A recent study also demonstrated that the increases in SREBP-1 and ChREBP-1-dependent fatty acid synthesis pathways, which are responsible for converting excess carbohydrate to fatty acid for long-term storage, are paralleled by markedly decreased PPAR-a, PPAR-d, and their target enzyme, acyl-CoA oxidase, which mediate fatty acid oxidation. It has been known that SREBP-1c is strongly linked to diabetic nephropathy, in which hyperglycemia activates mesangial SREBP-1c, ROS and mesangial proliferation and glomerular fibrosis. In the current study, fenofibrate decreased SREBP-1 and ChREBP-1 and increased phosphorylation of ACC, which correlated with decreased lipid contents in the kidney. We also demonstrated that high-glucose treatment of mesangial cells induced the expression of genes involved in fatty acid synthesis, such as those encoding SREBP-1 and ChREBP-1. Fenofibrate reversed all of these changes, suggesting that the renoprotective impact of fenofibrate may be mediated by shifting the gene expression profile of the cells to a state that inhibits lipogenesis. To date it has been known that PGC-1a is inactivated by the phosphorylation of Akt and Akt can have a negative impact on the PGC-1a expression via inactivation of the FoxOs factors, FoxO1 and FoxO3a which act as transcriptional regulators of PGC-1a expression. In obese or diabetic states, the FoxO1 and FoxO3a-dependent gene expression promotes some of the deleterious characteristics associated with hyperglycemia, glucose intolerance and lipotoxicity. Currently, it is not known whether there are differences in the activation levels of separate FoxO factors, particularly in different tissues. The renal expression of phospho-Ser256 FoxO1 and phosphor-Ser253 FoxO3a by fenofibrate treatment in overfed spontaneously hypertensive rats showed that phospho-Ser253 FoxO3a was strongly expressed in the cytoplasm of podocytes in the glomerulus and the collecting tubules, while phospho-Ser256 FoxO1 was strongly expressed in the proximal tubules and very weakly expressed in the glomerulus in the immunohistochemical staining. In this study, fenofibrate treatment markedly decreased the renal expression of phosphor-Ser253 FoxO3a, whereas it did not have any effect on the phospho-Ser256 FoxO1 expression in the diabetic mice. The inactivation of PI3K/Akt and the activation of FoxO3a were one of the main pathways to reduce lipoapoptosis and oxidative stress as represented by the decrease of urinary 8-epi PDF2a levels, which resulted in increases of anti-apoptotic BCL-2 and the antioxidants and a decrease of the pro-apoptotic gene BAX in diabetic mice. Interestingly, there is a strong overlap in the genes transcriptionally regulated by AMPK and those by PGC-1a, hence suggesting that PGC-1a might be an important mediator AMPK-induced gene expression. Supporting this hypothesis, AMPK activation leads to increased PGC-1a expression, and AMPK requires PGC-1.