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Ribosome profiling of metformin treatment in primary murine hepatocytes in WT, Raptor Ser-Ala mutant, Tsc2-null, Raptor mutant;Tsc2-null, and Ampk-null cells

ABSTRACT: Despite being the frontline therapy for Type 2 diabetes, the mechanisms of action of the biguanide drug metformin are still being discovered. In particular, the detailed molecular interplays between the AMPK and the mTORC1 pathway in the hepatic benefits of metformin are still ill-defined. Metformin-dependent activation of AMPK classically inhibits mTORC1 via TSC/RHEB. But several lines of evidence suggest additional mechanisms at play in metformin inhibition of mTORC1. Here we investigated the role of direct AMPK-mediated serine phosphorylation of RAPTOR in a new RaptorAA mouse model, in which AMPK phospho-serine sites Ser722 and Ser792 of RAPTOR were mutated to alanine. Metformin treatment of primary hepatocytes and intact murine liver requires AMPK regulation of both RAPTOR and TSC2 to fully inhibit mTORC1, and this regulation is critical for the translational response to metformin.

ORGANISM(S): Mus musculus

PROVIDER: GSE157050 | GEO | 2023/08/10

REPOSITORIES: GEO

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RNA-seq of metformin treatment in primary murine hepatocytes in WT, Raptor Ser-Ala mutant, Tsc2-null, Raptor mutant;Tsc2-null, and Ampk-null cells

Project description:Despite being the frontline therapy for Type 2 diabetes, the mechanisms of action of the biguanide drug metformin are still being discovered. In particular, the detailed molecular interplays between the AMPK and the mTORC1 pathway in the hepatic benefits of metformin are still ill-defined. Metformin-dependent activation of AMPK classically inhibits mTORC1 via TSC/RHEB. But several lines of evidence suggest additional mechanisms at play in metformin inhibition of mTORC1. Here we investigated the role of direct AMPK-mediated serine phosphorylation of RAPTOR in a new RaptorAA mouse model, in which AMPK phospho-serine sites Ser722 and Ser792 of RAPTOR were mutated to alanine. Metformin treatment of primary hepatocytes and intact murine liver requires AMPK regulation of both RAPTOR and TSC2 to fully inhibit mTORC1, and this regulation is critical for the transcriptional response to metformin. Transcriptionally, AMPK and mTORC1 were both important for regulation of anabolic metabolism and inflammatory programs triggered by metformin treatment.

2023-08-10 | GSE157048 | GEO

RNA-seq of metformin treatment in liver in WT, Raptor Ser-Ala mutant, Tsc2-null, Raptor mutant;Tsc2-null, and Ampk-null

Project description:Despite being the frontline therapy for Type 2 diabetes, the mechanisms of action of the biguanide drug metformin are still being discovered. In particular, the detailed molecular interplays between the AMPK and the mTORC1 pathway in the hepatic benefits of metformin are still ill-defined. Metformin-dependent activation of AMPK classically inhibits mTORC1 via TSC/RHEB. But several lines of evidence suggest additional mechanisms at play in metformin inhibition of mTORC1. Here we investigated the role of direct AMPK-mediated serine phosphorylation of RAPTOR in a new RaptorAA mouse model, in which AMPK phospho-serine sites Ser722 and Ser792 of RAPTOR were mutated to alanine. Metformin treatment of intact murine liver requires AMPK regulation of both RAPTOR and TSC2 to fully inhibit mTORC1, and this regulation is critical for the transcriptional response to metformin. Transcriptionally, AMPK and mTORC1 were both important for regulation of anabolic metabolism and inflammatory programs triggered by metformin treatment. The hepatic transcriptional response in mice on high fat diet treated with metformin was largely ablated by AMPK-deficiency under the conditions examined, indicating the essential role of this kinase and its targets in metformin action in vivo.

2023-08-10 | GSE157049 | GEO

Raptor/mTORC1-dependent metabolic programming of exit from quiescence underlies T cell activation and fate decisions

Project description:Naïve T cells respond to antigen stimulation by exiting from quiescence into clonal expansion and functional differentiation, but the control mechanism is elusive. Here we describe that Raptor/mTORC1-dependent metabolic reprogramming is a central determinant of this transitional process. Loss of Raptor abrogates T cell priming and Th2 cell differentiation, although Raptor function is less important for continuous proliferation of actively cycling cells. mTORC1 coordinates multiple metabolic programs in T cells including glycolysis, lipid synthesis and oxidative phosphorylation to mediate antigen-triggered exit from quiescence. mTORC1 further links glucose metabolism to the initiation of Th2 differentiation by orchestrating cytokine receptor expression and cytokine responsiveness. Activation of Raptor/mTORC1 integrates T cell receptor (TCR) and CD28 co-stimulatory signals in antigen-stimulated T cells. Our studies identify a Raptor/mTORC1-dependent pathway linking signal-dependent metabolic reprogramming to quiescence exit, and this in turn coordinates lymphocyte activation and fate decisions in adaptive immunity. We used microarrays to explore the gene expression profiles differentially expressed in CD4+ T-cells from wild-type (WT) and CD4(cre) x Raptor(fl/fl) mice before and after stimulation with anti CD3/CD28 antibodies.

2014-01-27 | E-GEOD-51668 | biostudies-arrayexpress

Raptor/mTORC1-dependent metabolic programming of exit from quiescence underlies T cell activation and fate decisions

2014-01-27 | GSE51668 | GEO

Gene-expression changes resulting from loss of the mTORC1 component Raptor in murine hematopoietic stem and progenitor cell-enriched populations (HSPC)

Project description:We investigated the role of mTORC1 in murine hematopoiesis by conditionally deleting the Raptor gene in murine hematopoietic stem cells. We observed mutliple alterations evoked by Raptor loss in hematopoiesis and profiled gene-expression alterations induced by raptor loss in Flt3-Lin-Sca1+cKit+ hematopoietic stem and progenitor enriched cell populations, 5 weeks post Raptor deletion. Flt3-Lin-Sca1+cKit+ cells were flow sorted from mice containing homozygous floxed alleles for exon 6 of the Raptor gene in the presence (MT group) or absence (WT group) of the MxCre transgene, which was induced with injections of mice with pIpC 5 weeks before cell isolation.

2012-09-19 | E-GEOD-32265 | biostudies-arrayexpress

Gene-expression changes resulting from loss of the mTORC1 component Raptor in murine hematopoietic stem and progenitor cell-enriched populations (HSPC)

2012-09-19 | GSE32265 | GEO

O-GlcNAcylation of Raptor transduces glucose signals to mTORC1

Project description:Complex molecular mechanisms ensure cellular homeostasis between nutrient sensing and energy metabolism. Strong evidence from many laboratories supports a role for the hexosamine biosynthetic pathway (HBP) and its end product, UDP-GlcNAc, as important nutrient sensors. Isotopic photocleavable tagging for O-GlcNAc profiling (isoPTOP) was performed for quantitative and site specific identification of O-GlcNAcylation upon glucose mediated nutrient fluctuation. Mammalian target of Rapamycin complex 1（mTORC1）is a metabolic hub, which can sense the availability of various nutrients. We found that Raptor, the scaffold of the mTORC1 complex, is O-GlcNAcylated at T700. Our finding provides a novel mechanism that UDP-GlcNAc mediates glucose signal to mTORC1 by O-GlcNAcylating Raptor at T700 to regulate mTORC1 activity and cell growth.

2023-08-03 | PXD039536 | Pride

Transcriptomic analysis of human laryngeal carcinoma cell line LIU-LSC-1 with depletion of Raptor

Project description:Recent studies have shown that mTOR signalling have a promotive effect on cancer. In our clinical work, we found that mTOR signalling is commonly activated in laryngeal cancer tissues and influence the metabolism of cancer cells. To investigate how mTORC1 exerts these functions and its downstream regulatory genes, we knocked down Raptor in the laryngeal cancer cell line LIU-LSC-1 and sequenced the transcriptome of wild-type and Raptor knockdown cells.

2022-11-03 | GSE180702 | GEO

Proteomic analysis of Raptor-proximal proteins in U2OS cells

Project description:The mammalian target of rapamycin complex 1 (mTORC1) is a key nutrient-sensing hub and a master regulator of cellular growth and metabolism. Activation of mTORC1 by amino acids and growth factors requires its recruitment to the lysosomes. Furthermore, lysosomal distribution has been shown to be intimately involved in the control of mTORC1, where localisation of lysosomes near plasma membrane increases mTORC1 activity. However, the underlying mechanisms by which lysosomal positioning impacts on mTORC1 signalling are not well understood. To understand better the spatial associations of mTORC1, we analysed the proximal ‘interactome’ of the constitutive component of mTORC1, Raptor, using BioID2-based proximity labelling and MS-based proteomics.

2021-09-08 | PXD012795 | Pride

mTORC1 maintains renal tubular homeostasis and is essential in response to ischemic stress

Project description:The mechanistic target of rapamycin mTORC1 is a key regulator of cell metabolism and autophagy. Despite widespread clinical use of mTOR inhibitors, the role of mTORC1 in renal tubular function and kidney homeostasis remains elusive. By utilizing constitutive and inducible deletion of conditional Raptor alleles in renal tubular epithelial cells, we discovered that mTORC1 deficiency caused a marked concentrating defect, loss of tubular cells and slowly progressive renal fibrosis. Transcriptional profiling revealed that mTORC1 maintains renal tubular homeostasis by controlling mitochondrial metabolism and biogenesis as well as transcellular transport processes involved in counter-current multiplication and urine concentration. Although mTORC2 partially compensated the loss of mTORC1, exposure to ischemia and reperfusion injury exaggerated the tubular damage in mTORC1-deficient mice, and caused pronounced apoptosis, diminished proliferation rates and delayed recovery. These findings identify mTORC1 as an essential regulator of tubular energy metabolism and as a crucial component of ischemic stress responses. Pharmacological inhibition of mTORC1 likely affects tubular homeostasis, and may be particularly deleterious if the kidney is exposed to acute injury. Furthermore, the combined inhibition of mTORC1 and mTORC2 may increase the susceptibility to renal damage. Raptor fl/fl*KspCre and Raptor fl/fl animals were sacrificed at P14 before the development of an overt functional phenotype. Kidneys were split in half and immediately snap frozen in liquid nitrogen.

2014-06-09 | E-GEOD-54417 | biostudies-arrayexpress

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