31 2 Macrophage Metabolic Reprogramming in Diabetes are associated with physiological and pathological tissue remodeling (e.g. fibrosis) and can have anti-inflammatory effects by secreting high levels of IL-10 and TGFβ. Depending on the stimulus, these macrophages (often still called M2 macrophages) are characterized by high expression of mannose receptors (CD206), high-affinity scavenger receptors (CD163), and transglutaminase 2 in humans (32) and they have poor antigen-presenting capabilities (33) These M2 macrophages have been further divided into subgroups, such as wound-healing and regulatory macrophages (34), or into M2a, M2b, M2c, and M2d subtypes (35), which rendered the nomenclature in the field more complex and has been advised against (25). The advent of new techniques like single-cell transcriptomics (36), proteomics (37), and metabolomics are helping to understand the enormous diversity in macrophages present in tissues and will hopefully lead to better classifications, although this point has not been reached yet. For the purpose of this review, the M1 and M2 nomenclature will only be used when citing studies that use these names. Adipose tissue macrophages are resident macrophages contributing to adipose tissue homeostasis. In vivo, adipose tissue macrophages from healthy mice express high levels of CD206, whereas adipose tissue macrophages from obese mice express low levels of CD206 (38) and high levels of integrin CD11c (39). These CD11cexpressing macrophages are associated with insulin resistance (40) and are situated in crown-like structures, surrounding necrotic adipocytes with the goal to remove them through exophagy. This will lead to free fatty acid and lipid internalization by macrophages and foam cells formation (41). Interestingly, it has been shown that murine bone marrow-derived macrophages can upregulate the expression of CD11c when differentiated in co-culture with normal adipocytes, underpinning the importance of the microenvironment in which macrophages grow (36). In adipose tissue, different kinds of immune cells may contribute to this change in macrophage polarization, including neutrophils through the protease elastase (42), T lymphocytes through interferon-γ (43), natural killer cells through TNFα and MCP1 (44), and B cells through IgG antibodies (45). As discussed above it is clear obesity changes macrophage activation status. Even though levels of pro-inflammatory cytokines produced by macrophages in obesity are higher compared to non-obese individuals, contributing to the onset of obesity related meta-inflammation, their activation status does not coincide with a classically activated status of macrophages (37). To identify which markers characterize these macrophages, monocyte-derived macrophages were cultured in media conditioned by adipose tissue of obese mice or humans to mimic the presence of the metabolic syndrome and it was shown that these macrophages accumulate lipids and have high expression of fatty acid transporters like CD36 but do not
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