Abstract 14421: CXCR3 Controls T Cell Accumulation in Fat Inflammation
Introduction: Obesity associates with increased numbers of inflammatory cells in visceral adipose tissue (VAT), including macrophages and T cells. Although previous studies have examined the mechanisms of macrophage accumulation in obese VAT, the mediators of local T cell accumulation remain unknown.
Hypothesis: We assessed the hypothesis that CXCR3 participates in VAT T cell accumulation, and thus in local inflammation and systemic metabolism.
Methods/Results: Male C57BL/6 and CXCR3-deficient mice (CXCR3−/−) consumed high-fat diet (HFD) for 8 or 16 weeks (wks). Lean C57BL/6 mice were maintained on low-fat diet (LFD). After 8 wks of HFD, VAT-derived stromal vascular cells (SVCs) from obese C57BL6 mice had higher CXCR3 mRNA levels than lean controls (fold change 2.4±0.2; p=0.017; n=5/group). After 8 and 16 wks of HFD, VAT from obese CXCR3−/− mice (n=14) contained significantly fewer T cells (% cells) than obese controls (n=15) according to flow-cytometry: CD3 (8 wks: 2.3±0.9 vs 3.3±0.5; 16 wks: 7±0.9 vs 13±2.4; p<0.01), CD4 (8 wks: 1.5±1 vs 2.6±0.7; 16 wks: 4±0.3 vs 10±3.5; p<0.02), and CD8 (8 wks: 0.8±0.3 vs 1.9±0.4; 16 wks: 3.4±0.4 vs 8.9±1.8; p<0.001). After 16 wks on HFD, CXCR3−/− mice also had fewer CD25-positive cells (3.5±0.44 vs 4.4±0.58; p=0.02). Obese CXCR3−/− mice had better glucose tolerance than obese controls (AUC: 22,001±5,599 vs 27,184±3,614; p<0.001; n=19–22/group) after 8 wks but not after 16 wks on HFD. CXCR3 deficiency also modulated the expression of genes that regulate inflammation in obese animals. CXCR3−/− mice fed HFD for 8 wks had reduced mRNA expression of pro-inflammatory mediators such as MCP-1 (fold-change 0.13±0.8; p=0.008) and RANTES (fold-change 0.35±0.2; p=0.001), while mice fed HFD for 16 wks had reduced levels of mRNAs that encode anti-inflammatory genes such as FoxP3 (fold-change 0.17± 0.27; p=0.001), IL-10 (0.26±0,34; p=0.005), and arginine-1 (0.12±0.2; p=0.001) in VAT compared to obese controls.
Conclusions: Despite the multiplicity of chemokines in obese VAT, these results demonstrate an important role for CXCR3 in local T cell accumulation. CXCR3 deficiency improves glucose tolerance earlier but not later, possibly due to participation of this chemokine receptor on accumulation of different T cell subsets in fat.
- © 2010 by American Heart Association, Inc.