This study investigates the mechanism of cardiac dysfunction in obese Zucker Diabetic Fatty (ZDF) rats, a model of obesity due to genetic unresponsiveness to leptin. The researchers found that high levels of triacylglycerol (TG) in the myocardium, driven by increased lipogenesis and decreased fatty acid oxidation, lead to lipotoxicity and apoptosis. Key findings include: 1. **TG and Ceramide Levels**: Myocardial TG levels were significantly higher in obese rats compared to lean controls, and ceramide levels, a mediator of apoptosis, were 2-3 times higher. Inducible nitric oxide synthase (iNOS) levels, which promote apoptosis, were 4 times greater than normal. 2. **Apoptosis Indicators**: DNA laddering, an indicator of apoptosis, was 20 times higher in obese rats. Echocardiographic analysis showed reduced contractility and dilated ventricles. 3. **Troglitazone Therapy**: Treatment with troglitazone (TZG), an antisteatotic agent, significantly reduced myocardial TG and ceramide levels, completely prevented DNA laddering, and restored cardiac function. 4. **Mechanism of Apoptosis**: The increased TG and ceramide levels were associated with upregulation of iNOS, leading to increased NO production and peroxynitrite formation, which causes apoptosis. 5. **Clinical Implications**: The study suggests that lipotoxicity and lipooappoptosis may contribute to cardiac dysfunction in human obesity, similar to the observed effects in ZDF rats. Anti-lipotoxic therapies, such as TZG, could potentially prevent or reverse these complications. The findings highlight the importance of addressing lipid accumulation and oxidative stress in the prevention and treatment of obesity-related cardiac disorders.This study investigates the mechanism of cardiac dysfunction in obese Zucker Diabetic Fatty (ZDF) rats, a model of obesity due to genetic unresponsiveness to leptin. The researchers found that high levels of triacylglycerol (TG) in the myocardium, driven by increased lipogenesis and decreased fatty acid oxidation, lead to lipotoxicity and apoptosis. Key findings include: 1. **TG and Ceramide Levels**: Myocardial TG levels were significantly higher in obese rats compared to lean controls, and ceramide levels, a mediator of apoptosis, were 2-3 times higher. Inducible nitric oxide synthase (iNOS) levels, which promote apoptosis, were 4 times greater than normal. 2. **Apoptosis Indicators**: DNA laddering, an indicator of apoptosis, was 20 times higher in obese rats. Echocardiographic analysis showed reduced contractility and dilated ventricles. 3. **Troglitazone Therapy**: Treatment with troglitazone (TZG), an antisteatotic agent, significantly reduced myocardial TG and ceramide levels, completely prevented DNA laddering, and restored cardiac function. 4. **Mechanism of Apoptosis**: The increased TG and ceramide levels were associated with upregulation of iNOS, leading to increased NO production and peroxynitrite formation, which causes apoptosis. 5. **Clinical Implications**: The study suggests that lipotoxicity and lipooappoptosis may contribute to cardiac dysfunction in human obesity, similar to the observed effects in ZDF rats. Anti-lipotoxic therapies, such as TZG, could potentially prevent or reverse these complications. The findings highlight the importance of addressing lipid accumulation and oxidative stress in the prevention and treatment of obesity-related cardiac disorders.