Crosstalk between xenobiotic metabolism and energy metabolism in the liver has provided a potential opportunity to target xenobiotic receptors to treat metabolic diseases. Activation of constitutive androstane receptor (CAR), a xenobiotic-sensing nuclear receptor, has been shown to inhibit obesity, suppress hepatic gluconeogenesis, and ameliorate hyperglycemia in rodent models of obesity and type 2 diabetes. However, the underlying molecular mechanism remains to be defined. The growth arrest and DNA damage-inducible gene 45b (Gadd45b), a well-known anti-apoptotic factor, has been shown to be an inducible coactivator of CAR in promoting rapid liver growth. It is unknown whether the effect of CAR on energy metabolism depends on GADD45B. In the present study and by using a high fat diet (HFD)-induced obesity model, we show that reduced body weight gain and improved insulin sensitivity by the CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) were markedly blunted in Gadd45b knockout mice. Mechanistically, the TCPOBOP-responsive inhibition of hepatic lipogenesis, gluconeogenesis, and adipose inflammation observed in wild type mice were largely abolished in Gadd45b knockout mice. We conclude that Gadd45b is required in part for the metabolic benefits of CAR activation.

异种生物代谢与肝脏中能量代谢之间的串扰为靶向异种受体治疗代谢性疾病提供了潜在的机会。构造型雄烷受体（CAR）（一种异源生物感应核受体）的激活已被证明可在肥胖和2型糖尿病的啮齿动物模型中抑制肥胖，抑制肝糖异生和改善高血糖症。然而，潜在的分子机制仍有待确定。生长停滞和DNA损伤诱导基因45b（Gadd45b），一种众所周知的抗凋亡因子，已被证明是CAR促进肝快速生长的诱导共激活因子。未知CAR对能量代谢的影响是否取决于GADD45B。在本研究中，通过使用高脂饮食（HFD）诱导的肥胖模型，我们显示CAR激动剂1,4-bis [2-（3,5-二氯吡啶氧基）可降低体重增加并改善胰岛素敏感性。Gadd45b基因敲除小鼠中，苯（TCPOBOP）明显变钝。从机理上讲，在Gadd45b基因敲除小鼠中，在野生型小鼠中观察到的TCPOBOP响应性肝脂肪生成，糖异生和脂肪炎症的抑制作用被大大消除。我们得出结论，Gadd45b部分是CAR激活的代谢益处所必需的。