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

Ryan Lafferty, Neil Tanday, Andrew Mc Closkey, Pradeep Bompada, Yang De Marinis, PR Flatt, Nigel Irwin

Research output: Contribution to journalArticle

Abstract

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) β-cell proliferative and anti-apoptotic benefits. Proliferative effects were almost entirely absent in β 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 β 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 β-cell benefits of human PYY (1–36) and have clear potential for the treatment of type 2 diabetes.

LanguageEnglish
JournalDiabetes, Obesity and Metabolism
Early online date6 Nov 2019
DOIs
Publication statusE-pub ahead of print - 6 Nov 2019

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Neuropeptide Receptors
Insulin-Secreting Cells
Fishes
Peptides
Survival
Petromyzon
Growth
Streptozocin
Glucagon
Hypoglycemic Agents
Glucose
Clustered Regularly Interspaced Short Palindromic Repeats
Insulin
Peptide YY
Dipeptidyl Peptidase 4
peptide YY (1-36)
Trout
Oncorhynchus mykiss
Appetite
Islets of Langerhans

Keywords

  • appetite
  • bowfin
  • degradation
  • insulin secretion
  • lamprey
  • peptide YY (PYY)
  • sturgeon
  • trout
  • β cell

Cite this

@article{bdd7b707537f48509c70e2b4fc9d468b,
title = "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",
abstract = "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) β-cell proliferative and anti-apoptotic benefits. Proliferative effects were almost entirely absent in β 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 β 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 β-cell benefits of human PYY (1–36) and have clear potential for the treatment of type 2 diabetes.",
keywords = "appetite, bowfin, degradation, insulin secretion, lamprey, peptide YY (PYY), sturgeon, trout, β cell",
author = "Ryan Lafferty and Neil Tanday and {Mc Closkey}, Andrew and Pradeep Bompada and {De Marinis}, Yang and PR Flatt and Nigel Irwin",
year = "2019",
month = "11",
day = "6",
doi = "10.1111/dom.13908",
language = "English",
journal = "Diabetes, Obesity and Metabolism",
issn = "1463-1326",

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TY - JOUR

T1 - 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

AU - Lafferty, Ryan

AU - Tanday, Neil

AU - Mc Closkey, Andrew

AU - Bompada, Pradeep

AU - De Marinis, Yang

AU - Flatt, PR

AU - Irwin, Nigel

PY - 2019/11/6

Y1 - 2019/11/6

N2 - 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) β-cell proliferative and anti-apoptotic benefits. Proliferative effects were almost entirely absent in β 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 β 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 β-cell benefits of human PYY (1–36) and have clear potential for the treatment of type 2 diabetes.

AB - 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) β-cell proliferative and anti-apoptotic benefits. Proliferative effects were almost entirely absent in β 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 β 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 β-cell benefits of human PYY (1–36) and have clear potential for the treatment of type 2 diabetes.

KW - appetite

KW - bowfin

KW - degradation

KW - insulin secretion

KW - lamprey

KW - peptide YY (PYY)

KW - sturgeon

KW - trout

KW - β cell

UR - http://www.scopus.com/inward/record.url?scp=85076213038&partnerID=8YFLogxK

U2 - 10.1111/dom.13908

DO - 10.1111/dom.13908

M3 - Article

JO - Diabetes, Obesity and Metabolism

T2 - Diabetes, Obesity and Metabolism

JF - Diabetes, Obesity and Metabolism

SN - 1463-1326

ER -