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Roles of pancreatic polypeptide in regulation of food intake
Peptides 23 (2002) 323–329
Roles of pancreatic polypeptide in regulation of food intake Goro Katsuuraa, Akihiro Asakawab, Akio Inuib a
b
Aburahi Laboratories, Shionogi & Co. Ltd. Shiga, 520-3423 Japan Division of Diabetes, Digestive and Kidney Diseases, Department of Clinical Molecular Medicine Kobe University Graduate School of Medicine, Kobe, 650-0017 Japan
Abstract Pancreatic polypeptide (PP) is produced in pancreatic islets of Langerhans and released into the circulation after ingestion of a meal. Peripherally administered PP suppresses food intake and gastric emptying. On the other hand, central administration of PP elicits food intake and gastric emptying. Therefore, PP actions on food intake may be, in part, attributable to gastric emptying. PP transgenic mice exhibit decreases in both food intake and gastric emptying rate that were clearly reversed by anti-PP antiserum. PP is an anorexigenic signal in the periphery and an orexigenic signal in the central nervous system. © 2002 Elsevier Science Inc. All rights reserved. Keywords: Pancreatic polypeptide; food intake; gastric emptying
1. Introduction Energy homeostasis regulated by the balance between food intake and energy expenditure is accomplished through a highly integrated and redundant neurohormonal system [31]. It is also recognized as playing a major role in maintenance of energy homeostasis and of rigidly maintaining the body weight around a set point. Abnormalities in the onset, periodicity, duration and magnitude of eating episodes generally underlie augmented feeding behavior [9,30, 57]. Increased food intake invariably culminates in an increased rate of body weight gain and obesity [30]. On the other hand, anorexia with a psychobiological basis [12] or in response to acute or chronic infection, inflammation, or trauma is followed by severe loss of body weight [19,41, 50]. Feeding behavior is known to be regulated by many mediators and regulatory pathways in the brain and periphery. There is now growing evidence that food intake is regulated by neurotransmitters and neuromodulators including anorexigenic and orexigenic neuropeptides in the hypothalamic nuclei in interaction with blood-borne hormones and nutrients. Thus, peptide hormones and neuropeptides play significant roles in energy homeostasis in both the peripherary and the central nervous system. * Corresponding author. Tel.: ⫹81-78-382-5862; fax: ⫹81-78-3822080. E-mail address: [email protected] (A. Inui).
Pancreatic polypeptide (PP) is a 36-amino acid peptide that belongs to a family including neuropeptide Y (NPY) and peptide YY (PYY). PP is produced in the endocrine type F cells located in the periphery of pancreatic islets and is released into the circulation after ingestion of food and exercise [1,26,35,54,59]. PP exerts a variety of regulatory actions, including inhibition of pancreatic exocrine secretion, gallbladder contraction, stimulation of glucocorticoid secretion, modulation of gastric acid secretion and gastrointestinal motility [21,40]. The amount of PP released is dependent on the digestive state [2,14,52]. Release of PP occurs at a low rate in the fasted state and is markedly increased throughout all phases of digestion. PP release is also sensitive to small decreases in blood glucose levels, and insulin-induced hypoglycemia is a potent stimulus for the cephalic phase of PP secretion. During the cephalic and gastric phases, the stimulation of PP release is dependent on intact vagal cholinergic reflex circuits because vagotomy and treatment of muscarinic receptor antagonist abolish this response, suggesting a key role of vagal-cholinergic mechanisms in stimulation of PP secretion [59]. Moreover, PP released into the circulation by vagal-cholinergic mechanisms traverses the blood-brain barrier (BBB) through leaky regions in the area postrema (AP) and then binds to specific receptors in the dorsal vagal complex (DVC) in a negative feedback mechanism [67]. Therefore, PP can directly regulate vagal input to the stomach, pancreas and other gastrointestinal organs [38,39,45,66]. PP may play a significant role in regulating feeding
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behavior to control energy balance. This session addressed the effects of PP on food intake and its possible mechanisms of actions.
2. Peripheral action of PP on food intake Hyperphasia and obesity in genetically obese (ob/ob) mice are reversed by parabiosis of lean littermates or by transplantation of functional islets from mice of normal weight [16,56]. These findings suggested that the ob/ob mice possess a functioning satiety center capable of responding to circulating satiety factors but lack the circulating satiety factors, which are pancreatic in origin. In this regard, Jia and Taylor observed no postparandial increase in plasma PP levels in ob/ob mice although pancreatic PP contents were significantly increased in ob/ob mice compared with lean littermates [6]. These findings indicated that the hyperphasia observed in ob/ob mice is, in part, due to the lower plasma PP levels and reduced sensitivity to PP. A congenital obesity syndrome in humans, the Prader-Willi syndrome, is characterized by hyperphasia, obesity, hyperglycemia and hyperinsulinemia similar to the phenotypes observed in ob/ob mice [22]. The subjects are severely deficient in basal and meal-stimulated PP secretion. In Prader-Willi subjects, intravenous (i.v.) infusion of PP was reported to increase serum PP levels and significantly reduce food intake [6]. These observations suggested that PP may be one of the satiety factors in the systemic circulation Malaisse-Lagae et al. first reported that bovine PP (bPP) injected intraperitorially twice daily for 2 weeks in genetically obese mice (C57BL/6J-ob/ob), reduced food intake, resulting in a significant reduction in daily body weight gain [36]. Moreover, McLaughlin and Baile demonstrated that bovine PP decreased food intake after food deprivation in ob/ob and lean mice, and that ob/ob mice were less sensitive to PP than lean mice [37]. Peripheral injection of PP was reported to reduce food intake, body weight and body weight gain in dogs [58]. However, the degree of reduction of food intake by PP is moderate, and in other studies it was not observed or was detected only after administration of high pharmacological doses. Billington reported that food intake evoked by 12 or 48-h starvation was not influenced by intraperitoneal (i.p.) injection of PP in rats [8]. Taylor et al. also reported that i.p. administered PP had no significant effect on food intake following 18-h food deprivation in rats [61]. Moreover, Taylor and Garcia demonstrated that PP did not influence food intake after 18-h starvation in either lean or obese mice [60]. Although PP has been sequenced in several mammals and its amino acid sequence was shown to be conserved among species, this discrepancy might be due to doses and species-specific differences in PP used in each study. To exclude these effects on the action of PP, i.p. injection of mouse PP at physiological doses was conformed and was
Fig. 1. (A) Effects of i.p. injection of mouse pancreatic polypeptide (mPP, nmol/mouse) on cumulative food intake in food-deprived mice. (B) Effects of intracerebroventricular injection of mouse pancreatic polypeptide (mPP, nmol/mouse) on cumulative food intake in non food-deprived mice. Each column represents mean ⫾ SE. *P ⬍ 0.05, **P ⬍ 0.01 compared with the saline and ACSF control group, respectively. (From Ref. 3)
shown to significantly suppress food intake in food-deprived mice (Fig. 1A) [3]. The mechanism by which peripheral administration of PP reduces food intake has been the subject of considerable research, but has not to be definitively determined. i.p. injection of PP suppresses gastric emptying in experimental animals (Fig. 2A) [44]. The dose of exogenous PP required for suppression of food intake is comparable to those required for inhibition of gastric emptying. This is consistent with the classic studies of Cannon and Washburn [10] and others [42,48] indicating the relationship between gastric distention and feeding, demonstrating that mechanical distention of the stomach inhibits food intake. McTigure et al. demonstrated that peripheral administration and microinjection of PP into the dorsomedial region of the DVC produced significant, long-lasting and dose-dependent increases in antral motility [39,40]. This response was attenuated by bilateral cervical vagotomy and the anticholinergic agent, atropine [3,45]. PP can directly regulate vagal input to the stomach, pancreas and other gastrointestinal organs [38,39,40,45,66] and PP release is dependent on vagal cholinergic reflex circuits because vagotomy abolished this response [59].
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Fig. 2. (A) Effect of i.p. injection of PP on gastric emptying in rats. (B) Effect of intracisternal injection of PP on gastric emptying in rats. PP or saline was injected just before administration of a test liquid meal. Rats were sacrificed and stomach was removed 20 min after meal ingestion to determine gastric emptying. Each column represents mean ⫾ SE. *P ⬍ 0.05 compared with saline control group. (From Ref. 41)
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demonstrated that circulating PP could enter the brain to bind to AP and influence the adjacent nuclei, such as NTS and DMN to inhibit gastric emptying, which in turn suppresses food intake. As both the NTS and DMN are essential components of gastrointestinal vagovagal reflexes, substances that influence the activity of NTS and/or DMN neurons may lead to modulation of gastrointestinal functions. Vagal afferents carrying primary sensory information from the gastrointestinal tract make synapses with neurons within the NTS and AP. The NTS processes this sensory input and sends axonal projections to terminate in the subjacent DMN. Vagal efferents originating from DMN neurons then project to enteric neurons in the gastrointestinal tract and pancreas. Thus, when a vagovagal reflex is activated by visceral afferents, the vagal efferents can stimulate or inhibit a variety of gastrointestinal actions, including PP release from the pancreas. Thus, circulating PP is in a position to modulate vagovagal reflex actions and may modulate autonomic regulation of gastrointestinal functions by gaining access directly to dorsal vagal neurons and altering their activity, resulting in decreased food intake. However, whether cholinergic or vagus nerves mediate PP-induced food intake was yet to be determined. In conclusion, circulating PP moderately, but significantly suppresses food intake in lean and obese animals, which is, in part, attributable to decreased gastric emptying rate regulated by the DVC influenced by circulating PP. PP released by food ingestion seems to be a signal to inhibit further food intake, and participates in control of meal size by modulating the rate of gastric emptying during the meal. Further studies are required to determine the particular actions of the proposed links in this integrative chain from the gastrointestinal tract to the brain to the stomach.
3. Central action of PP on food intake These observations suggest that the inhibitory effect of PP on food intake might be indirect and be regulated via vagal nerves. If PP acts centrally, it must either enter the brain by a specific transporter system or through circumventricular organs of the brain where the BBB is incomplete. Using autoradiography to identify radiolabeled PP binding to frozen sections of the rat brain, Whitcomb et al. identified saturable and specific PP receptors with high affinity in high concentrations in the interpeduncular nucleus, area postrema (AP), nucleus tractus solitarius (NTS), and dorsal motor nucleus (DMN) of the vagus [67]. This radiolabeled PP binding in these areas failed to be displaced by NPY or PYY, and was distinct in location from NPY and PYY receptors [67]. Moreover, they found increases in saturable radiolabeled PP accumulation in the small region including the AP when radiolabeled PP was injected through a peripheral vein [67]. The dorsomedial region of the NTS has fenestrated capillaries to allow circulating peptides, such as PP access to the NTS and neighboring DMN. These findings
Feeding behavior is regulated by neurotransmitters and neuromodulators in the central nervous system as well as blood-borne factors. PP may also act as a neurotransmitter/ neuromodulator in the central nervous system. Some investigators [25] have identified PP in the rat brain by sensitive radioimmunoassay (RIA), while others did not [13,18]. The difficulty in proving central expression of PP by RIA may be explained by the relatively limited areas of PP synthesis and concern over cross-reactivity with NPY and PYY. There are, however, several lines of evidence suggesting that PP is synthesized within some areas of the central nervous system as follows. PP-immunoreactive neurons have been identified in the brainstem and spinal cord [25]. The level of immunoreactive PP did not increase in the cerebrospinal fluid (CSF) with marked elevation of plasma PP in response to feeding or insulin hypoglycemia [26]. Furthermore, CSF PP did not increase after infusion of exogenous PP, but strenuous exercise evoked increases in both plasma and CSF PP levels [26], raising the possibility
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of PP release from a central source. The existence of PPcontaining neurons was demonstrated in the brain [23,46]. PP mRNA has been identified in the rat brain, including the ventromedial hypothalamus, by reverse transcription-PCR [7,64]. On the other hand, in situ hybridization analysis with PP specific probes did not demonstrate expression of PP mRNA in the CNS [49]. It is possible that a peptide that is structurally related, but not identical to PP is synthesized in the brain. Alternatively, blood-borne PP may reach small areas of the brain without a BBB and thus exert its action. In this regard, blood-borne PP has been shown to reach the circumventricular organs without the BBB and crosses the BBB by a saturable transporter system to reach its receptors behind the BBB to account for the PP-induced increase of food intake [4]. Further studies are required to confirm whether PP is synthesized in the rat brain and to address all of these possibilities, Interestingly, specific PP binding sites were detected in the hypothalamic nuclei, which are involved in the regulation of food intake. [125I]Human PP binding sites were found in the medial preoptic area, paraventricular nucleus of the hypothalamus, interpeduncular nucleus, NTS, area postrema and dorsal vagal nucleus, with the highest concentrations seen in the interpeduncular nucleus and AP [62,65,67]. Among the six subtypes of Y receptors identified to date, Y1 and Y5 receptors are known to contribute to feeding behavior [24,68]. Y1 receptors are specific for NPY and PYY, whereas Y5 receptors recognize not only NPY and PYY but also bovine and human (but not rodent) PP [34]. The Y4 receptor has extremely high affinity for PP with somewhat lower affinity for NPY [5,32,69]. In situ hybridization studies demonstrated enrichment of both Y4 and Y5 mRNAs in the hypothalamus, including the paraventricular nucleus, associated with food intake [5,17]. Previous studies have shown that centrally administered PP also produces a moderate increase in food intake. Clark et al. found that intracerebroventricular administration of human PP in satiated rats moderately, but significantly increased food intake with a late onset during the light phase of the day [11]. Inui et al. reported that porcine and human PPs, when administered into the third cerebral ventricle, increased food intake in satiated dogs [27]. However, Cterminal fragments, hPP-(18 –36) and hPP-(23–36), were much less effective [27]. Moreover, Nakajima et al. demonstrated that rat PP has an orexigenic action in mice, when injected into the third cerebroventricle [43]. As species specificity in the response to PP, mouse PP intracerebroventricularly administered in non-food-deprived mice increases food intake in a dose-related manner (Fig. 1B) [3]. These findings suggested that PP might be an orexigenic factor in the central nervous system and that the full-length molecule including the tertiary structure of PP is necessary for full expression of the orexigenic activity. The mechanism of the increase of food intake induced by PP remains to be clearly determined. Intracisternal administration of PP, that may bind to receptors in the DVC,
dose-dependently accelerated gastric emptying rate in rats, which was abolished following subdiaphragmatic vagotomy (Fig. 2B) [44]. As mentioned above, the increase of gastric emptying rate induced by centrally administered PP is responsible, at least in part, for the increased food intake caused by central injection of PP. The Y4 receptor has extremely high affinity for PP and the Y5 receptor has been suggest to play a role in the control of feeding by the central nervous system [5,17,20,32,55,69]. Therefore, centrally administered PP may act on Y4 or Y5 receptors to modulate food intake in the brain. In vivo administration of antisense phosphorothioated oligodeoxynucleotides corresponding to the Y5 receptor decreased basal food intake and suppressed the NPY-induced feeding response [15,53]. However, antisense oligos to the Y5 receptor injected intracerebroventricularly had no effect on food intake stimulated by central administration of PP [15]. A selective and potent Y5 antagonist, L-152,804, significantly suppressed the food intake induced by bovine PP. Human and bovine PPs stimulate food intake in mice, which was attenuated in Y5 ⫺/⫺ mice although it was not abolished [34]. The significant food intake was induced by human and bovine PPs in Y5 ⫺/⫺ mice. On the other hand, the increase of food intake by intracerebraventricular injection of PP was not suppressed following administration of Y5 receptor antisense oligo [27]. These observations suggested the participation of an other feeding receptor. Moreover, in Y1 ⫺/⫺ mice the stimulation of feeding by PP was also attenuated, but not abolished [34]. This indicated that the action of PP may be directly or indirectly modulated by Y1 receptors. The food consumption induced by centrally administered PP appears to be mediated by other receptor subtypes since the Y4-specific agonist rat PP failed to stimulate feeding behavior in rats and mice [34]. The involvement of Y4 receptors in the central action of PP, however, has yet to be confirmed. Intracerebroventricular injection of a purported Y1 antagonist and Y4 agonist, GR231118 (also known as 1229U91 and GW1229) significantly suppressed both physiological feeding behavior after fasting and NPYinduced food intake in obese and lean animals [28,33,47, 51], suggesting that Y4 receptor does not stimulate food intake. These findings indicated that other of Y receptor subtypes contribute to the feeding behavior elicited by PP.
4. PP transgenic mice Transgenic technology, which permits the introduction of genes into the germ line of mice, is a powerful tool to explore the pathophysiological relevance of transgenes. As mentioned above, PP has opposing effects on food intake when administered peripherally or centrally. Transgenic overproduction of PP using the cytomegalovirus immediate early enhancer-chicken -actin hybrid promoter allowed development of lean mice that showed overexpression of PP mostly in the pancreatic islets and reduction of fat mass as
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On the other hand, central administration of PP elicits food intake and gastric emptying via NPY receptors, such as Y5 or Y4 receptors. Therefore, PP actions on food intake may be, in part, attributable to gastric emptying. PP is an anorexigenic signal in the periphery and an orexigenic signal in the central nervous system.
References
Fig. 3. Food intake in PP transgenic (PP-Tg) and wild type mice. Results are expressed as mean ⫾ SE. *P ⬍ 0.05, **P ⬍ 0.01 compared with wild type. (From Ref. 58)
determined by body composition analysis [63]. Basal plasma PP concentrations were more than 20-fold higher than those of control littermates, and 2-fold increased PP concentrations found after a meal in control mice. PP transgenic mice exhibit significant decreases in total food intake as well as food intake in both light and dark phases (Fig. 3) [63]. No significant changes in water intake, oxygen consumption or plasma leptin levels were observed in the transgenic mice. The decrease of food intake in transgenic mice was associated with a reduced rate of gastric emptying of the solid meal (Fig. 4) [63]. i.p. administration of anti-PP antiserum in the transgenic mice significantly increased both food intake and body weight [63]. These findings strongly support the suggestion of a role of PP as a circulating satiety signal. 5. Conclusion PP released by food ingestion inhibits further food intake by modulating the rate of gastric emptying during the meal.
Fig. 4. Rate of gastric emptying of a solid meal in PP transgenic (PP-Tg) and wild type mice. The mice following 16-h food deprivation had free access to chow for 1 h, and gastric emptying was assessed 2, 3, and 4 h after eating. Results are expressed as mean ⫾ SE. *P ⬍ 0.05 compared with wild type. (From Ref. 58)
[1] Adrian TE, Besterman HS, Cooke TJ, Bloom SR, Bames AJ, Russell RC. Mechanism of pancreatic polypeptide release in man. Lancet 1997;I:161–3. [2] Adrian TE, Bloom SR, Besterman HS, Barnes AJ, Cooke TJC, Russell RCG, Faber RG. Mechanism of pancreatic polypeptide release in man. Lancet 1977;I:161–3. [3] Asakawa A, Inui A, Ueno N, Fujimiya M, Fujiko MA, Kasuga M. Mouse pancreatic polypeptide modulates food intake, while not influencing anxiety in mice. Peptides 1999;20:1445– 8. [4] Banks WA, Kastin AJ, Jaspan JB. Regional variation in transport of panceatic polypeptide across the blood-brain barrier of mice. Pharmacol Biochem Behav 1995;51:139 – 47. [5] Bard JA, Walker MW, Branchek TA, Weinshank RL. Cloning and functional expression of a human Y4 subtype receptor for pancreatic polypeptide, neuropeptide Y, and peptide YY. J Biol Chem 1995; 270:26762–5. [6] Berntson GG, Zipf WB, O’Dorisio TM, Hoffman JA, Chance RE. Pancreatic polypeptide infusions reduce food intake in Prader-Willi syndrome. Peptides 1993;14:497–503. [7] Bhattacharya S, Paul C, Mobbs C. Detection of rat prepropancreatic polypeptide mRNA in rat brain using RT-PCR. Soc Neurosci Abstr 1994;20:361.5. [8] Billington CJ, Levine AS, Morley JE. Are peptides truly satiety agents? A method of testing for neurohumoral satiety effects. Am J Physiol 1983;245:R920 – 6. [9] Bray GA. Mechanism for development of genetic, hypothalamic and dietary obesity. In: Bray GA, Ryan DH, editors. Molecular and genetic aspects of obesity. Baton Rouge, LA: LSU Press, 1996. p. 2– 66. [10] Cannon WB, Washburn AL. An explanation of hunger. Am J Physiol 1912;29:441–55. [11] Clark JT, Kalra PS, Croley WR, Kalra SP. Neuropeptide Y, and human pancreatic polypeptide stimulate feeding behavior in rats. Endocrinology 1984;115:427–9. [12] Crisp AH. The psychopathology of anorexia nervosa: getting the heat out of the system. In: Stunkard AJ, Stellar E, editors. Eating and its disorders. Association for research in nervous system and mental disease. Vol. 62. New York: Raven Press, 1984. p. 209 –34. [13] DiMaggio DA, Chronwall BM, Buchanan K, O’Donohue TL. Panreatic polypeptide immunoreactivity in rat brain is actually neuropeptide Y. Neuroscience 1985;15:1149 –57. [14] Floyd JC. Pancreatic polypeptide. Clin Gastroenterol 1980;9:657–78. [15] Flynn MC, Turrin NP, Plata-Salaman CR, Ffrench-Mullen JMH. Feeding response to neuropeptide Y-induced compounds in rats treated with Y5 receptor antisense or sense phosphothio-oligodeoxynucleotide. Physiol Behav 1999;66:881– 4. [16] Gates RJ, Hunt MJ, Lazarus NR. Further studies on the amelioration of the characteristics of New Zealand obese (NZO) mice following implantation of islets of Langerhans. Diabetologia 1974;10:401– 6. [17] Gerald C, Walker MW, Criscione L, Gustafson EL, Batzl-Hartmann C, Smith KE, Vaysse P, Durkin MM, Laz TM, Linemeyer DL, Schaffhauser AO, Whitebread S, Hofbauer KG, Taber RI, Branchek TA, Weinshank RL. A receptor subtype involved in neuropeptide-Yinduced food intake. Nature 1996;382:168 –71.
328
G. Katsuura / Peptides 23 (2002) 323–329
[18] Greeley GJ, Trowbridge J, Burdett J, Hill FL, Spannagel A, Thompson JC. Radioimmunoassay of pancreatic polypeptide in mammalian and submammalian vertebrates using a carboxyl-terminal hexapeptide antiserum. Reg Pept 1984;8:177– 87. [19] Grunfeld C, Feingold K. Metabolic disturbances and wasting in the acquired immuno-deficiency syndrome. N Engl J Med 1992;327: 329 –37. [20] Haynes AC, Arch JRS, Wilson S, Mac Clue S, Buckingham RE. Characterization of neuropeptide Y receptor that mediates feeding in the rat: a role for the Y5 receptor? Regul Pept 1998;75/76:355– 61. [21] Hazelwood RL. The pancreatic polypeptide (PP-fold) family: gastrointestinal, vascular, and feeding behavioral implication. Proc Soc Exp Biol Med 1993;202:44 – 63. [22] Holm VA. The diagnosis of Prader-Willi syndrome. In: Holm VA, Sulzbacher SJ, Pipes PL, editors. Prader-Willi syndrome. Baltimore, MD: University Park Press, 1979. p. 27– 45. [23] Hunt SP, Emson PC, Gilbert R, Goldstein M, Kimmel JR. Presence of avian pancreatic polypeptide-like immunoreactivity in catecholamine and methionine-enkephalin-containing neurons within the central nervous system. Neurosci Lett 1981;21:125–30. [24] Inui A. Neuropeptide Y feeding receptors – are multiple subtypes involved? Trends Pharmacol Sci 1999;20:43– 6. [25] Inui A, Mizuno N, Ooya M, Suenaga K, Morioka H, Ogawa T, Ishida M, Baba S. Cross-reactivities of neuropeptide Y, and peptide YY with pancreatic polypeptide antisera: evidence for the existence of pancreatic polypeptide in the brain. Brain Res 1985;330:386 –9. [26] Inui A, Okita M, Miura M, Hirosue Y, Mizuno N, Baba S, Kasuga M. Plasma and cerebroventricular fluid levels of pancreatic polypeptide in the dog: Effects of feeding, insulin-induced hypoglycemia, and physical exercise. Endocrinology 1993;132:1235–9. [27] Inui A, Okita M, Nakajima M, Inoue T, Sakatani N, Oya M, Morioka H, Okimura Y, Chihara K, Baba S. Neuropeptide regulation of feeding in dogs. Am J Physiol 1991;261:R588 –94. [28] Ishihara A, Tanaka T, Kanatani A, Fukami T, Ihara M, Fukuroda T. A potent neuropeptide Y antagonist, 1229U91, suppressed spontaneous food intake in Zucker fatty rats. Am. J. Physiol.;1998;274: R1500 – 4. [29] Jia BQ, Taylor IL. Failure of pancreatic polypeptide release in congenitally obese mice. Gastroenterology 1984;87:338 – 43. [30] Kalra SP. Appetite and body weight regulation: is it all in the brain? Neuron 1997;19:227–30. [31] Kalra SP, Dube MG, Pu S, Xu B, Horvath TL, Kalra PS. Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endoc Rev 1999;20:68 –100. [32] Kanatani A, Ishihara A, Iwaasa H, Nakamura K, Okamoto O, Hidaka M, Ito J, Fukuroda T, MacNeil DJ, Van der Ploeg LHT, Ishii Y, Okade T, Fukami T, Ihara M. L-152,804: Orally active, and selective neuropeptide Y Y5 receptor antagonist. Biochem Biophys Res Commun 2000;272:169 –73. [33] Kanatani A, Ishihara A, Asahi S, Tanaka T, Ozaki S, Ihara M. Potent neuropeptide Y Y1 receptor antagonist, 1229U91: blockade of neuropeptide Y-induced an physiological food intake. Endocrinology 1996;137:3177– 82. [34] Kanatani A, Mashiko S, Murai N, Sugimoto N, Ito J, Fukuroda T, Fukami T, Morin N, MacNeil DJ, Van der Ploeg LHT, Saga Y, Nishimura S, Ihara M. Role of the Y1 receptor in the regulation of neuropeptide Y-mediated feeding: Comparison of wild-type, Y1 receptor-deficient, and Y5 receptor-deficient mice. Endocrinology 2000;141:1011– 6. [35] Kimmel JR, Hayden LJ, Pollock HG. Isolation and characterization of a new pancreatic polypeptide hormone. J Biol Chem 1975;250:9369 – 76. [36] Malaisse-Lagae F, Carpentier J-L, Malaisse WJ, Orci L. Pancreatic polypeptide: A possible role in the regulation of food intake in the mouse. Experientia 1977;33:915–7.
[37] McLaughlin CL, Baile CA. Obese mice and satiety effects of cholecystokinin, bombesin and pancreatic polypeptide. Physiol Behav 1981;26:433–7. [38] McTigue DM, Chen C-H, Rogers RC, Stephens RL. Intracisternal rat pancreatic polypeptide stimulates gastric emptying in the rat. Am J Physiol 1995;269:R167–72. [39] McTigue DM, Edwards NK, Rogers RC. Pancreatic polypeptide in dorsal vagal complex stimulates gastric acid secretion and motility in rats. Am J Physiol 1993;265:G1169 –76. [40] McTigue DM, Rogers RC. Pancreatic polypeptide stimulates gastric motility through a vagal-dependent mechanism in rats. Neurosci Lett 1995;188:93– 6. [41] Moldawer LL, Lowry SF, Ceranii A. Cachectin: its impact on metabolism, and nutritional status. Annu Rev Nutr 1988;8:585– 609. [42] Moran TH, McHugh PR. Distinctions among three sugars in their effects on gastric emptying and satiety. Am J Physiol 1981;241:R25– 30. [43] Nakajima M, Inui A, Teranishi A, Miura A, Hirose Y, Okita M, Himori N, Baba S, Kasuga M. Effects of pancreatic polypeptide family peptides on feeding and learning behavior in mice. J Pharmacol Exp Ther 1994;268:1010 – 4. [44] Okumura T, Pappas TN, Taylor IL. Intracisternal injection of pancreatic polypeptide stimulates gastric emptying in rats. Neurosci Lett 1994;178:167–70. [45] Okumura T, Pappas TN, Taylor IL. Pancreatic polypeptide microinjection into the dorsal motor nucleus inhibits pancreatic secretion in rats. Gastroenterology 1995;108:1517–25. [46] Olschowka JA, O’Donohue TL, Jacobowitz DM. The distribution of bovine pancreatic polypeptide-like immunoreactive neurons in rat brain. Peptides 1981;2:309 –31. [47] Parker EM, Babij CK, Balasubramaniam A, Burrier RE, Guzzi M, Hamud F, Mukhopadhyay G, Rudinski MS, Tao Z, Ticw M, Xia L, Mullins DE, Salisbury BG. GR231118 (1229U91), and other analogues of the C-terminus of neuropeptide Y are potent neuropeptide Y Y1 receptor antagonists, and neuropeptide Y Y4 receptor agonists. Eur J Pharmacol 1998;349:97–105. [48] Patal AS. A study of gastric stretch receptors: their role in the peripheral mechanism of hunger, and thirst. J Physiol 1954;126:255– 70. [49] Pieribone VA, Brodin L, Friberg K, Dahlstrand J, Soderberg C, Larhammar D, Hokfelt T. Differential expression of mRNAs for neuropeptide Y-related peptides in rat nervous tissue: possible evolutionary conservation. J Neurosci 1992;12:3361–71. [50] Plata-Salaman CR. Immunoregulators in the nervous system. Neurosci Biobehav Rev 1991;15:185–215. [51] Schober DA, Van Abbema AM, Smiley DL, Bruns RF, Gehlert DR. The neuropeptide Y Y1 antagonist, 1229U91, apotent agonist for the human pancreatic polypeptide-preferring (NPY Y4) recpetor. Peptides 1998;19:537– 42. [52] Schwartz TW. Pancreatic polypeptide: a hormone under vagal control. Gastroenterology 1983;85:1411–25. [53] Schafhauser AO, Stricker-Krongrad A, Brunner L, Cumin F, Gerald C, Whitebead S, Criscione L, Hofbauer KG. Inhibition of food intake by neuropeptide Y Y5 receptor antisense oligodeoxynucleotides. Diabetes 1997;46:1792–98. [54] Sive AA, Vinik AI, van Tonder SV. Pancreatic polypeptide (PP) responses to oral and intravenous glucose in man. Am J Gastroenterol 1979;71:183–5. [55] Stanley BG, Leibowitz SF. Neuropeptide Y injected in the paraventricular hypothalamus: a powerful stimulant of feeding behavior. Proc Natl Acad Sci USA 1985;82:3940 –3. [56] Strautz RL. Studies of hereditary-obese mice (ob/ob) after implantation of pancreatic islets in Millipore Litter capsules. Diabetologia 1970;6:306 –12. [57] Stunkard AJ. Current views on obesity. Am J Med 1996;100:230 – 6. [58] Sun YS, Brunicardi FC, Druck P, Walfisch S, Berlin SA, Chance RE, Gingerich RL, Elahi D, Andersen DK. Reversal of abnormal glucose
G. Katsuura / Peptides 23 (2002) 323–329
[59]
[60] [61]
[62]
[63]
metabolism in chronic pancreatitis by administration of pancreatic polypeptide. Am J Surg 1985;151:130 – 40. Taylor IL, Impicciatore M, Carter DC, Walsh JH. Effect of atropine and vagotomy on pancreatic polypeptide response to a meal in dogs. Am J Physiol 1978;235:E443–7. Taylor IL, Garcia R. Effects of pancreatic polypeptide, caerulein, and bombesin on satiety in obese mice. Am J Physiol 1985;248:G277– 80. Taylor IL, Garcia R, Elashoff J. Effects of vagotomy on satiety induced by gastrointestinal hormones in the rat. Physiol Behav 1985; 34:957– 61. Trinh T, Dumont Y, Quirion R. High levels of specific neuropeptide Y/pancreatic polypeptide receptors in the rat hypothalamus and brainstem. Eur J Pharmacol 1996;318:R1–3. Ueno N, Inui A, Iwamoto M, Kaga T, Asakawa A, Okita M, Fujimiya M, Nakajima Y, Ohmoto Y, Ohnaka M, Nakaya Y, Miyazaki J, Kasuga M. Decreased food intake and body weight in pancreatic polypeptide-overexpressing mice. Gastroenterology 1999;117:1427– 32.
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[64] Whitcomb DC, Puccio AM, Leifer JM, Finley G, Ehrlich GD, Sved AF. Pancreatic polypeptide (PP) and peptide YY (PYY) mRNA in the brainstem of rats detected by reverse-transcriptase PCR (RT-PCR). Soc Neurosci Abstr 1994;20:1373. [65] Whitcomb DC, Puccio AM, Vigna SR, Taylor IL, Hoffman GE. Distribution of pancreatic polypeptide receptors in the rat brain. Brain Res 1997;760:137– 49. [66] Whitcomb DC, Taylor IL. A new twist in the brain-gut axis. Am J Med Sci 1992;304:334 – 8. [67] Whitcomb DC, Taylor IL, Vigna SR. Characterization of saturable binding sites for circulating pancreatic polypeptide in rat brain. Am J Physiol 1990;259:G687–91. [68] Woldbye DPD, Larsen PJ. The how and Y of eating. Nature Med 1998;4:671–2. [69] Yan H, Yang J, Marasco J, Yamaguchi K, Brenner S, Collins F, Karbon W. Cloning and functional expression of cDNAs encoding human and rat pancreatic polypeptide receptors. Proc Natl Acad Sci USA 1996;93:4661–5.
Roles of pancreatic polypeptide in regulation of food intake Goro Katsuuraa, Akihiro Asakawab, Akio Inuib a
b
Aburahi Laboratories, Shionogi & Co. Ltd. Shiga, 520-3423 Japan Division of Diabetes, Digestive and Kidney Diseases, Department of Clinical Molecular Medicine Kobe University Graduate School of Medicine, Kobe, 650-0017 Japan
Abstract Pancreatic polypeptide (PP) is produced in pancreatic islets of Langerhans and released into the circulation after ingestion of a meal. Peripherally administered PP suppresses food intake and gastric emptying. On the other hand, central administration of PP elicits food intake and gastric emptying. Therefore, PP actions on food intake may be, in part, attributable to gastric emptying. PP transgenic mice exhibit decreases in both food intake and gastric emptying rate that were clearly reversed by anti-PP antiserum. PP is an anorexigenic signal in the periphery and an orexigenic signal in the central nervous system. © 2002 Elsevier Science Inc. All rights reserved. Keywords: Pancreatic polypeptide; food intake; gastric emptying
1. Introduction Energy homeostasis regulated by the balance between food intake and energy expenditure is accomplished through a highly integrated and redundant neurohormonal system [31]. It is also recognized as playing a major role in maintenance of energy homeostasis and of rigidly maintaining the body weight around a set point. Abnormalities in the onset, periodicity, duration and magnitude of eating episodes generally underlie augmented feeding behavior [9,30, 57]. Increased food intake invariably culminates in an increased rate of body weight gain and obesity [30]. On the other hand, anorexia with a psychobiological basis [12] or in response to acute or chronic infection, inflammation, or trauma is followed by severe loss of body weight [19,41, 50]. Feeding behavior is known to be regulated by many mediators and regulatory pathways in the brain and periphery. There is now growing evidence that food intake is regulated by neurotransmitters and neuromodulators including anorexigenic and orexigenic neuropeptides in the hypothalamic nuclei in interaction with blood-borne hormones and nutrients. Thus, peptide hormones and neuropeptides play significant roles in energy homeostasis in both the peripherary and the central nervous system. * Corresponding author. Tel.: ⫹81-78-382-5862; fax: ⫹81-78-3822080. E-mail address: [email protected] (A. Inui).
Pancreatic polypeptide (PP) is a 36-amino acid peptide that belongs to a family including neuropeptide Y (NPY) and peptide YY (PYY). PP is produced in the endocrine type F cells located in the periphery of pancreatic islets and is released into the circulation after ingestion of food and exercise [1,26,35,54,59]. PP exerts a variety of regulatory actions, including inhibition of pancreatic exocrine secretion, gallbladder contraction, stimulation of glucocorticoid secretion, modulation of gastric acid secretion and gastrointestinal motility [21,40]. The amount of PP released is dependent on the digestive state [2,14,52]. Release of PP occurs at a low rate in the fasted state and is markedly increased throughout all phases of digestion. PP release is also sensitive to small decreases in blood glucose levels, and insulin-induced hypoglycemia is a potent stimulus for the cephalic phase of PP secretion. During the cephalic and gastric phases, the stimulation of PP release is dependent on intact vagal cholinergic reflex circuits because vagotomy and treatment of muscarinic receptor antagonist abolish this response, suggesting a key role of vagal-cholinergic mechanisms in stimulation of PP secretion [59]. Moreover, PP released into the circulation by vagal-cholinergic mechanisms traverses the blood-brain barrier (BBB) through leaky regions in the area postrema (AP) and then binds to specific receptors in the dorsal vagal complex (DVC) in a negative feedback mechanism [67]. Therefore, PP can directly regulate vagal input to the stomach, pancreas and other gastrointestinal organs [38,39,45,66]. PP may play a significant role in regulating feeding
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behavior to control energy balance. This session addressed the effects of PP on food intake and its possible mechanisms of actions.
2. Peripheral action of PP on food intake Hyperphasia and obesity in genetically obese (ob/ob) mice are reversed by parabiosis of lean littermates or by transplantation of functional islets from mice of normal weight [16,56]. These findings suggested that the ob/ob mice possess a functioning satiety center capable of responding to circulating satiety factors but lack the circulating satiety factors, which are pancreatic in origin. In this regard, Jia and Taylor observed no postparandial increase in plasma PP levels in ob/ob mice although pancreatic PP contents were significantly increased in ob/ob mice compared with lean littermates [6]. These findings indicated that the hyperphasia observed in ob/ob mice is, in part, due to the lower plasma PP levels and reduced sensitivity to PP. A congenital obesity syndrome in humans, the Prader-Willi syndrome, is characterized by hyperphasia, obesity, hyperglycemia and hyperinsulinemia similar to the phenotypes observed in ob/ob mice [22]. The subjects are severely deficient in basal and meal-stimulated PP secretion. In Prader-Willi subjects, intravenous (i.v.) infusion of PP was reported to increase serum PP levels and significantly reduce food intake [6]. These observations suggested that PP may be one of the satiety factors in the systemic circulation Malaisse-Lagae et al. first reported that bovine PP (bPP) injected intraperitorially twice daily for 2 weeks in genetically obese mice (C57BL/6J-ob/ob), reduced food intake, resulting in a significant reduction in daily body weight gain [36]. Moreover, McLaughlin and Baile demonstrated that bovine PP decreased food intake after food deprivation in ob/ob and lean mice, and that ob/ob mice were less sensitive to PP than lean mice [37]. Peripheral injection of PP was reported to reduce food intake, body weight and body weight gain in dogs [58]. However, the degree of reduction of food intake by PP is moderate, and in other studies it was not observed or was detected only after administration of high pharmacological doses. Billington reported that food intake evoked by 12 or 48-h starvation was not influenced by intraperitoneal (i.p.) injection of PP in rats [8]. Taylor et al. also reported that i.p. administered PP had no significant effect on food intake following 18-h food deprivation in rats [61]. Moreover, Taylor and Garcia demonstrated that PP did not influence food intake after 18-h starvation in either lean or obese mice [60]. Although PP has been sequenced in several mammals and its amino acid sequence was shown to be conserved among species, this discrepancy might be due to doses and species-specific differences in PP used in each study. To exclude these effects on the action of PP, i.p. injection of mouse PP at physiological doses was conformed and was
Fig. 1. (A) Effects of i.p. injection of mouse pancreatic polypeptide (mPP, nmol/mouse) on cumulative food intake in food-deprived mice. (B) Effects of intracerebroventricular injection of mouse pancreatic polypeptide (mPP, nmol/mouse) on cumulative food intake in non food-deprived mice. Each column represents mean ⫾ SE. *P ⬍ 0.05, **P ⬍ 0.01 compared with the saline and ACSF control group, respectively. (From Ref. 3)
shown to significantly suppress food intake in food-deprived mice (Fig. 1A) [3]. The mechanism by which peripheral administration of PP reduces food intake has been the subject of considerable research, but has not to be definitively determined. i.p. injection of PP suppresses gastric emptying in experimental animals (Fig. 2A) [44]. The dose of exogenous PP required for suppression of food intake is comparable to those required for inhibition of gastric emptying. This is consistent with the classic studies of Cannon and Washburn [10] and others [42,48] indicating the relationship between gastric distention and feeding, demonstrating that mechanical distention of the stomach inhibits food intake. McTigure et al. demonstrated that peripheral administration and microinjection of PP into the dorsomedial region of the DVC produced significant, long-lasting and dose-dependent increases in antral motility [39,40]. This response was attenuated by bilateral cervical vagotomy and the anticholinergic agent, atropine [3,45]. PP can directly regulate vagal input to the stomach, pancreas and other gastrointestinal organs [38,39,40,45,66] and PP release is dependent on vagal cholinergic reflex circuits because vagotomy abolished this response [59].
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Fig. 2. (A) Effect of i.p. injection of PP on gastric emptying in rats. (B) Effect of intracisternal injection of PP on gastric emptying in rats. PP or saline was injected just before administration of a test liquid meal. Rats were sacrificed and stomach was removed 20 min after meal ingestion to determine gastric emptying. Each column represents mean ⫾ SE. *P ⬍ 0.05 compared with saline control group. (From Ref. 41)
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demonstrated that circulating PP could enter the brain to bind to AP and influence the adjacent nuclei, such as NTS and DMN to inhibit gastric emptying, which in turn suppresses food intake. As both the NTS and DMN are essential components of gastrointestinal vagovagal reflexes, substances that influence the activity of NTS and/or DMN neurons may lead to modulation of gastrointestinal functions. Vagal afferents carrying primary sensory information from the gastrointestinal tract make synapses with neurons within the NTS and AP. The NTS processes this sensory input and sends axonal projections to terminate in the subjacent DMN. Vagal efferents originating from DMN neurons then project to enteric neurons in the gastrointestinal tract and pancreas. Thus, when a vagovagal reflex is activated by visceral afferents, the vagal efferents can stimulate or inhibit a variety of gastrointestinal actions, including PP release from the pancreas. Thus, circulating PP is in a position to modulate vagovagal reflex actions and may modulate autonomic regulation of gastrointestinal functions by gaining access directly to dorsal vagal neurons and altering their activity, resulting in decreased food intake. However, whether cholinergic or vagus nerves mediate PP-induced food intake was yet to be determined. In conclusion, circulating PP moderately, but significantly suppresses food intake in lean and obese animals, which is, in part, attributable to decreased gastric emptying rate regulated by the DVC influenced by circulating PP. PP released by food ingestion seems to be a signal to inhibit further food intake, and participates in control of meal size by modulating the rate of gastric emptying during the meal. Further studies are required to determine the particular actions of the proposed links in this integrative chain from the gastrointestinal tract to the brain to the stomach.
3. Central action of PP on food intake These observations suggest that the inhibitory effect of PP on food intake might be indirect and be regulated via vagal nerves. If PP acts centrally, it must either enter the brain by a specific transporter system or through circumventricular organs of the brain where the BBB is incomplete. Using autoradiography to identify radiolabeled PP binding to frozen sections of the rat brain, Whitcomb et al. identified saturable and specific PP receptors with high affinity in high concentrations in the interpeduncular nucleus, area postrema (AP), nucleus tractus solitarius (NTS), and dorsal motor nucleus (DMN) of the vagus [67]. This radiolabeled PP binding in these areas failed to be displaced by NPY or PYY, and was distinct in location from NPY and PYY receptors [67]. Moreover, they found increases in saturable radiolabeled PP accumulation in the small region including the AP when radiolabeled PP was injected through a peripheral vein [67]. The dorsomedial region of the NTS has fenestrated capillaries to allow circulating peptides, such as PP access to the NTS and neighboring DMN. These findings
Feeding behavior is regulated by neurotransmitters and neuromodulators in the central nervous system as well as blood-borne factors. PP may also act as a neurotransmitter/ neuromodulator in the central nervous system. Some investigators [25] have identified PP in the rat brain by sensitive radioimmunoassay (RIA), while others did not [13,18]. The difficulty in proving central expression of PP by RIA may be explained by the relatively limited areas of PP synthesis and concern over cross-reactivity with NPY and PYY. There are, however, several lines of evidence suggesting that PP is synthesized within some areas of the central nervous system as follows. PP-immunoreactive neurons have been identified in the brainstem and spinal cord [25]. The level of immunoreactive PP did not increase in the cerebrospinal fluid (CSF) with marked elevation of plasma PP in response to feeding or insulin hypoglycemia [26]. Furthermore, CSF PP did not increase after infusion of exogenous PP, but strenuous exercise evoked increases in both plasma and CSF PP levels [26], raising the possibility
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of PP release from a central source. The existence of PPcontaining neurons was demonstrated in the brain [23,46]. PP mRNA has been identified in the rat brain, including the ventromedial hypothalamus, by reverse transcription-PCR [7,64]. On the other hand, in situ hybridization analysis with PP specific probes did not demonstrate expression of PP mRNA in the CNS [49]. It is possible that a peptide that is structurally related, but not identical to PP is synthesized in the brain. Alternatively, blood-borne PP may reach small areas of the brain without a BBB and thus exert its action. In this regard, blood-borne PP has been shown to reach the circumventricular organs without the BBB and crosses the BBB by a saturable transporter system to reach its receptors behind the BBB to account for the PP-induced increase of food intake [4]. Further studies are required to confirm whether PP is synthesized in the rat brain and to address all of these possibilities, Interestingly, specific PP binding sites were detected in the hypothalamic nuclei, which are involved in the regulation of food intake. [125I]Human PP binding sites were found in the medial preoptic area, paraventricular nucleus of the hypothalamus, interpeduncular nucleus, NTS, area postrema and dorsal vagal nucleus, with the highest concentrations seen in the interpeduncular nucleus and AP [62,65,67]. Among the six subtypes of Y receptors identified to date, Y1 and Y5 receptors are known to contribute to feeding behavior [24,68]. Y1 receptors are specific for NPY and PYY, whereas Y5 receptors recognize not only NPY and PYY but also bovine and human (but not rodent) PP [34]. The Y4 receptor has extremely high affinity for PP with somewhat lower affinity for NPY [5,32,69]. In situ hybridization studies demonstrated enrichment of both Y4 and Y5 mRNAs in the hypothalamus, including the paraventricular nucleus, associated with food intake [5,17]. Previous studies have shown that centrally administered PP also produces a moderate increase in food intake. Clark et al. found that intracerebroventricular administration of human PP in satiated rats moderately, but significantly increased food intake with a late onset during the light phase of the day [11]. Inui et al. reported that porcine and human PPs, when administered into the third cerebral ventricle, increased food intake in satiated dogs [27]. However, Cterminal fragments, hPP-(18 –36) and hPP-(23–36), were much less effective [27]. Moreover, Nakajima et al. demonstrated that rat PP has an orexigenic action in mice, when injected into the third cerebroventricle [43]. As species specificity in the response to PP, mouse PP intracerebroventricularly administered in non-food-deprived mice increases food intake in a dose-related manner (Fig. 1B) [3]. These findings suggested that PP might be an orexigenic factor in the central nervous system and that the full-length molecule including the tertiary structure of PP is necessary for full expression of the orexigenic activity. The mechanism of the increase of food intake induced by PP remains to be clearly determined. Intracisternal administration of PP, that may bind to receptors in the DVC,
dose-dependently accelerated gastric emptying rate in rats, which was abolished following subdiaphragmatic vagotomy (Fig. 2B) [44]. As mentioned above, the increase of gastric emptying rate induced by centrally administered PP is responsible, at least in part, for the increased food intake caused by central injection of PP. The Y4 receptor has extremely high affinity for PP and the Y5 receptor has been suggest to play a role in the control of feeding by the central nervous system [5,17,20,32,55,69]. Therefore, centrally administered PP may act on Y4 or Y5 receptors to modulate food intake in the brain. In vivo administration of antisense phosphorothioated oligodeoxynucleotides corresponding to the Y5 receptor decreased basal food intake and suppressed the NPY-induced feeding response [15,53]. However, antisense oligos to the Y5 receptor injected intracerebroventricularly had no effect on food intake stimulated by central administration of PP [15]. A selective and potent Y5 antagonist, L-152,804, significantly suppressed the food intake induced by bovine PP. Human and bovine PPs stimulate food intake in mice, which was attenuated in Y5 ⫺/⫺ mice although it was not abolished [34]. The significant food intake was induced by human and bovine PPs in Y5 ⫺/⫺ mice. On the other hand, the increase of food intake by intracerebraventricular injection of PP was not suppressed following administration of Y5 receptor antisense oligo [27]. These observations suggested the participation of an other feeding receptor. Moreover, in Y1 ⫺/⫺ mice the stimulation of feeding by PP was also attenuated, but not abolished [34]. This indicated that the action of PP may be directly or indirectly modulated by Y1 receptors. The food consumption induced by centrally administered PP appears to be mediated by other receptor subtypes since the Y4-specific agonist rat PP failed to stimulate feeding behavior in rats and mice [34]. The involvement of Y4 receptors in the central action of PP, however, has yet to be confirmed. Intracerebroventricular injection of a purported Y1 antagonist and Y4 agonist, GR231118 (also known as 1229U91 and GW1229) significantly suppressed both physiological feeding behavior after fasting and NPYinduced food intake in obese and lean animals [28,33,47, 51], suggesting that Y4 receptor does not stimulate food intake. These findings indicated that other of Y receptor subtypes contribute to the feeding behavior elicited by PP.
4. PP transgenic mice Transgenic technology, which permits the introduction of genes into the germ line of mice, is a powerful tool to explore the pathophysiological relevance of transgenes. As mentioned above, PP has opposing effects on food intake when administered peripherally or centrally. Transgenic overproduction of PP using the cytomegalovirus immediate early enhancer-chicken -actin hybrid promoter allowed development of lean mice that showed overexpression of PP mostly in the pancreatic islets and reduction of fat mass as
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On the other hand, central administration of PP elicits food intake and gastric emptying via NPY receptors, such as Y5 or Y4 receptors. Therefore, PP actions on food intake may be, in part, attributable to gastric emptying. PP is an anorexigenic signal in the periphery and an orexigenic signal in the central nervous system.
References
Fig. 3. Food intake in PP transgenic (PP-Tg) and wild type mice. Results are expressed as mean ⫾ SE. *P ⬍ 0.05, **P ⬍ 0.01 compared with wild type. (From Ref. 58)
determined by body composition analysis [63]. Basal plasma PP concentrations were more than 20-fold higher than those of control littermates, and 2-fold increased PP concentrations found after a meal in control mice. PP transgenic mice exhibit significant decreases in total food intake as well as food intake in both light and dark phases (Fig. 3) [63]. No significant changes in water intake, oxygen consumption or plasma leptin levels were observed in the transgenic mice. The decrease of food intake in transgenic mice was associated with a reduced rate of gastric emptying of the solid meal (Fig. 4) [63]. i.p. administration of anti-PP antiserum in the transgenic mice significantly increased both food intake and body weight [63]. These findings strongly support the suggestion of a role of PP as a circulating satiety signal. 5. Conclusion PP released by food ingestion inhibits further food intake by modulating the rate of gastric emptying during the meal.
Fig. 4. Rate of gastric emptying of a solid meal in PP transgenic (PP-Tg) and wild type mice. The mice following 16-h food deprivation had free access to chow for 1 h, and gastric emptying was assessed 2, 3, and 4 h after eating. Results are expressed as mean ⫾ SE. *P ⬍ 0.05 compared with wild type. (From Ref. 58)
[1] Adrian TE, Besterman HS, Cooke TJ, Bloom SR, Bames AJ, Russell RC. Mechanism of pancreatic polypeptide release in man. Lancet 1997;I:161–3. [2] Adrian TE, Bloom SR, Besterman HS, Barnes AJ, Cooke TJC, Russell RCG, Faber RG. Mechanism of pancreatic polypeptide release in man. Lancet 1977;I:161–3. [3] Asakawa A, Inui A, Ueno N, Fujimiya M, Fujiko MA, Kasuga M. Mouse pancreatic polypeptide modulates food intake, while not influencing anxiety in mice. Peptides 1999;20:1445– 8. [4] Banks WA, Kastin AJ, Jaspan JB. Regional variation in transport of panceatic polypeptide across the blood-brain barrier of mice. Pharmacol Biochem Behav 1995;51:139 – 47. [5] Bard JA, Walker MW, Branchek TA, Weinshank RL. Cloning and functional expression of a human Y4 subtype receptor for pancreatic polypeptide, neuropeptide Y, and peptide YY. J Biol Chem 1995; 270:26762–5. [6] Berntson GG, Zipf WB, O’Dorisio TM, Hoffman JA, Chance RE. Pancreatic polypeptide infusions reduce food intake in Prader-Willi syndrome. Peptides 1993;14:497–503. [7] Bhattacharya S, Paul C, Mobbs C. Detection of rat prepropancreatic polypeptide mRNA in rat brain using RT-PCR. Soc Neurosci Abstr 1994;20:361.5. [8] Billington CJ, Levine AS, Morley JE. Are peptides truly satiety agents? A method of testing for neurohumoral satiety effects. Am J Physiol 1983;245:R920 – 6. [9] Bray GA. Mechanism for development of genetic, hypothalamic and dietary obesity. In: Bray GA, Ryan DH, editors. Molecular and genetic aspects of obesity. Baton Rouge, LA: LSU Press, 1996. p. 2– 66. [10] Cannon WB, Washburn AL. An explanation of hunger. Am J Physiol 1912;29:441–55. [11] Clark JT, Kalra PS, Croley WR, Kalra SP. Neuropeptide Y, and human pancreatic polypeptide stimulate feeding behavior in rats. Endocrinology 1984;115:427–9. [12] Crisp AH. The psychopathology of anorexia nervosa: getting the heat out of the system. In: Stunkard AJ, Stellar E, editors. Eating and its disorders. Association for research in nervous system and mental disease. Vol. 62. New York: Raven Press, 1984. p. 209 –34. [13] DiMaggio DA, Chronwall BM, Buchanan K, O’Donohue TL. Panreatic polypeptide immunoreactivity in rat brain is actually neuropeptide Y. Neuroscience 1985;15:1149 –57. [14] Floyd JC. Pancreatic polypeptide. Clin Gastroenterol 1980;9:657–78. [15] Flynn MC, Turrin NP, Plata-Salaman CR, Ffrench-Mullen JMH. Feeding response to neuropeptide Y-induced compounds in rats treated with Y5 receptor antisense or sense phosphothio-oligodeoxynucleotide. Physiol Behav 1999;66:881– 4. [16] Gates RJ, Hunt MJ, Lazarus NR. Further studies on the amelioration of the characteristics of New Zealand obese (NZO) mice following implantation of islets of Langerhans. Diabetologia 1974;10:401– 6. [17] Gerald C, Walker MW, Criscione L, Gustafson EL, Batzl-Hartmann C, Smith KE, Vaysse P, Durkin MM, Laz TM, Linemeyer DL, Schaffhauser AO, Whitebread S, Hofbauer KG, Taber RI, Branchek TA, Weinshank RL. A receptor subtype involved in neuropeptide-Yinduced food intake. Nature 1996;382:168 –71.
328
G. Katsuura / Peptides 23 (2002) 323–329
[18] Greeley GJ, Trowbridge J, Burdett J, Hill FL, Spannagel A, Thompson JC. Radioimmunoassay of pancreatic polypeptide in mammalian and submammalian vertebrates using a carboxyl-terminal hexapeptide antiserum. Reg Pept 1984;8:177– 87. [19] Grunfeld C, Feingold K. Metabolic disturbances and wasting in the acquired immuno-deficiency syndrome. N Engl J Med 1992;327: 329 –37. [20] Haynes AC, Arch JRS, Wilson S, Mac Clue S, Buckingham RE. Characterization of neuropeptide Y receptor that mediates feeding in the rat: a role for the Y5 receptor? Regul Pept 1998;75/76:355– 61. [21] Hazelwood RL. The pancreatic polypeptide (PP-fold) family: gastrointestinal, vascular, and feeding behavioral implication. Proc Soc Exp Biol Med 1993;202:44 – 63. [22] Holm VA. The diagnosis of Prader-Willi syndrome. In: Holm VA, Sulzbacher SJ, Pipes PL, editors. Prader-Willi syndrome. Baltimore, MD: University Park Press, 1979. p. 27– 45. [23] Hunt SP, Emson PC, Gilbert R, Goldstein M, Kimmel JR. Presence of avian pancreatic polypeptide-like immunoreactivity in catecholamine and methionine-enkephalin-containing neurons within the central nervous system. Neurosci Lett 1981;21:125–30. [24] Inui A. Neuropeptide Y feeding receptors – are multiple subtypes involved? Trends Pharmacol Sci 1999;20:43– 6. [25] Inui A, Mizuno N, Ooya M, Suenaga K, Morioka H, Ogawa T, Ishida M, Baba S. Cross-reactivities of neuropeptide Y, and peptide YY with pancreatic polypeptide antisera: evidence for the existence of pancreatic polypeptide in the brain. Brain Res 1985;330:386 –9. [26] Inui A, Okita M, Miura M, Hirosue Y, Mizuno N, Baba S, Kasuga M. Plasma and cerebroventricular fluid levels of pancreatic polypeptide in the dog: Effects of feeding, insulin-induced hypoglycemia, and physical exercise. Endocrinology 1993;132:1235–9. [27] Inui A, Okita M, Nakajima M, Inoue T, Sakatani N, Oya M, Morioka H, Okimura Y, Chihara K, Baba S. Neuropeptide regulation of feeding in dogs. Am J Physiol 1991;261:R588 –94. [28] Ishihara A, Tanaka T, Kanatani A, Fukami T, Ihara M, Fukuroda T. A potent neuropeptide Y antagonist, 1229U91, suppressed spontaneous food intake in Zucker fatty rats. Am. J. Physiol.;1998;274: R1500 – 4. [29] Jia BQ, Taylor IL. Failure of pancreatic polypeptide release in congenitally obese mice. Gastroenterology 1984;87:338 – 43. [30] Kalra SP. Appetite and body weight regulation: is it all in the brain? Neuron 1997;19:227–30. [31] Kalra SP, Dube MG, Pu S, Xu B, Horvath TL, Kalra PS. Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endoc Rev 1999;20:68 –100. [32] Kanatani A, Ishihara A, Iwaasa H, Nakamura K, Okamoto O, Hidaka M, Ito J, Fukuroda T, MacNeil DJ, Van der Ploeg LHT, Ishii Y, Okade T, Fukami T, Ihara M. L-152,804: Orally active, and selective neuropeptide Y Y5 receptor antagonist. Biochem Biophys Res Commun 2000;272:169 –73. [33] Kanatani A, Ishihara A, Asahi S, Tanaka T, Ozaki S, Ihara M. Potent neuropeptide Y Y1 receptor antagonist, 1229U91: blockade of neuropeptide Y-induced an physiological food intake. Endocrinology 1996;137:3177– 82. [34] Kanatani A, Mashiko S, Murai N, Sugimoto N, Ito J, Fukuroda T, Fukami T, Morin N, MacNeil DJ, Van der Ploeg LHT, Saga Y, Nishimura S, Ihara M. Role of the Y1 receptor in the regulation of neuropeptide Y-mediated feeding: Comparison of wild-type, Y1 receptor-deficient, and Y5 receptor-deficient mice. Endocrinology 2000;141:1011– 6. [35] Kimmel JR, Hayden LJ, Pollock HG. Isolation and characterization of a new pancreatic polypeptide hormone. J Biol Chem 1975;250:9369 – 76. [36] Malaisse-Lagae F, Carpentier J-L, Malaisse WJ, Orci L. Pancreatic polypeptide: A possible role in the regulation of food intake in the mouse. Experientia 1977;33:915–7.
[37] McLaughlin CL, Baile CA. Obese mice and satiety effects of cholecystokinin, bombesin and pancreatic polypeptide. Physiol Behav 1981;26:433–7. [38] McTigue DM, Chen C-H, Rogers RC, Stephens RL. Intracisternal rat pancreatic polypeptide stimulates gastric emptying in the rat. Am J Physiol 1995;269:R167–72. [39] McTigue DM, Edwards NK, Rogers RC. Pancreatic polypeptide in dorsal vagal complex stimulates gastric acid secretion and motility in rats. Am J Physiol 1993;265:G1169 –76. [40] McTigue DM, Rogers RC. Pancreatic polypeptide stimulates gastric motility through a vagal-dependent mechanism in rats. Neurosci Lett 1995;188:93– 6. [41] Moldawer LL, Lowry SF, Ceranii A. Cachectin: its impact on metabolism, and nutritional status. Annu Rev Nutr 1988;8:585– 609. [42] Moran TH, McHugh PR. Distinctions among three sugars in their effects on gastric emptying and satiety. Am J Physiol 1981;241:R25– 30. [43] Nakajima M, Inui A, Teranishi A, Miura A, Hirose Y, Okita M, Himori N, Baba S, Kasuga M. Effects of pancreatic polypeptide family peptides on feeding and learning behavior in mice. J Pharmacol Exp Ther 1994;268:1010 – 4. [44] Okumura T, Pappas TN, Taylor IL. Intracisternal injection of pancreatic polypeptide stimulates gastric emptying in rats. Neurosci Lett 1994;178:167–70. [45] Okumura T, Pappas TN, Taylor IL. Pancreatic polypeptide microinjection into the dorsal motor nucleus inhibits pancreatic secretion in rats. Gastroenterology 1995;108:1517–25. [46] Olschowka JA, O’Donohue TL, Jacobowitz DM. The distribution of bovine pancreatic polypeptide-like immunoreactive neurons in rat brain. Peptides 1981;2:309 –31. [47] Parker EM, Babij CK, Balasubramaniam A, Burrier RE, Guzzi M, Hamud F, Mukhopadhyay G, Rudinski MS, Tao Z, Ticw M, Xia L, Mullins DE, Salisbury BG. GR231118 (1229U91), and other analogues of the C-terminus of neuropeptide Y are potent neuropeptide Y Y1 receptor antagonists, and neuropeptide Y Y4 receptor agonists. Eur J Pharmacol 1998;349:97–105. [48] Patal AS. A study of gastric stretch receptors: their role in the peripheral mechanism of hunger, and thirst. J Physiol 1954;126:255– 70. [49] Pieribone VA, Brodin L, Friberg K, Dahlstrand J, Soderberg C, Larhammar D, Hokfelt T. Differential expression of mRNAs for neuropeptide Y-related peptides in rat nervous tissue: possible evolutionary conservation. J Neurosci 1992;12:3361–71. [50] Plata-Salaman CR. Immunoregulators in the nervous system. Neurosci Biobehav Rev 1991;15:185–215. [51] Schober DA, Van Abbema AM, Smiley DL, Bruns RF, Gehlert DR. The neuropeptide Y Y1 antagonist, 1229U91, apotent agonist for the human pancreatic polypeptide-preferring (NPY Y4) recpetor. Peptides 1998;19:537– 42. [52] Schwartz TW. Pancreatic polypeptide: a hormone under vagal control. Gastroenterology 1983;85:1411–25. [53] Schafhauser AO, Stricker-Krongrad A, Brunner L, Cumin F, Gerald C, Whitebead S, Criscione L, Hofbauer KG. Inhibition of food intake by neuropeptide Y Y5 receptor antisense oligodeoxynucleotides. Diabetes 1997;46:1792–98. [54] Sive AA, Vinik AI, van Tonder SV. Pancreatic polypeptide (PP) responses to oral and intravenous glucose in man. Am J Gastroenterol 1979;71:183–5. [55] Stanley BG, Leibowitz SF. Neuropeptide Y injected in the paraventricular hypothalamus: a powerful stimulant of feeding behavior. Proc Natl Acad Sci USA 1985;82:3940 –3. [56] Strautz RL. Studies of hereditary-obese mice (ob/ob) after implantation of pancreatic islets in Millipore Litter capsules. Diabetologia 1970;6:306 –12. [57] Stunkard AJ. Current views on obesity. Am J Med 1996;100:230 – 6. [58] Sun YS, Brunicardi FC, Druck P, Walfisch S, Berlin SA, Chance RE, Gingerich RL, Elahi D, Andersen DK. Reversal of abnormal glucose
G. Katsuura / Peptides 23 (2002) 323–329
[59]
[60] [61]
[62]
[63]
metabolism in chronic pancreatitis by administration of pancreatic polypeptide. Am J Surg 1985;151:130 – 40. Taylor IL, Impicciatore M, Carter DC, Walsh JH. Effect of atropine and vagotomy on pancreatic polypeptide response to a meal in dogs. Am J Physiol 1978;235:E443–7. Taylor IL, Garcia R. Effects of pancreatic polypeptide, caerulein, and bombesin on satiety in obese mice. Am J Physiol 1985;248:G277– 80. Taylor IL, Garcia R, Elashoff J. Effects of vagotomy on satiety induced by gastrointestinal hormones in the rat. Physiol Behav 1985; 34:957– 61. Trinh T, Dumont Y, Quirion R. High levels of specific neuropeptide Y/pancreatic polypeptide receptors in the rat hypothalamus and brainstem. Eur J Pharmacol 1996;318:R1–3. Ueno N, Inui A, Iwamoto M, Kaga T, Asakawa A, Okita M, Fujimiya M, Nakajima Y, Ohmoto Y, Ohnaka M, Nakaya Y, Miyazaki J, Kasuga M. Decreased food intake and body weight in pancreatic polypeptide-overexpressing mice. Gastroenterology 1999;117:1427– 32.
329
[64] Whitcomb DC, Puccio AM, Leifer JM, Finley G, Ehrlich GD, Sved AF. Pancreatic polypeptide (PP) and peptide YY (PYY) mRNA in the brainstem of rats detected by reverse-transcriptase PCR (RT-PCR). Soc Neurosci Abstr 1994;20:1373. [65] Whitcomb DC, Puccio AM, Vigna SR, Taylor IL, Hoffman GE. Distribution of pancreatic polypeptide receptors in the rat brain. Brain Res 1997;760:137– 49. [66] Whitcomb DC, Taylor IL. A new twist in the brain-gut axis. Am J Med Sci 1992;304:334 – 8. [67] Whitcomb DC, Taylor IL, Vigna SR. Characterization of saturable binding sites for circulating pancreatic polypeptide in rat brain. Am J Physiol 1990;259:G687–91. [68] Woldbye DPD, Larsen PJ. The how and Y of eating. Nature Med 1998;4:671–2. [69] Yan H, Yang J, Marasco J, Yamaguchi K, Brenner S, Collins F, Karbon W. Cloning and functional expression of cDNAs encoding human and rat pancreatic polypeptide receptors. Proc Natl Acad Sci USA 1996;93:4661–5.