Unsuppressed lipolysis in adipocytes is linked with enhanced gluconeogenesis and altered bile acid physiology in Insr(P1195L/+) mice fed high-fat-diet.
Unsuppressed lipolysis in adipocytes is linked with enhanced gluconeogenesis and altered bile acid physiology in Insr(P1195L/+) mice fed high-fat-diet.
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DOI：
10.1038/srep17565
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发表时间：
2015-11-30
影响因子：
4.6
通讯作者：
Miki T
中科院分区：
文献类型：
--
作者：
Lee EY;Sakurai K;Zhang X;Toda C;Tanaka T;Jiang M;Shirasawa T;Tachibana K;Yokote K;Vidal-Puig A;Minokoshi Y;Miki T
高脂饮食(HFD)会引发胰岛素抵抗和糖尿病，但它们之间的联系尚不清楚。暴露于HFD的胰岛素受体突变(InsrP1195L/+)小鼠(InsrP1195L/+/HFD小鼠)的显性高血糖特征显示，肝脏葡萄糖-6-磷酸酶(G6PC)表达增加，甘油糖异生增加。InsrP1195L/+/HFD小鼠白色脂肪组织的脂肪分解(WAT)和脂肪分解引起的血糖升高增加，而野生型Wat移植改善了高血糖和G6PC表达的增加。我们发现在InsrP1195L/+/HFD肝脏中胆汁酸代谢相关基因的表达发生了变化。其中BA合成酶Cyp7a1的表达呈胰岛素依赖性，在InsrP1195L/+/HFD肝组织中表达显著降低。Wat移植可挽救InsrP1195L/+/HFD小鼠肝脏中Cyp7a1的表达，而甘油可抑制野生型肝脏中Cyp7a1的表达。这些发现表明，高脂饲料引起的脂肪细胞未受抑制的脂解作用与甘油糖异生增强和InsrP1195L/+/高脂饲料肝脏BA生理改变有关。
High-fat diet (HFD) triggers insulin resistance and diabetes mellitus, but their link remains unclear. Characterization of overt hyperglycemia in insulin receptor mutant (InsrP1195L/+) mice exposed to HFD (InsrP1195L/+/HFD mice) revealed increased glucose-6-phosphatase (G6pc) expression in liver and increased gluconeogenesis from glycerol. Lipolysis in white adipose tissues (WAT) and lipolysis-induced blood glucose rise were increased in InsrP1195L/+/HFD mice, while wild-type WAT transplantation ameliorated the hyperglycemia and the increased G6pc expression. We found that the expressions of genes involved in bile acid (BA) metabolism were altered in InsrP1195L/+/HFD liver. Among these, the expression of Cyp7a1, a BA synthesis enzyme, was insulin-dependent and was markedly decreased in InsrP1195L/+/HFD liver. Reduced Cyp7a1 expression in InsrP1195L/+/HFD liver was rescued by WAT transplantation, and the expression of Cyp7a1 was suppressed by glycerol administration in wild-type liver. These findings suggest that unsuppressed lipolysis in adipocytes elicited by HFD feeding is linked with enhanced gluconeogenesis from glycerol and with alterations in BA physiology in InsrP1195L/+/HFD liver.