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Metformin enhances human oligodendrocyte function by altering metabolism

ABSTRACT: Metformin enhances human oligodendrocyte function by altering metabolism

PROVIDER: PRJNA1188459 | ENA |

REPOSITORIES: ENA

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	SRR31407800.fastq.gz	Fastqsanger.gz
	SRR31407774.fastq.gz	Fastqsanger.gz
	SRR31407775.fastq.gz	Fastqsanger.gz
	SRR31407776.fastq.gz	Fastqsanger.gz
	SRR31407777.fastq.gz	Fastqsanger.gz

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Metformin enhances human oligodendrocyte function by altering metabolism

Project description:Metformin rejuvenates adult rat oligodendrocyte progenitor cells (OPCs) allowing more efficient differentiation into oligodendrocytes and improved remyelination of CNS axons and therefore is of interest as a possible therapeutic in demyelinating diseases such as multiple sclerosis (MS). We set out to test whether metformin had a similar effect in human stem cell derived-OPCs. We assessed the suitability of human monoculture, organoid and transplantation into immunodeficient mice (chimera model) culture systems in simulating in vivo adult human oligodendrocytes, finding most close resemblance in the chimera model. Metformin increased myelin proteins and/or sheaths in all models even when human cells had fetal signatures. In the chimera model, metformin led to a marked increase in mitochondrial area both in the human transplanted cells and in the mouse axons with associated increase in transcripts related to mitochondrial function and metabolism. Human oligodendrocytes from MS brain donors treated pre-mortem with metformin also expressed similar transcripts suggesting that metformin’s brain effect is not cell-specific, altering metabolism in both oligodendrocytes and axons leading to more myelin production, in part through mitochondrial changes. This bodes well for ongoing clinical trials testing metformin for neuroprotection.

2024-12-10 | GSE282369 | GEO

Metformin Impairs Intestinal Fructose Metabolism

Project description:Objective: To investigate the effects of metformin on intestinal carbohydrate metabolism in vivo. Method: Male mice preconditioned with a high-fat, high-sucrose diet were treated orally with metformin or a control solution for two weeks. Fructose metabolism, glucose production from fructose, and production of other fructose-derived metabolites were assessed using stably labeled fructose as a tracer. Results: Metformin treatment decreased intestinal glucose levels and reduced incorporation of fructose-derived metabolites into glucose. This was associated with decreased intestinal fructose metabolism as indicated by decreased enterocyte F1P levels and diminished labeling of fructose-derived metabolites. Metformin also reduced fructose delivery to the liver. Proteomic analysis revealed that metformin coordinately down-regulated proteins involved carbohydrate metabolism including those involved in fructolysis and glucose production within intestinal tissue. Conclusion: Metformin reduces intestinal fructose metabolism, and this is associated with broad-based changes in intestinal enzyme and protein levels involved in sugar metabolism indicating that metformin's effects on sugar metabolism are pleiotropic.

2024-04-27 | PXD041833 | JPOST Repository

GPD1 enhances the anti-cancer effects of metformin by synergistically increasing total cellular glycerol-3-phosphate

Project description:GPD1 overexpression enhances the anti-cancer effect of metformin through synergistic inhibition of mitochondrial function, thereby providing new insight into metformin-mediated cancer therapy.

2020-03-15 | GSE146982 | GEO

RNAseq of C. elegans cultured on metformin sensitive and resistant E. coli strains with and without 50mM metformin treatment.

Project description:Metformin is the therapy of choice for treating type 2 diabetes and is currently repurposed for a wide range of diseases including aging. Recent evidence implicates the gut microbiota as a site of metformin action. Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we performed C. elegans RNAseq to investigate the role of the metformin sensitive OP50 and metformin resistant OP50-MR E. coli microbiota in the drug effects on the host. Our data suggest an evolutionarily conserved bacterial mediation of metformin effects on host lipid metabolism and lifespan.

2019-07-13 | E-MTAB-7272 | biostudies-arrayexpress

Age-dependent effects of metformin on human oligodendrocyte lineage cell ensheathment capacity.

Project description:Metformin restores myelination potential of aged rat A2B5+ oligodendroglia (OL) progenitor cells and may enhance recovery in children with post-radiation brain injury. Human late progenitor cells (O4+A2B5+) have superior capacity to ensheath nanofibers compared to mature OLs, with cells from pediatric sources exceeding adults. In this study we assessed effects of metformin on ensheathment capacity of human adult and pediatric progenitors and mature OLs and relate differences to transcriptional changes. A2B5+ progenitors and mature OLs, derived from surgical tissues by immune-magnetic separation, were assessed for ensheathment capacity in nanofiber plates over 2 weeks. Metformin (10µM every other day) was added to selected cultures. RNA was extracted from treated and control cultures after 2 days. For all ages, ensheathment by progenitors exceeded mature OLs. Metformin enhanced ensheathment by adult donor cells but reduced ensheathment by pediatric cells. Metformin marginally increased cell death in pediatric progenitors. Metformin induced changes in gene expression distinct for each cell type. Adult progenitors showed up-regulation of pathways involved in process outgrowth and promoting lipid biosynthesis. Pediatric progenitors showed a relatively greater proportion of down- versus up-regulated pathways, these involved cell morphology, development, and synaptic transmission. Metformin induced AMPK activation in all cell types; AMPK inhibitor BML-275 reduced functional metformin effects only with adult cells. Our results indicate age and differentiation stage related differences of human OL lineage cells in response to metformin. Clinical trials for demyelinating conditions will indicate how these differences translate in vivo.

2023-11-11 | GSE247159 | GEO

Age-dependent effects of metformin on human oligodendrocyte lineage cell ensheathment capacity.

Project description:Age-dependent effects of metformin on human oligodendrocyte lineage cell ensheathment capacity.

| PRJNA1036538 | ENA

Imeglimin, unlike metformin, does not perturb differentiation of human induced pluripotent stem cells towards pancreatic β-like cells and rather enhances gain in β cell identity gene sets

Project description:Aims/Introduction: Metformin treatment for hyperglycemia in pregnancy (HIP) beneficially improves maternal glucose metabolism and reduces perinatal complications. However, metformin could impede pancreatic β cell development via impaired mitochondrial function. A new anti-diabetes drug imeglimin, developed based on metformin, improves mitochondrial function. Here we examine the effect of imeglimin on β cell differentiation using human induced pluripotent stem cell (iPSC)-derived pancreatic islet-like spheroid (SC-islet) models. Materials and Methods: Human iPSCs are differentiated into SC-islets by three-dimensional culture with and without imeglimin or metformin. Differentiation efficiencies of SC-islets were analyzed by flow cytometry, immunostaining, quantitative PCR, and insulin secretion assay. RNA sequencing and oxygen consumption rate were obtained for further characterization of SC-islets. SC-islets were cultured with proinflammatory cytokines, in part mimicking the uterus environment in HIP. Results: Metformin perturbed SC-islet differentiation while imeglimin did not alter it. Furthermore, imeglimin enhanced the gene expressions of β cell lineage markers. Maintenance of mitochondrial function and optimization of TGF-β and Wnt signaling were considered potential mechanisms for augmented β cell maturation by imeglimin. In the presence of proinflammatory cytokines, imeglimin ameliorated β cell differentiation impaired by cytokines and metformin. Conclusions: Imeglimin does not perturb differentiation of SC-islet cells and rather enhances gain in β cell identity gene sets in contrast to metformin. This may lead to the improvement of in vitro β cell differentiation protocols.

2025-01-20 | GSE242776 | GEO

Genome-wide CRISPR screen identifies synthetic lethality between DOCK1 inhibition and metformin in liver cancer

Project description:To explore how DOCK1 deficiency enhances the anti-tumor effects of metformin, we performed RNA-seq analysis in PLC cells expressing NTC or shDOCK1 in the presence or absence of metformin.

2021-12-31 | GSE181521 | GEO

Redox state and altered pyruvate metabolism contribute to a dose-dependent metformin-induced lactate production of human myotubes

Project description:Metformin-induced lactate production can lead to lactate acidosis as life-threatening side effect, whereas lactate in a physiological range might also be involved in the therapeutic effect. How metformin increases systemic lactate concentrations is only partly understood. Since human skeletal muscle has a high capacity to produce lactate, we aim to elucidate the potential contribution of skeletal muscle and the dose-dependent regulation of metformin-induced lactate production in primary human myotubes after 48 h of metformin treatment (16-776 μM). At 78 µM, metformin induced lactate production and glucose consumption. Investigating the cellular redox state by mitochondrial respirometry, we found metformin to inhibit the respiratory chain complex I (776 µM, p<0.01) along with a decreased [NAD+]:[NADH] ratio (776 µM, p<0.001). RNA sequencing and phospho-immunoblot data indicate inhibition of pyruvate oxidation mediated through phosphorylation of PDH complex (39 µM, p<0.01). In vivo in human skeletal muscle, we found pyruvate metabolism altered by exercise and not by metformin. Nonetheless, blood lactate levels in the pre-exercise condition are increased under metformin treatment (p<0.05). Metformin-induced inhibition of pyruvate oxidation combined with altered cellular redox state, both shift the equilibrium of the LDH reaction leading to enhanced lactate production of human myotubes.

2023-09-04 | GSE229658 | GEO

ABCA7 deficiency causes neuronal dysregulation by altering mitochondrial lipid metabolism

Project description:ABCA7 deficiency causes neuronal dysregulation by altering mitochondrial lipid metabolism

| PRJNA1037158 | ENA