C-terminal degradation of PYY peptides in plasma abolishes effects on satiety and beta-cell function

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Abstract

The importance of dipeptidyl peptidase-4 mediated N-terminal metabolism of the enteroendocrine-derived hormone, Peptide YY (PYY), for receptor binding and subsequent biological action profile is well established. However, an intact C-terminus may be fundamental also for bioactivity of PYY peptides. The current study has demonstrated C-terminal degradation of the major recognised circulating forms of PYY, PYY(1-36) and PYY(3-36), in plasma, resulting in production of PYY(1-34) and PYY(3-34). Interestingly, the angiotensin-converting-enzyme (ACE) inhibitor, captopril, blocked formation of PYY(3-34) from PYY(3-36) in plasma, but did result in the appearance of PYY(3-35). In addition, we were able to evidence C-terminal truncation of PYY(1-35) and PYY(3-35) to PYY(1-34) and PYY(3-34), respectively. As expected, PYY(1-36) and PYY(3-36) inhibited (P<0.05 - P<0.001) glucose- and alanine-stimulated insulin secretion from BRIN-BD11 beta-cells. In contrast, PYY(1-34), PYY(3-34), PYY(1-35) and PYY(3-35) were devoid of insulinostatic actions. Both PYY(1-36) and PYY(3-36), but not related PYY metabolites, significantly (P<0.05 - P<0.001) enhanced proliferation of BRIN BD11 and 1.1B4 beta-cell lines, and protected (P<0.01 - P<0.001) these cell lines against cytokine-induced apoptosis. As expected, PYY(3-36) induced clear (P<0.05 - P<0.01) appetite suppressive effects in mice, but this action was eliminated by mono- or di-peptide C-terminal truncation. Interestingly, captopril significantly (P<0.05) augmented the anorexigenic effects of PYY(3-36) in mice. PYY(1-36), PYY(3-36), PYY(1-34) and PYY(3-34) lacked effects on in vivo glucose tolerance or glucose-induced insulin release. Taken together, these data highlight the unrecognised importance of C-terminal integrity of PYY peptides for biological activity and therapeutic usefulness in obesity-diabetes.
LanguageEnglish
Pages95-102
Number of pages7
JournalBIiochemical Pharmacology
Volume158
DOIs
Publication statusPublished - 5 Oct 2018

Fingerprint

Peptide YY
Plasmas
Degradation
Peptides
Captopril
peptide YY (3-36)
Bioactivity
Glucose
Cells
Insulin
Dipeptidyl Peptidase 4
Cell Line
Hormones
Appetite

Keywords

  • Peptide YY (PYY)
  • insulin secretion
  • Degradation
  • Angiotensin-converting enzyme (ACE)
  • appetite

Cite this

@article{7c5a2afbe7ed4cf08d8afc4b8ce79f87,
title = "C-terminal degradation of PYY peptides in plasma abolishes effects on satiety and beta-cell function",
abstract = "The importance of dipeptidyl peptidase-4 mediated N-terminal metabolism of the enteroendocrine-derived hormone, Peptide YY (PYY), for receptor binding and subsequent biological action profile is well established. However, an intact C-terminus may be fundamental also for bioactivity of PYY peptides. The current study has demonstrated C-terminal degradation of the major recognised circulating forms of PYY, PYY(1-36) and PYY(3-36), in plasma, resulting in production of PYY(1-34) and PYY(3-34). Interestingly, the angiotensin-converting-enzyme (ACE) inhibitor, captopril, blocked formation of PYY(3-34) from PYY(3-36) in plasma, but did result in the appearance of PYY(3-35). In addition, we were able to evidence C-terminal truncation of PYY(1-35) and PYY(3-35) to PYY(1-34) and PYY(3-34), respectively. As expected, PYY(1-36) and PYY(3-36) inhibited (P<0.05 - P<0.001) glucose- and alanine-stimulated insulin secretion from BRIN-BD11 beta-cells. In contrast, PYY(1-34), PYY(3-34), PYY(1-35) and PYY(3-35) were devoid of insulinostatic actions. Both PYY(1-36) and PYY(3-36), but not related PYY metabolites, significantly (P<0.05 - P<0.001) enhanced proliferation of BRIN BD11 and 1.1B4 beta-cell lines, and protected (P<0.01 - P<0.001) these cell lines against cytokine-induced apoptosis. As expected, PYY(3-36) induced clear (P<0.05 - P<0.01) appetite suppressive effects in mice, but this action was eliminated by mono- or di-peptide C-terminal truncation. Interestingly, captopril significantly (P<0.05) augmented the anorexigenic effects of PYY(3-36) in mice. PYY(1-36), PYY(3-36), PYY(1-34) and PYY(3-34) lacked effects on in vivo glucose tolerance or glucose-induced insulin release. Taken together, these data highlight the unrecognised importance of C-terminal integrity of PYY peptides for biological activity and therapeutic usefulness in obesity-diabetes.",
keywords = "Peptide YY (PYY), insulin secretion, Degradation, Angiotensin-converting enzyme (ACE), appetite",
author = "Ryan Lafferty and PR Flatt and Nigel Irwin",
year = "2018",
month = "10",
day = "5",
doi = "10.1016/j.bcp.2018.10.004",
language = "English",
volume = "158",
pages = "95--102",

}

TY - JOUR

T1 - C-terminal degradation of PYY peptides in plasma abolishes effects on satiety and beta-cell function

AU - Lafferty, Ryan

AU - Flatt, PR

AU - Irwin, Nigel

PY - 2018/10/5

Y1 - 2018/10/5

N2 - The importance of dipeptidyl peptidase-4 mediated N-terminal metabolism of the enteroendocrine-derived hormone, Peptide YY (PYY), for receptor binding and subsequent biological action profile is well established. However, an intact C-terminus may be fundamental also for bioactivity of PYY peptides. The current study has demonstrated C-terminal degradation of the major recognised circulating forms of PYY, PYY(1-36) and PYY(3-36), in plasma, resulting in production of PYY(1-34) and PYY(3-34). Interestingly, the angiotensin-converting-enzyme (ACE) inhibitor, captopril, blocked formation of PYY(3-34) from PYY(3-36) in plasma, but did result in the appearance of PYY(3-35). In addition, we were able to evidence C-terminal truncation of PYY(1-35) and PYY(3-35) to PYY(1-34) and PYY(3-34), respectively. As expected, PYY(1-36) and PYY(3-36) inhibited (P<0.05 - P<0.001) glucose- and alanine-stimulated insulin secretion from BRIN-BD11 beta-cells. In contrast, PYY(1-34), PYY(3-34), PYY(1-35) and PYY(3-35) were devoid of insulinostatic actions. Both PYY(1-36) and PYY(3-36), but not related PYY metabolites, significantly (P<0.05 - P<0.001) enhanced proliferation of BRIN BD11 and 1.1B4 beta-cell lines, and protected (P<0.01 - P<0.001) these cell lines against cytokine-induced apoptosis. As expected, PYY(3-36) induced clear (P<0.05 - P<0.01) appetite suppressive effects in mice, but this action was eliminated by mono- or di-peptide C-terminal truncation. Interestingly, captopril significantly (P<0.05) augmented the anorexigenic effects of PYY(3-36) in mice. PYY(1-36), PYY(3-36), PYY(1-34) and PYY(3-34) lacked effects on in vivo glucose tolerance or glucose-induced insulin release. Taken together, these data highlight the unrecognised importance of C-terminal integrity of PYY peptides for biological activity and therapeutic usefulness in obesity-diabetes.

AB - The importance of dipeptidyl peptidase-4 mediated N-terminal metabolism of the enteroendocrine-derived hormone, Peptide YY (PYY), for receptor binding and subsequent biological action profile is well established. However, an intact C-terminus may be fundamental also for bioactivity of PYY peptides. The current study has demonstrated C-terminal degradation of the major recognised circulating forms of PYY, PYY(1-36) and PYY(3-36), in plasma, resulting in production of PYY(1-34) and PYY(3-34). Interestingly, the angiotensin-converting-enzyme (ACE) inhibitor, captopril, blocked formation of PYY(3-34) from PYY(3-36) in plasma, but did result in the appearance of PYY(3-35). In addition, we were able to evidence C-terminal truncation of PYY(1-35) and PYY(3-35) to PYY(1-34) and PYY(3-34), respectively. As expected, PYY(1-36) and PYY(3-36) inhibited (P<0.05 - P<0.001) glucose- and alanine-stimulated insulin secretion from BRIN-BD11 beta-cells. In contrast, PYY(1-34), PYY(3-34), PYY(1-35) and PYY(3-35) were devoid of insulinostatic actions. Both PYY(1-36) and PYY(3-36), but not related PYY metabolites, significantly (P<0.05 - P<0.001) enhanced proliferation of BRIN BD11 and 1.1B4 beta-cell lines, and protected (P<0.01 - P<0.001) these cell lines against cytokine-induced apoptosis. As expected, PYY(3-36) induced clear (P<0.05 - P<0.01) appetite suppressive effects in mice, but this action was eliminated by mono- or di-peptide C-terminal truncation. Interestingly, captopril significantly (P<0.05) augmented the anorexigenic effects of PYY(3-36) in mice. PYY(1-36), PYY(3-36), PYY(1-34) and PYY(3-34) lacked effects on in vivo glucose tolerance or glucose-induced insulin release. Taken together, these data highlight the unrecognised importance of C-terminal integrity of PYY peptides for biological activity and therapeutic usefulness in obesity-diabetes.

KW - Peptide YY (PYY)

KW - insulin secretion

KW - Degradation

KW - Angiotensin-converting enzyme (ACE)

KW - appetite

U2 - 10.1016/j.bcp.2018.10.004

DO - 10.1016/j.bcp.2018.10.004

M3 - Article

VL - 158

SP - 95

EP - 102

ER -