Astrocytes on “cholesteroids”: The size‐ and function‐promoting effects of a high‐fat diet on hippocampal astroglia

In a recent publication in this journal, Popov et al1 report that a high-fat diet (HFD), increases size and enhances the function of adult mouse astrocytes. The authors found that exposure of mice to HFD, for 1 month during early adulthood, produced weight gain, and expanded adipose fat depots but also prompted unexpected, cell type-specific changes within the CNS. In the hippocampus, astrocytes but not neurons, increased their total lipid content by ~50% and cell cholesterol levels by ~20%, as assessed by immunohistochemistry-assisted Raman microscopy. Rather surprisingly, “fatty” astrocytes extended their processes to a larger territory (nearly 40% increase in the total volume occupied by astrocytic processes) and generated more secondary process branches (an apparent 20% surplus; Figure 1). Such increases in astrocytic size and complexity translated to enhancement in glutamate clearance by astrocytes and were associated with likely related changes in hippocampal long-term potentiation and animal behavior.1 One may ask what is the impact of these findings on our understanding of astrocytic and brain physiology? Astrocytes are arguably the most functionally complex cells in the brain. Their physiological roles morph from development through adulthood and range from guidance of neuroblast migration, to regulation of synaptogenesis, to control of extracellular ion and neurotransmitter homeostasis, to neurovascular coupling, to modulation, and coordination of neuronal activities within the CNS.2, 3 An ability of astrocytes to execute their supportive and instructive functions is closely related to their cytoarchitecture. Highly branched astrocytic processes make contact with blood vessels, and up to 100 000 synapses in the gray matter of rodents or as many as 2 000 000 in humans.3, 4 What is also critical, astrocytes control their spatial domains by contacting nearby cells and forming gap junctional connections and a functional syncytium.3, 4 Astrocytes are known to modify their morphology and functional interactions with neighboring cells in many physiological processes, e.g., in the hypothalamus during lactation or during changes in body hydration status3. Therefore, astroglial morphology matters, and there is an increasing interest and sophistication in studies exploring this issue. The reported by Popov et al1 diet-induced changes in astrocytic morphology and metabolism are highly intriguing but not without precedent. Hypercaloric or high-fat diets are known to change astrocytic architecture and produce reactive gliosis in the arcuate nucleus of humans and rodents.5 There, reactive gliosis is thought to be both the consequence of and the driver for metabolic disturbances in obesity.5 Likewise, the more recent study on the effects of a high-calorie “cafeteria diet” discovered astrocyte hypertrophy and impaired synaptic plasticity in the orbitofrontal cortex, a brain area involved in gustatory reward signaling.6 In this latter case, astrocytic hypertrophy was associated with reduced glutamate clearance and disrupted excitation-inhibition balance.6 Finally, a just-published manuscript in Glia identified very robust effects of a high-calorie/high-fat diet on astrocytic gene expression using a single cell RNAseq approach and proteomics.7 The critical aspect of this new work is that the observed changes in gene expression were time-dependent but also highly brain region-specific.7 Region specificity or timing of evaluation may explain the diverging effects, decrease vs increase, of HFD on glutamate clearance in the orbitofrontal cortex6 and hippocampus,1 the latter reported in the study highlighted in this editorial. The newly evolving knowledge on diet-induced changes in astrocytic properties raises as many important questions as there are answers. Clearly, not all high-calorie/high-fat diet-induced changes in astroglia are beneficial or benign.5, 6 It is not clear if the diet-induced differences are mediated through the “generic” changes in astroglial mitochondrial metabolism (increased substrate flow) or energy reserves (glycogen and lipid droplets). Perhaps, more specific alterations in lipid signaling are involved. The regional specificity of astroglial responses deserves additional attention and should be better understood. The critical factors of age and sexual dimorphism should be further explored as well. There are quite few recent epidemiologic and experimental studies indicating that high-fat diets can be particularly detrimental in aging animals, in postmenopausal females, or in conjunction with underlying brain disorders, such as Alzheimer's disease. These considerations and caveats notwithstanding, the new publication of Popov et al in Acta Physiologica1, together with other emerging work, points to the tantalizing possibility that dietary and perhaps pharmacological interventions can sculpt astrocyte physiology for better (and for worse). Work in the author's laboratory is supported by National Institutes of Health (grant R01 NS111943). The author of this editorial does not have any conflict of interest.