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. 2021 Apr 14;10(4):903. doi: 10.3390/cells10040903

Figure 2.

Figure 2

Glucose and lipid metabolism in TAMs. TAMs exhibit a pronounced glycolytic signature enhanced lipid uptake and accumulation. Glucose-derived pyruvate is partly converted to acetyl-CoA by the PDH complex to fuel the TCA cycle, supporting OXPHOS. ATP, from both glycolysis and OXPHOS, can be used to activate the JAK–STAT6 pathway in M2-like activation. 2-DG inhibits TAM phenotype and function due to impaired OXPHOS in addition to glycolysis. Activation of the JAK–STAT6 pathway induces gene expression related to FAO and FA uptake. The caspase1-mediated cleavage of PPARγ attenuates MCAD activity, and FAO promotes LD formation. The elevated level of the scavenger receptor CD36 plays a crucial role in lipid uptake and accumulation in TAMs. The LD formation is essential for TAMs as a stable source of fatty acids for fatty acid oxidation (FAO). Acetyl-CoA converted from citrate feeds FA synthesis and acetylates histones to regulate TAM gene expression. Etomoxir, an inhibitor of CPT1, inhibits FAO and inhibits complex I of the electron transport chain and depletes CoA, eventually impairing M2 activation and the protumor growth activity of TAMs. 2-DG: 2-deoxyglucose; αKG: α-ketoglutarate; CoA: coenzyme A; CPT: carnitine palmitoyltransferase; FA: fatty acid; LD: lipid droplet; MCAD: medium-chain acyl-CoA dehydrogenase; MGLL: monoacylglycerol lipase; OAA: oxaloacetate; OXPHOS: oxidative phosphorylation; PDH: pyruvate dehydrogenase; PDK1: pyruvate dehydrogenase kinase 1; TAMs: tumor-associated macrophages; TCA: tricarboxylic acid.