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      Growth Hormone Expression and Secretion in Pig Pituitary and Median Eminence Slices Are Not Influenced by the VGF Protein

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          Abstract

          Body homeostasis is maintained by a complex system that involves the brain and the periphery via many circulating hormones. In recent years the VGF protein has been indicated as an important peptide affecting the regulation of body composition. We examined the effects of VGF on growth hormone (GH) expression and secretion in porcine pituitary slices, incubated alone (group 1) or with stalk median eminence (SME) (group 2). After 2 h (time 0), medium was removed and replaced with a fresh one; tissues were challenged with VGF (10<sup>–6</sup> M, 10<sup>–8</sup> M) alone or with ghrelin (10<sup>–8</sup> M) or growth hormone-releasing hormone (GHRH) (10<sup>–8</sup> M). Medium was replaced again 2 h (+2) and 6 h (+6) later. None of the VGF concentrations influenced GH secretion in either group; the association with GHRH or ghrelin appeared ineffective in influencing GH secretion as compared with the effects of GH mRNA expression and was not influenced by VGF treatments. The presence of SME had an additive effect on GH expression. Collectively, our results confirm previous findings on GH regulation; however, further investigations are needed to establish whether the modulation of GH secretion in the absence of nutrients involves the balance of GHRH/ghrelin receptors at pituitary levels. As for VGF, a crucial aspect to clarify is whether its lack of effects depends on our experimental conditions or, alternatively, it is not effective at all.

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          Most cited references 23

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          Targeted deletion of the Vgf gene indicates that the encoded secretory peptide precursor plays a novel role in the regulation of energy balance.

          To determine the function of VGF, a secreted polypeptide that is synthesized by neurons, is abundant in the hypothalamus, and is regulated in the brain by electrical activity, injury, and the circadian clock, we generated knockout mice lacking Vgf. Homozygous mutants are small, hypermetabolic, hyperactive, and infertile, with markedly reduced leptin levels and fat stores and altered hypothalamic proopiomelanocortin (POMC), neuropeptide Y (NPY), and agouti-related peptide (AGRP) expression. Furthermore, VGF mRNA synthesis is induced in the hypothalamic arcuate nuclei of fasted normal mice. VGF therefore plays a critical role in the regulation of energy homeostasis, suggesting that the study of lean VGF mutant mice may provide insight into wasting disorders and, moreover, that pharmacological antagonism of VGF action(s) might constitute the basis for treatment of obesity.
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            VGF: a novel role for this neuronal and neuroendocrine polypeptide in the regulation of energy balance.

            Insight into the mechanisms of action of neurotrophic growth factors has been obtained through the identification and characterization of gene products that are regulated or modified at the transcriptional, translational, and/or posttranslational level in response to neurotrophin treatment. VGF (non-acronymic) was identified approximately 15 years ago as a nerve growth factor (NGF)-regulated transcript in rat PC12 pheochromocytoma cells. Subsequent studies have demonstrated that neurotrophins such as NGF and brain-derived neurotrophic factor induce vgf gene expression relatively rapidly in PC12 cells and cultured cortical neurons, respectively, in comparison to less robust regulation by epidermal growth factor (EGF) and insulin, growth factors which do not trigger the neuronal differentiation of PC12 cells. vgf gene expression is stimulated in vitro by NGF and the ras/map kinase signaling cascade through a CREB-dependent mechanism, while in vivo, VGF mRNA levels are regulated by neuronal activity, including long-term potentiation, seizure, and injury. Both the mRNA and encoded approximately 68-kDa protein (VGF) are selectively synthesized in neuroendocrine and neuronal cells. The predicted VGF sequence is rich in paired basic amino acid residues that are potential sites for proteolytic processing, and VGF undergoes regulated release from dense core secretory vesicles. Although VGF mRNA is synthesized widely, by neurons in the brain, spinal cord, and peripheral nervous system, its expression is particularly abundant in the hypothalamus. In addition, VGF peptides are found in hypophysial, adrenal medullary, gastrointestinal, and pancreatic endocrine cells, suggesting important neuroendocrine functions. Recent analysis of VGF knockout mice indeed demonstrates that VGF plays a critical role in the control of energy homeostasis. VGF knockout mice are thin, small, hypermetabolic, hyperactive, and relatively infertile, with markedly reduced leptin levels and fat stores and altered hypothalamic pro-opiomelanocortin, neuropeptide Y, and agouti-related peptide expression. Coupled with the demonstration that VGF mRNA levels are induced in the normal mouse hypothalamic arcuate nuclei in response to fasting, important central and peripheral roles for VGF in the regulation of metabolism are suggested. Here we review previous studies of VGF in the broader context of its newly recognized role in the control of energy balance and propose several models and experimental approaches that may better define the mechanisms of action of VGF. Copyright 2000 Academic Press.
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              Molecular cloning of a gene sequence regulated by nerve growth factor.

              Nerve growth factor (NGF) is essential for the development and differentiation of sympathetic or sensory neurons. A complementary DNA was cloned that corresponds to a gene sequence induced more than 50-fold in a cultured target cell line of pheochromocytoma cells (PC12 cells) 5 hours after the addition of NGF. The induced messenger RNA encodes a 90,000-dalton polypeptide that may represent one of the primary events in NGF-induced differentiation of neurons.
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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                2006
                August 2006
                25 August 2006
                : 83
                : 2
                : 89-96
                Affiliations
                aDepartment of Animal Production, Veterinary Biotechnology and Food Safety, Section of Veterinary Physiology, University of Parma, Parma, and bDIMORFIPA, University of Bologna, Bologna, Italy
                Article
                94149 Neuroendocrinology 2006;83:89–96
                10.1159/000094149
                16804334
                © 2006 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 3, References: 34, Pages: 8
                Categories
                Original Paper

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