title: Nuclear orphan receptor TAK1/TR4-deficient mice are protected against obesity-linked inflammation, hepatic steatosis, and insulin resistance.
abstract: OBJECTIVE
  The nuclear receptor TAK1/TR4/NR2C2 is expressed in several tissues that are important in the control of energy homeostasis. In this study, we investigate whether TAK1 functions as a regulator of lipid and energy homeostasis and has a role in metabolic syndrome.
  
  
  METHODS
  We generated TAK1-deficient (TAK1⁻(/)⁻) mice to study the function of TAK1 in the development of metabolic syndrome in aged mice and mice fed a high-fat diet (HFD). (Immuno)histochemical, biochemical, and gene expression profile analyses were performed to determine the effect of the loss of TAK1 expression on lipid homeostasis in liver and adipose tissues. In addition, insulin sensitivity, energy expenditure, and adipose-associated inflammation were compared in wild-type (WT) and TAK1⁻(/)⁻ mice fed a HFD.
  
  
  RESULTS
  TAK1-deficient (TAK1⁻(/)⁻) mice are resistant to the development of age- and HFD-induced metabolic syndrome. Histo- and biochemical analyses showed significantly lower hepatic triglyceride levels and reduced lipid accumulation in adipose tissue in TAK1⁻(/)⁻ mice compared with WT mice. Gene expression profiling analysis revealed that the expression of several genes encoding proteins involved in lipid uptake and triglyceride synthesis and storage, including Cidea, Cidec, Mogat1, and CD36, was greatly decreased in the liver and primary hepatocytes of TAK1⁻(/)⁻ mice. Restoration of TAK1 expression in TAK1⁻(/)⁻ hepatocytes induced expression of several lipogenic genes. Moreover, TAK1⁻(/)⁻ mice exhibited reduced infiltration of inflammatory cells and expression of inflammatory genes in white adipose tissue, and were resistant to the development of glucose intolerance and insulin resistance. TAK1⁻(/)⁻ mice consume more oxygen and produce more carbon dioxide than WT mice, suggesting increased energy expenditure.
  
  
  CONCLUSIONS
  Our data reveal that TAK1 plays a critical role in the regulation of energy and lipid homeostasis, and promotes the development of metabolic syndrome. TAK1 may provide a new therapeutic target in the management of obesity, diabetes, and liver steatosis.
authors.affiliation: Cell Biology Section, Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
authors.forename: Hong Soon
authors.initials: HS
authors.lastname: Kang
authors.forename: Kyoko
authors.initials: K
authors.lastname: Okamoto
authors.forename: Yong-Sik
authors.initials: YS
authors.lastname: Kim
authors.forename: Yukimasa
authors.initials: Y
authors.lastname: Takeda
authors.forename: Carl D
authors.initials: CD
authors.lastname: Bortner
authors.forename: Huaixin
authors.initials: H
authors.lastname: Dang
authors.forename: Taira
authors.initials: T
authors.lastname: Wada
authors.forename: Wen
authors.initials: W
authors.lastname: Xie
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Yang
authors.forename: Grace
authors.initials: G
authors.lastname: Liao
authors.forename: Anton M
authors.initials: AM
authors.lastname: Jetten
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency*; D000273:Adipose Tissue / Q000033:anatomy & histology / Q000473:pathology; D000818:Animals; D004041:Dietary Fats; D004822:Epididymis; D005234:Fatty Liver / Q000473:pathology / Q000517:prevention & control*; D005434:Flow Cytometry; D007249:Inflammation / Q000473:pathology / Q000517:prevention & control*; D007333:Insulin Resistance; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000150:complications*; D009929:Organ Size; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D011987:Receptors, Steroid / Q000172:deficiency*; D011988:Receptors, Thyroid Hormone / Q000172:deficiency*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004041:Dietary Fats; C490514:Nr2c2 protein, mouse; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; C498761:Tab2 protein, mouse; D012313:RNA