December 14, 2006; doi:10.1152/ajpregu.00761.2006.-Agonists of the peroxisome proliferator-activated receptor ␥ (PPAR␥) 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 PPAR␥ agonism. Male rats were treated with rosiglitazone (RSG; 15 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) for 1 to 4 days, and determinants of lipid metabolism were assessed postprandially. Serum triglycerides (TG) were lowered (Ϫ54%) 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 (Ϫ20%) 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 PPAR␥ agonism in the rat. triglycerides; triglyceride secretion; triglyceride clearance; lipoprotein lipase; nonesterified fatty acids PEROXISOME PROLIFERATOR-ACTIVATED receptor ␥ (PPAR␥) is a ligand-activated nuclear receptor that is highly expressed in white adipose tissue (WAT). PPAR␥ agonists of the thiazolidinedione (TZD) class are used clinically for the treatment of insulin resistance and type 2 diabetes. In addition to improving insulin sensitivity, TZDs tend to reduce circulating nonesterified fatty acid (NEFA) and, more modestly, triglycerides (TG) in humans but do so very robustly and within a few days in rodents (19,31,48). The precise mechanisms whereby TZD affect the metabolism of circulating lipids are not completely understood.Plasma TG levels represent the balance between gut-and liver-derived, TG-rich lipoprotein secretion and lipoprotein lipase (LPL)-mediated clearance in various extrahepatic tissues. The TZD rosiglitazone (RSG) given for 3 wk to insulinresistant hamsters was shown to reduce plasma TG by decreasing hepatic very low-density lipoprotein (VLDL)-TG secretion, without any apparent change in clearance (25), whereas a similar long-term treatment in obese Zucker rats reduced TG secretion but also increased their clearance (32). Thiazolidinediones strongly induce the expression of genes involved in lipid uptake, traf...