Ambient Air Pollution Exaggerates Adipose Inflammation and Insulin Resistance in a Mouse Model of Diet-Induced Obesity

Abstract

Background There is a strong link between urbanization and type 2 diabetes mellitus. Although a multitude of mechanisms have been proposed, there are no studies evaluating the impact of ambient air pollutants and the propensity to develop type 2 diabetes mellitus. We hypothesized that exposure to ambient fine particulate matter (<2.5 μm; PM2.5) exaggerates diet-induced insulin resistance, adipose inflammation, and visceral adiposity. Methods and Results Male C57BL/6 mice were fed high-fat chow for 10 weeks and randomly assigned to concentrated ambient PM2.5 or filtered air (n=14 per group) for 24 weeks. PM2.5-exposed C57BL/6 mice exhibited marked whole-body insulin resistance, systemic inflammation, and an increase in visceral adiposity. PM2.5 exposure induced signaling abnormalities characteristic of insulin resistance, including decreased Akt and endothelial nitric oxide synthase phosphorylation in the endothelium and increased protein kinase C expression. These abnormalilties were associated with abnormalities in vascular relaxation to insulin and acetylcholine. PM2.5 increased adipose tissue macrophages (F4/80+ cells) in visceral fat expressing higher levels of tumor necrosis factor-α/interleukin-6 and lower interleukin-10/N-acetyl-galactosamine specific lectin 1. To test the impact of PM2.5 in eliciting direct monocyte infiltration into fat, we rendered FVBN mice expressing yellow fluorescent protein (YFP) under control of a monocyte-specific promoter (c-fms, c-fmsYFP) diabetic over 10 weeks and then exposed these mice to PM2.5 or saline intratracheally. PM2.5 induced YFP cell accumulation in visceral fat and potentiated YFP cell adhesion in the microcirculation. Conclusion PM2.5 exposure exaggerates insulin resistance and visceral inflammation/adiposity. These findings provide a new link between air pollution and type 2 diabetes mellitus.

MECHANISMS IN ENDOCRINOLOGY: Effect of long-term exposure to air pollution on type 2 diabetes mellitus risk: a systemic review and meta-analysis of cohort studies

“…Insulin resistance is a main potential mechanism explaining the associations mentioned earlier. Both experimental and epidemiologic studies suggest that environmental exposures to air pollutants can increase the risk of insulin resistance, which may lead to an obvious link between air pollution and type 2 diabetes mellitus (35,36,37). Inflammation is another potential mechanism explaining the associations reported in this meta-analysis.…”

“…Previous studies also suggest that PM2.5 can recruit inflammatory cells via CC chemokine receptor 2-dependent mechanism, which is a known inflammatory mechanism in the pathogenesis underlying the association between air pollution and type 2 diabetes (35,41). In addition, previous experimental studies also show that tumor necrosis factor-a, interleukin-6, and leptin levels are also elevated on exposure to PM2.5, which suggests that exposure to ambient PM2.5 can be associated with elevated proinflammatory biomarkers and inflammatory responses (37,39,40). It is clear that further data from both experimental and epidemiologic studies are needed to provide more insights into the adverse effect of air pollution on type 2 diabetes risk.…”

Differential DNA methylation and PM2.5 species in a 450K epigenome-wide association study

“…For instance, long-term PM 2.5 exposure resulted in systemic inflammation, increased visceral adiposity, and insulin resistance among mice on a high fat diet. 52 In mice consuming normal diets, PM exposure was a risk factor for the development of type II diabetes, as it induced insulin resistance and impaired glucose tolerance. 53 Similarly, in humans, long-term exposure to particulate matter was linked to increased risk of type II diabetes in a large cohort study.…”

Chemical and non-chemical stressors affecting childhood obesity: a systematic scoping review

“…Much of the research conducted for chemical responses employs animal studies, where outcomes and trans-generational responses can be observed in a relatively short period of time. 127,147,148,[174][175][176] Based on the selection scheme detailed in this paper's methodology, only 33% of the studies included in the literature review considered environmental chemical exposures that were not a consequence of prenatal cigarette smoke exposure or physicianprescribed medications. The most common chemical exposures included perfluorinated compounds, phthalates, and outdoor air pollution.…”