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      The Long Form of the Leptin Receptor (OB-Rb) Is Widely Expressed in the Human Brain

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          Abstract

          Leptin exerts important effects on the regulation of food intake and energy expenditure by acting in the brain. Leptin action is mediated by the interaction with a receptor that is alternatively spliced, resulting in at least five different isoforms. The long form (OB-Rb) has a long intracellular domain that is essential for intracellular signal transduction. The specific aim of this study was to further investigate the role that the brain may play in the pathogenesis of obesity in humans. We studied the expression of OB-R mRNA (both short or common and long isoforms) in the brains of obese, lean and diabetic subjects, by in situ hybridization, semiquantitative RT-PCR and Northern blots analysis. We used two alternative probes: one that recognizes all known splice variants (OB-Ra) and a second that recognizes only the long form, OB-Rb. Several brain regions, including hypothalamus, cerebellum, neocortex, entorrhinal cortex, amygdala, and rostral medulla, were evaluated. In situ hybridization studies revealed that both OB-Ra and OB-Rb mRNAs are widely distributed in the human brain. The specific hybridization signal with both probes was detected exclusively in the cytoplasm of the cell body, dendrites and proximal axons of neurons. Hypothalamic nuclei, Purkinje cells and dentate nuclei of the cerebellum, inferior olivary and cranial nerves nuclei in the medulla, amygdala and neurons from both neocortex and entorrhinal cortex demonstrated positive signals. The hybridization signal obtained in ependyma was lower than that in neurons and no specific hybridization was detected in glial cells. No significant differences were identified among the regions or among the three groups studied. These results match those previously obtained by us [Couce et al.: Neuroendocrinology 1997;66:145] in which the distribution of the OB-R protein in the human brain was first described. RT-PCR indicated that the OB-Rb was highly expressed in the hypothalamus and cerebellum. No significant differences of OB-Ra or OB-Rb mRNA expression were identified in lean or obese individuals in these two cerebral regions. The levels of OB-Rb were significantly higher in cerebellum compared to hypothalamus in lean and obese individuals. The original hypothesis that OB-Rb is present only in the hypothalamus needs to be reconsidered. This OB-Rb isoform seems to be widely expressed in the human brain with highest levels in the cerebellum. Obesity and hyperleptinemia appears not to be associated with down-regulation of the OB-Rb in the human brain.

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          Most cited references 12

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          Identification and expression cloning of a leptin receptor, OB-R.

          The ob gene product, leptin, is an important circulating signal for the regulation of body weight. To identify high affinity leptin-binding sites, we generated a series of leptin-alkaline phosphatase (AP) fusion proteins as well as [125I]leptin. After a binding survey of cell lines and tissues, we identified leptin-binding sites in the mouse choroid plexus. A cDNA expression library was prepared from mouse choroid plexus and screened with a leptin-AP fusion protein to identify a leptin receptor (OB-R). OB-R is a single membrane-spanning receptor most related to the gp130 signal-transducing component of the IL-6 receptor, the G-CSF receptor, and the LIF receptor. OB-R mRNA is expressed not only in choroid plexus, but also in several other tissues, including hypothalamus. Genetic mapping of the gene encoding OB-R shows that it is within the 5.1 cM interval of mouse chromosome 4 that contains the db locus.
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            Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression.

            Nutritional deprivation suppresses immune function. The cloning of the obese gene and identification of its protein product leptin has provided fundamental insight into the hypothalamic regulation of body weight. Circulating levels of this adipocyte-derived hormone are proportional to fat mass but maybe lowered rapidly by fasting or increased by inflammatory mediators. The impaired T-cell immunity of mice now known to be defective in leptin (ob/ob) or its receptor (db/db), has never been explained. Impaired cell-mediated immunity and reduced levels of leptin are both features of low body weight in humans. Indeed, malnutrition predisposes to death from infectious diseases. We report here that leptin has a specific effect on T-lymphocyte responses, differentially regulating the proliferation of naive and memory T cells. Leptin increased Th1 and suppressed Th2 cytokine production. Administration of leptin to mice reversed the immunosuppressive effects of acute starvation. Our findings suggest a new role for leptin in linking nutritional status to cognate cellular immune function, and provide a molecular mechanism to account for the immune dysfunction observed in starvation.
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              A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction.

              The adipocyte-specific hormone leptin, the product of the obese (ob) gene, regulates adipose-tissue mass through hypothalamic effects on satiety and energy expenditure. Leptin acts through the leptin receptor, a single-transmembrane-domain receptor of the cytokine-receptor family. In rodents, homozygous mutations in genes encoding leptin or the leptin receptor cause early-onset morbid obesity, hyperphagia and reduced energy expenditure. These rodents also show hypercortisolaemia, alterations in glucose homeostasis, dyslipidaemia, and infertility due to hypogonadotropic hypogonadisms. In humans, leptin deficiency due to a mutation in the leptin gene is associated with early-onset obesity. Here we describe a homozygous mutation in the human leptin receptor gene that results in a truncated leptin receptor lacking both the transmembrane and the intracellular domains. In addition to their early-onset morbid obesity, patients homozygous for this mutation have no pubertal development and their secretion of growth hormone and thyrotropin is reduced. These results indicate that leptin is an important physiological regulator of several endocrine functions in humans.
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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                2000
                March 2000
                20 March 2000
                : 71
                : 3
                : 187-195
                Affiliations
                aEndocrine Research Unit and bDepartment of Pathology, Mayo Clinic, Rochester, Minn., USA
                Article
                54536 Neuroendocrinology 2000;61:187–195
                10.1159/000054536
                10729790
                © 2000 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: 5, References: 56, Pages: 9
                Categories
                Leptin and Neuroendocrine Control of Feeding

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