Metabolic Syndrome Is Associated with Increased Oxo-Nitrative Stress and Asthma-Like Changes in Lungs

Epidemiological studies have shown an increased obesity-related risk of asthma. In support, obese mice develop airway hyperresponsiveness (AHR). However, it remains unclear whether the increased risk is a consequence of obesity, adipogenic diet, or the metabolic syndrome (MetS). Altered L-arginine and nitric oxide (NO) metabolism is a common feature between asthma and metabolic syndrome that appears independent of body mass. Increased asthma risk resulting from such metabolic changes would have important consequences in global health. Since high-sugar diets can induce MetS, without necessarily causing obesity, studies of their effect on arginine/NO metabolism and airway function could clarify this aspect. We investigated whether normal-weight mice with MetS, due to high-fructose diet, had dysfunctional arginine/NO metabolism and features of asthma. Mice were fed chow-diet, high-fat-diet, or high-fructose-diet for 18 weeks. Only the high-fat-diet group developed obesity or adiposity. Hyperinsulinemia, hyperglycaemia, and hyperlipidaemia were common to both high-fat-diet and high-fructose-diet groups and the high-fructose-diet group additionally developed hypertension. At 18 weeks, airway hyperresponsiveness (AHR) could be seen in obese high-fat-diet mice as well as non-obese high-fructose-diet mice, when compared to standard chow-diet mice. No inflammatory cell infiltrate or goblet cell metaplasia was seen in either high-fat-diet or high-fructose-diet mice. Exhaled NO was reduced in both these groups. This reduction in exhaled NO correlated with reduced arginine bioavailability in lungs. In summary, mice with normal weight but metabolic obesity show reduced arginine bioavailability, reduced NO production, and asthma-like features. Reduced NO related bronchodilation and increased oxo-nitrosative stress may contribute to the pathogenesis.

流行病学研究表明，哮喘的肥胖相关风险显著升高。与此相印证，肥胖小鼠可出现气道高反应性（airway hyperresponsiveness, AHR）。然而，目前仍不清楚该风险升高究竟源于肥胖、致肥胖饮食，还是代谢综合征（metabolic syndrome, MetS）。L-精氨酸与一氧化氮（nitric oxide, NO）代谢紊乱是哮喘与代谢综合征共有的典型特征，且该特征似乎与体质量无关。由这类代谢改变引发的哮喘风险升高，将对全球公共卫生造成重要影响。鉴于高糖饮食可诱发代谢综合征却未必导致肥胖，探究其对精氨酸/NO代谢与气道功能的影响，或可阐明这一尚未明确的问题。本研究旨在探究：经高果糖饮食诱导产生代谢综合征的正常体质量小鼠，是否存在精氨酸/NO代谢功能异常以及哮喘相关表型。实验小鼠被分为三组，分别接受普通饲料饮食、高脂饮食或高果糖饮食干预18周。仅高脂饮食组小鼠出现肥胖或体脂堆积。高脂饮食组与高果糖饮食组小鼠均出现高胰岛素血症、高血糖症与高脂血症，且高果糖饮食组小鼠额外并发高血压。干预18周后，与普通饲料饮食组小鼠相比，高脂饮食诱导的肥胖小鼠与非肥胖的高果糖饮食小鼠均表现出气道高反应性。两组小鼠均未观察到炎性细胞浸润或杯状细胞化生。二者的呼出气一氧化氮水平均有所降低，且该降低与肺部精氨酸生物利用度下降呈显著相关。综上，体质量正常但存在代谢性肥胖的小鼠，可出现精氨酸生物利用度降低、NO生成减少以及类哮喘表型。NO相关支气管舒张功能受损与氧亚硝基应激增强，或参与了其发病过程。