Generation and characterization of two novel mouse models exhibiting the phenotypes of the metabolic syndrome: Apob48^−/−Lep^ob/obmice devoid of ApoE or Ldlr

Abstract

The metabolic syndrome is a group of disorders including obesity, insulin resistance, atherogenic dyslipidemia, hyperglycemia, and hypertension. To date, few animal models have been described to recapitulate the phenotypes 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 (Lepob/ob) or apolipoprotein B-48 but exclusively apolipoprotein B-100 (Apob100/100). These two lines are referred to as Apoe triple-knockout-Apoe 3KO (Apoe−/−Apob100/100Lepob/ob) and Ldlr triple-knockout-Ldlr 3KO (Ldlr−/−Apob100/100Lepob/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 independently 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 with features of the metabolic syndrome and will be useful in testing therapies targeted for combating the human condition.

Generation and characterization of a mouse model of the metabolic syndrome: apolipoprotein E and aromatase double knockout mice

“…While not all individuals with the metabolic syndrome have hypertension, clinical studies have demonstrated that individuals with hypertension as a component of the metabolic syndrome have increased atherosclerosis (13,18) and that the presence of the metabolic syndrome represents a strong and independent risk factor for future CVD in hypertensive patients (44). The presence of hypertension as a component of the phenotype of metabolic syndrome mice is critical for comprehensively studying this disorder and is a significant point of difference between this mouse model and other, previously reported models (5,12,16,21,29,31,48).…”

Rivaroxaban, a novel oral anticoagulant, attenuates atherosclerotic plaque progression and destabilization in ApoE-deficient mice

“…The thoracic aorta was excised, opened longitudinally, and fixed with 4% paraformaldehyde. To quantify the atherosclerotic lesion of the aortic arch, we performed en face Sudan IV staining [22]. Detailed protocol is described in Supplemental Materials and Methods.…”

Mouse models of the metabolic syndrome

“…Although these mice provide a better model for MetS than do Lep ob/ob and LepR db/db mice, because of their hyperlipidemia and susceptibility to atherosclerosis, the hyperlipidemia is quite extreme and the caveat remains that they are completely deficient in leptin signaling. ;apoE -/-mice onto an apoB100 only background (named LDLR 3KO and apoE 3KO, respectively) (Lloyd et al, 2008). These mice are obese (>40 grams), hyperinsulinemic (>30 ng/ml), hyperlipidemic (total cholesterol >750 mg/dl and TGs >250 mg/dl) and hypertensive (systolic pressure >150 mmHg), as measured by the tail cuff method.…”