Insulin acts on astrocytes to shift their substrate preference to fatty acids.

It is increasingly recognized that brain can β-oxidize fatty acids for use as an energy substrate. However, mechanism(s) by which neural cells switch their preference from glucose to fatty acids are not fully elucidated. Here we provide evidence that insulin acts directly on astrocytes to promote the uptake of glucose and fatty acids while modifying their substrate preference through a sequential shift in the expression of genes associated with fatty acid uptake, synthesis, transport, and metabolism. Under these conditions, fatty acids are converted into TCA cycle intermediates to satisfy astrocyte energy demands, allowing pyruvate derived from glucose to be directed toward the production of lactate; a preferred fuel for neurons. This shift in astrocyte energy substrate preference is required for insulin to enhance long-term potentiation in the Schaffer collateral. These findings establish a homeostatic mechanism where insulin promotes LTP by switching the energy substrate preference of astrocytes to fatty acids.