Macrophage infiltration of human adipose tissue and its association with systemic inflammation, obesity, and metabolic disease

Macrophages accumulate in expanding adipose tissue where they produce and secrete inflammatory cytokines known to impair insulin action. "Classically activated" (i.e., pro-inflammatory) adipose tissue macrophages (ATM) are therefore thought to play a crucial role in the development of insulin resistance. The Fcgamma receptor III, CD16, is considered a marker for inflammatory activation in peripheral blood monocytes and macrophages in synovial fluid and associated membranes. Increased CD16 expression in these cells has been linked to cardiovascular disease, rheumatoid arthritis, and inflammatory diseases of the skin and bowel. We therefore sought to determine whether CD16 is a marker for "classically activated", pro-inflammatory macrophages in adipose tissue associated with insulin resistance. In an initial cross-sectional study of 18 men and women varying widely in age, adiposity, and metabolic health, we observed that the number of CD16pos-ATM within the subcutaneous adipose tissue was associated with body mass index (BMI; r=0.60, p=0.009) and insulin resistance measured by homeostasis model assessment (HOMA; r=0.65, p=0.004). Moreover, the number of CD16pos-ATM was strongly associated with adipose tissue gene expression of key mediators of inflammation, including intracellular adhesion molecule-1 (ICAM-1; r=0.72, p=0.001) and tumor necrosis factor-alpha (TNF-alpha; r=0.67, p=0.002), and circulating levels of the inflammatory mediators interleukin-6 (IL-6; r=0.51, p=0.029) and C-reactive protein (CRP; r=0.66, p=0.003), while also being negatively correlated with both plasma (r=-0.70, p=0.001) and adipose tissue adiponectin expression (r=-0.57, p=0.014). However, these associations were not present in two additional study populations (n=36) in which we sought to confirm this initial finding. Of these, one consisted of 26 overweight to obese post-menopausal women while the other was comprised of 10 subjects, 8 of which were obese, undergoing abdominal surgery. Further, gene profiling of isolated CD16 pos-ATM revealed lower expression of the inflammatory genes TNF-alpha, IL-6 and interferon gamma (IFNgamma) when compared to CD16neg-ATM. We conclude therefore, that while CD16 may be a marker of inflammation in monocytes and synovial macrophages, it is not a marker for "classically activated" inflammatory macrophages in human subcutaneous adipose tissue.