Is NAD(P)H oxidase a missing link for air pollution-enhanced obesity?

Obesity has reached epidemic proportions in the developed and developing world. The rise in obesity prevalence has resulted in an increase in the myriad serious medical problems associated with excess body fatness. Above a BMI of 30, there appears to be a detectable increase in risk from obesity-related illnesses ¹. It is the most important common risk factor for type 2 diabetes and the incidence of this disease has closely tracked the increase in obesity rates worldwide ². Troublingly, obesity is also related to many other serious human health outcomes and the list includes malignant disease, liver disease, polycystic ovary syndrome and osteoarthritis ¹. Thus the overall health care burden attributable to obesity is immense. While the most commonly advanced reasons for obesity are the widening availability of low-cost high fat diets, certain food marketing practices and institutionally driven reductions in physical activity ³, alternative hypotheses have been posited. The multi-factorial causality for obesity is well established and includes genetic, dietary, economic, psychological, reproductive, pharmacological, and environmental factors ⁴.

Airborne pollution as a risk for human health other than pulmonary/respiratory disorders is an emerging concept with the recognition of novel mechanisms having been discovered in recent decades. Particulate air pollution or the presence of particulate matter (PM) in inspired air has received attention as the leading candidate for pollution-related increase in morbidity. Recently reports of the United States Environmental Protection Agency (EPA) have concluded that there are significant negative health effects that accrue from exposure to PM pollution. In general, data suggests that smaller particles may pose a greater threat to human health. Inhalable particles are generally defined to be smaller than 10 μ aerodynamic diameter (PM₁₀). Since the 1990s, even smaller particles have been implicated and these are of a size which allows penetration of the alveolar gas-exchange regions [up to 2.5 μ (PM_2.5)] and of these, those that are 0.1 μ or less can be directly absorbed into the systemic circulation ^{5, 6}. It has been conjectured that an exponential increase in the use of fossil fuel burning motor vehicles (a phenomenon that is very recent; likely only three decades old), is the primary contributor in the appearance of PM air pollution ⁷.

It has been demonstrated that inhaled air pollution particles in the fine or ultrafine range, such as PM2.5, can transgress into the systemic circulation and are linked strongly with the pathogenesis of metabolic and cardiovascular disease. However, the understanding of molecular and cellular mechanisms underlying PM2.5-associated systemic diseases remains incomplete. In this issue, Xu et al report a novel signaling pathway by which airborne PM2.5 perturbs redox homeostasis and inflammation. Using genetically modified mice which are unable to release superoxide anions and superoxide-derived oxidants from NAD(P)H oxidase, they found that PM2.5 increases obesity and insulin resistance in vivo by NAD(P)H oxidase-derived superoxide anions. Superoxide anions and their derived oxidants including hydrogen peroxide and peroxynitrite are known to suppress vascular endothelial function and lower insulin responsiveness ⁸. The NAD(P)H oxidase, a membrane-bound enzyme complex, consists of multiple subunits including p22^phox, p40^phox, p47^phox, p67^phox, NoxO1, NoxA1, Rac1 and gp91^phox-related unique isoforms of Nox ⁹. The complex is normally latent in neutrophils and is activated to assemble in the membranes during respiratory burst. The authors’ choice of targeting the p47^phox subunit of NAD(P)H was based on its homology in both phagocytic and non-phagocytic inflammatory pathways that are implicated in NAD(P)H mediated insulin resistance. In an elegant series of experiments using C57BL6 and p47^phox homozygous knockout mice, the investigators have systematically assembled evidence that PM_2.5 exposure when the animals were 3-week-old young pups, induced a later life phenotype that manifested increase in abdominal fat, increased adipocyte size and heightened inflammatory cellular response. This study suggests that early life exposure to PM_2.5 scale particulate pollution primes the system toward developing insulin resistance and a pro-inflammatory vascular phenotype in later life, likely via NAD(P)H oxidase-derived superoxide anions (Figure).

Figure.

Hypothesized mechanism of insulin resistance and adipocyte hypertrophy in mice exposed to PM_2.5. PM in inspired air can activate immune competent cells such as monocytes and macrophages. Xu et al report that such exposure induces increased adipocyte diameter via NAD(P)H oxidase activation and insulin resistance, ostensibly through immune activation and cytokine release. They also document changes in vasomotor responses in response to agonists as well as insulin. The dashed arrow with query is a less established mechanistic links between inspiring PM_2.5 and endothelial dysfunction. Insulin resistance and obesity, due to changes in adipocyte size and numbers, can in turn feedback to the vasculature compounding the deleterious phenotype.

Reactive oxygen species from oxidants-releasing enzymes such as NAD(P)H oxidase are known to play a causal role in the development of insulin resistance and endothelial dysfunction ¹⁰. Air pollutant such as PM_2.5 is known to cause endothelial dysfunction in hypertension ¹¹ and atherosclerosis ¹² by increasing the formation of reactive oxygen species. In current study, Xu et al also profiled vascular function by examining vasodilatory and vasorelaxative responses to pharmacological agonists including insulin. While animals that were exposed to PM_2.5 in air exhibited disturbed vasomotor responses to acetylcholine, phenylepherine and insulin, there did not appear to be significant differences in this regard between wild type mice and p47^phox knockout animals, suggesting other sources of reactive oxygen species or alternative mechanisms for abnormal endothelial functions caused by PM2.5. Indeed, this result would also not reconcile with the groups own previous findings that both p22^phox and p47^phox mRNA levels were increased in aortic tissues harvested from Sprague-Dawley rats which had been infused with angiotensin II (AngII) and exposed to PM_2.5 in inspired air. Whether the difference can be explained by inter species or different age of mice for PM2.5 exposure is unknown. In addition, why global improvement of insulin signaling in p47^phox knockout mice had minimal effects on endothelial function in PM2.5 exposed mice warrants further investigation.

This paper has provided novel biological insights into the molecular basis of PM2.5-induced intracellular events, highlighting the activation of NAD(P)H oxidase upon PM2.5 exposure. More specifically, it points to delayed effects of air pollution whose ultimate consequences may remain obscure for decades, which adds to the insidious nature of this proposed hazard. Thus, this study might be potentially important as it has addressed the impacts of airborne PM2.5 on the functioning of signaling pathways with significant roles in redox homeostasis and inflammation.