In vivo and in vitro degradation of peptide YY3-36 to inactive peptide YY3-34 in humans

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Signe Toräng, Kirstine N Bojsen-Møller, Maria S Svane, Bolette Hartmann, Mette Marie Rosenkilde, Sten Madsbad, Jens Juul Holst

Peptide YY (PYY) is a 36 amino acid peptide released from enteroendocrine cells upon food intake. The N-terminally truncated metabolite, PYY3-36 exerts anorexic effects and has received considerable attention as a possible anti-obesity drug target. The kinetics and degradation products of PYY metabolism are not well described. A related peptide, Neuropeptide Y, may be degraded from the C-terminus, and in vivo studies in pigs revealed significant C-terminal degradation of PYY. We therefore investigated PYY metabolism in vitro after incubation in human blood and plasma and in vivo after infusion of PYY1-36 and PYY3-36 in 8 young, healthy men. A metabolite, corresponding to PYY3-34, was formed after incubation in plasma and blood and during the infusion of PYY. PYY3-34 exhibited no agonistic or antagonistic effects on the Y2 receptor. PYY1-36 infused with and without co-administration of sitagliptin was eliminated with half-lives of 10.1 ± 0.5 and 9.4 ± 0.8 min (mean±SEM) and metabolic clearance rates of 15.7 ± 1.5 and 14.1 ± 1.1 mL/kg•min after infusion, whereas PYY3-36 was eliminated with a significantly longer half-life of 14.9 ± 1.3 minutes and a metabolic clearance rate of 9.4± 0.6 mL/kg•minutes . We conclude that upon intravenous infusion in healthy males, PYY is inactivated by cleavage of the two C-terminal amino acids. In healthy males, PYY3-36 has a longer half-life than PYY1-36.

Original languageEnglish
JournalA J P: Regulatory, Integrative and Comparative Physiology (Online)
Volume310
Issue number1
Pages (from-to)R866-R874
Number of pages9
ISSN1522-1490
DOIs
Publication statusPublished - 27 Jan 2016

ID: 160636620