Peptide YY

Generic protein structure example

Peptide YY (PYY) also known as peptide tyrosine tyrosine is a peptide that in humans is encoded by the PYY gene.^[1] 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.^[2]

Dietary fibers from fruits, vegetables, and whole grains, consumed, increase the speed of transit of intestinal chyme into the ileum, to raise PYY_3-36, and induce satiety. Peptide YY cannot be produced as the result of enzymatic breakdown of crude fish proteins and ingested as a food product.^[3]

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.^[4] The two major forms of peptide YY are PYY_1-36 and PYY_3-36, which have PP fold structural motifs. However, the most common form of circulating PYY immunoreactivity is PYY_3-36, which binds to the Y2 receptor (Y2R) of the Y family of receptors.^[5] Peptide YY_3-36 (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.^[6]

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.^[7] PYY concentration in the circulation increases postprandially (after food ingestion) and decreases by fasting.^[5] 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.^[8] 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.^[9]

PYY is released by the L-cells of the gastrointestinal tract following food intake, and there are two main endogenous forms: PYY_1-36 and PYY_3-36. PYY_1-36 is rapidly processed by the enzyme DPP4 to the 34-amino acid peptide PYY_3-36.<^[10] 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, PYY_3-36 has a high selectivity for the Y2-receptor, compared to PYY_1-36 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 PYY_3-36 on any other Y receptor other than Y2.^[11] Other studies replacing the amide bonds with ester bonds also confirm that the end section is important in binding and activation.^[12] 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.^[13] 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.^[14] 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.^{[citation needed]}

Animal studies

Several studies have shown acute peripheral administration of PYY_3-36 inhibits feeding of rodents and primates. Other studies on Y2R-knockout mice have shown no anorectic effect on them. These findings indicate PYY_3-36 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.^[5] PYY oral spray was found to promote fullness.^[15] Viral gene therapy of the salivary glands resulted in long-term intake reduction.^[16]

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,^[17] 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).^[18]

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 PYY_3-36. 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.^[5]

The consumption of protein boosts PYY levels, so some benefit was observed in experimental subjects in reducing hunger and promoting weight loss.^[19] 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.^[20]

See also

• Ghrelin
• Leptin

References

Further reading

External links

• Peptide+YY at the US National Library of Medicine Medical Subject Headings (MeSH)

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