Although recent studies have established that obesity is associated with the accumulation of macrophages in adipose tissue of rodents and humans, the mechanisms that regulate this process are just being studied. The first step in the recruitment of mono-cytes to a tissue is the adhesion to endothelial cells. In human studies, obesity and impaired insulin sensitivity are associated with elevated circulating concentrations of cellular adhesion molecules, including ICAM-1, VCAM-1, and E-selectin (103-107). In vitro adipocyte-conditioned medium can directly u pregulate the expression of ICAM-1 and platelet-endothelial cell adhesion molecule (PECAM), and increase adhesion, migration, and chemotaxis of monocytes (97). Recently leptin and adiponectin have been shown to have opposing effects on endothelial cells: leptin increases mono-cyte adhesion to endothelial cells, and adiponectin reduces expression of adhesion molecules and other proinflammatory molecules by endothelium (97,108).
Several lines of evidence have also implicated MCPs—in particular, CCL2 (MCP-1) and CCL7 (MCP-3)—as participating in the recruitment and chemotaxis of monocytes in adipose tissue. In both rodents and humans, adipose tissue expression of CCL2 and CCL7 are increased by obesity and reduced following weight loss or thiazolidinedione treatment (97,102,109-112). CCR2 is a high-affinity receptor for CCL2 and CCL7, and is expressed on hematopoietic cells, including circulating monocytes. Genetic deficiency of CCR2 in a C57BL/6J background partially protects mice from obesity when fed a high-fat diet (112). However, when obese mice are matched by body weight and adiposity, Ccr2-deficiency reduces the macrophage content of adipose tissue. This reduction of macrophages is associated with a reduction in proinflammatory gene expression and a coordinate upregulation of metabolically important genes in adipose tissue. Importantly, adiponectin adipose tissue expression and circulating adiponectin concentrations were increased in obese Ccr2-/- mice compared with wild-type obese animals. Glucose tolerance and insulin sensitivity were improved, and hepatosteatosis was reduced in obese mice deficient for Ccr2. Short-term pharmacological antagonism of CCR2 also reduced macrophage content of adipose tissue and improved glucose tolerance and insulin sensitivity in obese mice (112). In contrast, deficiency of Ccr2 in mice on the DBA/J background had no discernable effect on the inflammatory character of adipose tissue or systemic metabolic parameters when mice were fed a high-fat diet (113). The genotype-dependent differences in these two strains of Ccr2-/- mice may derive from inherent differences in these strains in developing obesity-induced inflammation or from differences in the manner in which the experiments were carried out. These differences may, therefore, provide important clues as to genetic and environmental modifiers of obesity-induced inflammation and complications.
An important unanswered question is what are the primary events that induce mono-cyte recruitment and macrophage differentiation in adipose tissue of obese individuals. One hypothesis is that obesity accelerates adipocyte death and turnover, and that consistent with the role of macrophages in other tissue, ATMs serve to clear dead cells. Genetically engineered mice in which apoptosis is induced specifically in adipocytes by treatment with an exogenous drug demonstrate that massive adipocyte apoptosis does indeed induce macrophage recruitment to adipose tissue (114). Cinti and colleagues have suggested that obesity induces adipocyte necrosis and that electron micrographic data suggest that macrophages form multinucleated giant cells specifically in response to adipocyte necrosis. They argue that ultrastructure analysis is not consistent with apoptosis but is distinctively characteristic of necrosis. They convincingly demonstrate that multinucleated giant cells contain lipid droplets that are not perilipin-coated (115). Further studies are needed to clarify whether the apoptosis or necrosis are in fact mechanistically involved in monocyte/macrophage recruitment to adipose tissue in the setting of obesity. Another compelling hypothesis suggests that obesity induces metabolic derangements in adipocytes that lead to the production of factors that activate endo-thelial cells, direct chemotaxis and induce differentiation. At this time little direct evidence exists to support this proposition (116).
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