Nuclear orphan receptor TAK1/TR4-deficient mice are protected against obesity-linked inflammation, hepatic steatosis, and insulin resistance.
Nuclear orphan receptor TAK1/TR4-deficient mice are protected against obesity-linked inflammation, hepatic steatosis, and insulin resistance.
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作者：
Kang HS;Okamoto K;Kim YS;Takeda Y;Bortner CD;Dang H;Wada T;Xie W;Yang XP;Liao G;Jetten AM
核受体 TAK1/TR4/NR2C2 在多种组织中表达，这些组织对于能量稳态的控制很重要。在这项研究中，我们研究了 TAK1 是否作为脂质和能量稳态的调节剂发挥作用，并在代谢综合征中发挥作用。我们培育了 TAK1 缺陷 (TAK1−/−) 小鼠，以研究 TAK1 在老年小鼠和高脂饮食 (HFD) 小鼠代谢综合征发展中的功能。进行（免疫）组织化学、生化和基因表达谱分析，以确定 TAK1 表达缺失对肝脏和脂肪组织脂质稳态的影响。此外，还比较了喂食 HFD 的野生型 (WT) 和 TAK1−/− 小鼠的胰岛素敏感性、能量消耗和脂肪相关炎症。 TAK1 缺陷 (TAK1−/−) 小鼠对年龄和 HFD 诱导的代谢综合征的发展具有抵抗力。组织和生化分析显示，与 WT 小鼠相比，TAK1−/− 小鼠的肝脏甘油三酯水平显着降低，脂肪组织中的脂质积累减少。基因表达谱分析表明，TAK1−/− 小鼠的肝脏和原代肝细胞中编码参与脂质摄取和甘油三酯合成和储存的蛋白质的几个基因（包括 Cidea、Cidec、Mogat1 和 CD36）的表达大大降低。 TAK1−/− 肝细胞中 TAK1 表达的恢复诱导了几种脂肪生成基因的表达。此外，TAK1−/−小鼠表现出白色脂肪组织中炎症细胞浸润和炎症基因表达减少，并且能够抵抗葡萄糖不耐受和胰岛素抵抗的发展。 TAK1−/− 小鼠比 WT 小鼠消耗更多的氧气并产生更多的二氧化碳，表明能量消耗增加。我们的数据表明，TAK1 在能量和脂质稳态的调节中发挥着关键作用，并促进代谢综合征的发展。 TAK1可能为肥胖、糖尿病和肝脂肪变性的治疗提供新的治疗靶点。
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. 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. 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. 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.