The Development Of Pancreatic Polypeptide Analogues As A Pharmacotherapy For Obesity

Abstract

Pancreatic polypeptide (PP) is a peptide hormone released post prandially from the endocrine F cells of the pancreas. Acute administration of PP to mice reduces both body weight and food intake, and an IV infusion of PP to healthy weight humans reduces food intake over 24 hours. However, the short half life of PP limits its utility as an obesity treatment. This thesis investigates the development of pancreatic polypeptide (PP) analogues, and their possible role as a novel obesity treatment. I hypothesised that specific amino acid substitutions in the PP molecule would increase, enzymatic resistance and affinity for the Y4 receptor, and would thus result in analogues of PP with improved biological function. I investigated the substitution of amino acids on the breakdown of PP analogues using reverse phase HPLC and MALDI-TOF MS. Receptor binding assays and food intake studies in fasted male C57/BL6 mice were used to investigate the effect of amino acid substitutions on receptor binding affinity and on the anorectic effects in vivo. Finally, long term chronic food intake studies using different models of obesity were used to investigate the long term effects of PP analogue XPP. The PP analogue XPP was shown to be more enzymatically resistant than PP, with improved binding to the hY4 receptor and greater acute inhibition of food intake when investigated in vivo. When administered chronically in two models of obesity, XPP was shown to reduce body weight in specific models at specific time points. These experiments demonstrated the potential of XPP as an obesity treatment. The development of PP analogues may thus provide a useful and novel treatment for obesity