Peptide YY explained

Peptide YY (PYY), also known as peptide tyrosine tyrosine, is a peptide that in humans is encoded by the gene. Peptide YY is a short (36-amino acid) peptide released from cells in the ileum and colon in response to feeding. In the blood, gut, and other elements of periphery, PYY acts to reduce appetite; similarly, when injected directly into the central nervous system, PYY is also anorexigenic, i.e., it reduces appetite.[1]

Dietary fibers from fruits, vegetables, and whole grains, consumed, increase the speed of transit of intestinal chyme into the ileum, to raise PYY3-36, and induce satiety. Peptide YY cannot be produced as the result of enzymatic breakdown of crude fish proteins and ingested as a food product.[2]

Structure

Peptide YY is related to the pancreatic peptide family by having 18 of its 36 amino acids located in the same positions as pancreatic peptide.[3] The two major forms of peptide YY are PYY1-36 and PYY3-36, which have PP fold structural motifs. However, the most common form of circulating PYY immunoreactivity is PYY3-36, which binds to the Y2 receptor (Y2R) of the Y family of receptors.[4] Peptide YY3-36 (PYY) is a linear polypeptide consisting of 34 amino acids with structural homology to NPY and pancreatic polypeptide.

The PP-fold motif is found throughout this family and relates to the 3D structure. The PP-fold is formed through the incorporation of certain residues which are predominately Pro2, Pro5, Pro8, Gly9, Tyr20 and Tyr27. This PP-fold has been found to protect the peptide against enzymatic attack as well as producing a hydrophobic pocket which is inherently overall energy reducing. In addition to containing the PP-fold motif, PYY and its derivative PYY3- 36 also have a high C-terminal α-helix proportion, suggested to be extremely important for the structural integrity of PYY.[5]

Release

PYY is found in L cells in the mucosa of gastrointestinal tract, especially in ileum and colon. Also, a small amount of PYY, about 1-10%, is found in the esophagus, stomach, duodenum and jejunum.[6] PYY concentration in the circulation increases postprandially (after food ingestion) and decreases by fasting.[4] In addition, PYY is produced by a discrete population of neurons in the brainstem, specifically localized to the gigantocellular reticular nucleus of the medulla oblongata.[7] C. R. Gustavsen et al. had found PYY-producing cells located in the islets of Langerhans in rats. They were observed either alone or co-localized with glucagon or PP.[8]

PYY is released by the L-cells of the gastrointestinal tract following food intake, and there are two main endogenous forms: PYY1-36 and PYY3-36. PYY1-36 is rapidly processed by the enzyme DPP4 to the 34-amino acid peptide PYY3-36.<[9] DPP4 hydrolyses PYY and removes the first two amino acids, tyrosine and proline, at the N-terminal, which changes the receptor selectivity. As a result of this, PYY3-36 has a high selectivity for the Y2-receptor, compared to PYY1-36 which has selectivity for the Y1, Y2, and Y5 receptors. It is thought that the Y1 receptor requires both the C-terminus and N-terminus for recognition, binding and then subsequent activation. The Y2 receptor is thought to have a smaller receptor site and also only requires the C-terminus for recognition.

This could explain the reduced affinity for PYY3-36 on any other Y receptor other than Y2.[10] Other studies replacing the amide bonds with ester bonds also confirm that the end section is important in binding and activation.[11] The Y2 receptors are located in the hippocampus, sympathetic and parasympathetic nerve fibres, intestines, and certain blood vessels, and have been implicated in regulating food intake and gastric emptying.[12] As a result of this, the Y2 receptor is considered a target for the treatment of obesity and type II diabetes.

Function

PYY exerts its action through NPY receptors; it inhibits gastric motility and increases water and electrolyte absorption in the colon.[13] PYY may also suppress pancreatic secretion. It is secreted by the neuroendocrine cells in the ileum and colon in response to a meal, and has been shown to reduce appetite. PYY works by slowing the gastric emptying; hence, it increases efficiency of digestion and nutrient absorption after a meal. Research has also indicated PYY may be useful in removing aluminium accumulated in the brain.

Animal studies

Several studies have shown acute peripheral administration of PYY3-36 inhibits feeding of rodents and primates. Other studies on Y2R-knockout mice have shown no anorectic effect on them. These findings indicate PYY3-36 has an anorectic (losing appetite) effect, which is suggested to be mediated by Y2R. PYY-knockout female mice increase in body weight and fat mass. PYY-knockout mice, on the other hand, are resistant to obesity, but have higher fat mass and lower glucose tolerance when fed a high-fat diet, compared to control mice. Thus, PYY also plays a very important role in energy homeostasis by balancing food intake.[4] PYY oral spray was found to promote fullness.[14] Viral gene therapy of the salivary glands resulted in long-term intake reduction.[15]

Relevance to obesity

Leptin also reduces appetite in response to feeding, but obese people develop a resistance to leptin. Obese people secrete less PYY than non-obese people,[16] and attempts to use PYY directly as a weight-loss drug have met with some success. Researchers noted the caloric intake during a buffet lunch offered two hours after the infusion of PYY was decreased by 30% in obese subjects (p < 0.001) and 31% in lean subjects (p < 0.001).[17]

While some studies have shown obese persons have lower circulating level of PYY postprandially, other studies have reported they have normal sensitivity to the anorectic effect of PYY3-36. Thus, reduction in PYY sensitivity may not be one of the causes of obesity, in contrast to the reduction of leptin sensitivity. The anorectic effect of PYY could possibly be a future obesity drug.[4]

The consumption of protein boosts PYY levels, so some benefit was observed in experimental subjects in reducing hunger and promoting weight loss.[18] This could partially explain the weight-loss experienced with high-protein diets, noting also the high thermic effect of protein.

Obese patients undergoing gastric bypass showed marked metabolic adaptations, resulting in frequent diabetes remission 1 year later. When the confounding of calorie restriction is factored out, β-cell function improves rapidly, very possibly under the influence of enhanced GLP-1 responsiveness. Insulin sensitivity improves in proportion to weight loss, with a possible involvement of PYY.[19]

See also

Further reading

Notes and References

  1. Woods SC, D'Alessio DA . Central control of body weight and appetite . The Journal of Clinical Endocrinology and Metabolism . 93 . 11 Suppl 1 . S37–S50 . November 2008 . 18987269 . 2585760 . 10.1210/jc.2008-1630 .
  2. Murashita K, Kurokawa T, Nilsen TO, Rønnestad I . Ghrelin, cholecystokinin, and peptide YY in Atlantic salmon (Salmo salar): molecular cloning and tissue expression . General and Comparative Endocrinology . 160 . 3 . 223–235 . February 2009 . 19073185 . 10.1016/j.ygcen.2008.11.024 .
  3. Book: DeGroot LJ . McGuigan JE . Endocrinology . Saunders . Philadelphia . 1989 . 978-0-7216-2888-2 . 2754 .
  4. Murphy KG, Bloom SR . Gut hormones and the regulation of energy homeostasis . Nature . 444 . 7121 . 854–859 . December 2006 . 17167473 . 10.1038/nature05484 . 1120344 . 2006Natur.444..854M .
  5. Tatemoto K . Isolation and characterization of peptide YY (PYY), a candidate gut hormone that inhibits pancreatic exocrine secretion . Proceedings of the National Academy of Sciences of the United States of America . 79 . 8 . 2514–8 . April 1982 . 6953409 . 346229 . 10.1073/pnas.79.8.2514 . 1982PNAS...79.2514T . free .
  6. Taylor IL . Distribution and release of peptide YY in dog measured by specific radioimmunoassay . Gastroenterology . 88 . 3 . 731–737 . March 1985 . 3838162 . 10.1016/0016-5085(85)90144-1 .
  7. Glavas MM, Grayson BE, Allen SE, Copp DR, Smith MS, Cowley MA, Grove KL . Characterization of brainstem peptide YY (PYY) neurons . The Journal of Comparative Neurology . 506 . 2 . 194–210 . January 2008 . 18022952 . 10.1002/cne.21543 . 16104580 .
  8. Gustavsen CR, Pillay N, Heller RS . An immunohistochemical study of the endocrine pancreas of the African ice rat, Otomys sloggetti robertsi . Acta Histochemica . 110 . 4 . 294–301 . 2008 . 18406449 . 10.1016/j.acthis.2007.11.003 .
  9. Ehrlich GK, Michel H, Truitt T, Riboulet W, Pop-Damkov P, Goelzer P, Hainzl D, Qureshi F, Lueckel B, Danho W, Conde-Knape K, Konkar A . Preparation and characterization of albumin conjugates of a truncated peptide YY analogue for half-life extension . Bioconjugate Chemistry . 24 . 12 . 2015–24 . December 2013 . 24251972 . 10.1021/bc400340z .
  10. Nygaard R, Nielbo S, Schwartz TW, Poulsen FM . The PP-fold solution structure of human polypeptide YY and human PYY3-36 as determined by NMR . Biochemistry . 45 . 27 . 8350–7 . July 2006 . 16819834 . 10.1021/bi060359l .
  11. Albertsen L, Andersen JJ, Paulsson JF, Thomsen JK, Norrild JC, Strømgaard K . Design and Synthesis of Peptide YY Analogues with C-terminal Backbone Amide-to-Ester Modifications . ACS Medicinal Chemistry Letters . 4 . 12 . 1228–32 . December 2013 . 24900634 . 4027376 . 10.1021/ml400335g .
  12. Keire DA, Bowers CW, Solomon TE, Reeve JR . Structure and receptor binding of PYY analogs . Peptides . 23 . 2 . 305–21 . February 2002 . 11825645 . 10.1016/s0196-9781(01)00602-7 . 7082920 .
  13. Liu CD, Aloia T, Adrian TE, Newton TR, Bilchik AJ, Zinner MJ, Ashley SW, McFadden DW . 6 . Peptide YY: a potential proabsorptive hormone for the treatment of malabsorptive disorders . The American Surgeon . 62 . 3 . 232–236 . March 1996 . 8607584 .
  14. News: UF researchers use oral peptide spray to stimulate weight loss in animals. Dec 19, 2013.
  15. Acosta A, Hurtado MD, Gorbatyuk O, La Sala M, Duncan D, Aslanidi G, Campbell-Thompson M, Zhang L, Herzog H, Voutetakis A, Baum BJ, Zolotukhin S . 6 . Salivary PYY: a putative bypass to satiety . PLOS ONE . 6 . 10 . e26137 . 2011 . 22028819 . 3189958 . 10.1371/journal.pone.0026137 . free . 2011PLoSO...626137A .
  16. Alvarez Bartolomé M, Borque M, Martinez-Sarmiento J, Aparicio E, Hernández C, Cabrerizo L, Fernández-Represa JA . Peptide YY secretion in morbidly obese patients before and after vertical banded gastroplasty . Obesity Surgery . 12 . 3 . 324–327 . June 2002 . 12082881 . 10.1381/096089202321088084 . 40358403 .
  17. Batterham RL, Cohen MA, Ellis SM, Le Roux CW, Withers DJ, Frost GS, Ghatei MA, Bloom SR . 6 . Inhibition of food intake in obese subjects by peptide YY3-36 . The New England Journal of Medicine . 349 . 10 . 941–948 . September 2003 . 12954742 . 10.1056/NEJMoa030204 . 11764433 . free .
  18. Batterham RL, Heffron H, Kapoor S, Chivers JE, Chandarana K, Herzog H, Le Roux CW, Thomas EL, Bell JD, Withers DJ . 6 . Critical role for peptide YY in protein-mediated satiation and body-weight regulation . Cell Metabolism . 4 . 3 . 223–233 . September 2006 . 16950139 . 10.1016/j.cmet.2006.08.001 . free .
  19. Nannipieri M, Baldi S, Mari A, Colligiani D, Guarino D, Camastra S, Barsotti E, Berta R, Moriconi D, Bellini R, Anselmino M, Ferrannini E . 6 . Roux-en-Y gastric bypass and sleeve gastrectomy: mechanisms of diabetes remission and role of gut hormones . The Journal of Clinical Endocrinology and Metabolism . 98 . 11 . 4391–4399 . November 2013 . 24057293 . 10.1210/jc.2013-2538 . free .

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