It might be possible that diacylglycerol accumulated in the intestinal cells following oil administration stimulates the release of GLP-1, since it has been known that this activation of phorbol ester-sensitive protein kinase C prospects to GLP-1 release. mice Compound B was further investigated for effects on obesity and insulin resistance in diet-induced-obese (DIO) mice. Results The 2 2 compounds comparably inhibited the DGAT1 enzyme activity and the cellular triglyceride synthesis as previously reported C. Moreover, both compounds inhibited the cellular triglyceride synthesis in HT-29, HepG2, and mouse skin homogenates. In spite of comparable profiles in vitro, we recognized that orally administered Compound A and B exhibited different distribution patterns in mice in vivo. The recent publication  indicates that distribution of DGAT1 inhibitors to the skin did correlate with its lipophilicity. However lipophilicity (Log WZ811 D) of Compound A and B were similarly low. Although the precise reason for the difference of distribution has not yet been recognized, the intestine-targeted distribution of Compound B may potentially be due to its transporter-mediated efflux from your intestine in the same way as previously discussed with another intestine-targeted DGAT1 inhibitor . It is noteworthy that this intestine/plasma and intestine/skin ratios for Compound B (10 and 74) were much higher than those for Compound A (0.32 and WZ811 5.6). Since there is a statement that Compound A shows beneficial metabolic effects , we focused on whether the predominantly intestine-targeted DGAT1 inhibitor could improve obesity and insulin resistance without skin aberrations in mice in the present study. In a model of postprandial hyperlipidemia measuring chylomicron-derived triglycerides in mice, single oral administration of Compound B reduced plasma triglyceride levels. This is consistent with the previous observations around the suppression by other DGAT1 inhibitors of postprandial hyperlipidemia C and the delayed excess fat absorption in DGAT1 null mice C. Furthermore, Compound B also increased plasma GLP-1 levels after corn oil administration. The present results WZ811 support the hypothesis that intestinal DGAT1 might directly regulate the releases of GLP-1 . It might be possible that diacylglycerol accumulated in the intestinal cells following oil administration stimulates the release of GLP-1, since it has been known that this activation of phorbol ester-sensitive protein kinase C prospects to GLP-1 release. These results highlighted that pharmacological as well as genetic inhibition of DGAT1 in the intestine would reduce dietary fat absorption and increase plasma GLP-1 levels. Long-time treatment with Compound B, which selectively inhibits intestinal DGAT1, reduced the body excess weight gain, excess weight of white adipose tissues, hepatic triglyceride and the hepatic cholesterol content in DIO mice. In addition, long-time treatment with Compound B reduced plasma glucose levels and tended to Nos3 reduce insulin concentrations, suggesting that Compound B would improve insulin resistance. In the recent publication , the pharmacokinetic/pharmacodynamic relationship of DGAT1 inhibitors between tissue concentration/IC50 and its effects was reported. High value (>1) of intestine/IC50 of Compound B in spite of its relatively low values of skin/IC50 and plasma/IC50 supports the concern that the effects of DGAT1 inhibitors are achieved by the compound in intestine. The beneficial metabolic effects of Compound B may, at least partly, be ascribed to suppressed excess fat absorption from your intestine via inhibited intestinal DGAT1, as postprandial hyperlipidemia is usually assumed to promote hepatic steatosis  and insulin resistance. In addition to reduction of excess fat absorption, since it is known that GLP-1 has beneficial metabolic effects such as reduction of body weight gain and improvement of insulin resistance, increased GLP-1 secretion via the inhibition of intestinal DGAT1 would also contribute to the favorable metabolic effects of Compound B. It is WZ811 well known that obesity, particularly excessive triglyceride deposition in the non-adipose tissues such as the skeletal muscle mass and the liver, is related to diabetes and insulin resistance C. DGAT1 inhibition in the whole body may reduce excessive triglyceride deposition in the non-adipose tissues including the skeletal muscle mass , resulting in amelioration of metabolic disorders. In contrast, however, the inhibition of DGAT1 WZ811 activities in the skeletal muscle mass or macrophage may cause insulin resistance, leading to aggravation of metabolic disorders, as a result of inhibited conversion of fatty acids substrates which induce insulin resistance into the form of triglyceride , . Those opposing actions of DGAT1 may explain the reasons why the reintroduction of DGAT1 into the intestine of DGAT1 null mice is sufficient to lose metabolic phenotypes such as for example level of resistance to hepatic steatosis and diet-induced weight problems, and just why long-time treatment with Substance B showed helpful metabolic effects such as for example insulin-sensitization and reduced amount of the body putting on weight and hepatic lipids. Long-time treatment with Chemical substance.