Abstract 558: Metabolic Syndrome in Mice Lacking All Nitric Oxide Synthase Isoforms
Background: Nitric oxide (NO) is synthesized by three different isoforms of NO synthase (NOS), including neuronal (nNOS), inducible (iNOS), and endothelial NOSs (eNOS). We have recently succeeded in developing mice in which all three NOS genes are totally disrupted (triply n/i/eNOS−/− mice) (PNAS 2005). In this study, we examined whether or not those mice manifest phenotypes of metabolic syndrome in humans.
Methods: Experiments were performed in 3-month-old male wild-type and triply n/i/eNOS−/− mice. Blood pressure was measured by the tail-cuff method. Plasma lipid profile was assessed by the high-performance liquid chromatography. Glucose metabolism and insulin resistance were evaluated by glucose tolerance test and by insulin-stimulated [3H]-2-deoxyglucose uptake in isolated soleus muscle, respectively.
Results: Triply n/i/eNOS−/− mice showed hypertension (systolic blood pressure; 150±3 vs. 112±2 mmHg) and hypertriglyceridemia (153±12 vs. 109±7 mg/dl) as compared with wild-type mice (P<0.05 each, n=6 –12). The triply n/i/eNOS−/− mice also exhibited impaired glucose tolerance (plasma glucose level at 15 min after intravenous glucose injection; 475±43 vs. 241±20 mg/dl) and severe insulin resistance (insulin-stimulated muscular [3H]-2-deoxyglucose uptake; 109±6% vs. 209±26%) compared with the wild-type mice (P<0.05 each, n=6 – 8). Furthermore, visceral obesity (amount of epididymal white adipose tissue; 0.28±0.02 vs. 0.19±0.01 g), associated with adipocyte hypertrophy (diameter of adipocytes; 10.3±0.2 vs. 7.2±0.2 μm), was noted in the triply n/i/eNOS−/− mice (P<0.05 each, n=8 –10). Importantly, supplementation of NO by long-term dermal application of isosorbide dinitrate (0.4 mg/day, 6 weeks) normalized those metabolic phenotypes (hypertriglyceridemia [105±6 mg/dl], impaired glucose tolerance [280±28 mg/dl], insulin resistance [153±10%], and visceral obesity [0.14±0.01 g]) in the triply n/i/eNOS−/− mice (all P<0.05, n=7–9).
Conclusions: These results provide the first evidence that genetic disruption of the whole NOS system results in the development of metabolic syndrome in mice in vivo. Our triply mutant mouse may be a new animal model of the disorder.