36 Chapter 2 Metabolic reprogramming of macrophages in DMTII and obesity The exact mechanism of how macrophages reprogram their metabolism after activation in DMTII and obesity is still unknown. As discussed in the previous paragraph, macrophages undergo metabolic reprogramming when classically activated, but also availability of energy sources influences their metabolism, implying that abundant availability of energy sources (for instance during hyperglycemia or obesity) can also impact their metabolism. Since it has been shown that the phenotype of metabolically activated macrophages differs from classically activated macrophages (36,37), this may indicate that their metabolism could differ as well. This situation is particularly relevant in DMTII and insulin resistance for adipose tissue macrophages. Similar to classically activated macrophages, metabolically activated macrophages have higher glycolytic rates and produce more lactate (Figure 4) compared to adipose tissue macrophages from lean subjects (11). The glucose transporter GLUT1 is overexpressed in metabolically activated adipose tissue macrophages of obese mice and rats (68) and overexpression of this transport was shown to drive more glycolysis and pentose phosphate pathway metabolism in these cells, in addition to higher ROS production (68). Moreover, a higher level of glucose present in the environment can affect macrophage activation state, inducing a phenotypic switch to CD11c+ macrophages (69). It has been shown that CD11c+ macrophages have enriched expression of genes encoding glucose metabolism, fatty acid metabolism, and lysosomal proteins (40) emphasizing a central role for these genes in adipose tissue macrophages. Lipid metabolism also seems to differ between metabolically and classically activated macrophages. As mentioned before, macrophages in crown-like structures in fat tissue internalize the free fatty acids and lipids released from dead adipocytes, thereby becoming foam cells (41). Xu et al. demonstrated that obesity induces lysosomal biogenesis and lipid metabolism pathways in adipose tissue macrophages due to the higher accumulation of lipids in these cells, events that do not take place in classically activated macrophages (36). Adipose tissue macrophages from obese subjects also metabolize lipids differently and a detailed description has been compiled by Dahik et al. (70). A combination of studies has shown that adipose tissue macrophages from obese subjects can synthesize lipids from free fatty acids, store them in lipid droplets, catabolize them through the lysosomal pathway or produce inflammatory lipid mediators called eicosanoids (70,71). In contrast, adipose tissue macrophages from lean subjects take up free fatty acids and subject them to oxidation (72) The higher levels of free fatty acids, coupled with higher levels of other inflammatory mediators like TNFα, IL6, and IL-1β will lead to the development of insulin resistance which can develop in obesity.
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