Ozone Exposure Triggers Insulin Resistance Through Muscle c-Jun N-Terminal Kinase Activation

Abstract

A growing body of evidence suggests that exposure to traffic-related air pollution is a risk factor for type 2 diabetes. Ozone, a major photochemical pollutant in urban areas, is negatively associated with fasting glucose and insulin levels, but most aspects of this association remain to be elucidated. Using an environmentally realistic concentration (0.8 parts per million), we demonstrated that exposure of rats to ozone induced whole-body insulin resistance and oxidative stress, with associated endoplasmic reticulum (ER) stress, c-Jun N-terminal kinase (JNK) activation, and disruption of insulin signaling in skeletal muscle. Bronchoalveolar lavage fluids from ozone-treated rats reproduced this effect in C2C12 myotubes, suggesting that toxic lung mediators were responsible for the phenotype. Pretreatment with the chemical chaperone 4-phenylbutyric acid, the JNK inhibitor SP600125, or the antioxidant N-acetylcysteine alleviated insulin resistance, demonstrating that ozone sequentially triggered oxidative stress, ER stress, and JNK activation to impair insulin signaling in muscle. This study is the first to report that ozone plays a causative role in the development of insulin resistance, suggesting that it could boost the development of diabetes. We therefore provide a potential mechanism linking pollutant exposure and the increased incidence of metabolic diseases.

Air Pollution and Insulin Resistance: Do All Roads Lead to Rome?

“…This is associated with impaired glucose homeostasis (8) and mobilization of energy sources during stress responses, an observation that might coincide with the adaptive insulin resistance in peripheral tissues (9) that was observed in the new work by Vella et al (5). A growing body of evidence supports the hypothesis that ozone exposure induces a neuronal response that activates stress-sensitive centers in the nucleus tractus solitarius (10,11).…”

“…On the basis of experimental studies examining the metabolic effects of ambient particulate matter (chemically complex mixtures consisting of many components) in mouse models, Rajagopalan and Brook (4) proposed that systemic inflammation, oxidative stress, and neuronal mechanisms might be involved in adipose inflammation and tissue insulin resistance. In this issue of Diabetes, Vella et al (5) report that although rats exposed to ozone did not show systemic inflammation associated with acute metabolic effects, they did exhibit insulin resistance in muscle tissue resulting from lipid and protein oxidation by-products.…”

“…This suggests that although NAC pretreatment was ineffective in protecting the lung from vascular leakage and inflammation, it reduced oxidation systemically and improved insulin signaling in muscle. Because incubation of myoblast cultures with BALF from ozone-exposed rats stimulated c-Jun N-terminal kinase-mediated signaling and replicated in vivo ozone effect on insulin signaling, Vella et al (5) believe that these oxidants are involved in muscle insulin resistance. This observation is supported by detection of labeled oxygen in the blood after inhalation of labeled ozone in rats (21).…”

“…Moreover, we are still far from understanding if transient insulin resistance can be exacerbated or if adaptation is likely over extended periods, as noted with other biological end points on repeated chronic episodic ozone exposure (7,8). Considering the magnitude of the health burden of air pollution on chronic neurological and cardiovascular disease, lipidemia, ectopic lipid accumulation, nonalcoholic steatohepatitis, and diabetes in healthy and genetically compromised individuals, more studies like that by Vella et al (5) are needed to fully understand the impact of this exposure on chronic disease. However, based on observed changes in a myriad of circulating factors (hormones, fatty acids, cholesterol, amino acids, and oxidation by-products of lipids and proteins) and alterations of peripheral metabolic homeostasis, it is quite possible that multiple mechanisms are involved in in vivo ozone-induced insulin resistance.…”

“…Vella et al (5) showed that oxidation of lipids and proteins can occur in the lung, leading to increases in oxidation by-products not only in the lung but also systemically and in muscle. They confirmed this observation by demonstrating the effectiveness of ingested N-acetyl cysteine (NAC) in reducing ozone-induced oxidation of lipids and proteins.…”