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      Central Ghrelin Affects Pituitary-Thyroid Axis: Histomorphological and Hormonal Study in Rats

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          Abstract

          Body weight depends on the balance between energy intake and consumption. An interaction between ghrelin and thyroid function has been reported only in pathophysiological states. We examined whether intracerebroventricular (ICV) administration of ghrelin affects the structure and function of the pituitary-thyroid axis in young adult male rats. Ghrelin (0.3 nmol/5 μl PBS) or an equal volume of PBS were injected every 24 h into the lateral cerebral ventricle for 5 days. Two hours after the last treatment the animals were killed, their pituitaries and thyroids excised and prepared for further histological, immunohistochemical and morphometric investigation. Serum TSH levels were measured by RIA, while the total T<sub>4</sub> and T<sub>3</sub> levels were examined by ECLIA. Ghrelin treatment increased pituitary weight (p < 0.05) when compared to the controls, with no effect on the thyroid weight. Smaller, degranulated TSH-immunopositive cells were noticed within the pituitaries of ghrelin-treated animals; their cellular and nuclear volume as well as the relative volume density of thyrotrophs decreased (p < 0.05) in comparison to the control values. The level of serum TSH was reduced (p < 0.05). In the thyroid parenchyma of ghrelin-treated rats, an increased number of hypofunctioning follicles was noticed, characterized by flattened, weakly Tg-immunoreactive epithelium and colloid distension. The relative volume densities of the follicles and colloid increased (p < 0.05), while the thyroid index of activation rate and the serum level of total T<sub>4</sub> decreased (p < 0.05). In conclusion, centrally applied ghrelin modulated the immunohistomorphometric features of pituitary TSH cells and decreased the level of serum TSH, consequently changing thyroid morphology and function, by reducing the T<sub>4</sub> hormone level in the serum.

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          Most cited references29

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          Chronic central infusion of ghrelin increases hypothalamic neuropeptide Y and Agouti-related protein mRNA levels and body weight in rats.

          Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor (GHS-R), was originally purified from the rat stomach. Like the synthetic growth hormone secretagogues (GHSs), ghrelin specifically releases growth hormone (GH) after intravenous administration. Also consistent with the central actions of GHSs, ghrelin-immunoreactive cells were shown to be located in the hypothalamic arcuate nucleus as well as the stomach. Recently, we showed that a single central administration of ghrelin increased food intake and hypothalamic agouti-related protein (AGRP) gene expression in rodents, and the orexigenic effect of this peptide seems to be independent of its GH-releasing activity. However, the effect of chronic infusion of ghrelin on food consumption and body weight and their possible mechanisms have not been elucidated. In this study, we determined the effects of chronic intracerebroventricular treatment with ghrelin on metabolic factors and on neuropeptide genes that are expressed in hypothalamic neurons that have been previously shown to express the GHS-R and to regulate food consumption. Chronic central administration of rat ghrelin (1 microg/rat every 12 h for 72 h) significantly increased food intake and body weight. However, it did not affect plasma insulin, glucose, leptin, or GH concentrations. We also found that chronic central administration of ghrelin increased both neuropeptide Y (NPY) mRNA levels (151.0 +/- 10.1% of saline-treated controls; P < 0.05) and AGRP mRNA levels (160.0 +/- 22.5% of saline-treated controls; P < 0.05) in the arcuate nucleus. Thus, the primary hypothalamic targets of ghrelin are NPY/AGRP-containing neurons, and ghrelin is a newly discovered orexigenic peptide in the brain and stomach.
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            Thyroid hormone control of thermogenesis and energy balance.

            The mechanisms whereby thyroid hormone increases heat production have been analyzed with emphasis in more recent developments. Thyroid hormone increases obligatory thermogenesis as a result of the stimulation of numerous metabolic pathways involved in development, remodeling, and delivery of energy to the tissues. In addition, thyroid hormone may specifically stimulate some thermogenic mechanisms selected during evolution of homeotherms (e.g., Na/K-ATPase, Ca2+ cycling in muscle). Thyroid hormone also plays an essential role in facultative thermogenesis interacting with the sympathetic nervous system (SNS) at various levels. Peripherally, thyroid hormone potentiates the effects of the SNS at the level of the adrenergic receptor and adenylyl cyclase complex as well as distal from this point. Synergistic interactions between T3 and cAMP on the regulation of gene expression have been described. Brown adipose tissue (BAT) T4-5'-deiodinase plays a central role in controlling heat production. When this enzyme is stimulated by norepinephrine in the euthyroid and hypothyroid condition, it provides high concentrations of T3 to BAT; inhibition by T4 in hyperthyroidism may limit brown fat thermogenic responses. Also, thyrotoxicosis uniquely reduces the expression of beta 3-adrenergic receptors in brown adipose tissue, and the increased obligatory thermogenesis of this condition, via afferent neural pathways, may reduce the hypothalamic stimulation of brown fat, providing additional mechanisms to limit brown adipose tissue thermogenesis in hyperthyroidism.
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              Ghrelin-induced food intake is mediated via the orexin pathway.

              The hypothalamus regulates energy intake by integrating the degree of starvation or satiation with the status of the environment through a variety of neuronal and blood-derived signals. Ghrelin, a peptide produced in the stomach and hypothalamus, stimulates feeding and GH secretion. Centrally administered ghrelin exerts an orexigenic activity through the neuropeptide Y (NPY) and agouti-related protein systems. The interaction between ghrelin and other hypothalamic orexigenic peptides, however, has not been clarified. Here, we investigated the anatomical interactions and functional relationship between ghrelin and two orexigenic peptides, orexin and melanin-concentrating hormone (MCH), present in the lateral hypothalamus. Ghrelin-immunoreactive axonal terminals made direct synaptic contacts with orexin-producing neurons. Intracerebroventricular administration of ghrelin induced Fos expression, a marker of neuronal activation, in orexin-producing neurons but not in MCH-producing neurons. Ghrelin remained competent to induce Fos expression in orexin-producing neurons following pretreatment with anti-NPY IgG. Pretreatment with anti-orexin-A IgG and anti-orexin-B IgG, but not anti-MCH IgG, attenuated ghrelin-induced feeding. Administration of NPY receptor antagonist further attenuated ghrelin-induced feeding in rats treated with anti-orexin-IgGs. Ghrelin-induced feeding was also suppressed in orexin knockout mice. This study identifies a novel hypothalamic pathway that links ghrelin and orexin in the regulation of feeding behavior and energy homeostasis.
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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                2009
                April 2009
                20 December 2008
                : 89
                : 3
                : 327-336
                Affiliations
                aInstitute for Biological Research ‘Siniša Stanković’, and bInstitute of Medical Physiology, School of Medicine, University of Belgrade, Belgrade, Serbia
                Article
                188603 Neuroendocrinology 2009;89:327–336
                10.1159/000188603
                19122448
                038f4e05-7263-4576-b785-468f57b33a45
                © 2008 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.

                History
                : 04 June 2008
                : 29 September 2008
                Page count
                Figures: 5, Tables: 1, References: 52, Pages: 10
                Categories
                Thyroid Hormones

                Endocrinology & Diabetes,Neurology,Nutrition & Dietetics,Sexual medicine,Internal medicine,Pharmacology & Pharmaceutical medicine
                Energy balance,Intracerebroventricular administration,Pituitary,Thyroid morphology,Ghrelin,TSH cells

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