Effects of dipeptidyl peptidase IV on the satiety actions of peptide YY

Aims/hypothesis 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).Materials and 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/interpretation 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.