The recent development of thiazolidinediones (TZDs) as insulin sensitizers presents a new line of therapy for the treatment of type 2 diabetes. In animal studies, TZDs increase body weight largely due to increased fat pad mass and alterations in adipocyte size and numbers. Accumulating evidence indicates that ghrelin plays a role in regulating food intake and energy homeostasis. We examined whether oral pioglitazone administration regulates plasma ghrelin concentration and body weights using Zucker fatty rats (ZFR). ZFRs were administered pioglitazone orally (20 mg/kg/day) for 4 weeks. Food consumption in the pioglitazone-treated group (ZFR/PIO (+)) was significantly greater than that of the control group (ZFR/PIO (-)). Body weight of the ZFR/PIO (+) was also significantly greater than that of the ZFR/PIO (-). The ZFR/PIO (+) exhibited a significant increase in whole body energy expenditure. Fasting plasma ghrelin concentration in the ZFR/PIO (+) was significantly lower than that in the ZFR/PIO (-). These findings indicate that increase in food consumption by pioglitazone is not associated with fasting plasma ghrelin and that ghrelin secretion is down-regulated under positive energy balance in rats. © 2007 Elsevier Ireland Ltd. All rights reserved.