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Bitter taste cells in the ventricular walls of the murine brain regulate glucose homeostasis

ABSTRACT: The median eminence (ME) is a circumventricular organ at the base of the brain that controls body homeostasis. Tanycytes are its specialized glial cells that constitute the ventricular walls and regulate different physiological states, however individual signaling pathways in these cells are incompletely understood. Here, we identify a functional tanycyte subpopulation that expresses key taste transduction genes including bitter taste receptors, the G protein gustducin and the gustatory ion channel TRPM5 (M5). M5 tanycytes have access to blood-borne cues via processes extended towards diaphragmed endothelial fenestrations in the ME and mediate bidirectional communication between the cerebrospinal fluid and blood. This subpopulation responds to metabolic signals including leptin and other hormonal cues and is transcriptionally reprogrammed upon fasting. Acute M5 tanycyte activation induces insulin secretion and acute diphtheria toxin-mediated M5 tanycyte depletion results in impaired glucose tolerance in diet-induced obese mice. We provide a cellular and molecular framework that defines how bitter taste cells in the ME integrate chemosensation with metabolism.

ORGANISM(S): Mus musculus

PROVIDER: GSE226066 | GEO | 2023/03/01

REPOSITORIES: GEO

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Project description:The ependyma lining the third ventricle (3V) in the mediobasal hypothalamus is recognized as a critical player in controlling energy balance and glucose homeostasis. Its molecularly distinct cell types, namely diverse tanycyte subpopulations and typical ependymal cells, confer a high functional heterogeneity and plasticity to this complex ependymal system, but the molecular mechanisms governing its features, especially in the context of metabolic regulation, are still not fully understood.Here, 5481 hypothalamic ependymocytes were cataloged using FACS-assisted single-cell RNA sequencing from fed, 12h-fasted, and 24h-fasted adult male mice. We first observed the limitations of using standard clustering analysis to characterize the different ependymal cell subpopulations lining the 3V. Indeed, while typical ependymal cells and β2-tanycytes are sharply defined at the molecular level using this approach, other subpopulations (i.e., β1- and α-tanycytes) display fuzzy boundaries and very few specific markers. Moreover, 12h- and 24h-fasting dynamically modulate gene expression, increasing tanycyte subgroup heterogeneity. To better analyze the dynamic changes in tanycytes’ gene expression profile, we implemented a pseudospatial analysis based on 3V neuroanatomical distribution, which we validated using in-situ hybridization, immunohistochemistry, and histologic staining. This approach improved the characterization of tanycyte markers, refining our knowledge of specific versus shared features and the segregation of subgroup-specific versus general tanycyte functions. Importantly, we showed that fasting dynamically shifts patterns in gene expression and transcription activity along the 3V, inducing metabolic and functional switches in tanycyte subpopulations, particularly regarding lipid metabolism. Additionally, numerous functions related to tanycyte-neuron and tanycyte-synapse interactions, notably through Nrxn1 expression, present a functional dorso→ventral shift towards the arcuate nucleus during fasting. Altogether, this data shows that changes in energy status lead to a spatial redistribution of distinct cell type-specific responses along the 3V and gives new insights into molecular and functional diversity and plasticity within the tanycyte population.

Project description:Purpose: Choline acetyltransferase (ChAT)-expressing epithelial cells are found in the upper and lower airways. In the trachea, they are referred to as brush cells. In the mouse nose two distinct populations of ChAT-eGFP+ cells had been previously described: a population of rare solitary chemosensory cells (SCCs) in the respiratory mucosa and a more abundant population of microvillous cells (MVCs) in the olfactory epithelium. Besides ChAT expression, SCCs share the expression of bitter taste receptors and signaling machinery with tracheal brush cells as well as close association with CGPR+ nerve fibers and an elongated shape. MVCs do not express bitter taste receptors, are not clearly associated with nerves and are smaller in size than SCCs. We have previously reported the transcriptional profile of tracheal ChAT-expressing brush cells but the transcriptional profile of nasal chemosensory ChAT+ epithelial cells has not been reported. Methods: In this study, we isolated nasal ChAT-eGFP+ cells by FACS from naïve ChAT(BAC)-eGFP mice with knockin of eGFP within a BAC spanning the ChAT locus, marking brush cells in the epithelium and performed transcriptome profiling using low input RNA sequencing. We sorted two distinct subsets of ChAT-eGFP+ epithelial cells from the nasal mucosa based on FACS ice and granularity characteristic: ChAT-eGFP+ EpCAM+ FSC/SSChigh (representing 5% of all ChAT-eGFP+ cells) and FSC/SSClow (representing 95% of all ChAT-eGFP+ cells), respectively. We compared them to unfractionated ChAT-eGFP- EpCAM+ epithelial cells. Results: Both nasal ChAT-eGFP subsets shared the core transcriptional profile of chemosensory cells from the intestine, trachea, gallbladder and thymus including the expression of Il25, Pou2f3, Trpm5, Avil, Plcb2 and transcripts of eicosanoid biosynthetic enzymes suggesting that most ChAT-eGFP+ cells in the nose belong to the chemosensory/tuft/brush cel family. The two subsets of nasal ChAT-eGFP+ cells differed in expression of taste receptors and taste receptor signaling machinery. Conclusions: Our study represents the first detailed analysis of the transcriptome of nasal ChAT-eGFP+ cells (brush cells) and identifies two subsets of nasal brush cells that share a core transcriptional signature but differ in expression of bitter taste receptors.

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Bitter taste cells in the ventricular walls of the murine brain regulate glucose homeostasis

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