Background: GLUT1 is the main glucose transporter in certain immune cells. Results: Overexpressing GLUT1 in macrophages results in increased glucose uptake and glucose utilization. Conclusion: Driving glucose uptake and metabolism through GLUT1 induces a proinflammatory response that is dependent upon glycolysis and reactive oxygen species. Significance: Understanding how macrophage substrate metabolism impacts inflammation is crucial to develop novel therapeutics for obesity and diabetes.

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Macrophage (MP) subtypes exist and modulate inflammation in adipose. “M1” MPs are pro‐inflammatory and rely upon glucose metabolism, while anti‐inflammatory “M2” MPs use fatty acid oxidation. The objective of this study is to investigate how fatty acid metabolism modulates MP activation. We stably overexpressed (OE) FATP1 in RAW264.7 MPs. FATP1‐dependent acyl‐coA synthetase (ACS) activity and fatty acid oxidation demonstrated functional FATP1. MPs were treated with 100ng/mL LPS to induce inflammation. qPCR and Westerns detected proinflammatory factors TNFα and MCP‐1, and glucose transporter 1(GLUT1), glucose uptake and glucose metabolism were examined. Bone marrow derived MPs (BMDM) from FATP1+/+ and FATP−/− mice were polarized to M1 and M2 subtypes and pro‐inflammatory factors, GLUT1 expression, glucose uptake and glucose metabolism were examined. Results show FATP1 OE drives ACS activity and fatty acid oxidation, and suppresses MP pro‐inflammatory responses vs. empty vector (EV). FATP1 OE blunts LPS‐induced GLUT1, glucose uptake, and oxidation. FATP1−/− BMDM display enhanced pro‐inflammatory M1 responses compared to FATP1+/+. FATP1−/− exacerbates the M1 phenotype with elevated cytokines, GLUT1 expression, and glucose uptake. In conclusion, FATP‐1 OE blunts the inflammatory response in MPs and drives M2 polarization, while FATP‐1 deficiency drives the M1 phenotype. R00 AA017376Grant Funding Source : NIH‐NIAAA