37 2 Macrophage Metabolic Reprogramming in Diabetes Figure 4: Comparison of metabolic reprogramming of classically and metabolically activated macrophages. (A) Classically activated macrophages and their metabolism. (B) Metabolically activated macrophages and their metabolism. Adipose tissue macrophages in obesity internalize free fatty acids (FFA) and lipids from the dying adipocytes, becoming foam cells. These FFA can be used to synthesize new lipids, can be stored in lipid droplets, can be catabolized through the lysosomal pathway or be used to produce inflammatory lipid mediators called eicosanoids. Glucose is the main source of energy also in metabolically activated macrophages, where the glucose transporter is overexpressed, and it is catabolized by glycolysis, which is upregulated, providing substrates for the pentose phosphate pathway (PPP), also upregulated. Also the metabolic pathway OXPHOS (oxidative phosphorylation) is upregulated in these cells, underlying their high energy demand. Succinate production is increased in these cells. This metabolite inhibits prolyl hydroxylase domain (PHD) proteins, resulting in less hydroxylation of hypoxia-inducible factor 1-alpha (HIF-1α), which circumvents its degradation, allowing its binding to hypoxia response elements (HRE) on target genes (61). HIF-1α is also promoted by FFA and we hypothesize it might promote the switch to glycolysis by inducing glycolytic enzymes as it happens in classically activated macrophages. Abbreviations: TCA (tricarboxylic acid) cycle, SLC25a1 (solute carrier family 25 member 1), ACLY (ATP citrate lyase), IDH (isocitrate dehydrogenase), SDH (succinate dehydrogenase), CAD (cis-aconitate decarboxylase), GABA (γ-aminobutyric acid), PHD (prolyl hydroxylase domain), ROS (reactive oxygen species), PKM2 (pyruvate kinase M2), GPI (glucose-6-phosphate isomerase), PEP (Phosphoenolpyruvate), PDH (Pyruvate dehydrogenase), PDK1 (pyruvate dehydrogenase kinase 1), FAO (fatty acid oxidation).
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