Lee Eun Young, Sakurai Kenichi, Zhang Xilin, Toda Chitoku, Tanaka Tomoaki, Jiang Meizi, Shirasawa Takuji, Tachibana Kaori, Yokote Koutaro, Vidal-Puig Antonio, Minokoshi Yasuhiko, Miki Takashi
Department of Medical Physiology, Chiba University, Graduate School of Medicine, Chiba 260-8670 Japan.
Department of Clinical Cell Biology and Medicine, Chiba University, Graduate School of Medicine, Chiba 260-8670 Japan.
Sci Rep. 2015 Nov 30;5:17565. doi: 10.1038/srep17565.
High-fat diet (HFD) triggers insulin resistance and diabetes mellitus, but their link remains unclear. Characterization of overt hyperglycemia in insulin receptor mutant (Insr(P1195L/+)) mice exposed to HFD (Insr(P1195L/+)/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 Insr(P1195L/+)/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 Insr(P1195L/+)/HFD liver. Among these, the expression of Cyp7a1, a BA synthesis enzyme, was insulin-dependent and was markedly decreased in Insr(P1195L/+)/HFD liver. Reduced Cyp7a1 expression in Insr(P1195L/+)/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 Insr(P1195L/+)/HFD liver.
高脂饮食（HFD）会引发胰岛素抵抗和糖尿病，但其关联尚不清楚。对暴露于高脂饮食的胰岛素受体突变（Insr(P1195L/+)）小鼠（Insr(P1195L/+) / HFD小鼠）明显高血糖的特征分析显示，肝脏中葡萄糖-6-磷酸酶（G6pc）表达增加，甘油的糖异生作用增强。Insr(P1195L/+) / HFD小鼠白色脂肪组织（WAT）中的脂肪分解以及脂肪分解诱导的血糖升高均增加，而野生型WAT移植改善了高血糖和G6pc表达的增加。我们发现，参与胆汁酸（BA）代谢的基因表达在Insr(P1195L/+) / HFD肝脏中发生了改变。其中，BA合成酶Cyp7a1的表达依赖胰岛素，在Insr(P1195L/+) / HFD肝脏中显著降低。Insr(P1195L/+) / HFD肝脏中Cyp7a1表达的降低通过WAT移植得以挽救，而在野生型肝脏中，甘油给药可抑制Cyp7a1的表达。这些发现表明，高脂饮食喂养引起的脂肪细胞中未受抑制的脂肪分解与甘油糖异生作用增强以及Insr(P1195L/+) / HFD肝脏中BA生理学改变有关。
