Research Paper
Subject Category: Neuropharmacology
British Journal of Pharmacology (2008) 153, 1550–1557; doi:10.1038/sj.bjp.0707683; published online 21 January 2008
Effect of peripheral obestatin on food intake and gastric emptying in ghrelin-knockout mice
I Depoortere1, T Thijs1, D Moechars2, B De Smet1, L Ver Donck2 and T L Peeters1
- 1Centre for Gastroenterological Research, Catholic University of Leuven, Leuven, Belgium
- 2Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium
Correspondence: Professor I Depoortere, Centre for Gastroenterological Research, Catholic University of Leuven, Gasthuisberg O&N1, box 701, Leuven B-3000, Belgium. E-mail: inge.depoortere@med.kuleuven.be
Received 28 September 2007; Revised 16 November 2007; Accepted 14 December 2007; Published online 21 January 2008.
Abstract
Background and purpose:
The finding that obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's stimulatory effect on food intake and gastric emptying has been questioned. The effect of obestatin has been mostly investigated in fasted rodents, a condition associated with high blood levels of ghrelin which may mask the effect of obestatin. We therefore investigated the effect of obestatin on food intake, gastric emptying and gastric contractility in ghrelin knockout mice.
Experimental approach:
The effect of obestatin on 6-h cumulative food intake was studied in fasted wildtype (ghrelin+/+) and ghrelin knockout (ghrelin-/-) mice. In both genotypes, the effect of obestatin and/or ghrelin was studied in vivo on gastric emptying measured with the 14C-octanoic acid breath test and in vitro on neural responses elicited by electrical field stimulation (EFS) of fundic smooth muscle strips.
Key results:
Administration of obestatin did not influence fasting-induced hyperphagia or gastric emptying in both genotypes. Injection of ghrelin accelerated gastric emptying in ghrelin+/+ and ghrelin-/- mice but the effect was not reversed by co-injection with obestatin. In fundic strips from ghrelin+/+ and ghrelin-/- mice, ghrelin increased EFS-induced contractions, but obestatin was without effect. However, co-administration with obestatin tended to reduce the excitatory effect of ghrelin in both genotypes.
Conclusions and implications:
In ghrelin-/- mice, obestatin failed to affect food intake and gastric motility. These results suggest that endogenous ghrelin does not mask the effect of obestatin and confirm that obestatin administered peripherally is not a major regulator of satiety signalling or gut motility.
Keywords:
obestatin, food intake, gastric emptying, 14C octanoic breath test, in vitro contractility, ghrelin, ghrelin knockout
Abbreviations:
EFS, electrical field stimulation; ghrelin-/-, ghrelin knockout; ghrelin+/+, ghrelin wild type; Thalf, gastric half excretion time; Tlag, lag time
