Abstract 1367: T Cell Accumulation in Adipose Tissue in Obesity-Related Insulin Resistance Induced by a High-Fat Diet
Obesity is associated with chronic inflammation, evidenced by elevated cytokine and chemokine expression and increased macrophage accumulation in adipose tissue (AT). T cells also play an important role in chronic inflammatory diseases such as atherosclerosis but have not been well studied in obesity. We hypothesize that elevated chemokines levels in AT in obesity are also associated with increased T cell accumulation. Using flow cytometry, we examined T cells in stromal/vascular cells from AT of diet-induced obese mice, which were C57BL/6 fed western high-fat diet 24 wk. Compared to lean controls on standard chow diet, obese male mice but not obese females had significantly increased T cell number in AT (CD3+ cells: 3.5 ± 0.4 x 105/g tissue in obese males vs 1.5 ± 0.2 x 105/g tissue in leans, P<0.01, n=5/group). mRNA levels of MCP-1, RANTES, and their receptors, CCR2 and CCR5, were upregulated in AT of obese males as examined by RNase protection assay (relative intensity to GAPDH and L32: MCP-1, 689 ± 63 vs 188 ± 6 in lean, P<0.01; RANTES, 558 ± 84 vs 171 ± 18, P<0.05; CCR2, 137 ± 8 vs 63 ± 4, P<0.01; CCR5, 135 ± 13 vs 34 ± 1, P<0.01; n=4/group). AT from obese males also secreted higher levels of MCP-1 and RANTES than AT from lean controls when cultured ex vivo for 8 hr (MCP-1, 247 ±2 8 vs 133 ± 14 ng/g tissue in lean, P<0.05; RANTES, 1716 ± 133 vs 537 ± 101 pg/g tissue in lean, P<0.01; n=4/group). In vitro chemotaxis study showed that conditioned culture medium from AT of obese males induced significantly more T cell transmigration than AT of lean controls (448 ± 90 vs 104 ± 22 in lean, P<0.05, n=3/group). Antibody neutralization of RANTES or MCP-1 markedly inhibited T cell transmigration induced by conditioned medium from AT of obese males (RANTES, inhibition 51 ± 8%, P<0.05; MCP-1, inhibition 74 ± 4%, P<0.05; n=3). In addition, mRNA levels of MCP-1, RANTES, CCR2 and CCR5 were increased in visceral AT compared to subcutaneous AT from morbidly obese humans. In conclusion, diet-induced obesity is associated with increased accumulation of T cells in AT. Elevated expression of MCP-1 and RANTES may be of critical importance in T cell recruitment into AT in obesity-related insulin resistance.