M. Characterization of the effects of pancreatic poypeptide in the regulation of energy balance.Gastroenterology. 2003; 124: 1325-1336Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar that pancreatic polypeptide (PP) inhibits food intake and stimulates energy expenditure following its peripheral administration adds yet another putative peptide signaling molecule to the list of those that are involved in overall energy balance. Since the identification of leptin as the protein product of the ob gene in 1995,2Zhang Y. Proenca R. Maffei M. Barone M. Leopold L. Friedman J.M. Positional cloning of the mouse obese gene and its human homologue.Nature. 1994; 372: 425-432Crossref PubMed Scopus (11622) Google Scholar multiple neuropeptides whose expression is modified by leptin and that affect food intake and/or energy expenditure following their exogenous administration have been uncovered and our understanding of how these signaling pathways interact to result in the regulation of food intake and body weight continues to evolve. While Asakawa et al.1Asakawa A. Inui A. Yuzuriha H. Ueno N. Katsuura G. Fujimiya M. Fujino M.A. Niijima A. Meguid M.M. Kasuga M. Characterization of the effects of pancreatic poypeptide in the regulation of energy balance.Gastroenterology. 2003; 124: 1325-1336Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar do not identify a new peptide, they do provide evidence for a new role for a gut hormone with known actions in gastrointestinal motility and secretion. Thus, PP may be added to the list of gut peptides with actions that affect overall energy balance. PP is a member of the peptide family that also includes neuropeptide Y (NPY) and peptide YY (PYY). The 3 peptides have different patterns of expression and distribution with PP and PYY localized to the pancreas and gastrointestinal tract respectively and NPY found in both brain and peripheral neurons.3Ekblad E. Sunbdler F. Distribution of pancreatic polypeptide and peptide YY.Peptides. 2002; 23: 251-261Crossref PubMed Scopus (200) Google Scholar Multiple receptor subtypes with different affinities for the endogenous peptides have been identified. NPY and PYY have high affinity for the Y1, Y2, and Y5 receptors while PP is the endogenous ligand for the Y4 site.4Michel M.C. Beck-Stickinger A. Cox H. Doods H.N. Herzog H. Larhammar D. Quiron R. Schwartz T. Westfall T. XV1 International Union of Pharmacology recommendations for the nomenclature of Neuropeptide Y, peptide YY and pancreatic polypeptide receptors.Pharmacol Rev. 1998; 50: 143-150PubMed Google Scholar An alternate endogenous form of PYY, PYY(3-36), demonstrates increased affinity for the Y2 site that is thought to be a primarily a presynaptic receptor found on NPY expressing neurons.4Michel M.C. Beck-Stickinger A. Cox H. Doods H.N. Herzog H. Larhammar D. Quiron R. Schwartz T. Westfall T. XV1 International Union of Pharmacology recommendations for the nomenclature of Neuropeptide Y, peptide YY and pancreatic polypeptide receptors.Pharmacol Rev. 1998; 50: 143-150PubMed Google Scholar Multiple actions for these peptides in food intake have now been described. High concentrations of NPY are found in hypothalamic nuclei implicated in energy balance. NPY is an orexigenic peptide in that it stimulates eating when injected into the brain. NPY expressing cells in the hypothalamic arcuate nucleus coexpress leptin receptors and NPY is one of the downstream mediators of leptin’s actions in overall energy balance.5Woods S.C. Seeley R.J. Ports Jr, D. Scxhwartz M.W. Signals that regulate food intake and energy homeostasis.Science. 1998; 280: 1378-1383Crossref PubMed Scopus (975) Google Scholar When leptin levels are low as in periods of food deprivation, NPY expression is elevated. When leptin levels are high, or following exogenous leptin administration, NPY expression decreases. Based on data from experiments using selective pharmacological tools and antisense oligonucleotides, the orexigenic actions of NPY are thought to be mediated through interactions with Y1 and Y5 receptors.4Michel M.C. Beck-Stickinger A. Cox H. Doods H.N. Herzog H. Larhammar D. Quiron R. Schwartz T. Westfall T. XV1 International Union of Pharmacology recommendations for the nomenclature of Neuropeptide Y, peptide YY and pancreatic polypeptide receptors.Pharmacol Rev. 1998; 50: 143-150PubMed Google Scholar Centrally administered PYY and PP also elevate food intake, mimicking the actions of NPY.6Morley J.E. Levine A.S. Grace M. Kneip L. Peptide YY (PYY) a potent orexigenic agent.Brain Res. 1985; 341: 200-203Crossref PubMed Scopus (118) Google Scholar, 7Campbell R.E. Smith M.S. Allen S.E. Grayson B.E. French-Mullen J.M.H. Grave K.L. Orexin neurons express a functional pancreatic poypetide Y4 receptor.J Neurosci. 2003; 23: 1487-1497PubMed Google Scholar Recent data from Batterham et al.8Batterham R.L. Cowley M.A.S. Small C.J. Herzog H. Cohen M.A. Dakin C.L. Wren A.M. Brynes A.E. Low M.L. Ghatel M.A. Cone R.D. Bloom S.B. Gut hormone PYY(3-36) physiologically inhibits food intake.Nature. 2002; 418: 650-654Crossref PubMed Scopus (1822) Google Scholar have demonstrated an anorexigenic action for PYY(3-36). This alternate form of PYY is released into circulation from the distal intestine in response to meal ingestion, reaching peak levels 60-90 minutes after meal initiation. Peripherally administered PYY(3-36) at doses that produced plasma levels similar to those found postprandially exerted prolonged inhibitory effects on food intake. The authors suggested a brain site for this feeding inhibitory action of PYY(3-36) mediated through an interaction with arcuate nucleus Y2 receptors. The arcuate site of action was supported by data demonstrating that direct arcuate nucleus injections of PYY(3-36) in doses as low as 100 fmol inhibited food intake. Mediation through a Y2 site was supported by findings indicating that the actions of PYY(3-36) were mimicked by administration of a specific Y2 agonist and data showing that PYY(3-36) did not affect food intake in Y2 null mice. This pattern of results suggests that postprandially released PYY(3-36) may directly access hypothalamic sites, bind to presynaptic Y2 receptors to inhibit the release of NPY and in that way suppress subsequent food intake. Importantly, infusions of PYY(3-36) in humans that resulted in normal postprandial plasma levels, reduced ratings of appetite and significantly decreased test meal intake. Although the data from Asakawa et al.1Asakawa A. Inui A. Yuzuriha H. Ueno N. Katsuura G. Fujimiya M. Fujino M.A. Niijima A. Meguid M.M. Kasuga M. Characterization of the effects of pancreatic poypeptide in the regulation of energy balance.Gastroenterology. 2003; 124: 1325-1336Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar demonstrate that PP has a similar inhibitory effect on food intake following its exogenous peripheral administration, the mode of action for PP and the underlying mechanisms for affecting food intake seem to be different from that proposed for PYY(3-36). Following its exogenous administration PP resulted in reductions in both deprivation-induced and dark-cycle food intake. The reductions had a rapid onset in that feeding was reduced within 20 minutes and a long duration of action resulting in significant decreases over a full 24 hours. Rather than directly accessing brain sites, PP appears to have a peripheral site of action. Data demonstrating that PP inhibits hepatic vagal afferent activity and vagotomy blocks the feeding inhibitory actions of PP, suggest that PP directly interacts with peripheral vagal afferent terminals and PP-related signals are then transmitted to the brain over afferent vagal axons. Given that the dorsal vagal complex, the central site of vagal afferent terminations, contains a dense population of PP (Y4) binding sites,9Whitcomb D.C. Puccio A.M. Vigna S.R. Taylor H. Hoffman G.E. Distribution of pancreatic polypeptide receptors in the rat brain.Brain Res. 1997; 760: 137-149Crossref PubMed Scopus (62) Google Scholar a vagally dependent action suggests that possibility that peripheral PP is directly interacting with vagal PP receptor sites. Also consistent with a peripheral site of action for PP’s feeding inhibition, Campbell et al. have recently identified Y4 receptor sites on lateral hypothalamic orexin neurons and demonstrated that PP injected at this central site activates these neurons and results in a stimulation rather than an inhibition of food intake.7Campbell R.E. Smith M.S. Allen S.E. Grayson B.E. French-Mullen J.M.H. Grave K.L. Orexin neurons express a functional pancreatic poypetide Y4 receptor.J Neurosci. 2003; 23: 1487-1497PubMed Google Scholar Although peripheral PP may not directly access hypothalamic sites, the feeding inhibitory action appears to depend on alterations in the expression of a number of central and peripheral peptides involved in feeding control. Thus, Asakawa et al.1Asakawa A. Inui A. Yuzuriha H. Ueno N. Katsuura G. Fujimiya M. Fujino M.A. Niijima A. Meguid M.M. Kasuga M. Characterization of the effects of pancreatic poypeptide in the regulation of energy balance.Gastroenterology. 2003; 124: 1325-1336Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar demonstrate that peripherally administered PP reduces deprivation induced mRNA expression for the hypothalamic orexigenic peptides NPY and orexin and of ghrelin within the stomach. PP also enhanced mRNA expression of the anorexigenic peptide urocortin. These data suggest that modulation of a vagal afferent pathway can have long-term effects on gene expression in brain and gut systems involved in food intake control. Together with the extended duration of action, these findings are different from those obtained with cholecystokinin (CCK), another gut peptide that inhibits food intake through vagal mechanisms. CCK is involved in terminating individual meals and has not been shown to result in longer-term alterations in hypothalamic gene expression.10Moran T.H. Cholecystokinin and satiety current perspectives.Nutrition. 2000; 16: 858-865Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar PP not only reduces food intake but also enhances energy expenditure as demonstrated by increased activity in sympathetic nerves innervating adipose tissue and increased oxygen consumption. Data such as these suggest that the overall effect of PP on body weight could be significant. Consistent with its effects on both food intake and energy expenditure, repeated PP administration resulted in significantly reduced body weight gain and fat pad weight in ob/ob mice. Although Asakawa et al. did not assess the potential for PP to affect food intake in human subjects, previous work has shown that PP administration will diminish the hyperphagia in patients with Prader-Willi syndrome.11Bernston G.G. Zipf W.B. O’Dorsio T.M. Hoffman J.A. Chance R.E. Pancreatic polypeptide infusions reduce food intake in Prader-Willi syndrome.Peptides. 1993; 14: 497-503Crossref PubMed Scopus (114) Google Scholar Prader-Willi syndrome is associated with low baseline and meal stimulated serum PP levels and high circulating ghrelin levels.12Cummings D.E. Clement K. Purnell J.Q. Vaisse C. Foster K.E. Frayo R.S. Schwartz M.W. Basdevant A. Weigle D.S. Elevated plasma ghrelin levels in Prader-Willi syndrome.Nature Medicine. 2002; 8: 643-644Crossref PubMed Scopus (513) Google Scholar Since exogenous PP down-regulates ghrelin expression, the effect of PP on food intake in Prader-Willi patients may depend in part on its ability to affect levels of circulating ghrelin. The identification of a role for PP in energy balance provides both potential insights into an etiology for obesity and an additional target for antiobesity drug development. Data from the most resent National Health and Nutrition Survey (NHANES) estimates that 64% of adults in the United States are either overweight or obese. This represents a significant increase in prevalence over results from previous surveys. Although we have made great strides in identifying brain and peripheral systems involved in the regulation of energy balance, we have yet to uncover how specific dysregulations in these systems may contribute to the growing obesity epidemic. As new signaling pathways that contribute to both food intake and energy expenditure are identified, the possibility of uncovering polymorphisms that may be associated with aspects of obesity phenotypes continues to grow. Finally, PP acting through peripheral Y4 receptors is an attractive target system for drug development. Since this appears to be a peripheral signaling pathway, there is the potential advantage of developing agents that would have little CNS involvement. At present, there are only 2 drugs available with FDA approval for long-term obesity treatment, olistat and sibutramine. Additional pharmacotherapies are clearly needed.