PPAR activation up-regulates thermogenesis-related genes in rodent white (WAT) and brown (BAT) adipose tissues without increasing whole-body energy expenditure. We tested here whether such dissociation is the result of a negative modulation of sympathetic activity to WAT and BAT and thyroid axis components by PPAR activation. Administration of the PPAR agonist rosiglitazone (15 mg/kg/day) for 7 days to male Sprague Dawley rats increased food intake (10%), feed efficiency (31%), weight gain (45%), spontaneous motor activity (60%), BAT and WAT mass, and reduced whole-body oxygen consumption. Consistent with an anabolic setting, rosiglitazone markedly reduced sympathetic activity to BAT and WAT (> 50%) and thyroid status as evidenced by reduced levels of plasma thyroid hormones (T4 and T3) and mRNA levels of BAT and liver T3-generating enzymes iodothyronine type 2 (–40%) and type 1 (–32%) deiodinases, respectively. Rosiglitazone also decreased mRNA levels of the thyroid hormone receptor (THR) isoforms 1 (–34%) and (–66%) in BAT and isoforms 1 (–20%) and 2 (–47%) in retroperitoneal WAT. These metabolic effects were associated with a reduction in mRNA levels of the pro-energy expenditure peptides CRH and CART in specific hypothalamic nuclei. A direct central action of rosiglitazone is, however, unlikely based on its low brain uptake and lack of metabolic effects of icv administration. In conclusion, a reduction in BAT sympathetic activity and thyroid status appears to, at least partly, explain the PPAR -induced reduction in energy expenditure and the fact that upregulation of thermogenic gene expression does not translate into functional stimulation of whole-body thermogenesis in vivo.