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      Effects of Leptin and Corticosterone on the Expression of Corticotropin-Releasing Hormone, Agouti-Related Protein, and Proopiomelanocortin in the Brain of ob/ob Mouse

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          Abstract

          The present study was conducted to assess the effect of leptin and corticosterone on the expression of corticotropin-releasing hormone (CRH), proopiomelanocortin (POMC) and agouti-related protein (AGRP) in the mouse brain. To this end, a 3 × 3 factorial experiment was designed in which adrenalectomized (ADX) ob/ob mice were treated with leptin and corticosterone. Leptin and corticosterone downregulated CRH expression in the paraventricular hypothalamic nucleus (PVH). Leptin prevented the stimulating effects of ADX on the expression of CRH and the combination of small doses of leptin and corticosterone was as potent as the high dose of corticosterone in suppressing CRH mRNA expression in the PVH. Leptin and corticosterone enhanced the expression of CRH in the central nucleus of amygdala and in the bed nucleus of the stria terminalis. In addition, the present results confirmed the downregulating effects of leptin on the expression of AGRP mRNA in the hypothalamic arcuate nucleus (ARC), and demonstrated that this effect was more apparent in ADX mice treated with corticosterone than in ADX mice not supplemented with corticosterone. Also, leptin and corticosterone had opposite effects on the expression of POMC in the ARC. The opposite effect of leptin and corticosterone on the expression of POMC and AGRP seems consistent with the reported effects that these hormones and peptides have on food intake and thermogenesis, suggesting that the modulation of POMC and AGRP expression can be a mechanism whereby leptin and corticosterone exert their effects in the regulation of energy balance. In contrast, the similarity in the action of leptin and corticosterone is not a priori consistent with a role of CRH in the effects of these hormones in the regulation of energy balance. The downregulating effect of leptin on the expression of CRH in the PVH strongly suggests that leptin can be a potent regulator of hypothalamic-pituitary-adrenal axis activity. Finally, the present results suggest that the effects of leptin on the expression of CRH, POMC and AGRP are not curbed by glucocorticoids.

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          Most cited references 7

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          The role of neuropeptide Y in the antiobesity action of the obese gene product.

          Recently Zhang et al. cloned a gene that is expressed only in adipose tissue of the mouse. The obese phenotype of the ob/ob mouse is linked to a mutation in the obese gene that results in expression of a truncated inactive protein. Human and rat homologues for this gene are known. Previous experiments predict such a hormone to have a hypothalamic target. Hypothalamic neuropeptide Y stimulates food intake, decreases thermogenesis, and increases plasma insulin and corticosterone levels making it a potential target. Here we express the obese protein in Escherichia coli and find that it suppresses food intake and decreases body weight dramatically when administered to normal and ob/ob mice but not db/db (diabetic) mice, which are thought to lack the appropriate receptor. High-affinity binding was detected in the rat hypothalamus. One mechanism by which this protein regulated food intake and metabolism was inhibition of neuropeptide-Y synthesis and release.
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            Antagonism of Central Melanocortin Receptors in Vitro and in Vivo by Agouti-Related Protein

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              Effects of corticosterone on CRH mRNA and content in the bed nucleus of the stria terminalis; comparison with the effects in the central nucleus of the amygdala and the paraventricular nucleus of the hypothalamus.

              We previously reported that corticosterone (CORT) increased corticotropin-releasing hormone (CRH) mRNA in the central nucleus of the amygdala (CEA), while reducing it in the paraventricular nucleus (PVN) of the hypothalamus by using in situ hybridization histochemistry. The bed nucleus of the stria terminalis (BNST) is closely related to the amygdala, and it is also a source of extrahypothalamic CRH; therefore, we examined CRH mRNA changes in the BNST following systemic treatment with CORT in adrenally-intact rats. Effects of adrenalectomy on CRH mRNA in the BNST, PVN and CEA were also examined. In addition, CRH content in these nuclei and in the median eminence (ME) were determined by micropunch dissection technique combined with CRH radioimmunoassay in CORT pellet implanted rats. Subcutaneous injections of high CORT (5 mg/day, over 14 days) increased CRH mRNA in the dorsal part of the lateral BNST (BSTLD) at 2, 4 and 8 days, although the low dose of CORT (1 mg/kg/day) had no significant effects. By contrast, in the ventral part of the BNST (BSTV) neither the high nor low dose of CORT altered CRH mRNA levels. In a second experiment, a slowly-releasing CORT pellet (200 mg, 60-day release) produced an elevation of CRH mRNA at both 1 and 2 weeks or at 1 week in the BSTLD or in the BSTV, respectively. These results show that glucocorticoids can facilitate CRH mRNA expression in the BSTLD in the same manner as seen in the CEA, and that CRH mRNA in the BSTLD can respond to CORT more than in the BSTV. In a third experiment, bilateral adrenalectomy, however, did not affect CRH mRNA in the BNST although there was a modest decrease in the CEA and a robust increase in the PVN. Finally, in CORT pellet (200 mg, for 2 weeks) implanted rats, CRH content in the ME significantly decreased and modestly increased in the CEA compared with control rats, whereas it did not change in the PVN and BNST. Taken together, these results suggest that (1) CRH in the BNST and the CEA may share some common functions in neuroendocrine and behavioral changes, but that (2) mechanisms of CRH synthesis or its releasing sites may be different in the BNST and CEA.
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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                2001
                April 2001
                24 April 2001
                : 73
                : 4
                : 227-236
                Affiliations
                Centre de Recherche de l’Hôpital Laval et Centre de Recherche sur le Métabolisme Energétique, Université Laval, Québec, Canada
                Article
                54639 Neuroendocrinology 2001;73:227–236
                10.1159/000054639
                11340336
                © 2001 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: 6, References: 47, Pages: 10
                Categories
                Neuroendocrine Correlates of Leptin

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