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Review
, 42 (4), 292-300

Similarities and Distinctions in the Effects of Metformin and Carbon Monoxide in Immunometabolism

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Review

Similarities and Distinctions in the Effects of Metformin and Carbon Monoxide in Immunometabolism

Jeongmin Park et al. Mol Cells.

Abstract

Immunometabolism, defined as the interaction of metabolic pathways with the immune system, influences the pathogenesis of metabolic diseases. Metformin and carbon monoxide (CO) are two pharmacological agents known to ameliorate metabolic disorders. There are notable similarities and differences in the reported effects of metformin and CO on immunometabolism. Metformin, an anti-diabetes drug, has positive effects on metabolism and can exert anti-inflammatory and anti-cancer effects via adenosine monophosphate-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms. CO, an endogenous product of heme oxygenase-1 (HO-1), can exert anti-inflammatory and antioxidant effects at low concentration. CO can confer cytoprotection in metabolic disorders and cancer via selective activation of the protein kinase R-like endoplasmic reticulum (ER) kinase (PERK) pathway. Both metformin and CO can induce mitochondrial stress to produce a mild elevation of mitochondrial ROS (mtROS) by distinct mechanisms. Metformin inhibits complex I of the mitochondrial electron transport chain (ETC), while CO inhibits ETC complex IV. Both metformin and CO can differentially induce several protein factors, including fibroblast growth factor 21 (FGF21) and sestrin2 (SESN2), which maintain metabolic homeostasis; nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of the antioxidant response; and REDD1, which exhibits an anticancer effect. However, metformin and CO regulate these effects via different pathways. Metformin stimulates p53- and AMPK-dependent pathways whereas CO can selectively trigger the PERK-dependent signaling pathway. Although further studies are needed to identify the mechanistic differences between metformin and CO, pharmacological application of these agents may represent useful strategies to ameliorate metabolic diseases associated with altered immunometabolism.

Keywords: PERK; heme oxygenase-1; metabolic diseases; metabolic homeostasis; mitochondrial ROS.

Figures

Fig. 1
Fig. 1
Metformin inhibits mitochondrial complex I and activates AMPK via decreasing ATP levels, thereby increasing glycolysis and lipolysis and inhibiting gluconeogenesis and lipogenesis. Metformin also increases glucose translocation and improves insulin sensitivity. See the text for more details.
Fig. 2
Fig. 2
Metformin acts through both AMPK-dependent and AMPK-independent pathways to control the survival of cells and metabolic homeostasis. See the text for more details.
Fig. 3
Fig. 3
Carbon monoxide inhibits mitochondrial complex IV and then activates PERK via increasing mitochondrial ROS. Activated PERK induces the Nrf2-HO-1 pathways. HO-1 is induced by the various stimulators such as CO, curcumin, resveratrol and flavonoids, thereby increasing endogenous CO production. And also, CO-releasing molecules (CORM-1, 2, 3, and A1) produce CO in cells. See the text for more details.
Fig. 4
Fig. 4
Carbon monoxide controls metabolic homeostasis via the PERK-eIF2α-ATF4-FGF21, SENS2, and REDD1 pathway. See the text for more details.

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