Obestatin Opposes Ghrelin’s Effects on Food Intake

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Ghrelin, primarily a product of the oxyntic cells of the gastric fundus, is an orexigenic agent that was originally identified as the endogenous ligand of the growth hormone (GH) secretagogue receptor. Ghrelin is a 28 amino acid peptide with its serine-3 residue n-octanoylated; it is encoded by GHRL (OMIM 605353, chromosome 3p26-p25) and is derived from a 117 amino acid precursor peptide. Ghrelin reduces peripheral energy expenditure and enhances appetite by activating neurons that express Agouti-related peptide and neuropeptide Y that in turn inhibit expression of the anorexigenic neuromodulators that function through melanocortin and MC4R to depress appetite as well as to increase peripheral energy utilization.¹ At the carboxyl terminal of the 117 amino acid precursor, Zhang and colleagues identified an amidated 23 amino acid peptide that suppressed appetite in rats and named it “obestatin”! Its name was derived from the Latin “obedere,” meaning “to devour.”² This peptide decreased food intake whether administered peripherally or centrally, suppressed body weight gain, delayed gastric emptying and inhibited jejunal contractility. The investigators next identified the putative receptor for obestatin–the orphan G-protein-coupled receptor (GPR)-39–that functioned by enhancing adenylyl cyclase activity ( gαs Gαs). Although derived from the same precursor, the secretory patterns of ghrelin and obestatin differed significantly. In response to fasting, serum concentrations of immunoreactive ghrelin increased while those of obestatin did not change. The investigators concluded that the physiological role of obestatin in the regulation of energy consumption and use had yet to be determined.

Zhang JV, Ren P-G, Avsian-Kretchmer O, et al. Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin’s effects on food intake. Science. 2005;310:996 - 999.

Editor’s Comment

That one gene can encode more than one peptide product is well illustrated by POMC whose primary product proopiomelanocortin is the precursor peptide from which ACTH, MSH, and β-endorphin are derived. Similarly, CALCA encodes calcitonin and calcitonin gene-related peptide. However, it appears unique that one peptide gives rise to products that apparently antagonize each other’s actions and yet are differentially secreted (or alternatively catabolized). One eagerly awaits elucidation of the regulation of obestatin secretion and its physiologic role. Although obestatin did not stimulate or suppress the secretion of growth hormone from cultured rat pituitary cells in vitro, its effects on ghrelin-stimulated growth hormone release were not examined. It would be of interest if it had properties similar to those of somatostatin in this regard. Study of the effect of obestatin on ghrelin-mediated food intake would also be of immense interest.

Allen W. Root, MD

The Yin and Yang Personalities of Ghrelin and Obestatin.
Both hormones derive from the same precursor protein and are predominantly secreted by the stomach and released into the blood. Each acts on a different receptor (GPR39 and GHS-R, as shown) and has an opposite effect on food intake, body weight, and gastrointestinal motility.

References - (linked to )

Last Updated: 04/30/2008