4‐1 BBL signaling promotes cell proliferation through reprogramming of glucose metabolism in monocytes/macrophages

Obesity‐induced monocyte/macrophage proliferation and activation play a crucial role in various chronic inflammatory metabolic disorders, such as insulin resistance, diabetes mellitus, and atherosclerosis. 4‐1 BBL , a member of the tumor necrosis factor superfamily expressed on monocytes/macrophages, provides inflammatory signals to modulate their proliferation, survival, and cytokine release. Previously, we demonstrated that 4‐1 BBL signaling promotes adipose inflammation through enhancement of macrophage activation. Here, we show that 4‐1 BBL stimulation on monocytes/macrophages enhanced reprogramming of glucose metabolism in the cells, and that this was accompanied by cell proliferation. 4‐1 BBL stimulation on macrophages increased glucose uptake, transcript/protein levels of glucose transporter 1 and glycolytic enzymes, and lactate production. It also enhanced transcript levels of genes involved in the pentose phosphate pathway and lipogenesis. The 4‐1 BBL ‐induced metabolic reprogramming was mediated by AKT –mammalian target of rapamycin signaling. The effect of 4‐1 BBL ‐induced macrophage proliferation was completely abolished by 2‐deoxyglucose, a glycolytic inhibitor. These findings suggest that 4‐1 BBL signaling promotes cell proliferation through reprogramming of glucose metabolism in monocytes/macrophages to support their energy demands and biomass production. The 4‐1 BBL signaling pathway may be a valid target for controlling macrophage‐mediated chronic inflammation in obesity and metabolic diseases.