title: Transcriptional profiling reveals a role for RORalpha in regulating gene expression in obesity-associated inflammation and hepatic steatosis.
abstract: Retinoid-related orphan receptor (ROR)α4 is the major RORα isoform expressed in adipose tissues and liver. In this study we demonstrate that RORα-deficient staggerer mice (RORα(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 RORα(sg/sg) mice. In contrast, overexpression of RORα in mouse hepatoma Hepa1-6 cells significantly increased the expression of genes that were repressed in RORα(sg/sg) liver, including Sult1b1, Adfp, Cidea, and ApoA4. ChIP and promoter analysis suggested that several of these genes were regulated directly by RORα. In addition to reduced lipid accumulation, inflammation was greatly diminished in white adipose tissue (WAT) of RORα(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 RORα(sg/sg) WAT. Moreover, RORα(sg/sg) mice fed with an HFD were protected from the development of insulin resistance. RORα(sg/sg) mice consumed more oxygen and produced more carbon dioxide, suggesting increased energy expenditure in this genotype. Our study indicates that RORα plays a critical role in the regulation of several aspects of metabolic syndrome. Therefore, RORα may provide a novel therapeutic target in the management of obesity and associated metabolic diseases.
authors.affiliation: Cell Biology Section, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Hong Soon
authors.initials: HS
authors.lastname: Kang
authors.forename: Kyoko
authors.initials: K
authors.lastname: Okamoto
authors.forename: Yukimasa
authors.initials: Y
authors.lastname: Takeda
authors.forename: Ju Youn
authors.initials: JY
authors.lastname: Beak
authors.forename: Kevin
authors.initials: K
authors.lastname: Gerrish
authors.forename: Carl D
authors.initials: CD
authors.lastname: Bortner
authors.forename: Laura M
authors.initials: LM
authors.lastname: DeGraff
authors.forename: Taira
authors.initials: T
authors.lastname: Wada
authors.forename: Wen
authors.initials: W
authors.lastname: Xie
authors.forename: Anton M
authors.initials: AM
authors.lastname: Jetten
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism / Q000473:pathology; D000375:Aging / Q000235:genetics / Q000473:pathology; D000818:Animals; D004041:Dietary Fats; D004734:Energy Metabolism / Q000235:genetics; D005234:Fatty Liver / Q000150:complications / Q000235:genetics* / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018149:Glucose Intolerance / Q000150:complications / Q000235:genetics; D007249:Inflammation / Q000150:complications / Q000235:genetics* / Q000473:pathology; D007333:Insulin Resistance / Q000235:genetics; D050155:Lipogenesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000150:complications / Q000235:genetics* / Q000473:pathology; D014158:Transcription, Genetic
chemical_list: D004041:Dietary Fats; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1