title: A role for metalloendopeptidases in the breakdown of the gut hormone, PYY 3-36.
abstract: Peptide YY(3-36) (PYY(3-36)) is a gut hormone that acts on Y2 receptors to reduce appetite. Obese humans are sensitive to the anorectic effects of PYY(3-36) and display a blunted postprandial rise in PYY(3-36). Bariatric surgery results in increased circulating PYY-immunoreactivity, which appears to play a role in postoperative weight loss. The utility of PYY(3-36) as an antiobesity treatment is limited by its short circulating half-life. Insight into the mechanisms by which PYY(3-36) is degraded may aid design of long-acting PYY(3-36) analogues or enzyme inhibitor therapies. We aimed to investigate the role of metalloendopeptidases in PYY(3-36) degradation and determine whether modulation of these enzymes enhanced PYY(3-36) plasma levels and bioactivity in vivo. Degradation and resultant cleavage products of PYY(3-36) were characterized after incubation with neprilysin and meprin β and with a kidney brush border preparation in vitro. Specific metalloendopeptidase inhibitors were coadministered with PYY(3-36) to mice and subsequent PYY(3-36) plasma levels and bioactivity determined. Meprin β cleaves PYY(3-36) at multiple conserved acidic sites. Blocking the actions of meprin β prevents the degradative effect of kidney brush borders on PYY(3-36). In mice, pretreatment with actinonin significantly prolonged the anorectic effect of PYY(3-36) and maintained higher PYY(3-36) plasma levels than treatment with PYY(3-36) alone. These studies suggest that inhibiting the degradation of PYY(3-36) using specific inhibitor therapies and/or the design of analogues resistant to cleavage by meprins may be useful to antiobesity therapeutics.
authors.affiliation: Section of Investigative Medicine, Imperial College London, Commonwealth Building, Du Cane Road, London W12 0NN, United Kingdom.
authors.forename: Melisande L
authors.initials: ML
authors.lastname: Addison
authors.forename: James S
authors.initials: JS
authors.lastname: Minnion
authors.forename: Joy C
authors.initials: JC
authors.lastname: Shillito
authors.forename: Keisuke
authors.initials: K
authors.lastname: Suzuki
authors.forename: Tricia M
authors.initials: TM
authors.lastname: Tan
authors.forename: Benjamin C T
authors.initials: BC
authors.lastname: Field
authors.forename: Natacha
authors.initials: N
authors.lastname: Germain-Zito
authors.forename: Christoph
authors.initials: C
authors.lastname: Becker-Pauly
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Ghatei
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Bloom
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Murphy
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005768:Gastrointestinal Hormones / Q000378:metabolism; D006207:Half-Life; D007668:Kidney / Q000378:metabolism; D008666:Metalloendopeptidases / Q000378:metabolism*; D051379:Mice; D019894:Peptide YY / Q000037:antagonists & inhibitors / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D055550:Protein Stability / Q000187:drug effects; D008625:Tiopronin / Q000494:pharmacology
chemical_list: D019440:Anti-Obesity Agents; D004791:Enzyme Inhibitors; D005768:Gastrointestinal Hormones; D019894:Peptide YY; D008625:Tiopronin; D008666:Metalloendopeptidases