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

Abstract

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.

Mitochondrial Function in Allergic Disease

“…Epidemiologic data strongly connects MetS, which is strongly associated with systemic mitochondrial dysfunction at a molecular level, with asthma [2]. While asthma-like changes in lungs can occur independent of any allergy [48], there is also a synergistic convergence between allergic inflammation and metabolic stress, at the level of mitochondria. In particular, arginine metabolism seems to be tightly interconnected between allergic and metabolic processes, in the context of mitochondrial function.…”

Mechanisms of Asthma in Obesity. Pleiotropic Aspects of Obesity Produce Distinct Asthma Phenotypes

“…One reason for the decreased levels of nitric oxide might relate to lower availability of the nitric oxide synthase substrate arginine, because of competition from increased asymmetric dimethyl arginine (11). Studies in animal models suggest that such alterations in nitric oxide metabolism can be induced by dietary changes independent of weight gain: a high-fructose diet increases asymmetric dimethyl arginine and decreases exhaled nitric oxide and is associated with increased airway resistance, even without the development of obesity (18). Changes in diet and other manifestations of the obese state could contribute to increased oxidative stress and decreased nitric oxide bioavailability in the airway, leading to the development of de novo airway disease in obesity.…”

Mechanisms by which obesity impacts upon asthma

“…For example, adiponectin, an anti-inflammatory mediator that normally reduces airway inflammation, is decreased in obesity, whereas leptin, which can increase AHR, is increased in obesity 13–15. In addition, tumour necrosis factor (TNF)-α16 and oxidative stress17 18 are thought to contribute to the development of obesity-associated asthma. However, the precise pathways by which adipokines, TNF-α and oxidative stress result in asthma remain elusive.…”