Novel enzyme‐resistant pancreatic polypeptide analogs evoke pancreatic beta‐cell rest, enhance islet cell turnover, and inhibit food intake in mice

IF 5 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

BioFactors Pub Date : 2024-04-18 DOI:10.1002/biof.2059

Wuyun Zhu, Neil Tanday, Ryan A. Lafferty, Peter R. Flatt, Nigel Irwin

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引用次数: 0

Abstract

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 [P3]PP, [K13Pal]PP, [P3,K13Pal]PP, [N‐Pal]PP, and [N‐Pal,P3]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 (10−8 and 10−6 M), and especially [P3]PP and [K13Pal]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,P3]PP. In mice, all peptides, except [N‐Pal]PP and [N‐Pal,P3]PP, evoked a dose‐dependent (25, 75, and 200 nmol/kg) suppression of appetite, with native PP and [P3]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, Pro3 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.

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新型耐酶胰多肽类似物可诱发小鼠胰岛β细胞休止、促进胰岛细胞更新并抑制食物摄入量

胰多肽（PP）是一种由胰岛分泌的餐后激素，可激活神经肽 Y4 受体（NPY4R）。众所周知，PP 能诱发饱腹感，但其在胰腺内分泌水平上的作用还不十分明确。此外，二肽基肽酶-4（DPP-4）对 PP 的快速代谢也限制了对原生肽作用的研究。因此，本研究合成了五种新型氨基酸取代和/或脂肪酸衍生化的 PP 类似物，即 [P3]PP、[K13Pal]PP、[P3,K13Pal]PP、[N-Pal]PP 和 [N-Pal,P3]PP，并研究了它们对胰岛β细胞功能以及食欲调节和葡萄糖稳态的影响。所有 PP 类似物对 DPP-4 降解的抵抗力都有所增强。此外，所有肽都能抑制 BRIN-BD11 β 细胞分泌丙氨酸诱导的胰岛素。原生 PP 和相关类似物（10-8 和 10-6 M），尤其是 [P3]PP 和 [K13Pal]PP 能显著防止细胞因子诱导的 beta 细胞凋亡，并促进细胞增殖，除 [N-Pal,P3]PP 外，所有肽的作用都依赖于 NPY4R。在小鼠体内，除[N-Pal]PP和[N-Pal,P3]PP外，所有肽都会引起剂量依赖性（25、75和200 nmol/kg）的食欲抑制，其中原生PP和[P3]PP会进一步增强胰高血糖素样肽-1（GLP-1）和胆囊收缩素（CCK）诱导的食物摄入量减少。PP 肽对葡萄糖耐量没有明显的不利影响，也没有明显损害 GLP-1 或 CCK 的葡萄糖调节作用。总之，PP 的 Pro3 氨基酸取代，无论是单独还是与中链酰化一起，都能产生 PP 类似物，对β细胞休息、胰岛细胞周转和能量调节都有好处，可能适用于糖尿病和肥胖症的治疗。

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来源期刊

BioFactors 生物-内分泌学与代谢

CiteScore

11.50

自引率

3.30%

发文量

审稿时长

6-12 weeks

期刊介绍： BioFactors, a journal of the International Union of Biochemistry and Molecular Biology, is devoted to the rapid publication of highly significant original research articles and reviews in experimental biology in health and disease. The word “biofactors” refers to the many compounds that regulate biological functions. Biological factors comprise many molecules produced or modified by living organisms, and present in many essential systems like the blood, the nervous or immunological systems. A non-exhaustive list of biological factors includes neurotransmitters, cytokines, chemokines, hormones, coagulation factors, transcription factors, signaling molecules, receptor ligands and many more. In the group of biofactors we can accommodate several classical molecules not synthetized in the body such as vitamins, micronutrients or essential trace elements. In keeping with this unified view of biochemistry, BioFactors publishes research dealing with the identification of new substances and the elucidation of their functions at the biophysical, biochemical, cellular and human level as well as studies revealing novel functions of already known biofactors. The journal encourages the submission of studies that use biochemistry, biophysics, cell and molecular biology and/or cell signaling approaches.