Activated Monocytes: Yet Another Link Between Systemic Inflammation and Obesity

A substantial and continually growing body of evidence supports the concept that chronic low-grade inflammation is a central characteristic of obesity contributing to development of insulin resistance in adipose tissue and other insulin target organs including muscle, liver, and the vasculature (recently reviewed in Refs. 1–3). The possibility of a link between inflammation, macrophages, and obesity-associated insulin resistance was first suggested by in vitro observations 20 years ago that the macrophage secretory product TNF impaired insulin-stimulated glucose uptake in 3T3-L1 adipocytes. Shortly thereafter, it was reported that TNF expression was increased in adipose tissue of obese, insulin-resistant rodent models and that systemic neutralization of TNF improved insulin resistance. With the discovery that adipose tissue in obesity contains more macrophages than adipose tissue of normal-weight individuals and evidence that adipose tissue macrophages in obesity are polarized to a more proinflammatory phenotype, the macrophage assumed a central role in the development of adipose tissue inflammation. The field of immunometabolism has now expanded to include studies of the interaction of many types of immune cells with adipocytes (4); however, a number of questions yet remain concerning the function and pathophysiological impact of macrophage infiltration into adipose tissue, particularly in obese humans. For example, it has been difficult to distinguish recently recruited cells from the resident pool of macrophages in human adipose tissue and to unequivocally identify in human adipose samples the polarization of macrophages to a uniquely proinflammatory phenotype, as has been more definitively observed in rodent models (5). In this issue of the JCEM, Krinninger et al (6) address the issue of recruitment of inflammatory cells into adipose tissue. These investigators examined monocytes, the circulating precursors of macrophages, from obese and normal-weight women to determine whether there exist phenotypic differences that could promote accumulation of proinflammatory macrophages in adipose tissue. These investigators find that the total monocyte population in obese women contains a greater percentage of activated, proinflammatory CD14 CD16 monocytes than in normal-weight women. Monocytes from obese women also exhibit increased surface expression of the chemokine receptors CCR2 and CCR5 and an enhanced in vitro migration response to the chemokines MCP-1 and RANTES, the production of which is increased in adipose tissue of obese subjects (3). The authors conclude that circulating monocytes in obese women are in an activated, proinflammatory state, and that they are primed to migrate into adipose tissue in response to enhanced chemotactic signals from the tissue in obesity. Human monocytes are phenotypically heterogeneous and in general are classified according to expression of the surface markers CD14 and CD16 (7). “Classical” CD14 CD16 monocytes constitute approximately 80% of the circulating population. However, in inflammatory situations such as sepsis, rheumatoid arthritis, and infection, there is an increase in monocytes positive for CD16 expression (CD14 CD16 ). These cells exhibit a more macrophage-like phenotype with enhanced antigen-presenting capacity, greater binding affinity for endothelial cells, and increased release of TNF and other proinflammatory cytokines. It should be noted that CD16 monocytes can also be phenotypically heterogeneous, with CD14 expression varying from very low to high (7), a characteristic not studied by Krinninger et al (6). Chemokine receptors (CCR2, CCR3, CCR5) are also variable across the different populations of monocytes, with