Recent advances in the treatment of non-insulin-dependent diabetes mellitus (NIDDM) include the use of thiazolidinediones (TZDs), agents that enhance insulin action, in part, through an activation of adipose tissue peroxisome proliferator-activated receptor gamma. Current evidence also indicates that these agents upregulate uncoupling protein 1 (UCP1) gene expression in brown adipocytes and increase interscapular brown adipose tissue (IBAT) mass in rodents, suggestive of a thermogenic component to their mechanism of action. In the present study, the TZD pioglitazone (PIO) and the beta3-adrenoceptor agonist CL 316,243 (CL), were used to determine whether the antidiabetic effects of PIO, like those of CL, may, in part, be mediated by an increase in either IBAT thermogenesis or whole-body energy expenditure. Treatment of obese, insulin resistant fa/fa Zucker rats with PIO for 10 days resulted in a 2- to 3-fold increase in IBAT mass, due largely to an increase in adipocyte size and number, and increased fatty acid biosynthesis. However, unlike the effects of CL, the PIO-induced IBAT changes were not associated with an increase in UCP1 expression or whole-body energy expenditure. In contrast to CL, PIO substantially increased body weight gains over the 10-day treatment period by increasing feeding efficiency. These data suggest that, unlike CL, the actions of PIO in the obese Zucker rat does not include increased energy expenditure, but rather strengthens its role as an adipogenic and lipogenic agent, which promotes energy storage.