A rapid microglial metabolic response controls metabolism and improves memory

Chronic high-fat feeding triggers widespread metabolic dysfunction including obesity, insulin resistance, and diabetes. While these ultimate pathological states are relatively well understood, we have a limited understanding of how high-fat intake first triggers physiological changes. Here, we identify an acute microglial metabolic response that rapidly translates intake of high-fat diet (HFD) to a surprisingly beneficial effect on spatial and learning memory. Acute high-fat intake increases palmitate levels in cerebrospinal fluid and triggers a wave of microglial metabolic activation characterized by mitochondrial membrane activation, fission and metabolic skewing towards aerobic glycolysis. These effects are generalized, detectable in the hypothalamus, hippocampus, and cortex all within 1–3 days of HFD exposure. In vivo microglial ablation and conditional DRP1 deletion experiments show that the microglial metabolic response is necessary for the acute effects of HFD. (13)C-tracing experiments reveal that in addition to processing via β-oxidation, microglia shunt a substantial fraction of palmitate towards anaplerosis and re-release of bioenergetic carbons into the extracellular milieu in the form of lactate, glutamate, succinate, and intriguingly, the neuro-protective metabolite itaconate. Together, these data identify microglial cells as a critical nutrient regulatory node in the brain, metabolizing away harmful fatty acids and liberating the same carbons instead as alternate bioenergetic and protective substrates. The data identify a surprisingly beneficial effect of short-term HFD on learning and memory.