Lowering Bile Acid Pool Size with a Synthetic Farnesoid X Receptor (FXR) Agonist Induces Obesity and Diabetes through Reduced Energy Expenditure
Lowering Bile Acid Pool Size with a Synthetic Farnesoid X Receptor (FXR) Agonist Induces Obesity and Diabetes through Reduced Energy Expenditure
复制标题
DOI：
10.1074/jbc.m111.248203
复制
发表时间：
2011-07-29
影响因子：
4.8
通讯作者：
Auwerx, Johan
中科院分区：
文献类型：
--
作者：
Watanabe, Mitsuhiro;Horai, Yasushi;Auwerx, Johan
我们通过给高脂饮食诱导肥胖的小鼠施用合成的 FXR 激动剂 (GW4064) 来评估法呢醇 X 受体 (FXR) 激活的代谢影响。服用 GW4064 会加重高脂肪饮食引起的体重增加和葡萄糖不耐受，并导致肝脏和脂肪组织变化明显恶化。从机制上讲，GW4064 治疗降低了胆汁酸 (BA) 生物合成、BA 池大小和能量消耗，而通过 BA 给药对这些 GW4064 治疗的动物中的 BA 池进行重建可剂量依赖性地恢复代谢异常。因此，我们的数据表明，用合成激动剂激活 FXR 对于代谢综合征的长期管理并无帮助，因为它会减少 BA 池的大小，从而减少能量消耗，从而导致体重增加和胰岛素抵抗。相比之下，通过 BA 给药可以扩大 BA 库的大小，这可能是控制代谢综合征的一个有趣的策略。
We evaluated the metabolic impact of farnesoid X receptor (FXR) activation by administering a synthetic FXR agonist (GW4064) to mice in which obesity was induced by a high fat diet. Administration of GW4064 accentuated body weight gain and glucose intolerance induced by the high fat diet and led to a pronounced worsening of the changes in liver and adipose tissue. Mechanistically, treatment with GW4064 decreased bile acid (BA) biosynthesis, BA pool size, and energy expenditure, whereas reconstitution of the BA pool in these GW4064-treated animals by BA administration dose-dependently reverted the metabolic abnormalities. Our data therefore suggest that activation of FXR with synthetic agonists is not useful for long term management of the metabolic syndrome, as it reduces the BA pool size and subsequently decreases energy expenditure, translating as weight gain and insulin resistance. In contrast, expansion of the BA pool size, which can be achieved by BA administration, could be an interesting strategy to manage the metabolic syndrome.