Figure 1.
KDT501 agonistic effect on PPAR reporter activity.
PPARα reporter cells were treated with various concentrations of GW590735 (round circles), rosiglitazone (black triangles) and KDT501 (black squares) (A). PPARγ reporter cells were treated with various concentrations of rosiglitazone, telmisartan (white squares), and KDT501 (B). PPARδ reporter cells were treated with GW0742 (white triangles), rosiglitazone and KDT501(C). Cells were treated for 20 hr and relative luminescence units (RLU) were measured as described in the methods. Agonist concentrations were transformed to log10 µM. Agonist dose- responses were plotted by non-linear regression. Data represent Mean± SD.
Figure 2.
KDT501 reduced TNF-α and LPS-mediated inflammatory markers in THP-1 monocytes.
THP-1 cells were pre-incubated in the absence or in the presence of various concentrations of KDT501, rosiglitazone, telmisartan, DHA and PGJ2 for 1 hour, and then stimulated with LPS (1 µg/mL) overnight. MCP-1, IL-6, IL-10 and RANTES levels in the medium were quantified as described in Methods. Data represent the mean ± SD from 4 independent samples. * Mean values significantly different from LPS stimulation (p<0.05).
Figure 3.
Effect of KDT501 on lipid accumulation in adipocytes.
(A) 3T3L1 adipocytes were treated with rosiglitazone (10 uM) or various concentrations of KDT501 for 6 days. (B) Human subcutaneous adipocytes were treated with rosiglitazone (1 µM), KDT501 (10 µM), telmisartan (10 µM), DHA (10 µM) or PGJ2 (10 µM) for 10 days. Intracellular lipid was quantified with Oil Red O staining and the data represented as fold induction compared to DMSO negative control. Representative data expressed as mean ± SD from 4 independent samples. * Mean values significantly different from control (p<0.05).
Figure 4.
Human subcutaneous adipocyte gene signatures.
Cells were treated with test compounds rosiglitazone (1 µM), telmisartan (10 µM) or KDT501 (25 µM) for 5 days. Gene arrays were performed and the probe sets selected were those with at least a 2-fold change as described in methods. Venn diagram represents up-regulated (A) and down regulated genes (B). KDT501-mediated (probe set 24) 3-way gene-intersection (rosiglitazone, KDT501 and telmisartan) were presented (C). * Probe set values for rosiglitazone and telmisartan are not qualified to include in the figure.
Table 1.
Gene expression profile in human subcutaneous adipocytes.
Figure 5.
KDT501 reduces body fat and improves glucose metabolism.
The test compounds were given orally twice daily for a month. Oral glucose tolerance test (OGTT) conducted as described in methods; glucose (A), insulin (B), glucose AUC (C) and insulin AUC (D) levels were presented. Body fat as determined by QNMR at the end of the study were presented (E). Data expressed as Mean ±SEM. * Mean values significantly different from vehicle control group (p<0.05).
Figure 6.
KDT501 reduces weight gain, improves glucose and fatty acid metabolism in ZDF rats.
Vehicle control (black circles) and test compounds KDT501 (100 mg = white circles, 150 mg = white triangles, 200 mg = white squares), metformin (black diamonds) and rosiglitazone (black squares) were administered orally twice daily for up to 32 days. Weight gain (A), hemoglobin A1c (B) and whole blood glucose levels (C) were presented. At the end of the study, oral glucose tolerance tests (OGTT) were conducted as described in the methods; glucose (D) and glucose AUC levels (E) were presented. Total cholesterol levels (F) were measured in the plasma. Triglyceride levels were measured at day 15 and day 30 (G). Data expressed as Mean ±SEM. * Mean values significantly different from vehicle control group (p<0.05).