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

doi:10.1111/dom.13908

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 journal › Article › peer-review

29 Citations (Scopus)

387 Downloads (Pure)

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.

Original language	English
Pages (from-to)	404-416
Number of pages	13
Journal	Diabetes, Obesity and Metabolism
Volume	22
Issue number	3
Early online date	6 Nov 2019
DOIs	https://doi.org/10.1111/dom.13908
Publication status	Published (in print/issue) - 31 Mar 2020

Bibliographical note

Funding Information:
Department for the Economy Northern Ireland, Grant/Award Number: PhD studentship; Hjelt Foundation; Stiftelsen för Strategisk Forskning; Ulster University, Grant/Award Number: Strategic research funding; Vetenskapsrådet; European Foundation for the Study of Diabetes; Swedish Foundation for Strategic Research; Swedish Research Council; University of Ulster; Invest Northern Ireland, Grant/Award Number: Proof of Concept Funding information

Funding Information:
This work was supported by a PhD studentship (awarded to R.A.L.) from the Department for the Economy Northern Ireland, an Invest Northern Ireland Proof of Concept grant and University of Ulster strategic research funding. Y.D.M. and P.B. were supported by the Swedish Research Council, Strategic Research Area Exodiab, Dnr 2009‐1039; and the Swedish Foundation for Strategic Research Dnr IRC15‐0067; a European Foundation for the Study of Diabetes (EFSD) grant and Hjelt Foundation grant.

Publisher Copyright:
© 2019 John Wiley & Sons Ltd

Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

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

Access to Document

10.1111/dom.13908

Accepted author manuscriptAuthor Accepted Manuscript, 3 MB

Cite this

Lafferty, R., Tanday, N., Mc Closkey, A., Bompada, P., De Marinis, Y., Flatt, PR., & Irwin, N. (2020). 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. Diabetes, Obesity and Metabolism, 22(3), 404-416. https://doi.org/10.1111/dom.13908

@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, beta cell",

author = "Ryan Lafferty and Neil Tanday and \{Mc Closkey\}, Andrew and Pradeep Bompada and \{De Marinis\}, Yang and PR Flatt and Nigel Irwin",

note = "Funding Information: Department for the Economy Northern Ireland, Grant/Award Number: PhD studentship; Hjelt Foundation; Stiftelsen f{\"o}r Strategisk Forskning; Ulster University, Grant/Award Number: Strategic research funding; Vetenskapsr{\aa}det; European Foundation for the Study of Diabetes; Swedish Foundation for Strategic Research; Swedish Research Council; University of Ulster; Invest Northern Ireland, Grant/Award Number: Proof of Concept Funding information Funding Information: This work was supported by a PhD studentship (awarded to R.A.L.) from the Department for the Economy Northern Ireland, an Invest Northern Ireland Proof of Concept grant and University of Ulster strategic research funding. Y.D.M. and P.B. were supported by the Swedish Research Council, Strategic Research Area Exodiab, Dnr 2009‐1039; and the Swedish Foundation for Strategic Research Dnr IRC15‐0067; a European Foundation for the Study of Diabetes (EFSD) grant and Hjelt Foundation grant. Publisher Copyright: {\textcopyright} 2019 John Wiley \& Sons Ltd Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2020",

month = mar,

day = "31",

doi = "10.1111/dom.13908",

language = "English",

volume = "22",

pages = "404--416",

journal = "Diabetes, Obesity and Metabolism",

issn = "1463-1326",

publisher = "John Wiley \& Sons, Inc.",

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}

Lafferty, R, Tanday, N , Mc Closkey, A, Bompada, P, De Marinis, Y, Flatt, PR & Irwin, N 2020, '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', Diabetes, Obesity and Metabolism, vol. 22, no. 3, pp. 404-416. https://doi.org/10.1111/dom.13908

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. / Lafferty, Ryan; Tanday, Neil ; Mc Closkey, Andrew et al.
In: Diabetes, Obesity and Metabolism, Vol. 22, No. 3, 31.03.2020, p. 404-416.

Research output: Contribution to journal › Article › peer-review

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

N1 - Funding Information: Department for the Economy Northern Ireland, Grant/Award Number: PhD studentship; Hjelt Foundation; Stiftelsen för Strategisk Forskning; Ulster University, Grant/Award Number: Strategic research funding; Vetenskapsrådet; European Foundation for the Study of Diabetes; Swedish Foundation for Strategic Research; Swedish Research Council; University of Ulster; Invest Northern Ireland, Grant/Award Number: Proof of Concept Funding information Funding Information: This work was supported by a PhD studentship (awarded to R.A.L.) from the Department for the Economy Northern Ireland, an Invest Northern Ireland Proof of Concept grant and University of Ulster strategic research funding. Y.D.M. and P.B. were supported by the Swedish Research Council, Strategic Research Area Exodiab, Dnr 2009‐1039; and the Swedish Foundation for Strategic Research Dnr IRC15‐0067; a European Foundation for the Study of Diabetes (EFSD) grant and Hjelt Foundation grant. Publisher Copyright: © 2019 John Wiley & Sons Ltd Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/3/31

Y1 - 2020/3/31

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

KW - beta cell

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UR - https://pure.ulster.ac.uk/en/publications/peptide-yy-136-peptides-from-phylogenetically-ancient-fish-target

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DO - 10.1111/dom.13908

M3 - Article

C2 - 31692207

SN - 1463-1326

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JO - Diabetes, Obesity and Metabolism

JF - Diabetes, Obesity and Metabolism

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ER -

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

Bibliographical note

UN SDGs

Keywords

Access to Document

Other files and links

Fingerprint

Evaluation of GPR55 and GPR120 as novel therapeutic targets for the treatment of type 2 diabetes

Exploiting natural, phylogenetically ancient, PYY peptides in the development of long-acting, NPYR-specific analogues for obesity-diabetes

Pharmacological modulation of pancreatic beta-to-alpha cell transdifferentiation in diabetes

Nigel Irwin

Cite this

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

Bibliographical note

UN SDGs

Keywords

Access to Document

Other files and links

Fingerprint

Student theses

Evaluation of GPR55 and GPR120 as novel therapeutic targets for the treatment of type 2 diabetes

Exploiting natural, phylogenetically ancient, PYY peptides in the development of long-acting, NPYR-specific analogues for obesity-diabetes

Pharmacological modulation of pancreatic beta-to-alpha cell transdifferentiation in diabetes

Profiles

Nigel Irwin

Cite this