In an apoE-/- mouse model, long-term exposure to low concentration of PM2.5 altered vasomotor tone, induced vascular inflammation, and potentiated atherosclerosis.

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.

Background DPP-4 inhibitors are increasingly used to accomplish glycemic targets in patients with Type II diabetes (T2DM). Since DPP-4 is expressed in inflammatory cells, we hypothesized that its inhibition will exert favorable effects in atherosclerosis. Methods and Results Male LDLR-/- mice (6 weeks) were fed with a high fat diet (HFD) or normal chow diet (NCD) for 4 weeks and then randomized to vehicle or Alogliptin, a high affinity DPP-4 inhibitor (40 mg/kg/day) for 12 weeks. Metabolic parameters, blood pressure, vascular function, atherosclerosis burden and indices of inflammation were obtained in target tissues including the vasculature, adipose and bone marrow with assessment of global and cell specific inflammatory pathways. In-vitro and in-vivo assays of DPP-4 inhibition (DPP-4i) on monocyte activation/migration were conducted in both human and murine cells and in a short-term ApoE-/- mouse model. DPP-4i improved markers of insulin resistance and reduced blood pressure. DPP-4i reduced visceral adipose tissue macrophage content (ATMs; CD11b+, CD11c+, Ly6Chi) concomitant with up-regulation of CD163. DPP-4 was highly expressed inbone-marrow derived CD11b+ cells with DPP-4i down-regulating pro-inflammatory genes in these cells. DPP-4i decreased aortic plaque with a striking reduction in plaque macrophages. DPP-4i prevented monocyte migration and actin polymerization in in-vitro assays via Rac dependent mechanisms and prevented in-vivo migration of labeled monocytes to the aorta in response to exogenous TNFα and DPP-4. Conclusion DPP-4i exerts anti-atherosclerotic effects and reduces inflammation via inhibition of monocyte activation/chemotaxis. These findings have important implications for the use of this class of drugs in atherosclerosis.

BackgroundThe development of insulin resistance (IR) in mouse models of obesity and type 2 diabetes mellitus (DM) is characterized by progressive accumulation of inflammatory macrophages and subpopulations of T cells in the visceral adipose. Regulatory T cells (Tregs) may play a critical role in modulating tissue inflammation via their interactions with both adaptive and innate immune mechanisms. We hypothesized that an imbalance in Tregs is a critical determinant of adipose inflammation and investigated the role of Tregs in IR/obesity through coordinated studies in mice and humans.Methods and Findings Foxp3-green fluorescent protein (GFP) “knock-in” mice were randomized to a high-fat diet intervention for a duration of 12 weeks to induce DIO/IR. Morbidly obese humans without overt type 2 DM (n = 13) and lean controls (n = 7) were recruited prospectively for assessment of visceral adipose inflammation. DIO resulted in increased CD3+CD4+, and CD3+CD8+ cells in visceral adipose with a striking decrease in visceral adipose Tregs. Treg numbers in visceral adipose inversely correlated with CD11b+CD11c+ adipose tissue macrophages (ATMs). Splenic Treg numbers were increased with up-regulation of homing receptors CXCR3 and CCR7 and marker of activation CD44. In-vitro differentiation assays showed an inhibition of Treg differentiation in response to conditioned media from inflammatory macrophages. Human visceral adipose in morbid obesity was characterized by an increase in CD11c+ ATMs and a decrease in foxp3 expression.ConclusionsOur experiments indicate that obesity in mice and humans results in adipose Treg depletion. These changes appear to occur via reduced local differentiation rather than impaired homing. Our findings implicate a role for Tregs as determinants of adipose inflammation.