Pancreatic polypeptide (PP) is found mainly in the endocrine pancreas and belongs to the pancreatic polypeptide fold family which also includes Peptide YY and Neuropeptide Y. PP, a 36 amino acid peptide, was first identified in 1970 from chicken pancreas. In the pancreas PP is produced in endocrine type F cells located in the periphery of the pancreatic islets, located adjacent to somatostatin and glucagon immunoreactive cells. Other sites of PP immunoreactivity include the exocrine pancreas, the human colon and rectum, and even the rat adrenal medulla. Its presence in the brain has not been established yet. In contrast to PYY, PP does not cross the Blood brain barrier. Like other members of its group, PP binds to Y receptors, with greatest affinity to Y4 and Y5 receptors.
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PP release and regulation
PP demonstrates circadian rhythm with lowest circulating levels at 0200 and peaks at 2100. Release of PP occurs at a low rate in the fasted state with increased levels occurring during all phases of digestion. Gastroenterology. 1983 Dec;85(6):1411-25. Meal related PP release shows a biphasic pattern. Release of PP is stimulated by nutrient intake, Lancet. 1977 Jan 22;1(8004):161-3. with post prandial plasma levels being proportional to calorie intake. Gastric distension with water also increases PP release. Vagal tone facilitates both diurnal and postprandial PP release with abolishment of the latter by vagotomy. The release of PP in the cephalic and gastric phase is mediated through vagal cholinergic reflex circuits as demonstrated by abolished response of PP following vagotomy or treatment with muscarinic receptor antagonists. Am J Physiol. 1978 Oct;235(4):E443-7. Hypoglycaemia and exercise Endocrinology. 1993 Mar;132(3):1235-9. stimulate PP release as does sympathetic stimulation. Insulin-induced hypoglycaemia is thus a potent stimulus for the cephalic phase of PP secretion. While somatostatin reduces plasma PP concentration, Secretin, Ghrelin and Motilin stimulate PP release. PP release is blunted in patients with chronic pancreatitis which is no surprise considering its main source of origin. Basal and meal stimulated PP levels were unaffected by gastric bypass, while ileal resection increases PP levels. PP levels are increased in anorexia nervosa. |
PP actions
PP inhibits pancreatic exocrine secretion, modulates gastric acid secretion, Am J Physiol. 1995 Nov;269(5 Pt 2):R983-7. stimulates glucocorticoid secretion and influences gastrointestinal motility Proc Soc Exp Biol Med. 1993 Jan;202(1):44-63 in rodents as well as gall bladder contraction. Mice over-expressing pancreatic polypeptide were lean with reduced food intake and reduced gastric emptying. Diabetologia. 2002 Jul;45(7):1048-9. ob/ob mice transplanted with functional islets from normal mice showed reversal of hyperphagia and obesity. Diabetologia. 1970 Jun;6(3):306-12. This suggests that the ob/ob mice lack a pancreatic factor that can influence the intact satiety centre in these mice. Intraperitoneal injection of bovine PP in fasted ob/ob mice suppressed appetite and decreased weight, Experientia. 1977 Jul 15;33(7):915-7. although the ob/ob mice were less sensitive to PP than lean mice. Physiol Behav. 1981 Mar;26(3):433-7. Peripheral administration of PP into mice reduced food intake for 24 hours with increase in energy expenditure (increased oxygen consumption) and delayed gastric emptying (increased vagal activity). Gastroenterology. 2003 May;124(5):1325-36 But not all studies have shown reduction in food intake with PP. Am J Physiol. 1983 Dec;245(6):R920-6. ; Physiol Behav. 1985 Jun;34(6):957-61 ; Am J Physiol. 1985 Mar;248(3 Pt 1):G277-80. Species-specific differences in PP is thought to account for the lack of effect on food intake demonstrated in these studies. Use of species- specific PP has been shown to produce significant suppression of food intake in food deprived rats. Peptides. 1999 Dec;20(12):1445-8. Transgenic mice over-expressing PP are lean and show significant decreases in total food intake, with no change in oxygen consumption. Gastroenterology. 1999 Dec;117(6):1427-32. A reduced rate of gastric emptying was evident in these transgenic animals. Intraperitoneal administration of anti-PP antiserum increased food intake and body weight. |
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Mechanism of action
Since Pancreatic polypeptide does not cross the blood brain barrier, the peripheral effects of PP on reduction of food intake may probably be mediated via Y4 receptors in the blood brain barrier deficient area postrema as evidenced by PP accumulation in this area post-injection and increase in c-fos. Brain Res. 1997 Jun 20;760(1-2):137-49 The PP that enters the area postrema may then bind to specific receptors in the dorsal vagal complex (DVC) with inhibition of vagal activity, Am J Physiol. 1990 Oct;259(4 Pt 1):G687-91. thus contributing to direct regulation of vagal input to the stomach, pancreas and other gastrointestinal organs. Gastroenterology. 1995 May;108(5):1517-25. The dorsomedial region of the NTS has fenestrated capillaries that allow PP to access the NTS and neighbouring DMN. Effects on the DMN (dorsal motor nucleus of vagus) as well as the NTS (nucleus of tractus solitarius) inhibit gastric emptying which in turn suppress food intake, both effects being elicited by similar pharmacological doses of PP. Hypothalamic orexigenic peptides NPY and Orexin mRNA were decreased by PP, while Urocortin an anorectic peptide was increased along with a reduction of the orexigenic gastric Ghrelin expression. |
Interestingly, central administration of PP increases food intake probably through accelerated gastric emptying Neurosci Lett. 1994 Aug 29;178(1):167-70. that has been demonstrated with this route of administration. This suggests actions of PP via different receptors. It is possible that the actions of centrally administered PP are mediated through Y4 and Y5 receptors. While Y1 receptors are specific for NPY and PYY, Y5 receptors recognise NPY, PYY as well as PP.Endocrinology. 2000 Mar;141(3):1011-6 Mice with deletion of Y5 receptors show decreased response to human or bovine-PP induced food intake. Y5 antagonist also attenuates the food intake induced by bovine PP. The Y4 receptor has extremely high affinity for PP, that is greater than for NPY. J Biol Chem.1995 Nov 10;270(45):26762-5. But, a Y4-specific agonist of PP did not stimulate feeding behaviour in rats and mice, and hence the involvement of Y4 receptors in the central action of PP is still not certain. Endocrinology. 2000 Mar;141(3):1011-6 Y1 receptor knock out mice showed attenuation but not total suppression of the feeding induced by PP, suggesting that Y1 receptors may directly or indirectly modulate the action of PP. Overall, PP seems to act as an anorexigen on peripheral administration, and an orexigen on central administration. |
PP, while being a gut hormone, might also function as a neurotransmitter in the brain. While exogenous PP infusion does not increase CSF PP levels, strenuous exercise increases CSF (and plasma) PP levels, Endocrinology. 1993 Mar;132(3):1235-9. suggesting local production of PP in the central nervous system. PP-immunoreactive neurons have been identified in the brainstem and spinal cord. Brain Res. 1985 Mar 25;330(2):386-9. Although PP mRNA has been described in the ventromedial hypothalamus of the rat using rt-PCR, Soc Neurosci Abst 1994; 20: 1373 further studies are awaited to rule out the possibility that a peptide structurally related to PP may be the one that has been identified rather than PP itself. |
PP and Obesity
Prader-Willi patients who are usually morbidly obese have lower basal and meal stimulated pancreatic polypeptide levels. In Prader-Willi patients who have marked hyperphagia and obesity, PP administration decreased appetite and food intake. Peptides. 1993 May-Jun;14(3):497-503 In common obesity, the levels of PP described are variable, with either no difference or lower levels in the obese compared to lean subjects. In normal-weight humans Pancreatic polypeptide reduces food intake for 24 hours with onset of effect within 2 hours . No effect on gastric emptying was demonstrable. J Clin Endocrinol Metab. 2003 Aug;88(8):3989-92. An increase in energy expenditure through sympathetic stimulation has been shown with peripheral PP administration. Gastroenterology. 2003 May;124(5):1325-36 Long term PP administration may have a therapeutic potential for obesity management.
Prader-Willi patients who are usually morbidly obese have lower basal and meal stimulated pancreatic polypeptide levels. In Prader-Willi patients who have marked hyperphagia and obesity, PP administration decreased appetite and food intake. Peptides. 1993 May-Jun;14(3):497-503 In common obesity, the levels of PP described are variable, with either no difference or lower levels in the obese compared to lean subjects. In normal-weight humans Pancreatic polypeptide reduces food intake for 24 hours with onset of effect within 2 hours . No effect on gastric emptying was demonstrable. J Clin Endocrinol Metab. 2003 Aug;88(8):3989-92. An increase in energy expenditure through sympathetic stimulation has been shown with peripheral PP administration. Gastroenterology. 2003 May;124(5):1325-36 Long term PP administration may have a therapeutic potential for obesity management.