Nuclear Orphan Receptor TAK1/TR4-Deficient Mice Are Protected Against Obesity-Linked Inflammation, Hepatic Steatosis, and Insulin Resistance

Abstract

OBJECTIVEThe 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.RESEARCH DESIGN AND METHODSWe 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.RESULTSTAK1-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.CONCLUSIONSOur 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.

Conjugated Linoleic Acid Negatively Regulates TR4 Activity in 3T3-L1 Adipocytes

“…However, the regulatory cascades of CLA leading to this preventive effect on adipogenesis remain unclear. Recent reports have shown that TR4-deficient mice exhibit markedly reduced white fat masses with smaller sizes of adipocytes (Kang et al, 2011;Kim et al, 2011). In parallel, we also found that overexpression of TR4 in 3T3-L1 adipocytes promoted lipid accumulation.…”

Nur77 inhibits TR4-induced PEPCK expression in 3T3-L1 adipocytes

“…Thus, it is highly possible that TR4 fine-tunes energy homeostasis in insulin-sensitive tissues such as liver, adipose, and skeletal muscle via cross-talk with other NRs. Recently, we and Kang et al found that fat mass is significantly reduced in TR4-deficient mice (Kang et al 2011;. Consistent with the phenotype of TR4-deficient mice, we also found that knockdown of TR4 in 3T3-L1 adipocytes results in decreased intracellular TG accumulation via downregulation of the FATP1 gene (submitted).…”

“…TR4 regulates gluconeogenesis through hepatic induction of the PEPCK gene (Liu et al 2007). In addition, TR4-deficient mice show reduced TG accumulation in adipose tissue (Kang et al 2011;.…”

“…TR4 is expressed in metabolic tissues such as adipose tissue, liver, and skeletal muscle and has been identified as an important regulator of energy homeostasis (Kim et al 2003Liu et al 2007;Kang et al 2011). TR4 regulates gluconeogenesis through hepatic induction of the PEPCK gene (Liu et al 2007).…”

Testicular Nuclear Receptor 4 (TR4) Regulates UV Light-induced Responses via Cockayne Syndrome B Protein-mediated Transcription-coupled DNA Repair

“…Recent studies with TR4 gene knock-out mice (TR4 Ϫ/Ϫ ) have revealed that TR4 is essential for normal spermatogenesis, cerebellum development, glucose metabolism, and insulin resistance (3)(4)(5)(6)(7). Mouse embryonic fibroblasts (MEFs) from TR4 Ϫ/Ϫ mice display a higher rate of apoptosis compared with wild-type MEFs when exposed to a high dose of UV irradiation (8).…”