Obesity is now considered as worldwide epidemic. Obesity is considered as an independent risk factor for cardiovascular diseases. It is associated with ectopic lipid accumulation in the heart that may alter cardiac structure and function, a process termed lipotoxicity. It was proposed that sterol regulatory element binding protein (SREBP) has potential role in lipotoxicity. Thus, our purpose in this study was to assess the effect of obesity on cardiac structure and function and to evaluate the role of SREBP before and after their treatment with pioglitazone (peroxisome proliferators activated receptor- γ agonist). Forty five rats were included in this study, divided into four groups: control rats fedstandard chow (SC), pioglitazone treated- normal rats, high fat diet (HFD) fed rats, HFD- fed rats treated with pioglitazone. HFD- fed rats showed insulin resistance, increased triglycerides (TG) and free fatty acids (FFA), fat accumulation in cardiomyocytes with increased SREBP expression than those fed SC. Echocardiography showed decreased ejection fraction (EF), fractional shortening (FS) and increased left ventricular diastolic dimension (LVDd) in HFD- fed rats compared to those fed SC. Pioglitazone treatment improved insulin resistance, decreased TG, FFA and fat accumulation in cardiomyocytes; also SREBP expression was decreased with improvement in EF and FS and more deterioration in LVDd. These results emphasize the effect of obesity oncardiac lipotoxicity and associated cardiac dysfunction, and SREBP as one of the mechanisms involved in this lipotoxicty. Pioglitazone could improve lipotoxic cardiomyopathy in spite its effect on cardiac dilatation.