A high-fat diet changes astrocytic metabolism to promote synaptic plasticity and behavior

Aim: A high-fat diet (HFD) is generally considered to negatively influence the body, the brain, and cognition. Nonetheless, fat and fatty acids are essential for nourishing and constructing brain tissue. Astrocytes are central for lipolysis and fatty acids metabolism. We tested how HFD affects astrocyte metabolism, morphology, and physiology. Methods: We used Raman microspectroscopy to assess the redox state of mitochondria and lipid content in astrocytes and neurons in hippocampal slices of mice subjected to HFD. Astrocytes were loaded with fluorescent dye through patch pipette for morphological analysis. Whole-cell voltage-clamp recordings were performed to measure transporter and potassium currents. Western blot analysis quantified the expression of astrocyte-specific proteins. Field potential recordings measured the magnitude of long-term potentiation (LTP). Open filed test was performed to evaluate the effect of HFD on animal behavior. Results: We found that exposure of young mice to 1 month of HFD increases lipid content and relative amount of reduced cytochromes in astrocytes but not in neurons. Metabolic changes were paralleled with an enlargement of astrocytic territorial domains due to an increased outgrowth of branches and leaflets. Astrocyte remodeling was associated with an increase in expression of ezrin and with no changes in glial fibrillary acidic protein (GFAP), glutamate transporter-1 (GLT-1), and glutamine synthetase (GS). Such physiological (non-reactive) enlargement of astrocytes in the brain active milieu promoted glutamate clearance and LTP and translated into behavioral changes. Conclusion: Dietary fat intake is not invariably harmful and might exert beneficial effects depending on the biological context.