| Corepressor SMRT promotes oxidative phosphorylation in adipose tissue and protects against diet-induced obesity and insulin resistance. | |
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MedLine Citation:
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PMID: 21300871 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The ligand-dependent competing actions of nuclear receptor (NR)-associated transcriptional corepressor and coactivator complexes allow for the precise regulation of NR-dependent gene expression in response to both temporal and environmental cues. Here we report the mouse model termed silencing mediator of retinoid and thyroid hormone receptors (SMRT)(mRID1) in which targeted disruption of the first receptor interaction domain (RID) of the nuclear corepressor SMRT disrupts interactions with a subset of NRs and leads to diet-induced superobesity associated with a depressed respiratory exchange ratio, decreased ambulatory activity, and insulin resistance. Although apparently normal when chow fed, SMRT(mRID1) mice develop multiple metabolic dysfunctions when challenged by a high-fat diet, manifested by marked lipid accumulation in white and brown adipose tissue and the liver. The increased weight gain of SMRT(mRID1) mice on a high-fat diet occurs predominantly in fat with adipocyte hypertrophy evident in both visceral and s.c. depots. Importantly, increased inflammatory gene expression was detected only in the visceral depots. SMRT(mRID1) mice are both insulin-insensitive and refractory to the glucose-lowering effects of TZD and AICAR. Increased serum cholesterol and triglyceride levels were observed, accompanied by increased leptin and decreased adiponectin levels. Aberrant storage of lipids in the liver occurred as triglycerides and cholesterol significantly compromised hepatic function. Lipid accumulation in brown adipose tissue was associated with reduced thermogenic capacity and mitochondrial biogenesis. Collectively, these studies highlight the essential role of NR corepressors in maintaining metabolic homeostasis and describe an essential role for SMRT in regulating the progression, severity, and therapeutic outcome of metabolic diseases. |
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Authors:
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Sungsoon Fang; Jae Myoung Suh; Annette R Atkins; Suk-Hyun Hong; Mathias Leblanc; Russell R Nofsinger; Ruth T Yu; Michael Downes; Ronald M Evans |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-02-07 |
Journal Detail:
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Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 108 ISSN: 1091-6490 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 2011 Feb |
Date Detail:
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Created Date: 2011-03-03 Completed Date: 2011-05-06 Revised Date: 2012-02-15 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: 3412-7 Citation Subset: IM |
Affiliation:
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Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adipose Tissue
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metabolism* Animals Diet / adverse effects* Homeostasis Insulin Resistance* Lipid Metabolism Liver / metabolism Mice Nuclear Receptor Co-Repressor 2 / physiology* Obesity / etiology* Oxidative Phosphorylation* |
| Grant Support | |
ID/Acronym/Agency:
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DK062434/DK/NIDDK NIH HHS; HD027183/HD/NICHD NIH HHS; R01 HD027183-19/HD/NICHD NIH HHS; R01 HL105278-21/HL/NHLBI NIH HHS; R24 DK090962-02/DK/NIDDK NIH HHS; R37 DK057978-34/DK/NIDDK NIH HHS; //Howard Hughes Medical Institute |
| Chemical | |
Reg. No./Substance:
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0/Nuclear Receptor Co-Repressor 2 |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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