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The Intermittent Fasting Mimetic, 2-deoxyglucose, Reprograms Brain Derived Neurotrophic Factor (BDNF) transcription via an Adaptive ER Stress-ATF4 Pathway and Improves Outcomes in Alzheimer’s and Stroke Models [RNA-seq]

ABSTRACT: In our preliminary in-vitro studies in primary neurons, we found that changing glucose utlization using 2-deoxyglucose (2-DG, a known glycolytic inhibitor, which inhibits glucose utilization) led to a dose dependent signficant increase in Bdnf gene expression. Additionally, the dose of 2-DG that induced Bdnf gene expression also normalized learning and memory in mouse model of AD (5xFAD mouse) and improved functional recovery in mice models of ischemic and hemorrhagic strokes. With RNA Sequencing of 2-DG treated primary neuronal samples, our first goal was to identify dominant gene signatures in response to 2-deoxyglucose in order to delineate critical pathways affected by changes in glucose metabolism and our second goal was to understand if 2-deoxyglucose affect a broad gene plasticity program or only a few selective plasticity genes.

ORGANISM(S): Mus musculus

PROVIDER: GSE217283 | GEO | 2023/11/28

REPOSITORIES: GEO

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The Intermittent Fasting Mimetic, 2-deoxyglucose, Reprograms Brain Derived Neurotrophic Factor (BDNF) transcription via an Adaptive ER Stress-ATF4 Pathway and Improves Outcomes in Alzheimer’s and Stroke Models [ChIP-seq]

Project description:Intermittent fasting (IF) has broad beneficial effects on brain pathophysiology. Here, we sought to identify the target required for beneficial effects of IF using its pharmacological mimic, 2-deoxyglucose (2-DG), which could also eliminate limitations of human IF application due to dosage and schedule issues. 2-DG transcriptionally induced plasticity gene, Bdnf in vitro and in vivo. A 2-DG dose that induced Bdnf transcription in vivo also normalized hippocampal long-term potentiation and memory in an AD mouse model (5xFAD) and significantly improved functional recovery in stroke models. 2-DG enhanced Bdnf transcription by decreasing N-linked glycosylation that induced ER stress and the activity of newly translated ATF4 at +3kb intronic enhancer region of Bdnf gene. These data highlight the critical role of N-linked glycosylation in glucose sensing and suggest that 2-DG can improve outcomes without inducing ketosis via an adaptive ER stress pathway culminating in the transcription of CNS-associated resilience genes including Bdnf. n our preliminary in-vitro studies in primary neurons, we found that changing glucose utlization using 2-deoxyglucose (2-DG, a known glycolytic inhibitor, which inhibits glucose utilization) led to a dose dependent signficant increase in Bdnf gene expression. Additionally, the dose of 2-DG that induced Bdnf gene expression also normalized learning and memory in mouse model of AD (5xFAD mouse) and improved functional recovery in mice models of ischemic and hemorrhagic strokes. With RNA Sequencing of 2-DG treated primary neuronal samples, our first goal was to identify dominant gene signatures in response to 2-deoxyglucose in order to delineate critical pathways affected by changes in glucose metabolism and our second goal was to understand if 2-deoxyglucose affect a broad gene plasticity program or only a few selective plasticity genes.

2023-11-28 | GSE217282 | GEO

2-Deoxyglucose induced transcription in control and MondoA knockdown cells

Project description:To determine the contibution of the transcription factor MondoA to 2-deoxyglucose-induced transcription expression analysis was carried out in control and MondoA knockdown cells HA1ER cells are human embryonic kidney cells transformed with hTERT, SV40 Early region and activated H-Ras Keywords: cell type comparision, genetic modification HA1ER cells, Control (NS) or MondoA knockdown (M2), were starved for glucose overnight and then treated with 2-deoxyglucose for 3 hours

2008-04-24 | E-GEOD-11242 | biostudies-arrayexpress

Effect of 2-deoxyglucose on the interferon gamma-mediated response to intracellular bacterial infection in mouse bone marrow-derived macrophages

Project description:We report transcriptional responses of mouse macrophages to Pam3CSK4 stimulation or L. pneumophila infection that are additionally stimulated with interferon gamma ± 2-deoxyglucose. We identify a strong transcriptional signature of the unfolded protein stress response in macrophages exposed to 2-deoxyglucose. Additionally we find that 2-deoxyglucose reduces the expression of several key interferon gamma-induced transcripts associated with an antimicrobial response to L. pneumophila.

2019-08-09 | GSE135385 | GEO

Proteomic response of yeast cells to 2-deoxyglucose exposure (0.2%, 2.5h)

Project description:Cancer cells display an altered metabolism with increased glycolysis and glucose uptake. Anti-cancer strategies targeting glycolysis through metabolic inhibitors have been considered. The glucose analog 2-deoxyglucose (2DG) is imported into cells and after phosphorylation becomes 2DG-6-phosphate, a toxic by-product that inhibits glycolysis. 2DG has other cellular effects and can induce resistance. Using yeast as a model, we performed an unbiased, mass-spectrometry-based approach to probe the cellular effects of 2DG on the proteome and study resistance mechanisms. We found that two 2DG-6-phosphate phosphatases, Dog1 and Dog2, were induced upon exposure to 2DG and participated in 2DG detoxication. 2DG induced Dog2 by activating several signaling pathways, such as the MAPK (the p38 ortholog Hog1)-based stress-responsive pathway, the unfolded protein response (UPR) triggered by 2DG-induced ER stress, and the MAPK (Slt2)-based cell wall integrity (CWI) pathway. Thus, 2DG-induced interference with cellular signaling rewired the expression of these endogenous phosphatases to promote 2DG resistance. Consequently, loss of the UPR or CWI pathways led to 2DG hypersensitivity. In contrast, DOG2 was transcriptionally repressed by glucose availability through the inhibition of the Snf1/AMPK pathway, and glucose-repression mutants were 2DG-resistant. The characterization and genome resequencing of spontaneous 2DG-resistant mutants revealed that DOG2 overexpression was a common strategy to achieve 2DG resistance. A human Dog2 homolog, HDHD1, also displays 2DG-6-phosphate phosphatase activity in vitro, and its overexpression conferred 2DG resistance in HeLa cells, suggesting potential interference with chemotherapies involving 2DG.

2019-09-09 | PXD014373 | Pride

2-Deoxyglucose induced transcription in control and MondoA knockdown cells

2008-04-24 | GSE11242 | GEO

Untargeted transcriptomic profiling of activated primary human CD4+ T cells treated with metformin and 2-deoxyglucose

Project description:Purpose: To investigate the effects of metabolic inhibitors metformin and 2-deoxyglucose on the global transcriptome of primary human CD4+ T cells. Methods: mRNA profiles of primary human CD4+ T cells were generated by RNA-Seq for 3 donors in triplicate using Illumina TruSeq library prep. Data was processed using Elucidata's workflow as described below. Results: Our study presents the first transcriptomic analysis of how metformin + 2-deoxyglucose combination treatment affects activation-induced remodeling of metabolic gene expression in primary human CD4+ T cells.

2020-06-15 | GSE144353 | GEO

Glycometabolic regulation of the biogenesis of small extracellular vesicles

Project description:The biogenesis of small extracellular vesicles (sEVs) is regulated by multiple molecular machineries, generating considerably heterogeneous vesicle populations, i.e., exosomes and non-exosomal vesicles, with distinct cargo molecules. However, the role of carbohydrate metabolism in generating such vesicle heterogeneity remains largely elusive. Here we discovered that 2-deoxyglucose (2-DG), a well-known glycolysis inhibitor, suppressed the secretion of non-exosomal vesicles by impairing asparagine-linked glycosylation (N-glycosylation) in mouse melanoma cells. In the present study, to gain deeper insight into the molecular signatures of non-exosomal vesicles, we performed label-free quantitative proteomics of sEVs released from cells that were treated with or without 2-DG or NGI-1.

2020-10-14 | PXD020670 | Pride

Effects of brain-derived neurotrophic factor on microRNA expression profile in human endothelial progenitor cells

Project description:The mechanisms underlying proangiogenic function of brain-derived neurotrophic factor (BDNF) are not fully understood. Current study was designed to explore the miRNA profile in human early endothelial progenitor cells (EPCs, also referred to as CFU-Hill cells) in response to BDNF treatment.

2017-12-05 | GSE107667 | GEO

Detection of Arc/Arg3.1 oligomers in rat brain: constitutive and synaptic activity-evoked dimer expression in vivo

Project description:The immediate early gene product activity-regulated cytoskeleton-associate protein (Arc or Arg3.1) is a major regulator long-term synaptic plasticity with critical roles in postnatal cortical development and memory formation. However, the molecular basis of Arc function is not defined. Arc is a hub protein with interaction partners in the postsynaptic neuronal compartment and nucleus. In vitro biochemical and biophysical analysis of purified recombinant Arc show formation of low-order oligomers and larger particles including retrovirus-like capsids. Here, we provide evidence for naturally occurring Arc oligomers in mammalian brain. Using in situ protein crosslinking to trap weak Arc-Arc interactions, we identified in various preparations a prominent Arc immunoreactive band on SDS-PAGE of molecular mass corresponding to a dimer. While heavier Arc species or putative trimers and tetramers were detected, they were of lower abundance. In the dentate gyrus (DG) of adult anesthetized rats, induction of long-term potentiation (LTP) by high-frequency stimulation (HFS) of medial perforant synapses or by brief intrahippocampal infusion of BDNF led to a massive increase in Arc dimer expression. Arc immunoprecipitation of crosslinked DG tissue showed enhanced expression of dimer during four hours of LTP maintenance. Mass spectrometric proteomic analysis of immunoprecipitated, gel-excised bands corroborated detection of Arc dimer. Furthermore, Arc dimer was constitutively expressed in naïve cortical, hippocampal and DG tissue, with lowest levels in the DG. Taken together the results implicate Arc dimers as the predominant low-oligomeric form in mammalian brain, exhibiting regional differences in its constitutive expression and pronounced enhanced expression during DG LTP.

2023-07-20 | PXD039612 | Pride

Brain-derived neurotrophic factor contributes to the cardiogenic potential of adult resident progenitor cells in failing murine heart

Project description:Aims: Resident cardiac progenitor cells show homing properties when injected into the injured but not into the healthy myocardium. The molecular background behind this difference in behavior needs to be studied to elucidate how adult progenitor cells can restore cardiac function of the damaged myocardium. Since the brain-derived neurotrophic factor (BDNF) moderates cardioprotection in injured hearts, we focused on delineating its regulatory role in the damaged myocardium. Methods and Results: Comparative gene expression profiling of freshly isolated undifferentiated Sca-1 progenitor cells derived either from heart failure transgenic αMHC-CyclinT1/Gαq overexpressing mice or wildtype littermates revealed transcriptional variations. Bdnf expression was up-regulated 5-fold during heart failure, which was verified by qRT-PCR and confirmed at the protein level. The migratory capacity of Sca-1 cells from transgenic heart was improved by 15% in the presence of 25ng/ml BDNF. Furthermore, BDNF-mediated effects on Sca-1 cells were studied via pulsed Stable Isotope Labeling of Amino acids in Cell Culture (pSILAC) proteomics approach. After BDNF treatment, significant differences between newly synthesized proteins in Sca-1 cells isolated from control and transgenic mice were observed for CDK1, SRRT, HDGF, and MAP2K3, which are known to regulate cell cycle, survival and differentiation. Moreover, BDNF repressed the proliferation of Sca-1 cells from transgenic hearts. Conclusion: Comparative profiling of resident Sca-1 cells revealed elevated BDNF levels in the failing heart. Exogenous BDNF (i) stimulated migration, which might improve the homing ability of Sca-1 cells derived from the failing heart and (ii) repressed the cell cycle progression suggesting its potency to ameliorate heart failure.

2015-03-26 | GSE58577 | GEO

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