A Role for Metalloendopeptidases in the Breakdown of the Gut Hormone, PYY3-36

Peptide YY3-36 (PYY3-36) is a gut hormone that acts on Y2 receptors to reduce appetite. Obese humans are sensitive to the anorectic effects of PYY3-36 and display a blunted postprandial rise in PYY3-36. Bariatric surgery results in increased circulating PYY-immunoreactivity, which appears to play a role in postoperative weight loss. The utility of PYY3-36 as an antiobesity treatment is limited by its short circulating half-life. Insight into the mechanisms by which PYY3-36 is degraded may aid design of long-acting PYY3-36 analogues or enzyme inhibitor therapies. We aimed to investigate the role of metalloendopeptidases in PYY3-36 degradation and determine whether modulation of these enzymes enhanced PYY3-36 plasma levels and bioactivity in vivo. Degradation and resultant cleavage products of PYY3-36 were characterized after incubation with neprilysin and meprin beta and with a kidney brush border preparation in vitro. Specific metalloendopeptidase inhibitors were coadministered with PYY3-36 to mice and subsequent PYY3-36 plasma levels and bioactivity determined. Meprin beta cleaves PYY3-36 at multiple conserved acidic sites. Blocking the actions of meprin beta prevents the degradative effect of kidney brush borders on PYY3-36. In mice, pretreatment with actinonin significantly prolonged the anorectic effect of PYY3-36 and maintained higher PYY3-36 plasma levels than treatment with PYY3-36 alone. These studies suggest that inhibiting the degradation of PYY3-36 using specific inhibitor therapies and/or the design of analogues resistant to cleavage by meprins may be useful to antiobesity therapeutics. (Endocrinology 152: 4630-4640, 2011)