Ambient Air Pollution: Adipose Inflammation

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

Qinghua Sun MD, PhD, Peibin Yue MD, PhD, Jeffrey A. Deiuliis PhD, Carey N. Lumeng MD, Thomas Kampfrath MS, Michael B. Mikolaj MD, Ying Cai MD, Michael C. Ostrowski PhD, Bo Lu PhD, Sampath Parthasarathy MBA, PhD, Robert D. Brook MD, Susan D. Moffatt-Bruce MD, PhD, Lung Chi Chen PhD, and Sanjay Rajagopalan MD^*

From the Davis Heart and Lung Research Institute (Q.S., P.Y., J.A.D., T.K., M.B.M., Y.C., S.P., S.R.), Division of Environmental Health Sciences (Q.S.), Division of Biostatistics (B.L.), Department of Molecular and Cellular Biochemistry (M.C.O.), and Division of Cardiothoracic Surgery (S.D.M.-B.), Colleges of Medicine and Public Health, Ohio State University, Columbus; Life Sciences Institute (C.N.L.) and Department of Internal Medicine (R.D.B.), University of Michigan, Ann Arbor; and Department of Environmental Medicine (L.C.C.), New York University School of Medicine, New York.

^* To whom correspondence should be addressed. E-mail: Sanjay.Rajagopalan@osumc.edu.

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>2.5) 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 PM_2.5 or filtered air (n=14 per group) for 24 weeks. PM_2.5-exposed C57BL/6 mice exhibited marked whole-body insulin resistance, systemic inflammation, and an increase in visceral adiposity. PM_2.5 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. PM_2.5 increased adipose tissue macrophages (F4/80⁺ cells) in visceral fat expressing higher levels of tumor necrosis factor-/interleukin-6 and lower interleukin-10/N-acetyl-galactosamine specific lectin 1. To test the impact of PM_2.5 in eliciting direct monocyte infiltration into fat, we rendered FVBN miceexpressing yellow fluorescent protein (YFP) under control of a monocyte-specific promoter (c-fms, c-fms^YFP) diabetic over 10 weeks and then exposed these mice to PM_2.5 or saline intratracheally. PM_2.5 induced YFP cell accumulation in visceral fat and potentiated YFP cell adhesion in the microcirculation.

Conclusion—PM_2.5 exposure exaggerates insulin resistance and visceral inflammation/adiposity. These findings provide a new link between air pollution and type 2 diabetes mellitus.