The metabolic syndrome is a group of disorders including obesity, insulin resistance, atherogenic dyslipidemia,hyperglycemia, and hypertension. To date, no animal model has been described to recapitulate all aspects of the syndrome. In this study, we generated and characterized two lines of triple knockout mice that are deficient in either Apolipoprotein E (Apoe^-/-) or low density lipoprotein receptor (Ldlr^-/-) and express no leptin (Lep^ob/ob) or Apolipoprotein B-48 but exclusively Apolipoprotein B-100 (Apob^100/100). These two lines are referred to as Apoe triple knockout-Apoe 3KO (Apoe^-/-Apob^100/100Lep^ob/ob) and Ldlr triple knockout-Ldlr 3KO (Ldlr^-/-Apob^100/100Lep^ob/ob) mice. Both lines develop obesity, hyperinsulinemia, hyperlipidemia, hypertension and atherosclerosis. However, only Apoe 3KO mice are hyperglycemic and glucose intolerant and are more obese than Ldlr 3KO mice. To evaluate the utility of these lines as pharmacological models, we treated both with leptin and found that leptin therapy ameliorated most metabolic derangements. Leptin was more effective in improving glucose tolerance in Ldlr 3KO than Apoe 3KO animals. The reduction of plasma cholesterol by leptin in Ldlr 3KO mice can be accounted for by its suppressive effect on food intake. However, in Apoe 3KO mice, leptin further reduced plasma cholesterol independent of its effect on food intake, and this improvement correlated with a smaller plaque lesion area. These effects suggest a direct role of leptin in modulating VLDL levels and, likewise, the lesion areas in VLDL-enriched animals. These two lines of mice represent new models of the metabolic syndrome and will be useful in testing therapies targeted for combating the human condition.