Abstract 4188: Tumor Necrosis Factor-Alpha Regulates Adipose Tissue Macrophage Recruitment and CCR2 Expression
Factors regulating adipose tissue macrophage recruitment are largely unknown. Since tnf-alpha may promote diabetes in obesity, we hypothesized that tnf-alpha may be an important mediator of both adipose tissue macrophage infiltration and CCR2 expression. To determine the role of tnf-alpha on adipose tissue macrophage infiltration we bred tnf-alpha deficient mice onto the leptin receptor deficient background and compared obese mice with and without tnf-alpha. Immunohistochemical analysis demonstrated significantly greater percentage of Mac-3 positive cells in the epididymal fat tissue of the obese tnf-alpha wild-type versus the obese tnf-alpha deficient mice (db/db tnf wt: 12.7 + 1.2 %; db/db tnf deficient: 6.5 + 1.0%; p=0.0026; n=3 per group). RT-PCR from adipose tissue revealed a three-fold elevation in CCR2 expression in the obese tnf-alpha wild-type mice compared to the obese tnf-alpha deficient mice. To determine whether CCR2 elevation in the adipose tissue was mediated by adipocyte tnf-alpha or macrophage tnf-alpha, we performed bone marrow transplantation from tnf-alpha deficient and wild-type mice to wild-type recipients. Fifteen weeks following transplantation we examined the expression of adipose derived cytokines via RT-PCR. Importantly, tnf-alpha was found to be reduced greater than 50% (n=5 per group; p=0.007) in the mice receiving tnf-alpha deficient bone marrow demonstrating an important contribution of macrophage tnf-alpha towards adipose tissue tnf-alpha. Furthermore, CCR2 expression was also significantly decreased in mice receiving tnf-alpha deficient marrow (tnf-alpha wt: 4.6 + 0.6; tnf deficient: 2.1 + 0.8; p=0.013; n=5 per group) providing evidence that macrophage derived tnf-alpha can mediate a significant change in CCR2 expression. These findings indicate a critical role for tnf-alpha towards adipose tissue inflammation.