Metabolic and structural properties of human obestatin {1-23} and two fragment peptides

Anusha P. Subasinghage, Brian D. Green, Peter Flatt, Nigel Irwin, Chandralal M. Hewage

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12 Citations (Scopus)

Abstract

Obestatin is a peptide produced in the oxyntic mucosa of the stomach and co-localizes with ghrelin on the periphery of pancreatic islets. Several studies demonstrate that obestatin reduces food and water intake, decreases body weight gain, inhibits gastrointestinal motility, and modulates glucose-induced insulin secretion. In this study we evaluated the acute metabolic effects of human obestatin {1-23} and fragment peptides {1-10} or {11-23} in high-fat fed mice, and then investigated their solution structure by NMR spectroscopy and molecular modelling. Obestatins {1-23} and {11-23} significantly reduced food intake (86% and 90% respectively) and lowered glucose responses to feeding, whilst leaving insulin responses unchanged. No metabolic changes could be detected following the administration of obestatin (1-10). In aqueous solution none of the obestatin peptides possessed secondary structural features. However, in a 2,2,2-trifluoroethanol (TFE-d(3))-H2O solvent mixture, the structure of obestatin {1-23} was characterized by an a-helix followed by a single turn helix conformation between residues Pro(4) and Gln(15) and His(19) and Ala(22) respectively. Obestatin {1-10} showed no structural components whereas {11-23} contained an a-helix between residues Val(14) and Ser(20) in a mixed solvent. These studies are the first to elucidate the structure of human obestatin and provide clear evidence that the observed a-helical structures are critical for in vivo activity. Future structure/function studies may facilitate the design of novel therapeutic agents based on the obestatin peptide structure. (C) 2010 Elsevier Inc. All rights reserved.
LanguageEnglish
Pages1697-1705
JournalPeptides
Volume31
Issue number9
DOIs
Publication statusPublished - Sep 2010

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Peptide Fragments
Ghrelin
Structural properties
Peptides
Insulin
Trifluoroethanol
human obestatin
Glucose
Molecular modeling
Polytetrafluoroethylene
Nuclear magnetic resonance spectroscopy
Conformations
Fats
Water

Cite this

Subasinghage, Anusha P. ; Green, Brian D. ; Flatt, Peter ; Irwin, Nigel ; Hewage, Chandralal M. / Metabolic and structural properties of human obestatin {1-23} and two fragment peptides. In: Peptides. 2010 ; Vol. 31, No. 9. pp. 1697-1705.
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Metabolic and structural properties of human obestatin {1-23} and two fragment peptides. / Subasinghage, Anusha P.; Green, Brian D.; Flatt, Peter; Irwin, Nigel; Hewage, Chandralal M.

In: Peptides, Vol. 31, No. 9, 09.2010, p. 1697-1705.

Research output: Contribution to journalArticle

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AB - Obestatin is a peptide produced in the oxyntic mucosa of the stomach and co-localizes with ghrelin on the periphery of pancreatic islets. Several studies demonstrate that obestatin reduces food and water intake, decreases body weight gain, inhibits gastrointestinal motility, and modulates glucose-induced insulin secretion. In this study we evaluated the acute metabolic effects of human obestatin {1-23} and fragment peptides {1-10} or {11-23} in high-fat fed mice, and then investigated their solution structure by NMR spectroscopy and molecular modelling. Obestatins {1-23} and {11-23} significantly reduced food intake (86% and 90% respectively) and lowered glucose responses to feeding, whilst leaving insulin responses unchanged. No metabolic changes could be detected following the administration of obestatin (1-10). In aqueous solution none of the obestatin peptides possessed secondary structural features. However, in a 2,2,2-trifluoroethanol (TFE-d(3))-H2O solvent mixture, the structure of obestatin {1-23} was characterized by an a-helix followed by a single turn helix conformation between residues Pro(4) and Gln(15) and His(19) and Ala(22) respectively. Obestatin {1-10} showed no structural components whereas {11-23} contained an a-helix between residues Val(14) and Ser(20) in a mixed solvent. These studies are the first to elucidate the structure of human obestatin and provide clear evidence that the observed a-helical structures are critical for in vivo activity. Future structure/function studies may facilitate the design of novel therapeutic agents based on the obestatin peptide structure. (C) 2010 Elsevier Inc. All rights reserved.

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