The Constitutive Androstane Receptor Is an Anti-obesity Nuclear Receptor That Improves Insulin Sensitivity
The Constitutive Androstane Receptor Is an Anti-obesity Nuclear Receptor That Improves Insulin Sensitivity
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DOI：
10.1074/jbc.m109.016808
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发表时间：
2009-09-18
影响因子：
4.8
通讯作者：
Xie, Wen
中科院分区：
文献类型：
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作者：
Gao, Jie;He, Jinhan;Xie, Wen
肥胖与2型糖尿病是高发的代谢性疾病。组成型雄甾烷受体（CAR）最初被认为是一种调节哺乳动物对异种毒物反应的异种受体。在这项研究中，我们发现了CAR在预防肥胖和缓解2型糖尿病方面意想不到的作用。通过高脂饮食（HFD）诱导的肥胖模型，我们发现用CAR激动剂1,4-双[2-（3,5二氯吡啶氧基）]苯（TCPOBOP）治疗野生型小鼠可以有效预防肥胖的发生或逆转预诱导肥胖。用TCPOBOP治疗可改善hfd诱导的2型糖尿病模型和ob/ob小鼠的胰岛素敏感性。相比之下，CAR缺失小鼠维持在食物饮食中表现出自发性胰岛素不敏感，TOPOBOP治疗无法缓解。TCPOBOP显著降低了hfd处理小鼠和ob/ob小鼠的肝脏脂肪变性。CAR激活的代谢益处可能是由于抑制脂肪生成、极低密度脂蛋白分泌和甘油三酯输出、糖异生以及棕色脂肪组织能量消耗和外周脂肪动员增加的综合作用。此外，car激活小鼠的骨骼肌显示不完全氧化减少，尽管过氧化物酶体增殖体激活受体α及其参与脂肪酸氧化的靶基因表达水平较低。总之，我们的研究结果揭示了CAR的重要代谢功能，并可能将这种“异种受体”作为预防和治疗肥胖和2型糖尿病的新治疗靶点。
Obesity and type 2 diabetes are related metabolic disorders of high prevalence. The constitutive androstane receptor (CAR) was initially characterized as a xenobiotic receptor regulating the responses of mammals to xenotoxicants. In this study, we have uncovered an unexpected role of CAR in preventing obesity and alleviating type 2 diabetes. Using a high fat diet (HFD)-induced obesity model, we showed that treatment of wild type mice with the CAR agonist 1,4-bis[2-(3,5 dichloropyridyloxy)] benzene (TCPOBOP) efficiently prevented obesity from happening or reversed preinduced obesity. Treatment with TCPOBOP improved insulin sensitivity in both the HFD-induced type 2 diabetic model and the ob/ob mice. In contrast, CAR null mice maintained on a chow diet showed spontaneous insulin insensitivity, which cannot be relieved by TOPOBOP treatment. The hepatic steatosis in HFD-treated mice and ob/ob mice was markedly reduced by the TCPOBOP treatment. The metabolic benefits of CAR activation may have resulted from the combined effect of inhibition of lipogenesis, very low density lipoprotein secretion and export of triglycerides, and gluconeogenesis as well as increases in brown adipose tissue energy expenditure and peripheral fat mobilization. Moreover, the skeletal muscle of CAR-activated mice showed a decreased incomplete oxidation, despite having a lower expression level of peroxisome proliferator-activated receptor alpha and its target genes involved in fatty acid oxidation. In summary, our results have revealed an important metabolic function of CAR and may establish this "xenobiotic receptor" as a novel therapeutic target for the prevention and treatment of obesity and type 2 diabetes.