PPAR agonists, thiazolidinediones, cause fluid retention and edema due to unknown mechanisms. We characterized the effect of rosiglitazone (RSG), a thiazolidinedione, to induce vascular permeability, vascular endothelial growth factor (VEGF) expression, and protein kinase C (PKC) activation with edema and wt gain. In lean, fatty and diabetic Zucker rats, and endothelial insulin receptor knockout mice, RSG increased wt and vascular permeability, selectively in fat and retina, but not in heart or skeletal muscle. H₂O content and wt of epididymal fat were increased by RSG and correlated to increases in capillary permeability in fat and body wt. RSG induced VEGF mRNA expression and PKC activation in fat and retina up to 2.5-fold. Ruboxistaurin, a PKC isoform inhibitor, in the latter 2 wk of a 4-wk study, normalized vascular permeability in fat and decreased total wt gain, H₂O content, and wt of fat vs. RSG alone but did not decrease VEGF expression, basal permeability, or food intake. Finally, RSG did not increase wt or vascular permeability in PKC knockout vs. control mice. Thus, thiazolidinedione’s effects on edema and wt are partially due to an adipose tissue-selective activation of PKC and vascular permeability that may be prevented by PKC inhibition.--Sotiropoulos, K. B., Clermont, A., Yasuda, Y., Rask-Madsen, C., Mastumoto, M., Takahashi, J., Della Vecchia, K., Kondo, T., Aiello, L. P., King, G. L. Adipose-specific effect of rosiglitazone on vascular permeability and protein kinase C activation: Novel mechanism for PPAR agonist’s effects on edema and weight gain.