Endocrine Abstracts

Pancreatic polypeptide (PP) is a 36 amino acid peptide, secreted from the endocrine pancreas. Previous work has shown that peripheral administration of PP inhibits food intake in rodents and humans. However, PP has a short circulating half-life that limits its use as an anti-obesity agent. Determining the mechanisms involved in the physiological breakdown of PP will allow the rational design of long-acting analogues with greater clinical utility in the treatment of obesity. PP is a member of the PP fold family of peptides which includes Neuropeptide Y (NPY) and Peptide YY (PYY). The endopeptidase neprilysin (NEP) is known to break down PYY. We investigated whether NEP breaks down PP in vitro using high performance liquid chromatography and matrix assisted laser desorption/ionisation-time of flight mass spectrometry. In vivo, we examined the effect of co-administration of the NEP inhibitor phosphoramidon with PP on food intake and plasma levels of PP in mice.

Our results demonstrate that NEP breaks down PP in vitro. Incubating 2 nmol PP with 200 μg NEP for 90 min at 37 °C resulted in breakdown of 33%±5.09 (n=3) of PP, as analysed by HPLC. MALDI-TOF MS analysis suggests NEP cleaves PP at amino acid positions 20 and 30 in vitro. Co-administration with the NEP inhibitor, phosphoramidon, significantly increased the plasma levels of PP at 45 min post-injection in mice compared to PP administration alone (n=3, P=0.01). Co-administration of PP with phosphoramidon, demonstrated a non-significant trend of an increased anorectic effect following s.c. injection of 150 nmol/kg of PP to fasted male mice at 2 h post-injection (n=10).

NEP may play a role in the physiological breakdown of PP. PP analogues resistant to breakdown by NEP may prove useful drug targets for obesity.