Peptide YY or Peptide tYrosine-tYrosine is a naturally occurring 36-amino acid gut hormone released post-prandially from the L cells in the gastrointestinal tract in proportion to the calorie content of a meal. Short term studies have shown that PYY decreases appetite and hence has potential for evolution as a pharmaceutical agent or modifiable target for the treatment of obesity. It belongs to the pancreatic polypeptide family along with pancreatic polypeptide (PP) andNeuropeptide Y (NPY).
PYY was first isolated in 1980 from porcine intestine. Nature. 1980 Jun 5;285(5764):417-8 exists in two endogenous forms. PYY is secreted as PYY(1-36) which is metabolised by DPP-IV (Dipeptidyl peptidase-4) Regul Pept. 1993 Dec 10;49(2):133-44. to PYY(3-36) which is the predominant form in circulation. Regul Pept. 1994 May 5;51(2):151-9. PYY is widely expressed in the GIT where it is co-localised with GLP-1. J Endocrinol. 1999 Aug;162(2):271-8 While PYY immunoreactive cells are absent in the stomach, they increase towards the lower portions of the gut, with highest levels in the colon and rectum. Peptides. 2002 Feb;23(2):251-61. PYY immunoreactive nerve terminals are present in the hypothalamus, medulla, pons and spinal cord. PYY immunoreactivity has also been demonstrated in the human adrenal medulla. PYY crosses the blood brain barrier freely through non-saturable mechanisms. J Pharmacol Exp Ther. 2003 Sep;306(3):948-53. Five receptors have been described for the pancreatic polypeptide family (Y1-Y5). PYY(3-36) shows selectivity for Y2 and Y5, although the existence of an as yet unidentified PYY- preferring receptor mediating the central effects on appetite stimulation is possible . Br J Pharmacol. 1998 Apr;123(8):1549-54.
PYY was first isolated in 1980 from porcine intestine. Nature. 1980 Jun 5;285(5764):417-8 exists in two endogenous forms. PYY is secreted as PYY(1-36) which is metabolised by DPP-IV (Dipeptidyl peptidase-4) Regul Pept. 1993 Dec 10;49(2):133-44. to PYY(3-36) which is the predominant form in circulation. Regul Pept. 1994 May 5;51(2):151-9. PYY is widely expressed in the GIT where it is co-localised with GLP-1. J Endocrinol. 1999 Aug;162(2):271-8 While PYY immunoreactive cells are absent in the stomach, they increase towards the lower portions of the gut, with highest levels in the colon and rectum. Peptides. 2002 Feb;23(2):251-61. PYY immunoreactive nerve terminals are present in the hypothalamus, medulla, pons and spinal cord. PYY immunoreactivity has also been demonstrated in the human adrenal medulla. PYY crosses the blood brain barrier freely through non-saturable mechanisms. J Pharmacol Exp Ther. 2003 Sep;306(3):948-53. Five receptors have been described for the pancreatic polypeptide family (Y1-Y5). PYY(3-36) shows selectivity for Y2 and Y5, although the existence of an as yet unidentified PYY- preferring receptor mediating the central effects on appetite stimulation is possible . Br J Pharmacol. 1998 Apr;123(8):1549-54.
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Actions and mechanisms
PYY has a 70% homology with NPY a strong orexigen. PYY injection centrally into the PVN was as potent as NPY in stimulating food intake Peptides. 1985 Nov-Dec;6(6):1205-11. with effects lasting for up to 4 hours. A facilitation of carbohydrate preference has been noted post PYY injection into the PVN. PYY remained effective in stimulating food intake even after multiple injections. Brain Res. 1985 Aug 19;341(1):200-3. Opioid antagonists and serotonin reuptake inhibitors can blunt the PYY induced hyperphagia in rats. Pharmacol Biochem Behav. 1993 Aug;45(4):941-4. While central administration of PYY (1-36) seems to be orexigenic, peripheral injection of PYY(3-36) in rats inhibits food intake and reduces weight gain but not inY2r-null mice Nature. 2002 Aug 8;418(6898):650-4 or mice treated with selective Y2r antagonist, Endocrinology. 2005 Sep;146(9):3748-56 which suggests that the anorectic effect of PYY requires the Y2 receptor. The Y2 receptor is a pre-synaptic inhibitory receptor of NPY neurones. PYY(3-36) inhibits electrical activity of NPY nerve terminals, thus activating adjacent pro-opiomelanocortin (POMC) neurons, which has been demonstrated by an increased activity of POMC neurones in hypothalamic explants injected with PYY (3-36). Despite this, POMC activity is not crucial for PYY effect, as POMC -/- mice Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4695-700 as well as MC4r knock out mice Endocrinology. 2004 Jun;145(6):2585-90 retain a normal acute anorectic response to peripherally administered PYY 3-36. Blockade of the vagus with capsaicin does not prevent the anorexigenic actions of PYY. Endocrinology. 2005 Sep;146(9):3748-56 Peripheral administration of PYY(3-36) increases c-Fos immunoreactivity in the arcuate nucleus and decreases hypothalamic NPY messenger RNA. Central administration of PYY or PYY (3-36) into the arcuate nucleus inhibits food intake in rats Nature. 2002 Aug 8;418(6898):650-4 with decreased food consumption and weight loss on long term administration. An interaction with the mesolimbic reward system has been proposed to explain the appetite increasing effects of centrally administered PYY (1-36). Peptides. 2002 Feb;23(2):377-82. PYY seems to influence cognitive function as demonstrated by increased memory (anticipation and learning) in rats J Pharmacol Exp Ther. 1994 Feb;268(2):1010-4. which might have a physiological role in nutrient procurement. |
Other Actions of PYY
PYY on its own inhibits gastric acid secretion in healthy volunteers and with more marked effect in combination with GLP-1. Proc Soc Exp Biol Med. 1997 Jun;215(2):165-7 Exogenous administration of intravenous and intra-colonic PYY stimulates water and electrolyte absorption in both the small and large intestines. Dis Colon Rectum. 1997 Apr;40(4):478-82 PYY also inhibits gut motility and meal induced pancreatic and gastric secretion Am J Physiol. 1985 Jan;248(1 Pt 1):G118-23. as well as gastric empting and gallbladder contractility. The decreased gut motility might contribute to its anorexigenic effects (ileal brake). As obese patients are deficient in Peptide YY with retained responsiveness to exogenously administered Peptide YY, it is potentially possible to use Peptide YY or its analogues to decrease the energy-intake drive in obese patients. As PYY release is partly dependent on food composition, modifying the diet to facilitate higher peptide YY release remains an option, although dietary modifications have historically never achieved maintainable weight loss!. The issue of whether the low levels of PYY in the obese is primary or secondary to obesity itself remains to be answered. Serotonin reuptake inhibitors Am J Psychiatry. 2000 Aug;157(8):1332-4. and opioid antagonists Pharmacol Biochem Behav. 1993 Aug;45(4):941-4. which attenuate PYY induced hyperphagia may have a role in treating bulimic patients who have been shown to have high levels of CSF PYY during abstinence and lower CSF levels after binge eating. Neuropsychobiology.1988;19(3):121-4. Combination therapies targeting different pathways simultaneously using PYY and Exendin 4 may be the way forward as suggested by the synergistic effect on food intake suppression noted when these hormones are administered together. Endocrinology. 2005 Sep;146(9):3748-56 |
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PYY Release and Regulation
PYY(3-36) concentrations in plasma rise within 15 min and plateau by approximately 90 min in response to food ingestion Ann N Y Acad Sci. 2003 Jun;994:162-8. PYY rise occurs before food reaches the distal parts of the intestine densely populated with PYY immunoreactive cells, suggesting that neural factors might play a role in initiating PYY release. Ileal resection results in increased basal levels and postprandial release of PYY, while levels are lower in patients undergoing colonic resection. Surgery. 1987 Jun;101(6):715-9. Calorie intake and Meal composition determine PYY release. Physiological concentrations of fibres, short-chain fatty acids, and bile salts (taurocholate, cholate, deoxycholate) are all potent stimulants of PYY release. J Endocrinol. 1996 Dec;151(3):421-9. Endocrinology. 1989 Oct;125(4):1761-5. Glucose and amino acids may mediate PYY release but only when they are present at high supraphysiological concentrations in the colon. Gastric acid, Cholecystokinin, IGF-1, bombesin and calcitonin-gene-related-peptide (CGRP) increase PYY release while GLP-1 reduces plasma PYY levels. Curr Drug Targets CNS Neurol Disord. 2004 Oct;3(5):379-88. |
PYY and Obesity
A significant negative correlation has been shown between PYY and BMI. Morbidly obese patients have a lower concentration of PYY, which has been demonstrated to rise to non obese levels following Vertical Banded Gastroplasty. Obes Surg. 2002 Jun;12(3):324-7. Food induced rise in PYY is also lower in the obese. N Engl J Med. 2003 Sep 4;349(10):941-8. In humans, infusion of PYY (3-36) to achieve physiological postprandial concentrations of PYY(3-36) significantly decreased appetite and reduced food intake by 33% over 24 h. Nature. 2002 Aug 8;418(6898):650-4. Thus the problem in obesity seems to be one of PYY deficiency rather than PYY resistance. PYY infusion decreases the pre-prandial levels of circulating Ghrelin which could contribute to the anorexigenic mechanism. N Engl J Med. 2003 Sep 4;349(10):941-8. A formulation of Peptide YY as a nasal spray is under development. Newer technologies (eg: eligen technology) might make oral treatment with PYY possible in the future. |