Thiazolidinedione (TZD)s are peroxisome proliferator-activated receptor gamma (PPARgamma) agonists regulating the expression of several genes involved in the regulation of glucose and lipid metabolism. Many clinical studies demonstrated that TZD not only improves hyperglycemia, but also has additional benefits on blood pressure, dyslipidemia, and inflammatory markers. As a result, it was expected that TZD would reduce the risk of cardiovascular disease. However, it was found that the positive data observed for surrogate markers did not necessarily correspond to positive cardiovascular outcomes. However, recently non-TZD, such as selective peroxisome proliferator-activated receptor gamma modulator are actively under investigation for treating hepatic steatosis and type 2 diabetes replacing PPARgamma agonist. For this reason PPARgamma is involved in the pathogenesis of numerous diseases including obesity, diabetes, and atherosclerosis, because of its role in decreasing insulin resistance and inflammation. We previously reported that TZD treatment may be associated with the depot-specific effects of lipid storage and energy expenditure genes on fat redistribution in individual adipose tissues and Sirt6 is also involved in TZD-mediated metabolic regulation. Taken together, these findings support the improvement of hepatic steatosis by TZD by activation of the Sirt6-AMPK pathway. In this review, we would like to discuss the actions of PPARgamma agonists on the various target organs and diseases through basic and clinical studies, on the basis of our study.