Loss of FXR Protects against Diet-Induced Obesity and Accelerates Liver Carcinogenesis in ob/ob Mice
Loss of FXR Protects against Diet-Induced Obesity and Accelerates Liver Carcinogenesis in ob/ob Mice
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DOI：
10.1210/me.2011-1157
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发表时间：
2012-02-01
影响因子：
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通讯作者：
Novak, Colleen M.
中科院分区：
文献类型：
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作者：
Zhang, Yanqiao;Ge, Xuemei;Novak, Colleen M.
法尼醇X受体（FXR）在胆汁酸、脂类和碳水化合物代谢中起重要的调节作用。老年（>12月龄）Fxr（-/-）小鼠也会发生自发性肝癌。在这份报告中，我们使用了三种小鼠模型来研究FXR缺乏在肥胖中的作用。与低密度脂蛋白受体（Ldlr）敲除（Ldlr（-/-））小鼠相比，Ldlr（-/-）Fxr（-/-）双敲除小鼠对饮食诱导的肥胖具有高度抵抗性，这与骨骼肌和棕色脂肪组织中参与能量代谢的基因表达增加有关。在Ldlr（-/-）背景下，FXR缺乏对肥胖的这种显著影响使我们研究单独的FXR缺乏是否足以影响肥胖。与野生型小鼠相比，Fxr（-/-）小鼠对饮食诱导的体重增加表现出抗性。有趣的是，只有雌性Fxr（-/-）小鼠对饮食诱导的肥胖表现出显著的抵抗力，这伴随着这些小鼠的能量消耗增加。最后，我们在遗传性肥胖和糖尿病小鼠模型中确定了FXR缺乏对肥胖的影响。我们产生了瘦素和Fxr都缺乏的ob（-/-）Fxr（-/-）小鼠。与ob/ob小鼠相比，普通饲料喂养的ob（-/-）Fxr（-/-）小鼠体重增加较少，体脂量减少。此外，我们观察到43%的年轻人患有肝癌（
Farnesoid X receptor (FXR) is known to play important regulatory roles in bile acid, lipid, and carbohydrate metabolism. Aged (>12 months old) Fxr (-/-) mice also develop spontaneous liver carcinomas. In this report, we used three mouse models to investigate the role of FXR deficiency in obesity. As compared with low-density lipoprotein receptor (Ldlr) knockout (Ldlr(-/-)) mice, the Ldlr(-/-) Fxr (-/-) double-knockout mice were highly resistant to diet-induced obesity, which was associated with increased expression of genes involved in energy metabolism in the skeletal muscle and brown adipose tissue. Such a striking effect of FXR deficiency on obesity on an Ldlr(-/-) background led us to investigate whether FXR deficiency alone is sufficient to affect obesity. As compared with wild-type mice, Fxr (-/-) mice showed resistance to diet-induced weight gain. Interestingly, only female Fxr (-/-) mice showed significant resistance to diet-induced obesity, which was accompanied by increased energy expenditure in these mice. Finally, we determined the effect of FXR deficiency on obesity in a genetically obese and diabetic mouse model. We generated ob(-/-) Fxr (-/-) mice that were deficient in both Leptin and Fxr. On a chow diet, ob(-/-) Fxr (-/-) mice gained less body weight and had reduced body fat mass as compared with ob/ob mice. In addition, we observed liver carcinomas in 43% of young (