Abstract
Microglia play a role in the regulation of metabolism and pathogenesis of obesity. Microglial activity is altered in response to changes in diet and the body’s metabolic state. Solute carrier family 2 member 5 (Slc2a5) that encodes glucose transporter 5 (GLUT5) is a fructose transporter primarily expressed in microglia within the central nervous system. However, little is known about the nutritional regulation of Slc2a5 expression in microglia and its role in the regulation of metabolism. The present study aimed to address the hypothesis that nutrients affect microglial activity by altering the expression of glucose transporter genes. Murine microglial cell line SIM-A9 cells and primary microglia from mouse brain were exposed to different concentrations of glucose and levels of microglial activation markers and glucose transporter genes were measured. High concentration of glucose increased levels of the immediate-early gene product c-Fos, a marker of cell activation, Slc2a5 mRNA, and pro-inflammatory cytokine genes in microglial cells in a time-dependent manner, while fructose failed to cause these changes. Glucose-induced changes in pro-inflammatory gene expression were partially attenuated in SIM-A9 cells treated with the GLUT5 inhibitor. These findings suggest that an increase in local glucose availability leads to the activation of microglia by controlling their carbohydrate sensing mechanism through both GLUT5-dependent and –independent mechanisms.
Highlights
Microglia are resident macrophages of the central nervous system (CNS) and comprise0.5–16.6% of the overall cells in the human brain under a healthy CNS environment [1]
Fructose induces the activation of the NF-κB pathway and increases the expression and release of pro-inflammatory cytokines by microglial cells [26,27]. These findings suggest that glucose and/or fructose might be nutrient factors that regulate microglial activity via glucose transporter 5 (GLUT5) and that the glucose-induced microglial inflammatory response mediates the anorexigenic action of glucose
The present study demonstrated that elevated glucose concentration leads to an increase in the level of microglial activation markers and the fructose transporter Slc2a5 mRNA in cultured microglial cells and glucose-induced changes in pro-inflammatory genes expression is partially attenuated in microglia treated with the GLUT5 inhibitor
Summary
Microglia are resident macrophages of the central nervous system (CNS) and comprise0.5–16.6% of the overall cells in the human brain under a healthy CNS environment [1]. It was found that a HFD feeding stimulates the recruitment of peripheral myeloid cells into the CNS, leading to an increase in the number of the microglia in the hypothalamus [7] These findings suggest that acute activation of hypothalamic microglia is an adaptive response to hypercaloric challenge and reduces food intake, while prolonged activation of microglia and hypothalamic inflammation may contribute to HFD-induced obesity. Forcing microglial activation is sufficient to stimulate microgliosis in the hypothalamus, which subsequently causes an increase in food intake and weight gain in standard chow-fed mice [8] Together, these findings emphasize the importance of the inflammatory activation state of microglia in the regulation of food intake and its role in the pathogenesis of HFD-induced obesity
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