Effects of dipeptidyl peptidase IV on the satiety actions of peptide YY.
OBJECTIVE
Dipeptidyl peptidase IV (DP IV) inhibitors are currently being developed to prolong the biological activity of insulinotropic peptides as a novel approach in the treatment of diabetes. We hypothesised that DP IV inhibition could attenuate the satiety actions of peptide YY (PYY) by altering the conversion of PYY(1-36) to PYY(3-36).


METHODS
The effects of PYY delivered by osmotic mini-pumps were assessed in rats treated with a DP IV inhibitor and in a rat model deficient in DP IV.


RESULTS
Pharmacological levels of total PYY were found in the circulation after the exogenous administration of PYY(3-36). While both PYY(1-36) and PYY(3-36) reduced food intake in normal rats, PYY(1-36) was ineffective in rats deficient in DP IV. When re-fed after a 24-h fast, DP IV-deficient rats exhibited higher food intake and weight gain than normal rats. Moreover, unlike controls, there was no postprandial increase in PYY levels in DP IV-deficient rats. Despite these findings, administration of a DP IV inhibitor, Pro-boroPro, did not alter the acute anorectic effects of exogenous PYY(1-36) in normal rats. This could be the result of the protection of other appetite regulatory peptides or the generation of PYY(3-36) by remaining DP IV activity or other dipeptidyl peptidases.


CONCLUSIONS
Although DP IV inhibition with Pro-boroPro attenuated the generation of PYY(3-36), our results indicate that short-term DP IV inhibition does not eliminate the satiety actions of exogenously administered PYY(1-36) at the doses tested.
Unniappan
S
S
Laboratory of Cellular and Molecular Medicine, Departments of Cellular and Physiological Sciences and Surgery, Life Sciences Institute, 2350 Health Sciences Mall, University of British Columbia, Vancouver, BC, V6T 1Z3 Canada.
McIntosh
C H S
CH
Demuth
H-U
HU
Heiser
U
U
Wolf
R
R
Kieffer
T J
TJ
D000818:Animals; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D006801:Humans; D007263:Infusions, Parenteral; D007700:Kinetics; D019894:Peptide YY / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D012528:Satiety Response / Q000187:drug effects / Q000502:physiology*
D011480:Protease Inhibitors; D019894:Peptide YY; D018819:Dipeptidyl Peptidase 4