Eighteen-month-old Sprague-Dawley rats present age-related alterations in lipid and glucose metabolism and are resistant to the effect of PPARalpha-activating hypolipidemic drugs, such as gemfibrozil. We tested if these animals were responsive to the administration of rosiglitazone, an insulin-sensitizer acting on PPARgamma. We determined in 18-month-old female Sprague-Dawley rats treated for 21 days with a daily dose of 3mg gemfibrozil/kg or 3mg rosiglitazone/kg: (i) plasma concentrations of total cholesterol (TC), triglycerides (TG), nonesterified fatty acids (NEFA), glucose, insulin and leptin, (ii) hepatic concentrations of TG, NEFA and cholesteryl esters (CE), and (iii) the liver expression and binding activity of peroxisome proliferator-activated receptor alpha (PPARalpha), and several of its target genes, hepatic nuclear factor-4 (HNF-4), and liver X receptor alpha (LXRalpha). Although gemfibrozil induced mild effects on hepatic PPARalpha, HNF-4, and LXRalpha, only rosiglitazone significantly reduced plasma TG (59%), glucose (19%), insulin (61%), and leptin (66%), and liver TG (43%), CE (49%), and NEFA (27%). These changes were associated to an increased body weight gain and a decrease in visceral fat (8.7-fold and 37% vs. control females, respectively). The beneficial effect of rosiglitazone treatment in 18-month-old female rats could be related to a direct effect on white adipose tissue.