Bezafibrate reduces the elevated hepatic fumarate level in insulin-deficient streptozotocin mice [visceral adipose tissue]

In addition to high intracellular glucose level, the diabetic state is also characterized by altered metabolites, which are pivotal regulators of glucotoxic pathways. In this study we analyzed Bezafibrate (BEZ) treated Streptozotocin (STZ) mice, which showed improved glucose metabolism compared to untreated STZ controls. In order to identify the key molecules and pathways, which participate in the beneficial effects of BEZ, we analyzed the skeletal muscle, white adipose tissue (WAT) and liver samples of BEZ-treated mice using non-targeted metabolomics (NMR spectroscopy), targeted metabolomics (mass spectrometry), microarrays and enzyme activity measurements with a particular focus on the liver. The analysis of muscle and WAT demonstrated that BEZ improved the expressions of genes and levels of metabolites, which could partly regulate the beneficial effects of BEZ on the glucose metabolism. Furthermore, in the liver, BEZ treatment reduced the elevated hepatic fumarate level of STZ mice, which was accompanied by a decreased expression of urea cycle genes. Since the urea cycle is involved in the production of fumarate, which is shown to be participated in glucotoxic pathways, our data suggest that BEZ could attenuate the urea cycle, reduce fumarate level and in turn ameliorate glucotoxicity in the liver of STZ mice We performed gene expression microarray analysis on visceral adipose tissue derived from mice treated with streptozotocin and bezafibrate