Overexpression of PGC-1&alpha Does NOT Reduce Glucose Uptake in Skeletal Muscle.

Type II, or insulin resistant, diabetes is characterized by the inability of the body to remove glucose from the blood and transport it to the muscle. It has been shown that the expression of both the primary glucose transporter (GLUT4) and PGC-1&alpha, a transcriptional coactivator, is decreased in diabetic muscles. PGC-1&alpha is a known regulator of metabolic enzyme gene expression, but the relationship between PGC-1&alpha and GLUT4 is unclear. Previous work has shown a controversy as to whether PGC-1&alpha downregulates or upregulates GLUT4. Using mice that overexpress PGC-1&alpha in skeletal muscle, we conducted a glucose tolerance test and an insulin tolerance test. These experiments showed that there was no difference in the way the PGC-1&alpha overexpressing mice took up glucose or responded to insulin compared to the wild type mice. Similarly, the results of quantitative RT-PCR experiments indicated no altering of GLUT4 expression level with PGC-1&alpha overexpression, yet another possibility. Even though the overexpression of PGC-1&alpha does not have an impact on GLUT4 expression, we examined whether PGC-1&alpha is required for GLUT4 expression level to change using PGC-1a knockout mice. Both wild type and knockout mice were swum everyday. Quantitative RT PCR on the exercised mice showed an increase of GLUT4 expression level in the wild type mice but a decrease in the GLUT4 expression level in the knock out mice, indicating that PGC-1&alpha is necessary for GLUT4 expression level to increase. Although it remains unclear whether PGC-1&alpha regulates GLUT4 expression level, these data show that PGC-1&alpha is necessary for induction of GLUT4 expression.