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

Roxane E. Vella; Nicolas J. Pillon; Bader Zarrouki; Marine L. Croze; Laetitia Koppe; Michel Guichardant; Sandra Pesenti; Marie-Agnès Chauvin; Jennifer Rieusset; Alain Géloën; Christophe O. Soulage


Diabetes. 2015;64(3):1011-1024. 

In This Article

Abstract and Introduction


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.


Type 2 diabetes (T2D) is one of the most prevalent metabolic diseases worldwide and is projected to increase dramatically over the next decades because of aging populations, chronic overnutrition, and sedentary lifestyle. Environmental and lifestyle-related factors can account for roughly 90% of adult-onset diabetes,[1] and it has been suggested that T2D can be prevented by lifestyle and diet modifications.[2] There is also growing evidence for an association between traffic-related air pollution and the incidence of T2D. For instance, the hazards for diabetes were increased with particulate matter (PM) exposure,[3] whereas a statistically significant association of nitrogen dioxide (NO2) was detected with confirmed cases of diabetes or with mortality from diabetes.[4,5] In advanced polluted air environments, the action of ultraviolet (UV) rays on volatile organic compounds or NO2 is responsible for the formation of ozone (O3), another major pollutant in urban areas.[6] O3 pollution has become a major environmental challenge because of large exposed human populations both in the Western world and in developing countries.[7] Children and the elderly are particularly sensitive to the pulmonary health effects of O3, inducing or worsening asthma, chronic obstructive pulmonary diseases, and lung inflammation.[8,9] In addition, many extrapulmonary effects of O3 have been described: activation of stress-responsive regions, catecholamine biosynthesis, cell degeneration, neurochemical alterations in the central nervous system,[10,11] increased production of nitric oxide, enhanced protein synthesis and inflammation in the liver,[12] compensatory changes, edema, and increased oxidative stress in heart tissue.[13,14] Taken together, these studies demonstrate that O3 can exert many deleterious effects in distant tissues.

The role of oxidative stress in the etiology and pathogenesis of human diseases has been widely described in the past 2 decades.[15] Many studies pinpoint oxidative stress as a potential cause to both the onset and progression of T2D[16–18] and its associated complications, such as endothelial dysfunction and cardiovascular diseases.[19,20] O3 is a strong oxidant, and, although not a radical species, most of its toxic effects are mediated through free radical reactions.[21,22] Oxidative stress is indeed implicated in many deleterious effects of O3, such as pulmonary inflammation and dysfunction,[23] Alzheimer's disease,[24] and cardiovascular diseases.[25] In a recent study, Bass et al.[26] demonstrated that O3 impaired glucose homeostasis in rats; however, very little is known about the effects of O3 on metabolism and metabolic diseases.

Despite being a key issue for public health, the putative role of O3 exposure in the onset and progression of diabetes remains poorly defined. Our study demonstrates for the first time that exposure to O3, at a concentration realistically mimicking human exposure, induces insulin resistance (IR) in rodents, therefore suggesting a significant contribution of O3 in the etiology of T2D.