Obestatin does not activate orphan G protein-coupled receptor GPR39.
ABSTRACT Recently, the ligand of the orphan G protein-coupled receptor GPR39 has been identified as obestatin, a 23-amino acid peptide derived from the ghrelin precursor protein. We used two methods to study the possible activation of GPR39 by obestatin: cAMP measurements based on a luminescent reporter gene and a fluorometric Ca(2+) flux method. The former was similar to that reported in the original publication of Zhang et al. [J.V. Zhang, P.G. Ren, O. Avsian-Kretchmer, C.W. Luo, R. Rauch, C. Klein, Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake, Science 310 (2005) 996-999]. The latter method used promiscuous as well as chimaeric G-proteins commonly used to couple orphan G protein-coupled receptors to the phospholipase C pathway, that leads to intracellular Ca(2+) rise. We could, however, not demonstrate activation of the GPR39 receptor by obestatin via any of these signal transduction pathways. We could activate GPR39 by high concentrations of Zn(2+), demonstrating cell surface expression of a functional receptor that could elicit a Ca(2+) response. The Zn(2+) response was not affected by obestatin. The identity of the native ligand for GPR39 remains to be elucidated.
Article: Peripheral administration of TAT-obestatin can influence the expression of liporegulatory genes but fails to affect food intake in mice.[show abstract] [hide abstract]
ABSTRACT: Obestatin is a 23-amino-acid peptide originally regarded as an anorexigenic factor. However, most of the subsequent studies failed to confirm the initially reported anorexigenic properties of obestatin. Obestatin is incapable of crossing the blood brain barrier (BBB), which may affect its biological function. Here, we report the physiological effects of obestatin in mice after intraperitoneal administration of obestatin conjugated to the cell-permeable peptide TAT, which is capable of delivering different types of proteins through the BBB. Acute peripheral administration of 1μmol/kg of TAT-obestatin did not influence the 24h cumulative food intake and body weight gain of mice that were fasted for 18h. Fed mice were injected intraperitoneally with 100 nmol/kg of TAT-obestatin daily for 25 d. Compared with control groups, on day 3, the gain in body weight was significantly altered; on day 7, abdominal fat mass was remarkably reduced; however, on day 25, there was a surprisingly notable increase in abdominal and epididymal fat mass. In comparison with control groups, on day 25, the expression levels of adiponectin, ADD1, C/EBPα, PPARG and GLUT4 were significantly up-regulated in liver tissues; in white adipose tissue, the expression level of C/EBPα was significantly up-regulated, but adiponectin and GLUT4 were significantly down-regulated. In addition, GPR39, the suspected receptor of obestatin, was up-regulated in white adipose tissue on day 25. These findings suggest that TAT-obestatin might play a role in white adipose tissue metabolism, but its physiological effects on food intake and body weight gain regulation remain unclear.Peptides 01/2013; · 2.43 Impact Factor
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ABSTRACT: During the last decade it has been shown that zinc may activate neural transmissions via the GPR39 Zn(2+-)sensing receptor, which can be involved in the regulation of neuronal plasticity. According to the neurotrophic hypothesis of depression, decreased brain derived neurotrophic factor (BDNF) levels in depressed patients plays a key role in the pathogenesis of this disorder. BDNF, similarly as zinc, is known to be involved in the process of neuron survival and the regulation of neuronal plasticity. The aim of the present study was to determine whether the administration of a 6-week diet deficient in zinc would cause depressive-like behaviour and if such behavioural alterations would correlate with changes in the expression of the BDNF protein and GPR39 receptor. In the first part of the present study the animal behaviour after a 6-week zinc-deficient diet, in the forced swim test (FST) was investigated. In the second part expression of the GPR39 and BDNF protein level in the frontal cortex was measured using the Western Blot method. Administration of a zinc-deficient diet for 6 weeks increased immobility time in the FST by 24%, so exerted depression-like behaviour. A biochemical study showed a significant reduction in GPR39 (by 53%) and BDNF (by 49%) protein expression in the frontal cortex in mice receiving the zinc deficient diet for 6 weeks. Our study provides evidence that the GPR39 Zn(2+-)sensing receptor may be responsible for lowering the BDNF protein level and in consequence may be involved in the pathogenesis of depression.Behavioural brain research 10/2012; · 3.22 Impact Factor
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ABSTRACT: Ingestion of food affects secretion of hormones from enteroendocrine cells located in the gastrointestinal mucosa. These hormones are involved in the regulation of various gastrointestinal functions including the control of food intake. One cell in the stomach, the X/A-like has received much attention over the past years due to the production of ghrelin. Until now, ghrelin is the only known orexigenic hormone that is peripherally produced and centrally acting to stimulate food intake. Subsequently, additional peptide products of this cell have been described including desacyl ghrelin, obestatin and nesfatin-1. Desacyl ghrelin seems to be involved in the regulation of food intake as well and could play a counter-balancing role of ghrelin's orexigenic effect. In contrast, the initially proposed anorexigenic action of obestatin did not hold true and therefore the involvement of this peptide in the regulation of feeding is questionable. Lastly, the identification of nesfatin-1 in the same cell in different vesicles than ghrelin extended the function of this cell type to the inhibition of feeding. Therefore, this X/A-like cell could play a unique role by encompassing yin and yang properties to mediate not only hunger but also satiety.Journal of neurogastroenterology and motility 04/2012; 18(2):138-49.