Liza Makowski, PhD, professor of Medicine in the Division of Hematology and Oncology in the College of Medicine at the University of Tennessee Health Science Center (UTHSC), has published a paper in the Journal of Immunology that provides novel insights into the biochemistry of the sugar glucose in immune cells critical to obesity and heart disease.
Glucose metabolism in white blood cells, or macrophages, has been thought to play an important role in the best way to fight infection or “turn on defense” in response to chronic stressors like high sugar or cholesterol in diabetes or heart disease.
“We wanted to test just how important glucose was in fighting disease,” said Dr. Makowski, the paper’s senior author.
Surprisingly, the researchers found that when they inhibited glucose transporter 1 (GLUT1), the most important sugar transporter in cells, the macrophages adapted to use other biochemical substrates or biochemicals as fuels. This metabolic adaptation, however, was not sufficient enough for the macrophages to behave normally.
“We had hoped that by knocking out glucose entry and metabolism through the main transporter GLUT1, the cells would be ‘metabolically reprogrammed’, or shifted from more aggressive glucose consumers to less aggressive, more protective white blood cells,” said Alex Freemerman, PhD, research associate in the Department of Nutrition at the University of North Carolina at Chapel Hill and co-first author on the manuscript. “Our hypothesis was incorrect because the biology is more complex that we initially thought. In fact, the cells proved very flexible and turned to fuels such as fats and proteins when restricted. Interestingly, we found that even with their adaptations, the white blood cells could not function normally.”
This led the research team to question how macrophages that cannot metabolize glucose behaved in chronic disease such as obesity and atherosclerosis. They discovered that adapted macrophages offered no protection against becoming obese or developing heart disease. “In fact, atherosclerosis was worse which supported our initial findings that although cells were flexible, they still could not function normally,” said Liyang Zhao, PhD, a master’s student in Dr. Makowski’s lab at the time of the study and a co-first author on the paper.
“Upon further investigation into the fundamental roles of macrophages, we discovered that glucose was needed for proteins involved in some critical functions of white blood cells,” said Dr. Zhao. “We tested how macrophages ‘eat’, a process called phagocytosis, and found that macrophages lacking GLUT1 could not effectively engulf particles. This exciting finding helped explain why macrophages lacking GLUT1 had worse disease outcomes compared to normal white blood cells.”
Dr. Makowski advises that these findings are significant because they show that glucose transportation is key for certain cellular functions and white blood cell stability.
“What is important about this study is that we showed that while macrophages are very flexible in the fuels that they metabolize, glucose itself is a special requirement for certain functions,” said. Dr. Makowski. “Thus, GLUT1-driven glucose transport is needed for white blood cells to do their job.”
Because macrophages and fuel metabolism are also important in cancer, Dr. Makowski’s group is now examining macrophages that lack GLUT1 in cancer models, with encouraging preliminary data. Finding novel ways to ‘rewire’ white blood cells to prevent communication between immune cells and cancer cells is an increased area of intense interest.