ABSTRACT

The aim of this study was to elucidate mechanisms whereby bile acids exert beneficial metabolic effects, using the Cyp8b1^−/- mouse as model. These mice are unable to synthesize cholic acid, resulting in increased synthesis of chenodeoxycholic acid and enlarged bile acid pool. Cyp8b1^−/- mice were found to be protected against high-fat diet induced obesity. Bomb calorimetry measurements showed increased faecal energy output in Cyp8b1^−/ mice. Indirect calorimetry measurements demonstrated increased energy expenditure in Cyp8b1^−/- mice. Meal tolerance tests revealed no differences in glucose disposal, but the insulin response was lower in Cyp8b1^−/- mice. Intravenous glucose tolerance tests, as well as static incubations of isolated islets, showed no difference between the groups, whereas insulin tolerance tests demonstrated improved insulin sensitivity in Cyp8b1^−/- mice. The genes encoding mitochondrial transcription factor A (TFAM) and type 2-iodothyronine deiodinase were upregulated in brown adipose tissue of Cyp8b1^/- mice and Western blot analyses showed increased abundance of TFAM, and a trend towards increased abundance of UCP1. The upregulation of TFAM and UCP1 was accompanied by increased mitochondrial density, as shown by transmission electron microscopy. White adipocytes of Cyp8b1^−/- mice exhibited increased responsiveness to both catecholamines and insulin in lipolysis experiments and increased insulin-stimulated lipogenesis. In conclusion, increased energy expenditure, mitochondrial density of brown adipocytes and faecal energy output may all contribute to the protection against diet-induced obesity of Cyp8b1^−/- mice. Enhanced insulin sensitivity of Cyp8b1^−/- mice is accompanied by increased hormonal responsiveness of white adipocytes.

摘要

这项研究的目的是阐明以Cyp8b1 ^-/- 小鼠为模型的胆汁酸发挥有益代谢作用的机制。这些小鼠无法合成胆酸，导致鹅去氧胆酸的合成增加，胆汁酸池增大。发现Cyp8b1 ^-/- 小鼠可以抵抗高脂饮食诱导的肥胖。炸弹量热法测量显示，Cyp8b1 ^-// 小鼠的粪便能量输出增加。间接量热法测量表明，Cyp8b1 ^-/- 小鼠的能量消耗增加。膳食耐受性测试显示葡萄糖处理无差异，但Cyp8b1 ^-/-的胰岛素反应较低 老鼠。静脉内葡萄糖耐量试验以及分离的胰岛的静态温育显示两组之间无差异，而胰岛素耐量试验证明Cyp8b1 ^-/- 小鼠的胰岛素敏感性提高。Cyp8b1 ^/ 小鼠的棕色脂肪组织中编码线粒体转录因子A（TFAM）和2型碘甲状腺素脱碘酶的基因被上调，Western印迹分析显示TFAM的丰度增加，UCP1的丰度增加。如透射电子显微镜所示，TFAM和UCP1的上调伴随着线粒体密度的增加。Cyp8b1白色脂肪细胞^-/- 在脂解实验中，小鼠表现出对儿茶酚胺和胰岛素的反应性增强，以及胰岛素刺激的脂肪生成。总之，增加的能量消耗，褐色脂肪细胞的线粒体密度和粪便能量输出均可能有助于预防 饮食引起的Cyp8b1 ^-/-小鼠肥胖。Cyp8b1 ^-/- 小鼠胰岛素敏感性增强，伴有白色脂肪细胞的激素反应增加。