Repeated ozone exposure exacerbates insulin resistance and activates innate immune response in genetically susceptible mice

Abstract

Background: Inhaled ozone (O₃) has been demonstrated as a harmful pollutant and associated with chronic inflammatory diseases such as diabetes and vascular disorders. However, the underlying mechanisms by which O₃ mediates harmful effects are poorly understood.

Objectives: To investigate the effect of O₃ exposure on glucose intolerance, immune activation and underlying mechanisms in a genetically susceptible mouse model.

Methods: Diabetes-prone KK mice were exposed to filtered air (FA), or O₃ (0.5 ppm) for 13 consecutive weekdays (4 h/day). Insulin tolerance test (ITT) was performed following the last exposure. Plasma insulin, adiponectin, and leptin were measured by ELISA. Pathologic changes were examined by H&E and Oil-Red-O staining. Inflammatory responses were detected using flow cytometry and real-time PCR.

Results: KK mice exposed to O₃ displayed an impaired insulin response. Plasma insulin and leptin levels were reduced in O₃-exposed mice. Three-week exposure to O₃ induced lung inflammation and increased monocytes/macrophages in both blood and visceral adipose tissue. Inflammatory monocytes/macrophages increased both systemically and locally. CD4 + T cell activation was also enhanced by the exposure of O₃ although the relative percentage of CD4 + T cell decreased in blood and adipose tissue. Multiple inflammatory genes including CXCL-11, IFN-γ, TNFα, IL-12, and iNOS were up-regulated in visceral adipose tissue. Furthermore, the expression of oxidative stress-related genes such as Cox4, Cox5a, Scd1, Nrf1, and Nrf2, increased in visceral adipose tissue of O₃-exposed mice.

Conclusions: Repeated O₃ inhalation induces oxidative stress, adipose inflammation and insulin resistance.

• Air pollution
• inflammation
• insulin resistance
• oxidative stress
• ozone exposure

Declaration of interest

The authors declare no conflict of interests in this paper.

Funding information

This publication was made possible by US Environmental Protection Agency grant (R834797 to Drs. Rajagopalan and Harkema). SR was supported by RO1 ES015146 and R01 ES017290. JZ was supported by grants from NIDDK/NIH (K01 DK105108), American Heart Association (15SDG25700381 and 13POST17210033) and Mid-Atlantic Nutrition Obesity Research Center under NIH award number P30DK072488. XW was supported by a grant from Natural Science Foundation of Jiangsu Province (13KJB330007).