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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\u20104 (DPP\u20104) 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\n                    <jats:sup>3<\/jats:sup>\n                    ]PP, [K\n                    <jats:sup>13<\/jats:sup>\n                    Pal]PP, [P\n                    <jats:sup>3<\/jats:sup>\n                    ,K\n                    <jats:sup>13<\/jats:sup>\n                    Pal]PP, [N\u2010Pal]PP, and [N\u2010Pal,P\n                    <jats:sup>3<\/jats:sup>\n                    ]PP, and their impact on pancreatic beta\u2010cell function, as well as appetite regulation and glucose homeostasis investigated. All PP analogs displayed increased resistance to DPP\u20104 degradation. In addition, all peptides inhibited alanine\u2010induced insulin secretion from BRIN\u2010BD11 beta cells. Native PP and related analogs (10\n                    <jats:sup>\u22128<\/jats:sup>\n                    and 10\n                    <jats:sup>\u22126<\/jats:sup>\n                    \u2009M), and especially [P\n                    <jats:sup>3<\/jats:sup>\n                    ]PP and [K\n                    <jats:sup>13<\/jats:sup>\n                    Pal]PP, significantly protected against cytokine\u2010induced beta\u2010cell apoptosis and promoted cellular proliferation, with effects dependent on the NPY4R for all peptides barring [N\u2010Pal,P\n                    <jats:sup>3<\/jats:sup>\n                    ]PP. In mice, all peptides, except [N\u2010Pal]PP and [N\u2010Pal,P\n                    <jats:sup>3<\/jats:sup>\n                    ]PP, evoked a dose\u2010dependent (25, 75, and 200\u2009nmol\/kg) suppression of appetite, with native PP and [P\n                    <jats:sup>3<\/jats:sup>\n                    ]PP further augmenting glucagon\u2010like peptide\u20101 (GLP\u20101) 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\u2010regulatory actions of GLP\u20101 or CCK. In conclusion, Pro\n                    <jats:sup>3<\/jats:sup>\n                    amino acid substitution of PP, either alone or together with mid\u2010chain acylation, creates PP analogs with benefits on beta\u2010cell rest, islet cell turnover, and energy regulation that may be applicable to the treatment of diabetes and obesity.\n                  <\/jats:p>","DOI":"10.1002\/biof.2059","type":"journal-article","created":{"date-parts":[[2024,4,18]],"date-time":"2024-04-18T11:59:15Z","timestamp":1713441555000},"page":"1101-1112","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Novel enzyme\u2010resistant pancreatic polypeptide analogs evoke pancreatic beta\u2010cell rest, enhance islet cell turnover, and inhibit food intake in mice"],"prefix":"10.1002","volume":"50","author":[{"given":"Wuyun","family":"Zhu","sequence":"first","affiliation":[{"name":"Diabetes Research Centre Schools of Biomedical Sciences and Pharmacy &amp; Pharmaceutical Sciences, Ulster University  Coleraine UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil","family":"Tanday","sequence":"additional","affiliation":[{"name":"Diabetes Research Centre Schools of Biomedical Sciences and Pharmacy &amp; Pharmaceutical Sciences, Ulster University  Coleraine UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan A.","family":"Lafferty","sequence":"additional","affiliation":[{"name":"Diabetes Research Centre Schools of Biomedical Sciences and Pharmacy &amp; Pharmaceutical Sciences, Ulster University  Coleraine UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter R.","family":"Flatt","sequence":"additional","affiliation":[{"name":"Diabetes Research Centre Schools of Biomedical Sciences and Pharmacy &amp; Pharmaceutical Sciences, Ulster University  Coleraine UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4855-964X","authenticated-orcid":false,"given":"Nigel","family":"Irwin","sequence":"additional","affiliation":[{"name":"Diabetes Research Centre Schools of Biomedical Sciences and Pharmacy &amp; Pharmaceutical Sciences, Ulster University  Coleraine 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