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      Peroxisome Proliferator-Activated Receptor-γ and Insulin Action: Insights from Human Genetics

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          Abstract

          Peroxisome proliferator-activated receptor-γ (PPARγ), an orphan nuclear receptor, mediates adipocyte differentiation and is the cellular target for the thiazolidinedione group of insulin-sensitizing antidiabetic agents. We screened this receptor gene in a cohort of subjects with severe insulin resistance and have identified heterozygous missense mutations in several individuals from three families. Functional studies indicate that the receptor mutants are transcriptionally impaired and inhibit wild type PPARγ action in a dominant-negative manner. The clinical phenotype of patients includes partial lipodystrophy, early-onset hypertension, dyslipidaemia and hepatic steatosis. Factors which contribute to the severe insulin resistance in affected individuals include diminished body fat mass, impaired lipid flux in adipose tissue and reduced circulating levels of adiponectin. In a large kindred of five individuals with severe insulin resistance, we have identified frameshift/premature stop mutations in PPARγ and the muscle-specific regulatory subunit of protein phosphatase 1 (PPP1R3A). The frameshift PPARγ mutant exhibits complete loss of function with no dominant-negative activity; the PPP1R3A truncation mutant is mislocalized intracellularly. Individuals harbouring either gene defect alone have normal circulating insulin levels, but a combination of both genetic abnormalities co-segregates with severe insulin resistance.

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          Most cited references 8

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          Peroxisome Proliferator-Activated Receptors: Nuclear Control of Metabolism

           B. Desvergne (1999)
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            Fusion proteins of the retinoic acid receptor-alpha recruit histone deacetylase in promyelocytic leukaemia.

            The transforming proteins of acute promyelocytic leukaemias (APL) are fusions of the promyelocytic leukaemia (PML) and the promyelocytic leukaemia zinc-finger (PLZF) proteins with retinoic acid receptor-alpha (RARalpha). These proteins retain the RARalpha DNA- and retinoic acid (RA)-binding domains, and their ability to block haematopoietic differentiation depends on the RARalpha DNA-binding domain. Thus RA-target genes are downstream effectors. However, treatment with RA induces differentiation of leukaemic blast cells and disease remission in PML-RARalpha APLs, whereas PLZF-RARa APLs are resistant to RA. Transcriptional regulation by RARs involves modifications of chromatin by histone deacetylases, which are recruited to RA-target genes by nuclear co-repressors. Here we show that both PML-RARalpha and PLZF-RARalpha fusion proteins recruit the nuclear co-repressor (N-CoR)-histone deacetylase complex through the RARalpha CoR box. PLZF-RARalpha contains a second, RA-resistant binding site in the PLZF amino-terminal region. High doses of RA release histone deacetylase activity from PML-RARalpha, but not from PLZF-RARalpha. Mutation of the N-CoR binding site abolishes the ability of PML-RARalpha to block differentiation, whereas inhibition of histone deacetylase activity switches the transcriptional and biological effects of PLZF-RARalpha from being an inhibitor to an activator of the RA signalling pathway. Therefore, recruitment of histone deacetylase is crucial to the transforming potential of APL fusion proteins, and the different effects of RA on the stability of the PML-RARalpha and PLZF-RARalpha co-repressor complexes determines the differential response of APLs to RA.
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              Sensitization of diabetic and obese mice to insulin by retinoid X receptor agonists.

              Retinoic acid receptors (RAR), thyroid hormone receptors (TR), peroxisome proliferator activated receptors (PPARs) and the orphan receptor, LXR, bind preferentially to DNA as heterodimers with a common partner, retinoid X receptor (RXR), to regulate transcription. We investigated whether RXR-selective agonists replicate the activity of ligands for several of these receptors? We demonstrate here that RXR-selective ligands (referred to as rexinoids) function as RXR heterodimer-selective agonists, activating RXR: PPARgamma and RXR:LXR dimers but not RXR:RAR or RXR:TR heterodimers. Because PPARgamma is a target for antidiabetic agents, we investigated whether RXR ligands could alter insulin and glucose signalling. In mouse models of noninsulin-dependent diabetes mellitus (NIDDM) and obesity, RXR agonists function as insulin sensitizers and can decrease hyperglycaemia, hypertriglyceridaemia and hyperinsulinaemia. This antidiabetic activity can be further enhanced by combination treatment with PPARgamma agonists, such as thiazolidinediones. These data suggest that the RXR:PPARgamma heterodimer is a single-function complex serving as a molecular target for treatment of insulin resistance. Activation of the RXR:PPARgamma dimer with rexinoids may provide a new and effective treatment for NIDDM.
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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
                978-3-8055-7687-1
                978-3-318-01053-4
                1663-2818
                1663-2826
                2003
                December 2003
                17 November 2004
                : 60
                : Suppl 3
                : 51-55
                Affiliations
                Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK
                Article
                74501 Horm Res 2003;60(suppl 3):51–55
                10.1159/000074501
                14671397
                © 2003 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: 2, References: 22, Pages: 5
                Categories
                The Adipocyte as an Endocrine Organ

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