Freemerman, A J, et al. Metabolic Reprogramming of Macrophages: Glucose Transporter (GLUT1)-Mediated Glucose Metabolism Drives a Pro-Inflammatory Phenotype. The Journal of Biological Chemistry, 2014.
Glucose is a critical component in the pro-inflammatory response of macrophages (MФs)6. However, the contribution of glucose transporters (GLUTs) and the mechanisms regulating subsequent glucose metabolism in the inflammatory response are not well understood. Since MФs contribute to obesity-induced inflammation, it is important to understand how substrate metabolism may alter inflammatory function. We report that GLUT1 (SLC2A1) is the primary rate limiting glucose transporter on pro-inflammatory polarized MФs. Furthermore, in high fat diet-fed rodents, MФs in crown-like structures and inflammatory loci in adipose and liver, respectively, stain positively for GLUT1. We hypothesized that metabolic reprogramming via increased glucose availability could modulate the MФ inflammatory response. To increase glucose uptake, we stably over-expressed the GLUT1 transporter in RAW264.7 MФs (GLUT1-OE MΦs). Cellular bioenergetics analysis, metabolomics and radiotracer studies demonstrated that GLUT1 overexpression resulted in elevated glucose uptake and metabolism, increased pentose phosphate pathway intermediates, with a complimentary reduction in cellular oxygen consumption rates. Gene expression and proteome profiling analysis revealed that GLUT1-OE MΦs demonstrated a hyper-inflammatory state characterized by elevated secretion of inflammatory mediators and that this effect could be blunted by pharmacologic inhibition of glycolysis. Finally, reactive oxygen species production and evidence of oxidative stress were significantly enhanced in GLUT1-OE MФs; antioxidant treatment blunted the expression of inflammatory mediators such as PAI-1, suggesting that glucose-mediated oxidative stress was driving the pro-inflammatory response. Our results indicate that increased utilization of glucose induces a ROS-driven pro-inflammatory phenotype in MФs, which may play an integral role in the promotion of obesity-associated insulin resistance.