PYY(1-36) peptides from phylogenetically ancient fish targeting mammalian NPY1 receptors demonstrate potent effects on pancreatic beta-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: Activation of neuropeptide Y1 receptors (NPYR1’s) by the peptide hormone, Peptide YY (PYY), evokes benefits on pancreatic beta-cells. However, rapid N-terminal enzymatic cleavage of PYY in the circulation dramatically diminishes NPYR1 specificity. The aim of the current study was to investigate antidiabetic efficacy of enzymatically stable PYY peptides. Materials and Methods: N-terminally stabilised, PYY(1-36) sequences from phylogenetically ancient fish, namely Amia calva (bowfin), Oncorhynchus mykiss (trout), Petromyzon marinus (sea lamprey) and Scaphirhynchus albus (sturgeon), were synthesised and both biological actions and antidiabetic therapeutic efficacy 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: The current 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 possess clear potential for the treatment of type 2 diabetes.
LanguageEnglish
Pagesxx
JournalDiabetes, Obesity and Metabolism
Volumexx
Issue numberx
Early online date6 Nov 2019
DOIs
Publication statusE-pub ahead of print - 6 Nov 2019

Fingerprint

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

Keywords

  • Peptide YY (PYY)
  • Degradation
  • insulin secretion
  • Beta cell
  • appetite
  • bowfin
  • trout
  • sturgeon
  • sea lamprey

Cite this

@article{bdd7b707537f48509c70e2b4fc9d468b,
title = "PYY(1-36) peptides from phylogenetically ancient fish targeting mammalian NPY1 receptors demonstrate potent effects on pancreatic beta-cell function, growth and survival",
abstract = "Aim: Activation of neuropeptide Y1 receptors (NPYR1’s) by the peptide hormone, Peptide YY (PYY), evokes benefits on pancreatic beta-cells. However, rapid N-terminal enzymatic cleavage of PYY in the circulation dramatically diminishes NPYR1 specificity. The aim of the current study was to investigate antidiabetic efficacy of enzymatically stable PYY peptides. Materials and Methods: N-terminally stabilised, PYY(1-36) sequences from phylogenetically ancient fish, namely Amia calva (bowfin), Oncorhynchus mykiss (trout), Petromyzon marinus (sea lamprey) and Scaphirhynchus albus (sturgeon), were synthesised and both biological actions and antidiabetic therapeutic efficacy 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: The current 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 possess clear potential for the treatment of type 2 diabetes.",
keywords = "Peptide YY (PYY), Degradation, insulin secretion, Beta cell, appetite, bowfin, trout, sturgeon, sea lamprey",
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",
volume = "xx",
pages = "xx",
journal = "Diabetes, Obesity and Metabolism",
issn = "1463-1326",
number = "x",

}

TY - JOUR

T1 - PYY(1-36) peptides from phylogenetically ancient fish targeting mammalian NPY1 receptors demonstrate potent effects on pancreatic beta-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: Activation of neuropeptide Y1 receptors (NPYR1’s) by the peptide hormone, Peptide YY (PYY), evokes benefits on pancreatic beta-cells. However, rapid N-terminal enzymatic cleavage of PYY in the circulation dramatically diminishes NPYR1 specificity. The aim of the current study was to investigate antidiabetic efficacy of enzymatically stable PYY peptides. Materials and Methods: N-terminally stabilised, PYY(1-36) sequences from phylogenetically ancient fish, namely Amia calva (bowfin), Oncorhynchus mykiss (trout), Petromyzon marinus (sea lamprey) and Scaphirhynchus albus (sturgeon), were synthesised and both biological actions and antidiabetic therapeutic efficacy 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: The current 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 possess clear potential for the treatment of type 2 diabetes.

AB - Aim: Activation of neuropeptide Y1 receptors (NPYR1’s) by the peptide hormone, Peptide YY (PYY), evokes benefits on pancreatic beta-cells. However, rapid N-terminal enzymatic cleavage of PYY in the circulation dramatically diminishes NPYR1 specificity. The aim of the current study was to investigate antidiabetic efficacy of enzymatically stable PYY peptides. Materials and Methods: N-terminally stabilised, PYY(1-36) sequences from phylogenetically ancient fish, namely Amia calva (bowfin), Oncorhynchus mykiss (trout), Petromyzon marinus (sea lamprey) and Scaphirhynchus albus (sturgeon), were synthesised and both biological actions and antidiabetic therapeutic efficacy 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: The current 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 possess clear potential for the treatment of type 2 diabetes.

KW - Peptide YY (PYY)

KW - Degradation

KW - insulin secretion

KW - Beta cell

KW - appetite

KW - bowfin

KW - trout

KW - sturgeon

KW - sea lamprey

U2 - 10.1111/dom.13908

DO - 10.1111/dom.13908

M3 - Article

VL - xx

SP - xx

JO - Diabetes, Obesity and Metabolism

T2 - Diabetes, Obesity and Metabolism

JF - Diabetes, Obesity and Metabolism

SN - 1463-1326

IS - x

ER -