38 Chapter 2 In accordance with their activated status, metabolically activated macrophages were also shown to contain a higher number of mitochondria and have higher mitochondrial activity compared to adipose tissue macrophages from lean subjects (40,73) and this was associated with higher OXPHOS activity (73,74).In addition, expression of insulin-like growth factor 1 receptors (IGF1R) was shown to be suppressed in adipose tissue macrophages from obese subjects (75), altering the insulin receptor pathway leading to lower phosphorylation of IRS1-2, lower PI3K activation, and decreased Akt serine phosphorylation. Lower Akt phosphorylation translates into lower mTOR activity and activation of glycolysis (46). Another major characteristic of adipose tissue in obesity is the hypoxia present and therefore HIF-1α may be overexpressed in adipose tissue macrophages due to oxidative stress, due to a higher content of the metabolite succinate (73,76), due to the higher levels of free fatty acids (73), or a combination thereof. Therefore, one could speculate that the glycolytic enzymes that are induced by HIF-1α in classically activated macrophages are also induced in metabolic syndrome, but more studies on this topic are needed. In summary, the metabolic changes found in metabolically activated macrophages resemble the ones that occur when macrophages polarize toward a proinflammatory phenotype but rely mostly on high levels of free fatty acids present in the microenvironment and differ in the induction of oxidative phosphorylation. METABOLIC CHANGES, LYSINE ACETYLATION AND GENE EXPRESSION In recent years it has also become apparent how variations in metabolite levels due to the onset of disease are connected to epigenetic modifications, which lead to changes in gene expression (77). As mentioned above when discussing the interruptions in the TCA cycle, levels of acetyl-CoA may change due to changes in macrophage metabolism. Acetyl-CoA is generated in the mitochondrial matrix from pyruvate by the pyruvate dehydrogenase complex as part of glycolysis, by β-oxidation of fatty acids, or by the catabolism of branched-chain amino acids. Mitochondrial acetyl-CoA enters the tricarboxylic acid cycle and is converted to citrate (78). It can then be transported out of the mitochondria and reconverted to acetyl-CoA, thus contributing to cytoplasmic protein acetylation. It can also be transported into the nucleus as citrate and reconverted to acetyl-CoA by ATP citrate lyase to serve as a substrate for lysine acetyl transferases.
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