Bile acids (BAs) not only facilitate fat digestion but also protect against obesity. Here, we show that a genetic mouse model for BA overload (Farnesoid X receptor; Small heterodimer double knockout (DKO)) exhibits mitochondrial dysfunction resulting in a thermogenic defect. By housing DKO mice at thermoneutrality, the poor mitochondrial function in brown fat protects them from diet-induced obesity. Compared to control, we find higher adipose BA levels with excess accumulation of taurocholic acid in the DKO mice. We report that the expression of genes responsible for BA de novo synthesis, conjugation and transporters and accumulation of BAs are present in both brown and white adipocytes. We determine that BA overload is sufficient to cause adipocyte mitochondrial dysfunction and induce the expression of cellular senescence genes in vitro. Taken together, we uncover that BA levels within the adipose tissue may modulate its overall function.

中文翻译：

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胆汁酸过多会损害棕色脂肪组织的生热功能

胆汁酸（BAs）不仅可以促进脂肪消化，还可以防止肥胖。在这里，我们表明遗传学模型为BA超载（Farnesoid X受体；小异二聚体双敲除（DKO））显示线粒体功能障碍，导致致热缺陷。通过将DKO小鼠置于热中性状态，褐色脂肪中的线粒体功能较弱，可以保护它们免于饮食引起的肥胖。与对照组相比，我们发现在DKO小鼠中脂肪BA含量较高，而牛磺胆酸过量积累。我们报告说，棕色和白色脂肪细胞中都存在负责BA从头合成，缀合和转运蛋白以及BA积累的基因表达。我们确定BA超载足以引起脂肪细胞线粒体功能障碍并诱导体外细胞衰老基因的表达。