Diet triggers specific responses of hypothalamic astrocytes in time and region dependent manner

Abstract

Hypothalamic astrocytes are particularly affected by energy-dense food consumption. How the anatomical location of these glial cells and their spatial molecular distribution in the arcuate nucleus of the hypothalamus (ARC) determine the cellular response to a high caloric diet remains unclear. In this study, we investigated their distinctive molecular responses following exposure to a high-fat high-sugar (HFHS) diet, specifically in the ARC. Using RNA sequencing and proteomics, we showed that astrocytes have a distinct transcriptomic and proteomic profile dependent on their anatomical location, with a major proteomic reprogramming in hypothalamic astrocytes. By ARC single-cell sequencing, we observed that a HFHS diet dictates timeand cell-specific transcriptomic responses, revealing that astrocytes have the most distinct regulatory pattern compared to other cell types. Lastly, we topographically and molecularly characterized astrocytes expressing glial fibrillary acidic protein and/or aldehyde dehydrogenase 1 family member L1 in the ARC, of which the Luiza Maria Lutomska and Viktorian Miok contributed equally to this work.

Effects of High-Fat and High-Fat High-Sugar Diets in the Anxiety, Learning and Memory, and in the Hippocampus Neurogenesis and Neuroinflammation of Aged Rats

“…Naturally, other mechanisms are involved in the deleterious effects of high-caloric diets, including neuroinflammation [ 51 ]. Astrocytes are glial cells that interact intimately with neurons and ensure they receive, process, and propagate information to other neurons.…”

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

“…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 .…”

“…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 cortex 6 and hippocampus, 1 the latter reported in the study highlighted in this editorial.…”

“…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 cortex 6 and hippocampus, 1 the latter reported in the study highlighted in this editorial.…”

Astrocytic circadian clock control of energy expenditure by transcriptional stress responses in the ventromedial hypothalamus

“…Moreover, optogenetic stimulation of astrocytes in the medial basal hypothalamus induces adenosine-mediated anorexigenic effects of high-fat diet (HFD) (Sweeney et al, 2016). High-fat diet also induces transcriptional reprogramming in astrocytes residing in the ARC (Lutomska et al, 2022). Furthermore, a direct functional astrocyte-neuron interplay within the PVN in the control of glucose metabolism and thermogenesis has been recently revealed (Herrera Moro Chao et al, 2022).…”