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-d(3))-H(2)O solvent mixture, the structure of obestatin {1-23} was characterized by an alpha-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 alpha-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 alpha-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.
Subasinghage
Anusha P
AP
UCD School of Biomolecular and Biomedical Science, Centre for Synthesis and Chemical Biology, SEC Strategic Research Cluster, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
Green
Brian D
BD
Flatt
Peter R
PR
Irwin
Nigel
N
Hewage
Chandralal M
CM
D000595:Amino Acid Sequence; D000818:Animals; D019440:Anti-Obesity Agents / Q000009:adverse effects / Q000737:chemistry* / Q000627:therapeutic use*; D001069:Appetite Regulation / Q000187:drug effects; D001786:Blood Glucose / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D004041:Dietary Fats / Q000008:administration & dosage; D005260:Female; D054439:Ghrelin; D006801:Humans; D007328:Insulin / Q000097:blood; D051379:Mice; D008958:Models, Molecular; D009765:Obesity / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D010446:Peptide Fragments / Q000009:adverse effects / Q000737:chemistry* / Q000627:therapeutic use*; D036361:Peptide Hormones / Q000009:adverse effects / Q000737:chemistry* / Q000627:therapeutic use*; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D012997:Solvents / Q000737:chemistry; D013696:Temperature; D013997:Time Factors
D019440:Anti-Obesity Agents; D001786:Blood Glucose; D004041:Dietary Fats; D054439:Ghrelin; D007328:Insulin; D010446:Peptide Fragments; D036361:Peptide Hormones; D012997:Solvents; C505799:obestatin, human