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Transcriptomic Analysis Links the Response of Diverse Hypothalamic Cell Types to Sustained Diabetes Remission Induced by Fibroblast Growth Factor 1

ABSTRACT: Transcriptomic Analysis Links the Response of Diverse Hypothalamic Cell Types to Sustained Diabetes Remission Induced by Fibroblast Growth Factor 1

PROVIDER: PRJNA643220 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11574800.fastq.gz	Fastqsanger.gz
	SRR11574801.fastq.gz	Fastqsanger.gz
	SRR11574802.fastq.gz	Fastqsanger.gz
	SRR11574803.fastq.gz	Fastqsanger.gz
	SRR11574716.fastq.gz	Fastqsanger.gz

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Transcriptomic Analysis Links the Response of Diverse Hypothalamic Cell Types to Sustained Diabetes Remission Induced by Fibroblast Growth Factor 1 [bulk RNA-seq]

Project description:In rodent models of type 2 diabetes (T2D), sustained remission of hyperglycemia can be induced by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1), and the hypothalamus was recently identified as a key target for this effect. To investigate how FGF1 action in this brain area achieves this effect, we combined single-nucleeus RNA sequencing (RNA-seq) with single-cell and traditional RNA-seq to identify >70,000 single-cell transcriptomes from the hypothalamus of diabetic Lepob/ob mice obtained on Days 1, 5 and 42 after icv injection of either FGF1 or vehicle. In addition to robust transcriptomics effects on Agrp neurons, which persisted through Day 42, rapid inhibition of Agrp neurons by FGF1 was shown by both electrophysiology and cFos studies. This effect is predicted to increase hypothalamic melanocortin signaling, and we show that FGF1-induced diabetes remission is melanocortin-dependent, as it was prevented by either genetic or pharmacological blockade of central melanocortin receptors. Combined with dramatic transcriptional and morphological changes induced by icv FGF1 injection in tanycytes, astrocytes and oligodendrocytes, including increased cellular contacts between astrocytes and Agrp neurons, these findings implicate glial-neuron interactions as mediators of the sustained remission of diabetes induced by the hypothalamic action of FGF1 action.

2020-07-01 | GSE153549 | GEO

Transcriptomic Analysis Links the Response of Diverse Hypothalamic Cell Types to Sustained Diabetes Remission Induced by Fibroblast Growth Factor 1 [single-cell RNA-seq]

2020-04-21 | GSE148946 | GEO

Role of hypothalamic MAPK/ERK signaling in diabetes remission induced by the central action of fibroblast growth factor 1

Project description:The capacity of the brain to elicit sustained remission of hyperglycemia in rodent models of type 2 diabetes (T2D) following intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) is well established. Here, we show that icv FGF1 injection induces signaling by extracellular signal-regulated kinases 1 and 2 (ERK1/2), members of the mitogen-activated protein kinase (MAPK) family in the hypothalamus, and that this activation persists for at least 24h. Further, we show that in diabetic Lepob/ob mice, this prolonged response is required for the sustained antidiabetic action of FGF1, since it is abolished by sustained (but not acute) pharmacologic blockade of hypothalamic MAPK/ERK signaling. We also demonstrate that FGF1 R50E, a FGF1 mutant that activates FGF receptors but induces only transient hypothalamic MAPK/ERK signaling, elicits transient but not sustained glucose lowering. These data implicate sustained hypothalamic MAPK/ERK signaling in the mechanism underlying diabetes remission induced by icv FGF1.

2021-07-12 | GSE179918 | GEO

Transcriptomic Analysis Links the Response of Diverse Hypothalamic Cell Types to Sustained Diabetes Remission Induced by Fibroblast Growth Factor 1 [bulk RNA-seq]

Project description:Transcriptomic Analysis Links the Response of Diverse Hypothalamic Cell Types to Sustained Diabetes Remission Induced by Fibroblast Growth Factor 1 [bulk RNA-seq]

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Transcriptomic Analysis Links the Response of Diverse Hypothalamic Cell Types to Sustained Diabetes Remission Induced by Fibroblast Growth Factor 1 [single-cell RNA-seq]

Project description:Transcriptomic Analysis Links the Response of Diverse Hypothalamic Cell Types to Sustained Diabetes Remission Induced by Fibroblast Growth Factor 1 [single-cell RNA-seq]

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Transcriptomic analysis links diverse hypothalamic cell types to fibroblast growth factor 1-induced sustained diabetes remission.

Project description:In rodent models of type 2 diabetes (T2D), sustained remission of hyperglycemia can be induced by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1), and the mediobasal hypothalamus (MBH) was recently implicated as the brain area responsible for this effect. To better understand the cellular response to FGF1 in the MBH, we sequenced >79,000 single-cell transcriptomes from the hypothalamus of diabetic Lepob/ob mice obtained on Days 1 and 5 after icv injection of either FGF1 or vehicle. A wide range of transcriptional responses to FGF1 was observed across diverse hypothalamic cell types, with glial cell types responding much more robustly than neurons at both time points. Tanycytes and ependymal cells were the most FGF1-responsive cell type at Day 1, but astrocytes and oligodendrocyte lineage cells subsequently became more responsive. Based on histochemical and ultrastructural evidence of enhanced cell-cell interactions between astrocytes and Agrp neurons (key components of the melanocortin system), we performed a series of studies showing that intact melanocortin signaling is required for the sustained antidiabetic action of FGF1. These data collectively suggest that hypothalamic glial cells are leading targets for the effects of FGF1 and that sustained diabetes remission is dependent on intact melanocortin signaling.

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Transcriptomic Analysis Links the Response of Diverse Hypothalamic Cell Types to Sustained Diabetes Remission Induced by Fibroblast Growth Factor 1

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-07-01 | GSE153551 | GEO

Hypothalamic perineuronal net assembly is required for sustained diabetes remission induced by fibroblast growth factor 1 in rats.

Project description:We recently showed that perineuronal nets (PNNs) enmesh glucoregulatory neurons in the arcuate nucleus (Arc) of the mediobasal hypothalamus (MBH)1, but whether these PNNs play a role in either the pathogenesis of type 2 diabetes (T2D) or its treatment remains unclear. Here we show that PNN abundance within the Arc is markedly reduced in the Zucker diabetic fatty (ZDF) rat model of T2D, compared with normoglycaemic rats, correlating with altered PNN-associated sulfation patterns of chondroitin sulfate glycosaminoglycans in the MBH. Each of these PNN-associated changes is reversed following a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) at a dose that induces sustained diabetes remission in male ZDF rats. Combined with previous work localizing this FGF1 effect to the Arc area2-4, our finding that enzymatic digestion of Arc PNNs markedly shortens the duration of diabetes remission following icv FGF1 injection in these animals identifies these extracellular matrix structures as previously unrecognized participants in the mechanism underlying diabetes remission induced by the central action of FGF1.

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Predicting drug-free remission in rheumatoid arthritis: the Biomarkers of Remission in Rheumatoid Arthritis (BioRRA) Study

Project description:Sustained remission is now an achievable goal in rheumatoid arthritis (RA) using modern treat-to-target regimens of disease-modifying anti-rheumatic drugs (DMARDs). Recent studies have demonstrated that up to half of patients in remission can discontinue DMARDs and maintain drug-free remission (DFR), with consequent benefits of avoidance of drug toxicity and the need for regular and expensive safety monitoring. However, there are currently no reliable biomarkers that can predict DFR prior to withdrawal of DMARDs. Aim: As part of a wider study of DMARD withdrawal (the BioRRA study), we aimed to identify predictors of time-to-flare following DMARD cessation using whole-genome bulk RNA sequencing data from circulating CD4+ T cells.

2019-07-12 | GSE122612 | GEO

Role of hypothalamic MAPK/ERK signaling in diabetes remission induced by the central action of fibroblast growth factor 1

Project description:Role of hypothalamic MAPK/ERK signaling in diabetes remission induced by the central action of fibroblast growth factor 1

| PRJNA745684 | ENA