Macrophages infiltrate adipose tissue at the onset of weight gain and directly contribute to adipose inflammation, insulin resistance, and obesity . The type of fuel substrate utilized by macrophages is central to the formation of obesity, a global epidemic . Our goal is to understand the role of macrophage glucose metabolism in the promotion of inflammation and insulin resistance during high fat diet-induced obesity. We hypothesize that macrophages with blunted or elevated glucose metabolism will display limited or exaggerated immune responses, and modulate susceptibility to insulin resistance and obesity, respectively.
Materials and methods
GLUT1 is the glucose transporter expressed by macrophages . We manipulated macrophage glucose metabolism using GLUT1 over-expression and deletion techniques in vitro, ex vivo, and in vivo. In vitro studies involved over-expression of GLUT1 in RAW264.7 cells. A high fat diet-induced obesity model involving a novel macrophage-specific Glut1 knockout mouse (Glut1MΦ-/-) was used to assess total body weight, glucose tolerance, tissue histological alterations, and gene expression changes resulting from Glut1 deletion. Bone marrow-derived macrophages (BMDMs), isolated from Glut1MΦ-/-mice fed a control diet, were used for measures of polarization, and glucose uptake and metabolism.
GLUT1 over-expression resulted in elevated glucose uptake and metabolism, as well as a hyper-inflammatory state characterized by elevated secretion of MCP-1 and PAI-1, all of which could be blunted with a pharmacologic inhibitor of glycolysis. Preliminary data suggests that Glut1MΦ-/- mice fed a high fat diet were resistant to obesity, remained normoglycemic and demonstrated blunted inflammation in liver and adipose. Glut1MΦ-/- BMDMs were viable, but metabolized less glucose at baseline and after LPS stimulation.
The capacity to use glucose as a fuel is correlated to the inflammatory status of macrophages which likely plays an integral role in the promotion of obesity-related insulin resistance. Possible mechanisms linking glucose metabolism to inflammation are being investigated. Understanding macrophage glucose metabolism and inflammation will identify metabolic and/or signaling pathways that will serve as novel therapeutic targets in the treatment of diabetes and obesity.