Obestatin (OB(1-23) is a 23
amino acid peptide encoded on the preproghrelin gene, originally reported to have metabolic actions related to food intake, gastric emptying and
body weight. The
biological instability of OB(1-23) has recently been highlighted by studies demonstrating its rapid enzymatic cleavage in a number of
biological matrices. We assessed the stability of both OB(1-23) and an N-terminally PEGylated analog (
PEG-OB(1-23)) before conducting chronic in vivo studies.
Peptides were incubated in rat liver homogenate and degradation monitored by LC-MS.
PEG-OB(1-23) was approximately 3-times more stable than OB(1-23). Following a 14 day infusion of Sprague-Dawley rats with 50 nmol/kg/day of OB(1-23) or a N-terminally PEGylated analog (
PEG-OB(1-23)), we found no changes in food/fluid intake,
body weight and plasma
glucose or
cholesterol between groups. Furthermore, morphometric liver, muscle and white adipose tissue (WAT) weights and tissue
triglyceride concentrations remained unaltered between groups. However, with stabilized
PEG-OB(1-23) we observed a 40% reduction in plasma
triglycerides. These findings indicate that
PEG-OB(1-23) is an OB(1-23) analog with significantly enhanced stability and suggest that
obestatin could play a role in modulating physiological lipid metabolism, although it does not appear to be involved in regulation of food/fluid intake,
body weight or fat deposition.