Moderate GLUT4 overexpression improves insulin sensitivity and fasting triglyceridemia in high-fat diet-fed transgenic mice.
Moderate GLUT4 overexpression improves insulin sensitivity and fasting triglyceridemia in high-fat diet-fed transgenic mice.
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作者：
Atkinson BJ;Griesel BA;King CD;Josey MA;Olson AL
GLUT4促进性葡萄糖转运蛋白介导胰岛素依赖型葡萄糖摄取。我们验证了在人类GLUT4启动子的调控下，小鼠中人类GLUT4的适度过表达可以预防肥胖导致的高胰岛素血症的假设。表达人类GLUT4基因和启动子（hGLUT4 TG）及其非转基因对应物（NT）的转基因小鼠分别饲喂对照饮食（CD）或高脂饮食（HFD）长达10周。胰岛素抵抗评分的稳态模型评估显示，喂食HFD的hGLUT4 TG小鼠仍然高度胰岛素敏感。GLUT4转基因的存在并没有完全阻止对HFD的代谢适应。例如，HFD导致禁食和精制NT和hGLUT4 TG小鼠肝脏中几种代谢基因表达的动态调控丧失。饲喂CD的hGLUT4 TG小鼠在从禁食到摄食的过渡过程中，SREBP-1c和脂肪酸合成酶（FAS） mRNA的表达无摄食依赖性调节。同样，HFD改变了两种菌株SREBP-1c和FAS mRNA表达对摄食的反应。这些肝脏基因表达的变化伴随着细胞核磷酸化- creb的增加。综上所述，适度增加GLUT4的表达是治疗胰岛素抵抗的良好靶点。
The GLUT4 facilitative glucose transporter mediates insulin-dependent glucose uptake. We tested the hypothesis that moderate overexpression of human GLUT4 in mice, under the regulation of the human GLUT4 promoter, can prevent the hyperinsulinemia that results from obesity. Transgenic mice engineered to express the human GLUT4 gene and promoter (hGLUT4 TG) and their nontransgenic counterparts (NT) were fed either a control diet (CD) or a high-fat diet (HFD) for up to 10 weeks. Homeostasis model assessment of insulin resistance scores revealed that hGLUT4 TG mice fed an HFD remained highly insulin sensitive. The presence of the GLUT4 transgene did not completely prevent the metabolic adaptations to HFD. For example, HFD resulted in loss of dynamic regulation of the expression of several metabolic genes in the livers of fasted and refed NT and hGLUT4 TG mice. The hGLUT4 TG mice fed a CD showed no feeding-dependent regulation of SREBP-1c and fatty acid synthase (FAS) mRNA expression in the transition from the fasted to the fed state. Similarly, HFD altered the response of SREBP-1c and FAS mRNA expression to feeding in both strains. These changes in hepatic gene expression were accompanied by increased nuclear phospho-CREB in refed mice. Taken together, a moderate increase in expression of GLUT4 is a good target for treatment of insulin resistance.
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DOI：
10.1073/pnas.0914798107
发表时间：
2010-02-23
影响因子：
11.1
作者：
Li, Shijie;Brown, Michael S.;Goldstein, Joseph L.
通讯作者：
Goldstein, Joseph L.
影响因子：
7.7
作者：
HOLLENBECK, CB;CHEN, YDI;REAVEN, GM
通讯作者：
REAVEN, GM
影响因子：
7.7
作者：
EZAKI, O;HIGUCHI, M;ITAKURA, H
通讯作者：
ITAKURA, H
影响因子：
4.8
作者：
Hansen, PA;Han, DH;Holloszy, JO
通讯作者：
Holloszy, JO
DOI：
10.1073/pnas.92.8.3096
发表时间：
1995-04-11
影响因子：
11.1
作者：
IKEMOTO, S;THOMPSON, KS;EZAKI, O
通讯作者：
EZAKI, O