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.See related editorial: Mongin A. A. 2022. Astrocytes on "cholesteroids": The size-and function-promoting effects of a high-fat diet on hippocampal astroglia. Acta Physiol (Oxf). e13859.

How aging affects cellular components of the human brain active milieu remains largely unknown. We analyzed astrocytes and neurons in the neocortical access tissue of younger (22 - 50 years) and older (51 - 72 years) adult patients who underwent glioma resection. Aging decreased the amount of reduced mitochondrial cytochromes in astrocytes but not neurons. The total amount of protein was decreased in astrocytes and increased in neurons. Aged astrocytes showed morphological dystrophy quantified by the decreased length of branches, decreased volume fraction of leaflets, and shrinkage of the anatomical domain. Dystrophy correlated with the loss of gap junction coupling between astrocytes and increased input resistance. Aging was accompanied by the upregulation of glial fibrillary acidic protein (GFAP) and downregulation of membrane-cytoskeleton linker Ezrin associated with leaflets. No significant changes in neuronal excitability or spontaneous inhibitory postsynaptic signaling were observed. Thus, brain aging is associated with the impaired morphological presence and mitochondrial malfunction of astrocytes, but not neurons.

SummaryA high-fat diet (HFD) is generally considered to negatively influence the body, the brain, and cognitive abilities. On the other hand, fat and fatty acids are essential for nourishing and constructing brain tissue. Astrocytes are central for lipolysis and fatty acids metabolism. Here we show that exposure of young mice to one month of HFD elevates lipid content and increases the 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 long-term potentiation. These changes translated into improved exploratory behavior. Thus, dietary fat intake is not invariably harmful and might exert beneficial effects depending on the biological context.In BriefA high-fat diet stimulates the metabolism and growth of astrocytes, which improves glutamate clearance, synaptic plasticity, and exploratory behavior in young mice. Thus, dietary fat arguably is an essential component of the diet for children and young adults, supporting the optimal development of the brain.HighlightsExposure of young mice to a high-fat diet elevated lipid content and increased 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.Astrocytic enlargement was associated with increased expression of ezrin but not GFAP, hence was not reactive but physiologicalExpansion of astrocytes in the brain active milieu improved glutamate clearance and long-term potentiation.The high-fat diet improved exploratory behavior in young mice.