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Abstract
Adipose tissue inflammation and specifically, pro-inflammatory macrophages are believed to contribute to insulin resistance (IR) in obesity in humans and animal models. Recent studies have invoked T cells in the recruitment of pro-inflammatory macrophages and the development of IR. To test the role of the T cell response in adipose tissue of mice fed an obesogenic diet, we used two agents (CTLA-4 Ig and anti-CD40L antibody) that block co-stimulation, which is essential for full T cell activation. C57BL/6 mice were fed an obesogenic diet for 16 weeks, and concomitantly either treated with CTLA-4 Ig, anti-CD40L antibody or an IgG control (300 µg/week). The treatments altered the immune cell composition of adipose tissue in obese mice. Treated mice demonstrated a marked reduction in pro-inflammatory adipose tissue macrophages and activated CD8+ T cells. Mice treated with anti-CD40L exhibited reduced weight gain, which was accompanied by a trend toward improved IR. CTLA-4 Ig treatment, however, was not associated with improved IR. These data suggest that the presence of pro-inflammatory T cells and macrophages can be altered with co-stimulatory inhibitors, but may not be a significant contributor to the whole body IR phenotype.
Highlights
Obesity is associated with significant comorbidity, including increased risk for type 2 diabetes and cardiovascular disease [1]
Epididymal white adipose tissue (EWAT) weights were similar among animals fed the obesogenic diet, but liver weights did differ in the treated mice as compared to the control high fat diet mice (Figure 1D)
Despite previous studies that indicated T regulatory cells were enriched in lean adipose tissue versus obese adipose tissue [9], we showed an increased number of T regulatory cells in obese adipose tissue, and the total number declined when mice were treated with CTLA-4 Ig and anti-CD40L (Figure 2C)
Summary
Obesity is associated with significant comorbidity, including increased risk for type 2 diabetes and cardiovascular disease [1]. It is believed that the chronic low grade inflammation that accompanies obesity contributes to systemic insulin resistance, which is a component of type 2 diabetes [2]. Obesity is characterized by the accumulation of diverse immune cell types in adipose tissue [4]. Recruitment of pro-inflammatory macrophages to adipose tissue appears to be a cardinal feature of obesity [5]. Characterization of these cells by cell membrane markers includes those that are positive for F4/80, CD11b and CD11c. It was determined that pro-inflammatory cytokines produced by these macrophages, such as TNF-a, can interfere with insulin signaling [6]
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