Pancreatic polypeptide (PP) is a postprandial hormone secreted from pancreatic islets that activates neuropeptide Y4 receptors (NPY4Rs). PP is known to induce satiety but effects at the level of the endocrine pancreas are less well characterized. In addition, rapid metabolism of PP by dipeptidyl peptidase-4 (DPP-4) limits the investigation of the effects of the native peptide. Therefore, in the present study, five novel amino acid substituted and/or fatty acid derivatized PP analogs were synthesized, namely [P]PP, [KPal]PP, [P,KPal]PP, [N-Pal]PP, and [N-Pal,P]PP, and their impact on pancreatic beta-cell function, as well as appetite regulation and glucose homeostasis investigated. All PP analogs displayed increased resistance to DPP-4 degradation. In addition, all peptides inhibited alanine-induced insulin secretion from BRIN-BD11 beta cells. Native PP and related analogs (10 and 10 M), and especially [P]PP and [KPal]PP, significantly protected against cytokine-induced beta-cell apoptosis and promoted cellular proliferation, with effects dependent on the NPY4R for all peptides barring [N-Pal,P]PP. In mice, all peptides, except [N-Pal]PP and [N-Pal,P]PP, evoked a dose-dependent (25, 75, and 200 nmol/kg) suppression of appetite, with native PP and [P]PP further augmenting glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK) induced reductions of food intake. The PP peptides had no obvious detrimental effect on glucose tolerance and they did not noticeably impair the glucose-regulatory actions of GLP-1 or CCK. In conclusion, Pro amino acid substitution of PP, either alone or together with mid-chain acylation, creates PP analogs with benefits on beta-cell rest, islet cell turnover, and energy regulation that may be applicable to the treatment of diabetes and obesity.
