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

https://doi.org/10.1016/j.regpep.2006.12.023Get rights and content

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.

Section snippets

Prepro-ghrelin generates ghrelin and ghrelin-associated peptide, originally named obestatin

During the past decade, numerous gastrointestinal (GI)-derived peptides have been associated with significant effects on food intake and GI motility [1], [2]. Among those peptides, ghrelin, a 28-amino acid acylated peptide identified by Kojima et al. in 1999, is to date the only gut peptide that is orexigenic [3], [4]. Ghrelin is mainly synthesized in the endocrine cells of the oxyntic mucosa of the stomach and is also found at lower levels in the intestine, pituitary and hypothalamus [4], [5].

Obestatin does not hold its promise to regulate satiety in rodents

Zhang et al.'s initial findings indicated that amidated human obestatin suppressed food intake during the first 5 h following a single injection into the peritoneal cavity (intraperitoneal, ip) in doses ranging from 320 μg/kg to 2.5 mg/kg (125–1000 nmol/kg) in fasted mice and reduced the spontaneous body weight gain upon repeated daily ip administrations at large doses in lean mice [7]. In addition, the peptide injected into the mouse lateral brain ventricle at 20 μg/kg inhibited food intake

Lack of reproducible interaction between obestatin and other gut peptides influencing satiety

Over the past years, it has become increasingly recognized that different signals governing meal initiation, meal-ending satiation and inter-meal satiety could modulate each other. Interaction between these signals results in a more potent satiety effect than each signal alone or alternatively, one signal can reduce the effects of that induced by another. For instance, we and others have previously established the synergistic interactions between CCK and leptin at the level of

Lack of reproducible inhibitory action of obestatin on upper gastrointestinal motor function

Most of the gut peptides that display significant effects on food intake also exert biological actions on digestive motor function, especially on the upper GI [28]. Such effects were also tested in the first report describing the anorexigenic properties of obestatin [7]. Obestatin diminished the contractile activity of jejunal muscular strips in vitro while ghrelin displayed the opposite effect, suggesting a role for obestatin to slow down upper GI transit [7]. This was expended by in vivo

G protein-coupled receptor 39 (GPR39) still orphan?

Biological activities of peptides are mediated by receptors located at the site of action. Zhang et al. [7] reported that obestatin is the cognate ligand for the orphan GPR39 receptor. GPR39 was originally cloned in 1997 and characterized to belong to the class A of 7 transmembrane domain G protein-coupled receptors (R) as part of the ghrelin subfamily that also includes ghrelin R (GHS-R1a), motilin R (GPR38), neurotensin R1, neurotensin R2, neuromedin U-R1 (GPR66) and neuromedin U-R2 [31], [32]

Obestatin: Toward new physiological role(s)?

Obestatin displays a very short half-life in blood circulation and does not have specific uptake by endothelia cells composing the blood-brain barrier [38], indicative that the peptide actions are most likely local. A recent study found obestatin immunoreactivity within the rat and guinea pig myenteric plexi, colocalizing with choline acetyltransferase [39]. Therefore, we cannot conclude so far that obestatin has no role to play within the GI tract, and its potential effects on sensory,

Should obestatin be renamed ghrelin-associated peptide?

The discovery that the processing of ghrelin gene yields obestatin opens new insight to the post-translational processing of prepro-ghrelin [41]. Obestatin was initially reported to reduce food intake, body weight gain, gastric emptying and suppress intestinal motility through an interaction with the orphan receptor GPR39 [7]. In addition, obestatin was originally found to abrogate ghrelin stimulatory action on these end points [7]. Therefore, this new ghrelin-associated peptide was proposed to

Acknowledgments

The authors' work was supported by NIH grants R01 DK-33061 (YT), Center grant DK-41301 (Animal Core; YT), VA Career Scientist and Merit Awards (YT), and the French Society of Gastroenterology (S.N.F.G.E.; GG). We thank Miss Teresa Olivas for her help in the preparation of the manuscript.

References (41)

  • D. Moechars et al.

    Altered gastrointestinal and metabolic function in the GPR39-obestatin receptor-knockout mouse

    Gastroenterology

    (2006)
  • W. Pan et al.

    Differential BBB interactions of three ingestive peptides: obestatin, ghrelin, and adiponectin

    Peptides

    (2006)
  • E. Szentirmai et al.

    Obestatin alters sleep in rats

    Neurosci Lett

    (2006)
  • O. Gualillo et al.

    One ancestor, several peptides post-translational modifications of preproghrelin generate several peptides with antithetical effects

    Mol Cell Endocrinol

    (2006)
  • K.C. Baynes et al.

    Regulation of food intake by gastrointestinal hormones

    Curr Opin Gastroenterol

    (2006)
  • M. Kojima et al.

    Ghrelin: structure and function

    Physiol Rev

    (2005)
  • T.L. Peeters

    Ghrelin: a new player in the control of gastrointestinal functions

    Gut

    (2005)
  • D.H. St Pierre et al.

    Ghrelin: a novel player in the gut–brain regulation of growth hormone and energy balance

    News Physiol Sci

    (2003)
  • K. Toshinai et al.

    Des-acyl ghrelin induces food intake by a mechanism independent of the growth hormone secretagogue receptor

    Endocrinology

    (2006)
  • J.V. Zhang et al.

    Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake

    Science

    (2005)
  • Cited by (105)

    • Biochemical properties and biological actions of obestatin and its relevence in type 2 diabetes

      2018, Peptides
      Citation Excerpt :

      Specifically, Harsch et al. [77] found that patients with gastroparesis (a condition associated with delayed gastric emptying) displayed unchanged levels of circulating obestatin and unaltered ghrelin/obestatin ratio, whilst obestatin is seemingly incapable of preventing ghrelin-mediated acceleration of gastric emptying or intestinal motility [27,67]. Many more studies now dispute the previously proposed beneficial effects of obestatin on food intake and body weight [9,16,17,19,22,25,59,60,61,62,67,69,70,71,76,78,79,80,81,82,83,84,85] than suppor [20,33,86,87,88,89,90,91]. Interestingly, however, obestatin has been associated with beneficial effects in a pathological setting further to gastrointestinal disease/injury.

    • Hypothalamic regulation of body growth and appetite by ghrelin-derived peptides during balanced nutrition or undernutrition

      2016, Molecular and Cellular Endocrinology
      Citation Excerpt :

      The initial effects on gastrointestinal motility were also questioned (Annemie et al., 2009). Thus it remains an open question whether obestatin is a physiologically relevant peptide to regulate energy homeostasis and gastric motility (Gourcerol et al., 2007). Some of the robust effects of obestatin seem to be in peripheral control of glucose and lipid metabolism (Cowan et al., 2016).

    • Obestatin partially suppresses ghrelin stimulation of appetite in "high-responders" grass carp, Ctenopharyngodon idellus

      2015, Comparative Biochemistry and Physiology -Part A : Molecular and Integrative Physiology
      Citation Excerpt :

      The initial report by Zhang et al. (2005) reported that obestatin has suppressive effects on food intake in rat and mouse after peripheral and central administration. After that, some experimenters managed to reproduce the food-suppressive effects of the obestatin peptide after IP administration, whereas many other studies yielded negative results (Seoane et al., 2006; Gourcerol et al., 2007; Mondal et al., 2008; Annemie et al., 2009). Consistent with the majority of published articles, we did not succeed in confirming the suppressive effects of obestatin on food intake in grass carp.

    View all citing articles on Scopus
    View full text