[Review]: The Role of Oxyntomodulin and Peptide Tyrosine-Tyrosine (PYY) in Appetite Control

Katie Wynne; Stephen R Bloom

Disclosures

Nat Clin Pract Endocrinol Metab. 2006;2(11):612-620. 

In This Article

Oxyntomodulin and PYY Synthesis in the Gastrointestinal Tract

Oxyntomodulin and PYY are synthesized within the gastrointestinal tract in specialized enteroendocrine cells, named L cells,[6] many of which co-secrete these hormones.[7] After a meal, oxyntomodulin and PYY are released synchronously.[8] The rapid rise of circulating hormone levels signals a change in energy status to the brain and also acts locally to enhance digestive processes. Within the gastrointestinal tract, oxyntomodulin delays gastric emptying and decreases gastric acid secretion;[9] PYY increases ileal absor ption, slows gastric emptying and delays gallbladder and pancreatic secretion.[10,11,12]

Oxyntomodulin is a 37-amino-acid peptide that contains the 29-amino-acid structure of glucagon, followed by an octapeptide C-terminal extension.[3] It is one of the products of the glucagon gene GCG, which is expressed in the intestine, pancreas and central nervous system.[13] Proglucagon is cleaved by prohormone convertases 1 and 2 into different breakdown products dependent on the tissue.[14] In the pancreas, glucagon is the primary product. Within the gut and brain, post-translational processing of proglucagon results in the production of glicentin, glucagon-like peptide 1 (GLP-1) and GLP-2 ( Box 1 ). Glicentin (also known as enteroglucagon) is broken down to produce oxyntomodulin. Significant amounts of oxyntomodulin have been found in human distal intestine.[15] In rodents, the gastrointestinal tissue concentration of oxyntomodulin gradually increases along the gastrointestinal tract from the duodenum to ileum, and thereafter decreases in the cecum and colon.[16] Oxyntomodulin is released from the intestinal L cells 5-10 min after meal ingestion, in amounts proportional to the calorie intake.[17,18] Levels of oxyntomodulin peak at around 30 min after ingestion.[8] Circulating levels of oxyntomodulin are estimated by assays for glicentin-like immunoreactivity (which is mainly attributable to oxyntomodulin). Oxyntomodulin demonstrates a diurnal variation, independent of food intake, with levels highest in the evening and lowest in the early morning.[18]

PYY is a 36-amino-acid peptide, and its name derives from the fact that this peptide contains tyrosine residues at both the C and N termini. PYY belongs to the same peptide family as pancreatic polypeptide and neuropeptide Y (NPY). These peptides all exhibit a characteristic U-shaped fold in their tertiary structure,[19] and share considerable sequence homology that is highly conserved across species.[20,21] The highest tissue concentrations of PYY are found in the rectum, followed by the colon and ileum.[22] PYY immunoreactivity can also be found in selected neurons within the central nervous system, including the hypothalamus ( Box 2 ).[23] PYY release from the gastrointestinal tract is proportional to calorie intake; levels rise to a plateau 1-2 h after a meal and remain elevated for up to 6 h.[22] There is a greater rise in levels after intake of fat, compared with isocaloric intakes of protein or carbohydrate,[24] an effect that is dependent on the degree of lipase-mediated digestion within the small intestine.[25] PYY release occurs before nutrients come into contact with the L cells of the distal intestine, which suggests that initial PYY release could be the consequence of a neural reflex: direct nutrient contact results in a later PYY response.[8,26]

PYY is synthesized and secreted into the circulation in two forms: PYY1-36 and the truncated form PYY3-36.[27] The truncated form is thought to be the biologically active satiety signal, which is the product of cleavage of the N-terminal tyrosine and proline residues from PYY1-36 by dipeptidyl peptidase 4 (DPP-4).[28] DPP-4 preferentially cleaves substrates with an N-terminal proline or alanine residue at position two. This enzyme is involved in the cleavage of multiple hormones, including the products of the glucagon gene. Oxyntomodulin is a candidate substrate for DPP-4.[29,30]

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