Toxicity beyond the Lung: Connecting PM2.5, Inflammation, and Diabetes

Toxicity beyond the Lung Connecting PM 2.5 , Inflammation, and DiabetesExposure to fine particulate matter (PM 2.5 ) has been associated with increased risk of heart disease, 1 insulin resistance (IR), 2 and diabetes, 3 all conditions that are characterized by inflammation.4 Experimental data suggest a high-fat diet 2 may exacerbate the health effects of inhaled PM 2.5 ; obese people also appear to be at increased risk. 1 In this issue of EHP, investigators tease out some of the complex cellular mechanisms that could explain how PM 2.5 may work with a high-fat diet to cause IR. 5 Some of the authors previously reported that mice breathing PM 2.5 and eating a high-fat diet developed IR, systemic inflammation, and increased abdominal fat, compared with mice eating the same diet but breathing filtered air. 2 For the current study, the investigators focused on CCR2, a protein that recruits innate immune cells to insulin-sensitive tissues such as visceral fat and the liver, where it induces the inflammation characteristically seen in animal models of obesity and type 2 diabetes.6 They compared wild-type mice that produce CCR2 with "knockout" (CCR2 -/-) mice that don't.All the mice were fed a high-fat diet and then for 17 weeks were exposed to either filtered air or air containing 117 µg/m 3 of PM 2.5 .Among the key findings, PM 2.5 exposure was associated with increased IR and increased levels of liver lipids in the wild-type mice.The elevated liver lipids resulted from a rise in SREBP-1c activity 5 ; this protein helps regulate fatty acid synthesis.7 In contrast, liver lipid levels and SREBP-1c activity in CCR2 -/-mice were equivalent whether the mice were exposed to PM 2.5 or breathing filtered air. 5 IR is also characterized by abnormal insulin signaling through the AKT pathway.Reduced phosphorylation of this enzyme is associated with inflammation.8 The researchers found that phosphorylation of AKT was reduced in wild-type mice exposed to PM 2.5 but unchanged in CCR2 -/-mice.PM 2.5 exposure also was associated with higher levels of inflammatory F4/80 macrophages in visceral fat stores, but only in wild-type mice.5 The important message in all these findings is that PM 2.5 recruits inflammatory cells via CCR2-dependent mechanisms."This mechanism directly ties a known inflammatory mechanism in the pathogenesis of type 2 diabetes to exposure to environmental air