Air Pollution–Mediated Susceptibility to Inflammation and Insulin Resistance: Influence of CCR2 Pathways in Mice

Background: Epidemiologic and experimental studies support an association between PM(2.5) exposure and insulin resistance (IR). Innate immune cell activation has been suggested to play a role in the pathogenesis of these effects. Objectives: We sought to evaluate the role of CC-chemokine receptor 2 (CCR2) in PM(2.5)-mediated inflammation and IR. Methods: Wild-type C57BL/6 and CCR2(–/–) male mice were fed a high-fat diet and exposed to either concentrated ambient PM(2.5) or filtered air for 17 weeks via a whole-body exposure system. We evaluated glucose tolerance and insulin sensitivity. At euthanasia, blood, spleen, and visceral adipose tissue (VAT) were collected, and inflammatory cells were measured using flow cytometry. We used standard immunoblots, immunohistochemical methods, and quantitative PCR (polymerase chain reaction) to assess pathways of interest involving insulin signaling, inflammation, and lipid and glucose metabolism in various organs. Vascular function was assessed using myography. Results: PM(2.5) exposure resulted in whole-body IR and increased hepatic lipid accumulation in the liver, which was attenuated in CCR2(–/–) mice by inhibiting SREBP1c-mediated transcriptional programming, decreasing fatty acid uptake, and suppressing p38 MAPK activity. Abnormal phosphorylation levels of AKT, AMPK in VAT, and adipose tissue macrophage content in wild-type mice were not present in CCR2(–/–) mice. However, the impaired whole-body glucose tolerance and reduced GLUT-4 in skeletal muscle in response to PM(2.5) was not corrected by CCR2 deficiency. Conclusions: PM(2.5) mediates IR by regulating VAT inflammation, hepatic lipid metabolism, and glucose utilization in skeletal muscle via both CCR2-dependent and -independent pathways. These findings provide new mechanistic links between air pollution and metabolic abnormalities underlying IR. Citation: Liu C, Xu X, Bai Y, Wang TY, Rao X, Wang A, Sun L, Ying Z, Gushchina L, Maiseyeu A, Morishita M, Sun Q, Harkema JR, Rajagopalan S. 2014. Air pollution–mediated susceptibility to inflammation and insulin resistance: influence of CCR2 pathways in mice. Environ Health Perspect 122:17–26; http://dx.doi.org/10.1289/ehp.1306841