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 TNFα impaired insulin-stimulated glucose uptake in 3T3-L1 adipocytes. Shortly thereafter, it was reported that TNFα expression was increased in adipose tissue of obese, insulin-resistant rodent models and that systemic neutralization of TNFα 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 TNFα 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 CD14+CD16− monocytes generally having high CCR2 and low CCR5 receptor expression. In contrast, CD14+CD16+ monocytes are low/negative for CCR2 and have high CCR5 expression (7). Krinninger et al (6) not only find a greater percentage of circulating CD14+CD16+ monocytes in obese women, in agreement with previous observations (8), but also find that CCR2 and CCR5 expression and/or density of receptors is increased across the entire population of CD14+CD16− and CD14+CD16+ monocytes. The greater chemokine receptor expression and enhanced in vitro migratory capacity strongly infer that the increase in macrophages in the adipose tissue of obese humans results, at least in part, from recruitment of new cells into the tissue. However, the temporal relationship of the change in monocyte phenotype with respect to development of obesity remains to be investigated. Why are monocytes in obese subjects in a more activated proinflammatory state? Is this a response to changes in other cytokines or hormones that are altered during the progression to obesity? Is it due to dietary influences? Can we intervene to reduce or prevent this change in monocyte phenotype that, at a minimum, perpetuates the inflammatory cycle in obesity? C-Reactive protein is elevated in obese humans and has been shown to increase monocyte CCR2 expression and chemotaxis in vitro (9). However, after removing subjects with C-reactive protein >10 mg/L from their analyses, Krinninger et al (6) still observe increased CCR2 expression and enhanced migration by monocytes from obese women, effectively ruling out an effect unique to highly inflamed states. Adiponectin is anti-inflammatory and has been shown to prime human monocytes to differentiate into anti-inflammatory macrophages (10). Although not measured by Krinninger et al (6), it is very likely that adiponectin is low in the obese women in their study, and perhaps this permits development of a more proinflammatory monocyte. Krinninger et al (6) found a positive correlation between monocyte migration index and fasting insulin, raising the possibility that insulin could influence monocyte function. However, hyperinsulinemia is anti-inflammatory in monocytes, reducing nuclear factor κB signaling (11); effects of insulin on in vitro migratory capacity have not been evaluated. Overall, more work will be needed to determine whether hormones and inflammatory factors associated with the obese state have effects on monocyte receptor expression and function. It has been known for some time that there is an acute rise in inflammation after meal intake, with monocytes and macrophages mounting an inflammatory response to the postprandial elevation of several dietary factors (12). The most efficient triggers of postprandial inflammation are triglycerides, saturated fatty acids, oxysterols, and glucose. Krinninger et al (6) found no relationship between monocyte migration index and fasting glucose, but this may not rule out a repeated effect of postprandial excursions on monocytes. Triglycerides were not statistically higher in the obese women studied here, but again the effect of repeated postprandial excursions is not known. Finally, it is possible that endotoxin that has entered the blood stream during consumption of a high-fat diet may have long-term effects on monocyte phenotype in addition to acting as an inflammatory stimulus (13, 14). Other bacterial-derived factors that differ between lean and obese subjects due to variation in the microbiome (15) should also be considered for effects on monocyte phenotype. In summary, the work of Krinninger et al (6) identifies yet another effect of obesity on immune function and sets the stage for additional studies to understand in greater detail how monocyte phenotype and function are altered by excess adipose tissue. Such studies will have an impact beyond insight into the potential of proinflammatory CD14+CD16+ monocytes to migrate into adipose tissue. CD14+CD16+ monocytes have been implicated in progression of atherosclerosis and in heart failure (14), with a recent report suggesting increased frequency of CD14+CD16+ monocytes predicting future cardiovascular events in patients referred for elective coronary angiography (16). Thus, CD14+CD16+ monocytes appear to be a link between obesity and cardiovascular disease. Importantly, at least one study has found that bariatric surgery-induced weight loss can reduce CD14+CD16+ monocytes and that diminution of this subset of monocytes is linked to a reduction in subclinical atherosclerosis (8). Future work will be needed to more fully understand the biology of monocytes in obese humans. Disclosure Summary: The author has nothing to disclose that is relevant to this editorial.