Transcriptional profiling reveals a role for RORα in regulating gene expression in obesity-associated inflammation and hepatic steatosis

被引:77
|
作者
Kang, Hong Soon [1 ]
Okamoto, Kyoko [1 ]
Takeda, Yukimasa [1 ]
Beak, Ju Youn [1 ]
Gerrish, Kevin [2 ]
Bortner, Carl D. [3 ]
DeGraff, Laura M. [1 ]
Wada, Taira [4 ,5 ]
Xie, Wen [4 ,5 ]
Jetten, Anton M. [1 ]
机构
[1] NIEHS, Cell Biol Sect, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA
[2] NIEHS, Microarray Grp, NIH, Res Triangle Pk, NC 27709 USA
[3] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA
[4] Univ Pittsburgh, Ctr Pharmacogenet, Pittsburgh, PA USA
[5] Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA USA
关键词
staggerer mice; obesity; metabolic syndrome; macrophage; insulin-resistance; diabetes; retinoid-related orphan receptors; ORPHAN NUCLEAR RECEPTOR; DIET-INDUCED OBESITY; INDUCED LUNG INFLAMMATION; ADIPOSE-TISSUE; DEFICIENT MICE; INSULIN SENSITIVITY; ENERGY-EXPENDITURE; RETINOIC ACID; ADIPOCYTE DIFFERENTIATION; MACROPHAGE ACCUMULATION;
D O I
10.1152/physiolgenomics.00206.2010
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Retinoid-related orphan receptor (ROR)alpha 4 is the major ROR alpha isoform expressed in adipose tissues and liver. In this study we demonstrate that ROR alpha-deficient staggerer mice (ROR alpha(sg/sg)) fed with a high-fat diet (HFD) exhibited reduced adiposity and hepatic triglyceride levels compared with wild-type (WT) littermates and were resistant to the development of hepatic steatosis, adipose-associated inflammation, and insulin resistance. Gene expression profiling showed that many genes involved in triglyceride synthesis and storage, including Cidec, Cidea, and Mogat1, were expressed at much lower levels in liver of ROR alpha(sg/sg) mice. In contrast, overexpression of ROR alpha in mouse hepatoma Hepa1-6 cells significantly increased the expression of genes that were repressed in ROR alpha(sg/sg) liver, including Sult1b1, Adfp, Cidea, and ApoA4. ChIP and promoter analysis suggested that several of these genes were regulated directly by ROR alpha. In addition to reduced lipid accumulation, inflammation was greatly diminished in white adipose tissue (WAT) of ROR alpha(sg/sg) mice fed with an HFD. The infiltration of macrophages and the expression of many immune response and proinflammatory genes, including those encoding various chemo/cytokines, Toll-like receptors, and TNF signaling proteins, were significantly reduced in ROR alpha(sg/sg) WAT. Moreover, ROR alpha(sg/sg) mice fed with an HFD were protected from the development of insulin resistance. ROR alpha(sg/sg) mice consumed more oxygen and produced more carbon dioxide, suggesting increased energy expenditure in this genotype. Our study indicates that ROR alpha plays a critical role in the regulation of several aspects of metabolic syndrome. Therefore, ROR alpha may provide a novel therapeutic target in the management of obesity and associated metabolic diseases.
引用
收藏
页码:818 / 828
页数:11
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