Lack of obestatin effects on food intake: Should obestatin be renamed ghrelin-associated peptide (GAP)?

Abstract

Obestatin is a newly identified ghrelin-associated peptide (GAP) that is derived from post-translational processing of the prepro-ghrelin gene. Obestatin has been reported initially to be the endogenous ligand for the orphan receptor G protein-coupled receptor 39 (GPR39), and to reduce refeeding- and ghrelin-stimulated food intake and gastric transit in fasted mice, and body weight gain upon chronic peripheral injection. However, recent reports indicate that obestatin is unlikely to be the endogenous ligand for GPR39 based on the lack of specific binding on GRP39 receptor expressing cells and the absence of signal transduction pathway activation. In addition, a number of studies provided convergent evidence that ghrelin injected intracerebroventricularly or peripherally did not influence food intake, body weight gain, gastric transit, gastrointestinal motility, and gastric vagal afferent activity, as well as pituitary hormone secretions, in rats or mice. Similarly, obestatin did not alter ghrelin-induced stimulation of food intake or gastric transit. Therefore, the present state-of-knowledge on obestatin and GPR39 is leaving many unanswered questions that deserve further consideration. Those relate not only to redefining the biological action of obestatin that should be renamed GAP, but also the identification of the native ligand for GPR39.

Peripheral obestatin has no effect on feeding behavior and brain Fos expression in rodents

“…Moreover, our data reveal that the effect of peripherally administered obestatin on food intake in rats depends neither on time in the circadian rhythm when the experiment is conducted, nor on the metabolic conditions of the experimental animals. The present findings are also consistent with the lack of effect of peripherally administered obestatin on gastric motor function as assessed by monitoring changes in gastric motility or emptying in both rats and mice [3,11,14,16,17] contrasting with the initial report [51].…”

“…These findings suggest that obestatin may be involved in the regulation of energy homeostasis in rodents. However, several recent studies performed in rats and mice under various experimental conditions showed that obestatin injected intraperitoneally (ip) has no inhibitory effect on short-term food intake [11,[14][15][16][17]21,32,41,54] and body weight gain [32,42]. The responsiveness to exogenous obestatin could be influenced by circadian rhythm and might account for the varying effects of peripheral obestatin on food intake found in recent studies [7,15,18,21,27,32,[40][41][42]51,54].…”

Influence of Obestatin and Short-Term Treadmill Exercise on Plasma Acyl-Ghrelin and Body Weight in Wistar Rat

“…Studies indicating the lack of obestatinimpact on food intake are related to fasted-rodents which is a condition associatedwith the highest endogenous circulating levels of ghrelin [14][15][16].…”

Two alternatively spliced GPR39 transcripts in seabream: molecular cloning, genomic organization, and regulation of gene expression by metabolic signals

“…The putative natural ligand for GPR39 was suggested to be an amidated 23-amino acid (aa) peptide designated as obestatin isolated from rat stomach (Zhang et al 2005). However, recent studies failed to demonstrate that obestatin could bind and activate GPR39 (Lauwers et al 2006, Chartrel et al 2007, Gourcerol et al 2007. It was suggested that the impure obestatin used in the original report might be responsible for the aberrant results (Zhang et al 2007).…”