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      Association of ADRB1 and UCP3 Gene Polymorphisms with Insulin Sensitivity but Not Obesity

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          Abstract

          Background: The uncoupling proteins (UCPs) and β-adrenoceptors (ADRBs) are important for energy balance and may be involved in the pathogenesis of insulin resistance. Obesity is strongly hunted by insulin resistance and susceptibility genes for the two conditions could be separate or common. Variations within the UCPs and ADRBs genes may give important clues to their involvement in disease. Methods: A total of four single nucleotide polymorphisms (SNPs) in the genes UCP1, UCP2, UCP3, and ADRB1 were examined for association with obesity and insulin sensitivity (HOMA<sub>IR</sub>) in obese (n = 292) and healthy non-obese (n = 481) females. Results: None of the SNPs was associated with obesity status or body mass index. However, ADRB1 (rs1801253) was nominally associated with serum insulin (nominal p = 0.034) and HOMA<sub>IR</sub> (nominal p = 0.022). UCP3 (rs1800006) was in post-hoc analysis nominally associated with serum insulin and HOMA<sub>IR</sub> (nominal p = 0.013 and 0.048, respectively). UCP1 and UCP2 showed no association with insulin sensitivity. Conclusion: Polymorphisms in ADRB1 and UCP3 may contribute to insulin resistance rather than obesity among Swedish women.

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          Most cited references20

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          Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese.

          The mitochondrial uncoupling protein (UCP) in the mitochondrial inner membrane of mammalian brown adipose tissue generates heat by uncoupling oxidative phosphorylation. This process protects against cold and regulates energy balance. Manipulation of thermogenesis could be an effective strategy against obesity. Here we determine the role of UCP in the regulation of body mass by targeted inactivation of the gene encoding it. We find that UCP-deficient mice consume less oxygen after treatment with a beta3-adrenergic-receptor agonist and that they are sensitive to cold, indicating that their thermoregulation is defective. However, this deficiency caused neither hyperphagia nor obesity in mice fed on either a standard or a high-fat diet. We propose that the loss of UCP may be compensated by UCP2, a newly discovered homologue of UCP; this gene is ubiquitously expressed and is induced in the brown fat of UCP-deficient mice.
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            Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: studies in subjects with various degrees of glucose tolerance and insulin sensitivity

            To evaluate whether the homeostasis model assessment (HOMA) is a reliable surrogate measure of in vivo insulin sensitivity in humans.
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              Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production.

              The gene Ucp2 is a member of a family of genes found in animals and plants, encoding a protein homologous to the brown fat uncoupling protein Ucp1 (refs 1-3). As Ucp2 is widely expressed in mammalian tissues, uncouples respiration and resides within a region of genetic linkage to obesity, a role in energy dissipation has been proposed. We demonstrate here, however, that mice lacking Ucp2 following targeted gene disruption are not obese and have a normal response to cold exposure or high-fat diet. Expression of Ucp2 is robust in spleen, lung and isolated macrophages, suggesting a role for Ucp2 in immunity or inflammatory responsiveness. We investigated the response to infection with Toxoplasma gondii in Ucp2-/- mice, and found that they are completely resistant to infection, in contrast with the lethality observed in wild-type littermates. Parasitic cysts and inflammation sites in brain were significantly reduced in Ucp2-/- mice (63% decrease, P<0.04). Macrophages from Ucp2-/- mice generated more reactive oxygen species than wild-type mice (80% increase, P<0.001) in response to T. gondii, and had a fivefold greater toxoplasmacidal activity in vitro compared with wild-type mice (P<0.001 ), which was absent in the presence of a quencher of reactive oxygen species (ROS). Our results indicate a role for Ucp2 in the limitation of ROS and macrophage-mediated immunity.
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                Author and article information

                Journal
                HRE
                Horm Res Paediatr
                10.1159/issn.1663-2818
                Hormone Research in Paediatrics
                S. Karger AG
                1663-2818
                1663-2826
                2008
                December 2007
                04 December 2007
                : 69
                : 1
                : 31-36
                Affiliations
                aDepartment of Molecular Medicine, National Public Health Institute/Department of Medical Genetics, University of Helsinki, Biomedicum, Helsinki, Finland; bDepartment of Medicine, Huddinge, Karolinska Institutet, Karolinska University Hospital and cDepartment of Bioscience and Nutrition, Karolinska Institutet, Stockholm, Sweden, and dDepartment of Genetics, University of Leicester, Leicester, UK
                Article
                111793 Horm Res 2008;69:31–36
                10.1159/000111793
                18059082
                4774b840-8cbc-44d9-8c47-f75daa3ddadf
                © 2007 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
                : 29 September 2006
                : 15 February 2007
                Page count
                Tables: 4, References: 28, Pages: 6
                Categories
                Original Paper

                Endocrinology & Diabetes,Neurology,Nutrition & Dietetics,Sexual medicine,Internal medicine,Pharmacology & Pharmaceutical medicine
                Gene polymorphisms,Insulin resistance,Insulin sensitivity,Uncoupling proteins,Obesity

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