Insulin receptors in tanycytes gate hypothalamic insulin uptake and regulate AgRP neuronal activity
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ABSTRACT:
PROVIDER: PRJNA767609 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR16127353_1.fastq.gz | Fastqsanger.gz | |||
| SRR16127353_2.fastq.gz | Fastqsanger.gz | |||
| SRR16127354_1.fastq.gz | Fastqsanger.gz | |||
| SRR16127354_2.fastq.gz | Fastqsanger.gz | |||
| SRR16127355_1.fastq.gz | Fastqsanger.gz |
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Project description:We reveal a critical role of tanycyte insulin receptors in gating feeding state-dependent regulation of AgRP neurons and systemic insulin sensitivity, and show that insulin resistance in tanycytes contributes to the pleiotropic manifestations of obesity-associated insulin resistance
2021-12-13 | GSE185074 | GEO
Project description:Insulin acts on neurons and glial cells to regulate systemic glucose metabolism and feeding. However, the mechanisms of insulin access in discrete brain regions are incompletely defined. Here we show that insulin receptors in tanycytes, but not in brain endothelial cells, are required to regulate insulin access to the hypothalamic arcuate nucleus. Mice lacking insulin receptors in tanycytes (IR∆Tan mice) exhibit systemic insulin resistance, while displaying normal food intake and energy expenditure. Tanycytic insulin receptors are also necessary for the orexigenic effects of ghrelin, but not for the anorexic effects of leptin. IR∆Tan mice exhibit increased agouti-related peptide (AgRP) neuronal activity, while displaying blunted AgRP neuronal adaptations to feeding-related stimuli. Lastly, a highly palatable food decreases tanycytic and arcuate nucleus insulin signalling to levels comparable to those seen in IR∆Tan mice. These changes are rooted in modifications of cellular stress responses and of mitochondrial protein quality control in tanycytes. Conclusively, we reveal a critical role of tanycyte insulin receptors in gating feeding-state-dependent regulation of AgRP neurons and systemic insulin sensitivity, and show that insulin resistance in tanycytes contributes to the pleiotropic manifestations of obesity-associated insulin resistance.
| S-EPMC8688146 | biostudies-literature
Project description:Hypothalamic neurons expressing Agouti-related peptide (AgRP) are critical for initiating food intake, but druggable biochemical pathways that control this response remain elusive. Thus, genetic ablation of insulin or leptin signaling in AgRP neurons is predicted to reduce satiety but fails to do so. FoxO1 is a shared mediator of both pathways, and its inhibition is required to induce satiety. Accordingly, FoxO1 ablation in AgRP neurons of mice results in reduced food intake, leanness, improved glucose homeostasis, and increased sensitivity to insulin and leptin. Expression profiling of flow-sorted FoxO1-deficient AgRP neurons identifies G-protein-coupled receptor Gpr17 as a FoxO1 target whose expression is regulated by nutritional status. Intracerebroventricular injection of Gpr17 agonists induces food intake, whereas Gpr17 antagonist cangrelor curtails it. These effects are absent in Agrp-Foxo1 knockouts, suggesting that pharmacological modulation of this pathway has therapeutic potential to treat obesity. We used microarrays to detail the change of gene expression in AgRP neurons after knocking out FoxO1. AgRP neurons from control and KO mice were collected by FACS. Gene expression was analyzed by microarray.
2013-04-09 | E-GEOD-45858 | biostudies-arrayexpress
Project description:Purpose: highthroughput sequencing (scRNA-Seq) to study hypothalamic tanycytes and astrocytes with NrCAM KO
2021-12-29 | GSE192766 | GEO
Project description:Hypothalamic tanycytes, radial glial cells that share many features with neuronal progenitors, can generate small numbers of neurons in the postnatal hypothalamus, but the identity of these neurons and the molecular mechanisms that control tanycyte-derived neurogenesis are unknown. We report that tanycyte-specific disruption of the NFI family of transcription factors (Nfia/b/x) stimulates proliferation and tanycyte-derived neurogenesis. Single-cell RNA- and ATAC-Seq analysis reveals that NFI factors repress Shh and Wnt signaling in tanycytes, and small molecule inhibition of these pathways blocks proliferation and tanycyte-derived neurogenesis in Nfia/b/x-deficient mice. We show that Nfia/b/x-deficient tanycytes give rise to multiple mediobasal hypothalamic neuronal subtypes that can mature, integrate into hypothalamic circuitry, and selectively respond to changes in internal states. These findings identify molecular mechanisms controlling tanycyte-derived neurogenesis that can potentially be targeted to selectively remodel hypothalamic neural circuitry controlling homeostatic physiological processes.
2020-10-30 | GSE160377 | GEO
Project description:Hypothalamic tanycytes, radial glial cells that share many features with neuronal progenitors, can generate small numbers of neurons in the postnatal hypothalamus, but the identity of these neurons and the molecular mechanisms that control tanycyte-derived neurogenesis are unknown. We report that tanycyte-specific disruption of the NFI family of transcription factors (Nfia/b/x) stimulates proliferation and tanycyte-derived neurogenesis. Single-cell RNA- and ATAC-Seq analysis reveals that NFI factors repress Shh and Wnt signaling in tanycytes, and small molecule inhibition of these pathways blocks proliferation and tanycyte-derived neurogenesis in Nfia/b/x-deficient mice. We show that Nfia/b/x-deficient tanycytes give rise to multiple mediobasal hypothalamic neuronal subtypes that can mature, integrate into hypothalamic circuitry, and selectively respond to changes in internal states. These findings identify molecular mechanisms controlling tanycyte-derived neurogenesis that can potentially be targeted to selectively remodel hypothalamic neural circuitry controlling homeostatic physiological processes.
2020-10-30 | GSE160375 | GEO
Project description:Environments with seasonal fluctuations requires inhabitants to anticipate their metabolic demands to survive. Drastic changes in food availability and temperature impose pressing challenges, especially during the first weeks of life. Offspring born early and late in the breeding season require different metabolic strategies. The mother’s melatonin levels ensures this in utero, acting as an internal mirror of day length. The melatonin levels programs the offspring to either grow fast and reproduce quickly (early born), or grow slow and delay maturation until next spring (late born). Thyroid hormone availability is altered by the melatonin signal and drives these differing metabolic strategies. Tanycytes located in the ependymal zone of the 3rd ventricle of the hypothalamus are at the crux of this change in thyroid hormone availability. Current literature provide ample evidence that these cells serve as a gatekeeper of metabolic feedback circuits, and photoperiodic history cues. Despite recent advances, our mechanistic understanding of how tanycytes regulate metabolic trajectories remains elusive. Here we used a well-established maternal photoperiodic programming paradigm to decipher the mechanism tanycytes utilise to dictate the offspring metabolic trajectory. The paradigm only rely on variable gestational light exposure to alter metabolic phenotype. Laser capture microdissection of ependymal zone enabled us to perform RNAseq on tanycyte enriched samples.
2023-11-02 | GSE204883 | GEO
Project description:We have found that acute activation of AgRP-neurons lead to inhibition of insulin-stimulated glucose uptake into BAT. Based on this finding, we asked whether this effect was accompanied by acute changes in gene expression, which could point to the mechanism(s) underlying the impaired insulin sensitivity. In summary, our data suggest that activation of AgRP-neurons actuely reprograms gene expression in BAT towards a myogenic profile. The arcuate nucleus of 4 mice expressing channelrhodopsin 2 in AgRP-neurons through Cre-mediated recombination (ChR2-AgRP) and 4 Cre-negative controls (ChR2-fl/WT, Ctrl), were stimulated with blue laser light for one hour, total RNA from BAT was isolated and subjected to a microarray-based gene expression analysis.
2016-02-10 | E-GEOD-77766 | biostudies-arrayexpress
Project description:Background: Neuronal and glial differentiation in the murine hypothalamus is not complete at birth, but continues over the first two weeks postnatally. Nutritional status and Leptin deficiency can influence the maturation of neuronal projections and glial patterns, and hypothalamic gliosis occurs in mouse models of obesity. Gnasxl constitutes an alternative transcript of the genomically imprinted Gnas locus and encodes a variant of the signalling protein Gαs, termed XLαs, which is expressed in defined areas of the hypothalamus. Gnasxl-deficient mice show postnatal growth retardation and undernutrition, while surviving adults remain lean and hypermetabolic with increased sympathetic nervous system (SNS) activity. Effects of this knock-out on the hypothalamic neural network have not yet been investigated. Results: RNAseq analysis for gene expression changes in hypothalami of Gnasxl-deficient mice indicated Glial fibrillary acid protein (Gfap) expression to be significantly down-regulated in adult samples. Histological analysis confirmed a reduction in Gfap-positive glial cell numbers specifically in the hypothalamus. This reduction was observed in adult tissue samples, whereas no difference was found in hypothalami of postnatal stages, indicating an adaptation in adult Gnasxl-deficient mice to their earlier growth phenotype and hypermetabolism. Especially noticeable was a loss of many Gfap-positive α-tanycytes and their processes, which form part of the ependymal layer that lines the medial and dorsal regions of the 3rd ventricle, while β-tanycytes along the median eminence (ME) and infundibular recesses appeared unaffected. This was accompanied by local reductions in Vimentin and Nestin expression. Hypothalamic RNA levels of glial solute transporters were, unchanged, indicating a potential compensatory up-regulation in the remaining astrocytes and tanycytes. Conclusion: Gnasxl deficiency does not directly affect glial development in the hypothalamus, since it is expressed in neurons, and Gfap-positive astrocytes and tanycytes appear normal during early postnatal stages. The loss of Gfap-expressing cells in adult hypothalami appears to be a consequence of the postnatal undernutrition, hypoglycaemia and continued hypermetabolism and leanness of Gnasxl-deficient mice, which contrasts with gliosis observed in obese mouse models. Since α-tanycytes also function as adult neural progenitor cells, these findings might indicate further developmental abnormalities in hypothalamic formations of Gnasxl-deficient mice, potentially including neuronal composition and projections. 6 wildtype and 6 Gnasxlm+/p- RNA isolates were used, which were pooled in pairs in equal concentrations prior to rRNA removal using the RiboMinus kit (Life Technologies)
2016-04-14 | E-GEOD-75878 | biostudies-arrayexpress
Project description:Hypothalamic neurons expressing Agouti-related peptide (AgRP) are critical for initiating food intake, but druggable biochemical pathways that control this response remain elusive. Thus, genetic ablation of insulin or leptin signaling in AgRP neurons is predicted to reduce satiety but fails to do so. FoxO1 is a shared mediator of both pathways, and its inhibition is required to induce satiety. Accordingly, FoxO1 ablation in AgRP neurons of mice results in reduced food intake, leanness, improved glucose homeostasis, and increased sensitivity to insulin and leptin. Expression profiling of flow-sorted FoxO1-deficient AgRP neurons identifies G-protein-coupled receptor Gpr17 as a FoxO1 target whose expression is regulated by nutritional status. Intracerebroventricular injection of Gpr17 agonists induces food intake, whereas Gpr17 antagonist cangrelor curtails it. These effects are absent in Agrp-Foxo1 knockouts, suggesting that pharmacological modulation of this pathway has therapeutic potential to treat obesity. We used microarrays to detail the change of gene expression in AgRP neurons after knocking out FoxO1.
2013-04-09 | GSE45858 | GEO