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

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-d3)–H2O solvent mixture, the structure of obestatin {1–23} was characterized by an α-helix followed by a single turn helix conformation between residues Pro4 and Gln15 and His19 and Ala22 respectively. Obestatin {1–10} showed no structural components whereas {11–23} contained an α-helix between residues Val14 and Ser20 in a mixed solvent. These studies are the first to elucidate the structure of human obestatin and provide clear evidence that the observed α-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.