1. The blood glucose-lowering efficacy of rosiglitazone (RSG) and the mechanisms of associated weight gain were determined in dietary obese rats (DIOs). DIO and chow-fed rats received RSG 0.3-30 mg kg-1 daily for 21 days. 2. In DIOs, plasma glucose and insulin concentrations were reduced by RSG at dosages of 3 and 10 mg kg-1, respectively. Homeostasis model assessment (HOMA) indicated the threshold for a reduction of insulin resistance was 1 mg kg-1. Neither glucose nor insulin levels were affected by treatment in chow-fed rats. 3. RSG 0.3 mg kg-1 lowered free fatty acids (FFAs) in DIOs, whereas for plasma triglycerides (TGs), the threshold was 3 mg kg-1. By contrast, the threshold for reducing packed red cell volume (PCV) and increasing cardiac mass was 10 mg kg-1. Thus, the therapeutic index for RSG in DIOs was >3 and < or = 10. 4. Energy intake and weight gain increased in treated DIOs (by 20% and 50 g, at 30 mg kg-1) and chow-fed rats (by 25% and 35 g, at 30 mg kg-1). In DIOs, these increases coincided with falls in plasma leptin (40% lower at 30 mg kg-1) and insulin (43% lower at 30 mg kg-1). By contrast, in chow-fed rats, weight gain and hyperphagia occurred without changes in either leptin or insulin. However, reductions in FFAs below 0.4 - 0.3 mM were associated with hyperphagia and weight gain in DIO and chow-fed rats. 5. We conclude that increased energy intake and body weight did not attenuate the improved metabolism evoked by RSG in DIO rats, and that insulin action was enhanced at a dose >3 fold below the threshold for causing haemodilution and cardiac hypertrophy in DIO rats.