Artemisia herbs have been reported to have anti-diabetic and anti-hyperlipidemic activities in diabetic patients and rats. However, molecular mechanisms whereby Artemisia exerts its benefit on lipid and glucose metabolism remain unknown. In this study, we screened medicinal herbs to search for natural PPARd ligands. We found that a 95% ethanol extract of Artemisia iwayomogi directly interacted with PPARd, enhanced the expression of genes involved in lipid catabolism and induced PPARd-dependent activation of fatty acid oxidation. Furthermore, administration of 95EEAI to mice fed a high-fat diet enhanced fatty acid oxidation in the skeletal muscle and protected against diet-induced obesity. Since PPARd activators have been shown to improve insulin resistance and reduce plasma glucose in rodent models of type 2 diabetes and reduce serum triglycerides in sedentary human, we aimed to test whether AI extracts have the ability to activate PPARd as a potential mechanism of action in mediating its beneficial effects. We showed that 95EEAI interacted with the PPARd LBD leading to its activation. A 95 EEAI increased the expression of genes involved in lipid catabolism,Ginsenoside-F1 enhanced fatty acid oxidation and insulin-stimulated glucose uptake in vivo as well as in human skeletal muscle cells, protected against diet-induced obesity. Furthermore, in PPARd knockdown cells, the positive effects of 95EEAI on fatty acid oxidation and their related genes expression were no longer observed, suggesting that 95EEAI-mediated lipid metabolism would be PPARd-dependent. However, knockdown of PPARd expression did not alter the 95EEAI-mediated increase in insulin-stimulated glucose uptake. This result is in line with the report by Kramer et al. suggesting that direct activation of PPARd itself is not necessary for the stimulation of glucose uptake. In vivo study, administration of 95EEAI to mice fed a HFD had no effect on fasting levels of blood glucose. Our finding is in line with the work of Tanka et al. who was also unable to detect changes in blood glucose levels Protopanaxtriol in PPARd agonist-treated mice, despite the marked improvement in glucose tolerance and insulin sensitivity. Brunmair et al. have reported that activation of PPARd acts to suppress glucose utilization as a result of a switch in substrate preference from carbohydrates to lipids in skeletal muscle, thus PPARd agonist fails to exert any effect on glucose uptake. Lee et al. suggest that the improved glucose tolerance and insulin sensitivity triggered by PPARd agonist is due to promoting an increase in glucose flux through the pentosephosphate pathway and enhancing hepatic fatty acid synthesis. More studies are needed to elucidate the exact relationship between glucose utilization and 95EEAI-induced PPARd activation During starvation, glucose uptake and oxidation are reduced rapidly in muscle, which shifts to use free fatty acids and ketone bodies. In this study, 95EEAI-treated mice on an HFD showed a significant decrease in the plasma levels of free fatty acids and ketone bodies. Tanka et al. showed that the changes in gene expression by PPARd agonist are very similar to the gene expression profile induced by fasting in skeletal muscle. Hence, we speculate that the changes in levels of ketone bodies may be attributed to, at least in part, an increased uptake of ketone bodies in muscle through an activation of PPARd by 95EEAI. The major compounds isolated from Artemisia species include terpenoids, flavonoids, coumarins, acetylenes, caffeoylquinic acids, and sterols. Major compounds of 95EEAI had no detectable effect on activation of PPARd protein. Saturated and unsaturated fatty acids, such as arachidonic acid and eicosapentaenoic acid, are reported to be natural ligands for PPARd.