Peptide YY (PYY), also known as peptide tyrosine tyrosine, is a peptide that in humans is encoded by the PYYgene.[5] 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.[6]
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.[7]
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.[8] 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.[9] 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.[10]
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.<[14] 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.[15] Other studies replacing the amide bonds with ester bonds also confirm that the end section is important in binding and activation.[16] 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.[17] 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.[18] PYY may also suppress pancreaticsecretion. 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.[citation needed]
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.[9] PYY oral spray was found to promote fullness.[19] Viral gene therapy of the salivary glands resulted in long-term intake reduction.[20]
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,[21] 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).[22]
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.[9]
The consumption of protein boosts PYY levels, so some benefit was observed in experimental subjects in reducing hunger and promoting weight loss.[23] 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.[24]
^Murashita K, Kurokawa T, Nilsen TO, Rønnestad I (February 2009). "Ghrelin, cholecystokinin, and peptide YY in Atlantic salmon (Salmo salar): molecular cloning and tissue expression". General and Comparative Endocrinology. 160 (3): 223–235. doi:10.1016/j.ygcen.2008.11.024. PMID19073185.
^Taylor IL (March 1985). "Distribution and release of peptide YY in dog measured by specific radioimmunoassay". Gastroenterology. 88 (3): 731–737. doi:10.1016/0016-5085(85)90144-1. PMID3838162.
^Glavas MM, Grayson BE, Allen SE, Copp DR, Smith MS, Cowley MA, Grove KL (January 2008). "Characterization of brainstem peptide YY (PYY) neurons". The Journal of Comparative Neurology. 506 (2): 194–210. doi:10.1002/cne.21543. PMID18022952. S2CID16104580.
^Gustavsen CR, Pillay N, Heller RS (2008). "An immunohistochemical study of the endocrine pancreas of the African ice rat, Otomys sloggetti robertsi". Acta Histochemica. 110 (4): 294–301. doi:10.1016/j.acthis.2007.11.003. PMID18406449.
^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 (December 2013). "Preparation and characterization of albumin conjugates of a truncated peptide YY analogue for half-life extension". Bioconjugate Chemistry. 24 (12): 2015–24. doi:10.1021/bc400340z. PMID24251972.
^Nygaard R, Nielbo S, Schwartz TW, Poulsen FM (July 2006). "The PP-fold solution structure of human polypeptide YY and human PYY3-36 as determined by NMR". Biochemistry. 45 (27): 8350–7. doi:10.1021/bi060359l. PMID16819834.
^Liu CD, Aloia T, Adrian TE, Newton TR, Bilchik AJ, Zinner MJ, et al. (March 1996). "Peptide YY: a potential proabsorptive hormone for the treatment of malabsorptive disorders". The American Surgeon. 62 (3): 232–236. PMID8607584.
^Alvarez Bartolomé M, Borque M, Martinez-Sarmiento J, Aparicio E, Hernández C, Cabrerizo L, Fernández-Represa JA (June 2002). "Peptide YY secretion in morbidly obese patients before and after vertical banded gastroplasty". Obesity Surgery. 12 (3): 324–327. doi:10.1381/096089202321088084. PMID12082881. S2CID40358403.
Eberlein GA, Eysselein VE, Schaeffer M, Layer P, Grandt D, Goebell H, et al. (1989). "A new molecular form of PYY: structural characterization of human PYY(3-36) and PYY(1-36)". Peptides. 10 (4): 797–803. doi:10.1016/0196-9781(89)90116-2. PMID2587421. S2CID3857458.
Hort Y, Baker E, Sutherland GR, Shine J, Herzog H (March 1995). "Gene duplication of the human peptide YY gene (PYY) generated the pancreatic polypeptide gene (PPY) on chromosome 17q21.1". Genomics. 26 (1): 77–83. doi:10.1016/0888-7543(95)80085-Z. PMID7782089.
Kohri K, Nata K, Yonekura H, Nagai A, Konno K, Okamoto H (June 1993). "Cloning and structural determination of human peptide YY cDNA and gene". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. 1173 (3): 345–349. doi:10.1016/0167-4781(93)90136-2. PMID8318545.
