Peptide YY and Related Peptides、YY肽及相關(guān)肽

Definition

Peptide YY (PYY) is an important gut hormone synthesized and secreted by the gastrointestinal tract.

Related Peptide

PYY is a straight chain polypeptide. PYY shares structural homology with neuropeptide Y (NPY) and pancreatic polypeptide (PP) 1, and together form the Neuropeptide Y Family of Peptides, which is also called the Pancreatic Polypeptide-Fold Family of Peptides.

The PP family of peptides includes PYY and NPY, which were discovered based upon their chemical structure (possessing a carboxyl-terminal tyrosine amide) 2. PP, PYY, and NPY are all 36 amino acids in length and despite structural similarities; they are found in different locations throughout the gastrointestinal tract and nervous system and possess different biological actions. PP is expressed in endocrine cells of the gut and pancreas, PYY is located in enteroendocrine cells of the ileum and colon and nerves of the enteric nervous system, and NPY is found in the central and peripheral nervous system. This wide distribution suggests that these peptides regulate many different physiological processes.

Structural Characteristics

Human PYY consists of a linear chain of 36 amino acid residues and the complete amino acid sequence is: Tyr-Pro-Ile-Lys-Pro-Glu-Ala-Pro-Gly-Glu-Asp-Ala-Ser-Pro-Glu-Glu-Leu-Asn-Arg-Tyr-Tyr-Ala-Ser-Leu-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2. The differences between the structures of porcine and human PYY are at positions 3 (Ala/Ile replacement) and 18 (Ser/Asn). Synthetic human PYY prepared using a solid-phase synthetic technique was found to be structurally identical to the natural peptide3.

Mode of Action

PYY is co-secreted with glucagon-like peptide 1. Produced by the intestinal L-cells, the highest tissue concentrations of PYY are found in distal segments of the gastrointestinal tract, although it is present throughout the gut. PYY release is stimulated by intraluminal nutrients, including glucose, bile salts, lipids, short-chain fatty acids and amino acids. Regulatory peptides such as cholecystokinin (CCK), vasoactive intestinal polypeptide (VIP), gastrin and GLP-1 modulate PYY release. The proximal GI tract may also participate in the regulation of PYY release through vagal fibers. After release, dipeptidyl peptidase IV (DPP-IV; CD 26) cleaves the N-terminal tyrosine-proline residues forming PYY (3-36). PYY (1-36) represents about 60% and PYY (3-36) 40% of circulating PYY. PYY acts through Y-receptor subtypes: Y1, Y2, Y4 and Y5 in humans. PYY (1-36) shows high affinity to all four receptors while PYY (3-36) is a specific Y2 agonist. PYY inhibits many GI functions, including gastric acid secretion, gastric emptying, small bowel and colonic chloride secretion, mouth to cecum transit time, pancreatic exocrine secretion and pancreatic insulin secretion. PYY also promotes postprandial naturesis and elevates systolic and diastolic blood pressure4, 5.

Functions

PYY as a growth factor for intestinal epithelium: PYY is an abundant distal gut hormone that may play a significant role in intestinal epithelial proliferation. Gut epithelial cells express specific receptors for PYY, PYY induces proliferation in intestinal cells in vivo and in vitro, and the Y1 receptor subtype couples to mitogenic signaling pathways. In addition to proposed physiologic effects on gut mucosal maintenance, PYY proliferative effects may be hypothesized to contribute to pathophysiologic consequences of stimulated growth6.

PYY, appetite and food intake: Following food intake PYY is released into the circulation. PYY concentrations are proportional to meal energy content and peak plasma levels appear postprandially after 1 hr. PYY3-36 is a major form of PYY in both the gut mucosal endocrine cells and the circulation. Peripheral administration of PYY3-36 inhibits food intake for several hours in both rodents and man. The binding of PYY3-36 to the Y2 receptor leads to an inhibition of the NPY neurones and a possible reciprocal stimulation of the pro-opiomelanocortin neurones. Thus, PYY3-36 appears to control food intake by providing a powerful feedback on the hypothalamic circuits. The effect on food intake has been demonstrated at physiological concentrations and, therefore, PYY3-36 may be important in the everyday regulation of food intake7.

Central and peripheral regulation of gastric acid secretion by PYY: PYY released postprandially from the ileum and colon displays a potent inhibition of cephalic and gastric phases of gastric acid secretion through both central and peripheral mechanisms. To modulate vagal regulation of gastric functions, circulating PYY enters the brain through the area postrema and the nucleus of the solitary tract, where it exerts a stimulatory action through PYY-preferring Y1-like receptors, and an inhibitory action through Y2 receptors. In the gastric mucosa, PYY binds to Y1 receptors in the enterochromaffin-like cells to inhibit gastrin-stimulated histamine release and calcium signaling via a pertussis toxin-sensitive pathway8.

References

1.Tatemoto K, Carlquist M, Mutt V (1982). Neuropeptide Y--a novel brain peptide with structural similarities to peptide YY and pancreatic polypeptide. Nature, 296(5858):659-660.

2.Tatemoto K (1982). Neuropeptide Y: Complete amino acid sequence of the brain peptide. PNAS., 79(18):5485-5489.

3.Tatemoto K, Nakano I, Makk G, Angwin P, Mann M, Schilling J, Go VL (1988). Isolation and primary structure of human peptide YY. Biochem Biophys Res Commun., 157(2):713-717.

4.Ballantyne GH (2006). Peptide YY (1-36) and peptide YY(3-36): Part I. Distribution, release and actions. Obes Surg., 16(5):651-658.

5.Batterham RL, Bloom SR (2003). The gut hormone peptide YY regulates appetite. Ann N Y Acad Sci., 994:162-168.

6.Mannon PJ (2002). Peptide YY as a growth factor for intestinal epithelium. Peptides, 23(2):383-388.

7.Ie Roux CW, Bloom SR (2005). Peptide YY, appetite and food intake. Proc Nutr Soc., 64(2):213-216.

8.Yang H (2002). Central and peripheral regulation of gastric acid secretion by peptide YY. Peptides, 23(2):349-358.