Peptide YY (1-36) peptides from phylogenetically ancient fish targeting mammalian neuropeptide Y1 receptors demonstrate potent effects on pancreatic β-cell function, growth and survival
Peptide YY (1-36) peptides from phylogenetically ancient fish targeting mammalian neuropeptide Y1 receptors demonstrate potent effects on pancreatic β-cell function, growth and survival
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DOI：
10.1111/dom.13908
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发表时间：
2019-12-09
影响因子：
5.8
通讯作者：
Irwin, Nigel
中科院分区：
文献类型：
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作者：
Lafferty, Ryan A.;Tanday, Neil;Irwin, Nigel
目的研究古鱼类酶解稳定肽YY（PYY）的抗糖尿病作用。材料与方法合成了N-末端稳定的PYY（1-36）序列，并对其生物学活性和抗糖尿病疗效进行了评价。结果鱼PYY（1-36）肽均能抵抗二肽基肽酶-4（DPP-4）的降解，抑制葡萄糖和丙氨酸诱导的胰岛素分泌（P < 0.05 ~ P < 0.001）。此外，PYY（1-36）肽赋予显著（P < 0.05至P < 0.001）的β-细胞增殖和抗凋亡益处。在CRISPR-Cas9诱导敲除Npyr 1的β细胞中几乎完全不存在抑制作用。与人PYY（1-36）相反，鱼源肽缺乏食欲抑制作用。每天两次给予海鳗PYY（1-36）（一种上级生物活性肽），持续21天，可显着（P < 0.05至P < 0.001）降低链脲佐菌素（STZ）诱导的糖尿病小鼠的液体摄入量、非空腹血糖和胰高血糖素。此外，葡萄糖耐量、胰岛素敏感性、胰腺胰岛素和胰高血糖素含量均明显改善。代谢益处与胰岛形态的积极变化有关，这是β细胞增殖增强（P < 0.001）和凋亡减少的结果。鲟鱼PYY（1-36）在STZ小鼠中发挥了类似但不太令人印象深刻的作用。结论这些观察结果首次揭示了来自遗传学上古老鱼类的PYY（1-36）肽序列复制了人PYY（1-36）的胰腺β细胞益处，并且具有治疗2型糖尿病的明确潜力。
Aim To investigate the antidiabetic efficacy of enzymatically stable Peptide YY (PYY) peptides from phylogenetically ancient fish. Materials and methods N-terminally stabilized, PYY (1-36) sequences from Amia calva (bowfin), Oncorhynchus mykiss (trout), Petromyzon marinus (sea lamprey) and Scaphirhynchus albus (sturgeon), were synthesized, and both biological actions and antidiabetic therapeutic efficacy were assessed. Results All fish PYY (1-36) peptides were resistant to dipeptidyl peptidase-4 (DPP-4) degradation and inhibited glucose- and alanine-induced (P < 0.05 to P < 0.001) insulin secretion. In addition, PYY (1-36) peptides imparted significant (P < 0.05 to P < 0.001) beta-cell proliferative and anti-apoptotic benefits. Proliferative effects were almost entirely absent in beta cells with CRISPR-Cas9-induced knockout of Npyr1. In contrast to human PYY (1-36), the piscine-derived peptides lacked appetite-suppressive actions. Twice-daily administration of sea lamprey PYY (1-36), the superior bioactive peptide, for 21 days significantly (P < 0.05 to P < 0.001) decreased fluid intake, non-fasting glucose and glucagon in streptozotocin (STZ)-induced diabetic mice. In addition, glucose tolerance, insulin sensitivity, pancreatic insulin and glucagon content were significantly improved. Metabolic benefits were linked to positive changes in pancreatic islet morphology as a result of augmented (P < 0.001) proliferation and decreased apoptosis of beta cells. Sturgeon PYY (1-36) exerted similar but less impressive effects in STZ mice. Conclusion These observations reveal, for the first time, that PYY (1-36) peptide sequences from phylogenetically ancient fish replicate the pancreatic beta-cell benefits of human PYY (1-36) and have clear potential for the treatment of type 2 diabetes.