By feeding APOE*3-Leiden.CETP mice a diet rich in fat and cholesterol, we mimicked a situation in which a positive energy balance induces many aspects of the metabolic syndrome, including insulin resistance, obesity with increased fat accumulation, and hepatic lipotoxicity indicated by hepatomegaly with aberrant accumulation of TG as well as TC. The gene discussed is APOE; the disease is obesity due to melanocortin 4 receptor deficiency.