Table 1.
Targets for Macrophage Metabolic Reprogramming in Adipose Tissue Macrophages
| Targets for macrophage metabolic reprogramming | M1 macrophages | M2 macrophages | In vivo effects relating to monocyte/macrophage function | Link with intracellular macrophage metabolism | Ref. |
|---|---|---|---|---|---|
| GLUT1 | Overexpression in RAW cells increases M1 cytokines: IL-1, IL-6, and TNF-α. An increase in IL-6 is not seen in J774 cells. | — | Endogenous expression is increased in inflamed obese adipose tissue. | Overexpression increases glucose uptake, glycolytic rate, and lactate production. | (27) |
| Overexpression in monocytes increases glucose uptake but did not alter cytokine production. | (74) | ||||
| FATP | Endogenous expression reduced on differentiation. | Endogenous expression maintained on differentiation. | Mice lacking FATP in leukocytes show increased weight gain, adiposity, and glucose tolerance on a high-fat diet. | Knockout of FATP increases energy production by OXPHOS in M1 and M2 macrophages. | (50) |
| FATP−/− M1 macrophages show M1 priming, with increased iNOS expression. | FATP−/− M2 macrophages show blunted arginase expression | FATP overexpression decreases glycolytic rate in resting and M1 macrophages | |||
| FATP overexpression reduces GLUT1 expression. | |||||
| Notch | Notch1-RBP-J signaling promotes M1 polarization. | Notch-RBP-J signaling inhibits M2 macrophage polarization by downregulating JMJD3. | Notch inhibitor DAPT attenuated glycolysis, reducing glucose uptake and lactate formation in hepatic macrophages in response to alcoholic steatohepatitis. | Notch induces pyruvate dehydrogenase phosphatase that supports the TCA cycle. | (101) |
| Notch1−/− hepatic macrophages show reduced M1 gene expression after LPS stimulation in vitro. | Notch regulates transcription of respiratory chain proteins. | (70) | |||
| (108) | |||||
| IL-10 | IL-10 is induced by M1 macrophages and acts as a cell-autonomous regulator of glycolysis. | IL-10 is highly upregulated by M2 macrophages. | IL-10−/− macrophages from an inflammatory colitis model show a buildup of damaged mitochondria and increased inflammation because of inflammasome activation. | IL-10−/− M1 macrophages show increased glycolytic activity and reduced OXPHOS. | (45) |
| IL-10 reduces GLUT1 expression on the cell surface. | (6) | ||||
| CARKL | LPS downregulates endogenous CARKL expression. | M2 macrophages upregulate CARKL | — | CARKL is an orphan receptor in the pentose phosphate pathway. | (37) |
| CARKL overexpression reduces IL-6 and TNF-α in response to LPS. | CARKL−/−macrophages show enhanced glycolysis, without additional stimulation. | ||||
| CARKL−/− macrophages expression of M1 cytokines without further stimulation. | |||||
| IL-4 | IL-4 treatment is not sufficient to repolarize M1 macrophages. Nitric oxide produced by M1 macrophages prevents repolarization. | IL-4 promotes M2 polarization. Repolarization to M2 requires mitochondrial function. | — | Inhibition of iNOS allows IL-4 to repolarize M1 cells, reducing glycolysis and promoting OXPHOS. | (97) |
| mTOR pathway | Inhibition of both mTORC1 and mTORC2 promotes M1 polarization. | Tsc−/− macrophages show defective M2 polarization in response to IL-4. | Macrophage-specific mTORC1−/− mice show less inflammation after high-fat feeding. | Tsc−/− macrophages show no increase in FAO in response to IL-4. | (49) |
| mTORC1/2 are multisubunit complexes within the pathway | Deletion of Tsc1 enhances mTORC1 activity. Tsc1−/− macrophages show increased proinflammatory cytokine production and reduced IL-10 production. | Global mTORC1 inhibition with rapamycin increases the number of M1 macrophages after high-fat feeding. | mTORC2-deficient macrophages show defective OXPHOS utilization after IL-4 stimulation. | (13) | |
| (83) |
CARKL, carbohydrate kinase-like protein; FAO, fatty acid oxidation; FATP, fatty acid transport protein; GLUT-1, glucose transporter-1; IL-6, interleukin-6; iNOS, inducible NOS; JMJD3, Jumonji domain-containing 3; LPS, lipopolysaccharide; mTORC, mechanistic target of rapamycin complex; OXPHOS, oxidative phosphorylation; RBP-J, recombining binding protein suppressor of hairless; TCA, tricarboxylic acid; TNF-α, tumor necrosis factor alpha.