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The anti-ghrelin Spiegelmer NOX-B11-3 blocks ghrelin- but not fasting-induced neuronal activation in the hypothalamic arcuate nucleus


Becskei, C; Bilik, K U; Klussmann, S; Jarosch, F; Lutz, T A; Riediger, T (2008). The anti-ghrelin Spiegelmer NOX-B11-3 blocks ghrelin- but not fasting-induced neuronal activation in the hypothalamic arcuate nucleus. Journal of Neuroendocrinology, 20(1):85-92.

Abstract

The hypothalamic arcuate nucleus (Arc) is the presumed target site for the orexigenic hormone ghrelin which is secreted from the stomach during fasting. Ghrelin directly activates Arc neurones. Similar to exogenous ghrelin, overnight food deprivation also induces c-Fos expression in the Arc of mice. In this study we tested the role of endogenous ghrelin in the fasting-induced c-Fos expression in the Arc of mice. We used NOX-B11-3, the latest generation of the recently developed ghrelin-binding compounds, so-called RNA Spiegelmers (SPM) to block endogenous ghrelin action during food deprivation. The specificity and potency of this compound was also tested in electrophysiological and immunohistological experiments. In electrophysiological in vitro single cell recordings NOX-B11-3 effectively blocked the excitatory effect of ghrelin in the medial Arc (ArcM) of rats while the biologically inactive control SPM had no effect. Furthermore, NOX-B11-3 (15 mg/kg ip) potently suppressed ghrelin-induced (25 µg/kg sc, 12h after SPM injection) c-Fos expression in the Arc. However, the same dose of NOX-B11-3 when injected at the beginning of a 14h fasting period had no effect on the c-Fos expression in the Arc of mice. These results demonstrate that NOX-B11-3 is a long acting compound, which effectively blocks the effect of exogenous ghrelin on neuronal activity in the Arc under in vitro and in vivo conditions. Furthermore, increased ghrelin signalling does not appear to be a necessary factor for the activation of Arc neurones during food deprivation or other fasting-related signals might have masked or compensated the loss of the ghrelin effect.

The hypothalamic arcuate nucleus (Arc) is the presumed target site for the orexigenic hormone ghrelin which is secreted from the stomach during fasting. Ghrelin directly activates Arc neurones. Similar to exogenous ghrelin, overnight food deprivation also induces c-Fos expression in the Arc of mice. In this study we tested the role of endogenous ghrelin in the fasting-induced c-Fos expression in the Arc of mice. We used NOX-B11-3, the latest generation of the recently developed ghrelin-binding compounds, so-called RNA Spiegelmers (SPM) to block endogenous ghrelin action during food deprivation. The specificity and potency of this compound was also tested in electrophysiological and immunohistological experiments. In electrophysiological in vitro single cell recordings NOX-B11-3 effectively blocked the excitatory effect of ghrelin in the medial Arc (ArcM) of rats while the biologically inactive control SPM had no effect. Furthermore, NOX-B11-3 (15 mg/kg ip) potently suppressed ghrelin-induced (25 µg/kg sc, 12h after SPM injection) c-Fos expression in the Arc. However, the same dose of NOX-B11-3 when injected at the beginning of a 14h fasting period had no effect on the c-Fos expression in the Arc of mice. These results demonstrate that NOX-B11-3 is a long acting compound, which effectively blocks the effect of exogenous ghrelin on neuronal activity in the Arc under in vitro and in vivo conditions. Furthermore, increased ghrelin signalling does not appear to be a necessary factor for the activation of Arc neurones during food deprivation or other fasting-related signals might have masked or compensated the loss of the ghrelin effect.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:05 Vetsuisse Faculty > Institute of Veterinary Physiology
04 Faculty of Medicine > Center for Integrative Human Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:January 2008
Deposited On:20 May 2008 08:51
Last Modified:05 Apr 2016 12:23
Publisher:Wiley-Blackwell
ISSN:0953-8194
Additional Information:The definitive version is available at www.blackwell-synergy.com
Publisher DOI:https://doi.org/10.1111/j.1365-2826.2007.01619.x
PubMed ID:18081556
Permanent URL: https://doi.org/10.5167/uzh-2502

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