Adipose tissue macrophages

Increased adipose mass associated with obesity has been linked with a low-grade, chronic inflammatory response, characterized by altered production of adipokines and increases in biological markers of inflammation, such as tumour necrosis factor-α, interleukin-6 or monocyte-chemoattractant protein-1 (MCP-1)plasminogen activated inhibitor (PAI-1), colony stimulating factor (CSF) or inducible nitric oxide synthase (iNOS). However, studies in recent years have revealed that adipocytes are not the major source of inflammatory cytokine secretion from adipose tissue. Non-adipose cells, that constitute the stromal vascular fraction, which includes preadipocytes, endothelial cells, fibroblasts, leukocytes and macrophages seem to be responsible for the chronic inflammatory response observed in obesity. Macrophages residing in lean adipose tissue are characterized by increased expression of genes such as Ym-1, arginase-1 and the anti-inflammatory cytokine IL10. They show an increased capacity for tissue repair and angiogenesis and are commonly described as M2 or “alternatively activated” macrophages. However, in recent years it has been found that the expansion of adipose tissue in obesity is associated with an increased infiltration with macrophages of the M1 or “classically activated” phenotype from the circulation. These macrophages are usually recruited to sites of tissue damage and have been reported to be in a pro-inflammatory state with increased expression of TNF-α and iNOS .
The cellular mechanisms responsible for this enhanced macrophage recruitment remain largely unknown, but it has been suggested that dysregulated adipokine production and increased adipocyte size might contribute to this phenomenon in a crosstalk between adipocytes and macrophages. Adipocyte-derived factors, such as MCP-1 or CSF-1 are overexpressed in obesity and can promote the recruitment of circulating monocytes. Furthermore, obesityis characterized by decreased secretion of adiponectin, which has been shown to exert anti-inflammatory effects on macrophages, whereas the production of the pro-inflammatory adipokine leptin is increased. Another contributing factor might be the increased levels of free fatty acids released from enlarged adipose tissue in
obesity. Recently, it has been demonstrated that saturated fatty acids can act as ligands for TLR-4 and induce the production of inflammatory cytokines from macrophages through the activation of the NFκ-B pathway. In addition, free fatty acids may contribute to the accumulation of bioactive lipids, such as
DAGsand ceramides within the macrophage which are also thought to be an upstream activator of NFκ-B.