Agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma) are insulin sensitizers that potently improve lipemia in rodents. This study aimed to determine the contribution of lipid secretion vs. clearance and the involvement of white adipose tissue (WAT) and brown adipose tissue (BAT) in the rapid hypolipidemic action of PPARgamma agonism. Male rats were treated with rosiglitazone (RSG; 15 mg x kg(-1) x day(-1)) for 1 to 4 days, and determinants of lipid metabolism were assessed postprandially. Serum triglycerides (TG) were lowered (-54%) after 3 days of RSG treatment, due to accelerated clearance from blood without contribution of changes in secretion rates. Both BAT and WAT were the major sites of RSG action on TG clearance, the increase in TG-derived fatty acid (FA) uptake reaching threefold in BAT and 60-90% in WAT depots. Accelerated TG clearance was associated with increased lipoprotein lipase (LPL) activity mostly in BAT. Serum nonesterified FA were lowered (-20%) by a single dose of RSG, an effect associated with increased expression levels of FA binding/transport (fatty acid binding protein-4), esterification (diacylglycerol acyltransferase-1), and recycling glycerol kinase and phosphoenolpyruvate carboxykinase enzymes in BAT and WAT, suggesting FA trapping. After 4 days of RSG treatment, nonesterified fatty acid (NEFA) uptake was also stimulated in both BAT (2.5-fold) and WAT (40%). These findings demonstrate the causal involvement of increased efficiency of LPL-mediated TG clearance and reveal the important contribution of TG-derived and albumin-bound FA uptake by BAT in the rapid hypolipidemic action of PPARgamma agonism in the rat.