Obestatin, a Peptide Encoded by the Ghrelin Gene, Opposes Ghrelin's Effects on Food Intake

Department of Obstetrics and Gynecology, Stanford University, Palo Alto, California, United States
Science (Impact Factor: 33.61). 12/2005; 310(5750):996-9. DOI: 10.1126/science.1117255
Source: PubMed


Ghrelin, a circulating appetite-inducing hormone, is derived from a prohormone by posttranslational processing. On the basis of the bioinformatic prediction that another peptide also derived from proghrelin exists, we isolated a hormone from rat stomach and named it obestatin-a contraction of obese, from the Latin "obedere," meaning to devour, and "statin," denoting suppression. Contrary to the appetite-stimulating effects of ghrelin, treatment of rats with obestatin suppressed food intake, inhibited jejunal contraction, and decreased body-weight gain. Obestatin bound to the orphan G protein-coupled receptor GPR39. Thus, two peptide hormones with opposing action in weight regulation are derived from the same ghrelin gene. After differential modification, these hormones activate distinct receptors.

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    • "Structurally related synthesis impurities encompass amino acid deletion or insertion, incomplete removal of protection groups, oxidation or reduction of amino acid residues, diastereoisomerization, dimers and oligomers, as well as side and end chain impurities [5]. In literature, several examples are available in which the presence of related peptide impurities complicate the interpretation of study results or cause erroneous study conclusions [6] [7] [8] [9]. Moreover, the major peak found during QC analysis of peptide batches was not always the ordered peptide as already demonstrated for the quorum sensing peptide CVFSLFKKCN and obestatin, emphasizing the importance of thorough identification and purity evaluation of the test compound prior to performing biomedical experiments [4] [10]. "
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    ABSTRACT: During fundamental research, it is recommended to evaluate the test compound identity and purity in order to obtain reliable study outcomes. For peptides, quality control (QC) analyses are routinely performed using reversed-phase liquid chromatography coupled to an ultraviolet (UV) detector system. These traditional QC methods, using a C18 column and a linear gradient with formic acid (FA) as acidic modifier in the mobile phase, might not result in optimal chromatographic performance for basic peptides due to their cationic nature and hence may lead to erroneous results. Therefore, the influence of the used chromatographic system on the final QC results of basic peptides was evaluated using five cationic cell-penetrating peptides and five C18-chromatographic systems, differing in the column particle size (high performance liquid chromatography (HPLC) versus ultra-high performance liquid chromatography (UHPLC)), the acidic modifier (FA versus trifluoroacetic acid (TFA)), and the column temperature (30°C versus 60°C). Our results indicate that a UHPLC system with the C18 column thermostated at 30°C and a mobile phase containing TFA, provides the most suitable routine QC analysis method for cationic peptides, outperforming in sensitivity and resolution compared to the other systems. We also demonstrate the use of a single quad mass spectrometry (MS) detector system during QC analysis of (cationic) peptides, allowing identification of the peptide and its impurities, as well as the evaluation of the peak purity.
    Full-text · Article · Jan 2016 · Journal of pharmaceutical and biomedical analysis
    • "In the past decades two different peptides, encoded by the same preproghrelin gene were isolated from the rat gastric mucosa: ghrelin [1] and obestatin [2] Obestatin is a 23-amino-acid peptide which was found to be present in the GI tract (gastric mucosa, small and large intestine, pancreas), saliva, plasma, breast milk, Leydig cells of the testis [3] and the pituitary gland [4]. The original study by Zhang has reported that obestatin is the natural ligand of the G protein coupled receptor 39 (GPR39) and acute or chronic administration in rodents inhibits food intake, decreasing the body weight under basal and ghrelin-stimulated conditions [2]. Subsequent studies using different experimental protocols gave contradictory results [5] [6] [7] [8] [9] [10] [11] and only the acute food-intake-suppressive effects of obestatin were substantiated [12]. "
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    ABSTRACT: Obestatin is a 23 amino acid-peptide, derived from the same preproghrelin-gene as ghrelin. Obestatin was originally reported as a ghrelin antagonist with anorexigenic activity, but later it was proven to be involved in multiple processes including sleep, memory retention, anxiety, morphine-induced analgesia and withdrawal. In the present study, in male CFLP mice, by using computerised open field (OF) and elevated plus maze (EPM) tests we have investigated the behavioural effects of the acute intracerebroventricular (icv) administration of obestatin alone, and following ghrelin receptor blockage with [D-Lys3]-Growth Hormone Releasing Peptide-6 ([D-Lys3]- GHRP6) or corticotropin-releasing hormone (CRH) receptor 1 antagonism with antalarmin. Plasma corticosterone levels were measured for each treatment group by using chemofluorescent assay. Our results in the EPM test showed that obestatin reduced the percent of time spent in the open arms. The basal locomotor activity (ambulation distance and time, rearing and jumping) was not influenced significantly neither in the obestatin-treated groups, nor in those receiving pre-treatment with antalarmin or [D-Lys3]-GHRP6. The percentage of central ambulation distance however was decreased by obestatin, while the percentage of time spent in the central zone showed a decreasing tendency. The administration of antalarmin or [D-Lys3]-GHRP6 have both reversed the effect of obestatin on central ambulation. Plasma corticosterone levels were elevated by obestatin, which effect was antagonised by the injection of antalarmin. These are the first results to indicate that obestatin exerts anxiogenic-like effect in mice, which might be mediated through ghrelin receptor and CRH activation. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · Jul 2015 · Behavioural brain research
    • "Given the identified role of ghrelin in GH secretion and appetite stimulation, it was surprising when the ghrelin knockout (KO) mouse was reported to have no change in size, growth rate, food intake, body composition and behaviour compared to WT littermates (Sun et al. 2003). More recently there has been a focus on the role of multiple alternative products from the ghrelin gene (e.g., obestatin; Zhang et al. 2005), the role of unacetylated ghrelin (comprising 75% of circulating ghrelin) and non-endocrine roles of ghrelin in psychiatric disorders (Wittekind & Kluge 2015), tumour progression (Xu et al. 2015), brain injury (Xie et al. 2015) and heart failure (Khatib et al. 2014). Like the multifunctional SST, ghrelin, initially a GHS, is now recognised as a pleiotropic hormone. "
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    ABSTRACT: At the time of the publication of Geoffrey Harris's monograph on 'Neural Control of the Pituitary Gland' 60 years ago, the pituitary was recognised to produce a growth factor and extracts administered to children with hypopituitarism could accelerate growth. Since then our understanding of the neuroendocrinology of the growth hormone (GH) axis has included identification of the key central components of the GH axis - GHRH and somatostatin in the 1970's and 80's - and in the 1990's ghrelin. Characterisation of the physiological control of the axis was significantly advanced by frequent blood sampling studies in the 1980's and 90's; the pulsatile pattern of GH secretion and the factors that influenced the frequency and amplitude of the pulses has been defined. Over the same time, spontaneously occurring and targeted mutations in the GH axis in rodents combined with the recognition of genetic causes of familial hypopituitarism demonstrated the key factors controlling pituitary development. As understanding of the control of growth hormone secretion advanced, so developments of treatments for GH axis disorders have evolved. Administration of pituitary derived human growth hormone was followed by the introduction of recombinant human growth hormone in the 1980's, and more recently long-acting GH preparations. For growth hormone excess disorders, firstly dopamine agonists were used followed by somatostatin analogues and in 2005 the introduction of the GH receptor blocker pegvisomant. This review will cover the evolution of these discoveries, and build a picture of our current understanding the hypothalamo-growth hormone axis.
    No preview · Article · Jun 2015 · Journal of Endocrinology
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