Abstract
Microglia are highly motile cells that continuously monitor the brain environment and respond to damage-associated cues. While glucose is the main energy substrate used by neurons in the brain, the nutrients metabolized by microglia to support surveillance of the parenchyma remain unexplored. Here, we use fluorescence lifetime imaging of intracellular NAD(P)H and time-lapse two-photon imaging of microglial dynamics in vivo and in situ, to show unique aspects of the microglial metabolic signature in the brain. Microglia are metabolically flexible and can rapidly adapt to consume glutamine as an alternative metabolic fuel in the absence of glucose. During insulin-induced hypoglycemia in vivo or in aglycemia in acute brain slices, glutaminolysis supports the maintenance of microglial process motility and damage-sensing functions. This metabolic shift sustains mitochondrial metabolism and requires mTOR-dependent signaling. This remarkable plasticity allows microglia to maintain their critical surveillance and phagocytic roles, even after brain neuroenergetic homeostasis is compromised.
Highlights
Microglia are highly motile cells that continuously monitor the brain environment and respond to damage-associated cues
Further metabolic changes come from the glutamine-dependent regulation of mammalian target of rapamycin, a serine/threonine kinase that acts as a master regulator of cellular growth and metabolism by regulating a variety of processes, from autophagy to glycolysis[42,43,44]
In situ and in vitro that microglia, highly glycolytic under resting conditions, adapt to glucose deprivation by rapidly switching their energy use to glutaminolysis in an mammalian target of rapamycin (mTOR)-dependent manner
Summary
Microglia are highly motile cells that continuously monitor the brain environment and respond to damage-associated cues. During insulin-induced hypoglycemia in vivo or in aglycemia in acute brain slices, glutaminolysis supports the maintenance of microglial process motility and damage-sensing functions This metabolic shift sustains mitochondrial metabolism and requires mTOR-dependent signaling. In situ and in vitro that microglia, highly glycolytic under resting conditions, adapt to glucose deprivation by rapidly switching their energy use to glutaminolysis in an mTOR-dependent manner. This metabolic reprogramming allows microglia to maintain their critical immune surveillance functions even in glucose-deprived conditions where neuronal function is impaired
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