MTORC1 to AMPK Switching Underlies β-Cell Metabolic Plasticity During Maturation and Diabetes
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA547067 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9207210_1.fastq.gz | Fastqsanger.gz | |||
| SRR9207210_2.fastq.gz | Fastqsanger.gz | |||
| SRR9207201_1.fastq.gz | Fastqsanger.gz | |||
| SRR9207201_2.fastq.gz | Fastqsanger.gz | |||
| SRR9207211_1.fastq.gz | Fastqsanger.gz |
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Project description:Pancreatic beta cells (β-cells) differentiate during fetal life, but only postnatally acquire the capacity for glucose-stimulated insulin secretion (GSIS). The molecular mechanisms driving this maturation of β-cell function remain incompletely understood. Here, we show that the control of cellular signaling in β-cells fundamentally switches from the nutrient sensor target of rapamycin (mTORC1) to the energy sensor 5'-adenosine monophosphate-activated protein kinase (AMPK), and that this is critical for functional maturation. Moreover, AMPK is activated by the dietary transition taking place during weaning, and this in turn inhibits mTORC1 activity to drive the adult β-cell phenotype. While forcing constitutive mTORC1 signaling in adult β-cells relegates them to a functionally immature phenotype with characteristic transcriptional and metabolic profiles, engineering the switch from mTORC1 to AMPK signaling is sufficient to promote β-cell mitochondrial biogenesis, a shift to oxidative metabolism, and functional maturation. We also show that type 2 diabetes, a condition marked by both mitochondrial degeneration and dysregulated GSIS, is associated with a remarkable reversion of the normal AMPK-dependent adult β-cell signature to a more neonatal one characterized by mTORC1 activation. Manipulating the way in which cellular nutrient signaling pathways regulate β-cell metabolism may thus offer new targets to improve β-cell function in diabetes.
2019-06-06 | GSE132261 | GEO
Project description:Pancreatic beta cells (β-cells) differentiate during fetal life, but only postnatally acquire the capacity for glucose-stimulated insulin secretion (GSIS). How this happens is not clear. In exploring what molecular mechanisms drive the maturation of β-cell function, we found that the control of cellular signaling in β-cells fundamentally switched from the nutrient sensor target of rapamycin (mTORC1) to the energy sensor 5'-adenosine monophosphate-activated protein kinase (AMPK), and that this was critical for functional maturation. Moreover, AMPK was activated by the dietary transition taking place during weaning, and this in turn inhibited mTORC1 activity to drive the adult β-cell phenotype. While forcing constitutive mTORC1 signaling in adult β-cells relegated them to a functionally immature phenotype with characteristic transcriptional and metabolic profiles, engineering the switch from mTORC1 to AMPK signaling was sufficient to promote β-cell mitochondrial biogenesis, a shift to oxidative metabolism, and functional maturation. We also found that type 2 diabetes, a condition marked by both mitochondrial degeneration and dysregulated GSIS, was associated with a remarkable reversion of the normal AMPK-dependent adult β-cell signature to a more neonatal one characterized by mTORC1 activation. Manipulating the way in which cellular nutrient signaling pathways regulate β-cell metabolism may thus offer new targets to improve β-cell function in diabetes.
| S-EPMC6763225 | biostudies-literature
Project description:mTORC1/AMPK responses define a core gene set for developmental cell fate switching
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Project description:The kinases mTORC1 and AMPK are at the nexus of nutrient responses and control of cellular growth. However, responses to nutrient loss are complex and affect multiple transcriptional pathways. We are interested in the mTORC1-directed regulation of transcription networks that specifically regulate developmental decisions. Dictyostelium grow logarithmically as single cells in nutrient-rich media, but, upon nutrient withdrawal, growth ceases and cells enter a program for multi-cellular development. Within 30 minutes of starvation, >4,000 genes show significant (p<0.05) changes in gene expression patterns. However, we hypothesize that not all these gene changes are required for development and that many expression changes reflect stress response to a media shift supplementary to nutrient loss, apart from developmental effects. We, thus, sought ways to promote development in the absence of nutrient loss, to better focus on developmentally essential gene sets. Since kinases mTORC1 and AMPK function as nutrient and energy sensors, we first examined their relative activities in Dictyostelium during phases of rapid growth and starvation-induced development. We found that these kinases exhibited reciprocal patterns of activation under various conditions. With this knowledge, we identified rich media conditions that permitted rapid cell growth, but a growth/development switch upon the directed and reciprocal inactivation/activation of mTORC1/AMPK. Examination of gene expression under conditions of development in nutrient-rich media indicated that changes in expression of most starvation-regulated genes were not required for development. Our data suggest that the up-regulation of ~300 genes defines essential early signaling pathways for developmental induction, integrating cAMP/PKA circuitries and including many unclassified genes.
2019-05-22 | GSE123599 | GEO
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2016-04-22 | GSE68209 | GEO
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
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
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 translational response to metformin.
2023-08-10 | GSE157050 | GEO
Project description:Amino acids (aa) are not only building blocks for proteins, but also signalling molecules, with the mammalian target of rapamycin complex 1 (mTORC1) acting as a key mediator. However, little is known about whether aa, independently of mTORC1, activate other kinases of the mTOR signalling network. To delineate aa-stimulated mTOR network dynamics, we here combine a computational–experimental approach with text mining-enhanced quantitative proteomics. We report that AMP-activated protein kinase (AMPK), phosphatidylinositide 3-kinase (PI3K) and mTOR complex 2 (mTORC2) are acutely activated by aa-readdition in an mTORC1-independent manner. AMPK activation by aa is mediated by Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ). In response, AMPK impinges on the autophagy regulators Unc-51-like kinase-1 (ULK1) and c-Jun. AMPK is widely recognized as an mTORC1 antagonist that is activated by starvation. We find that aa acutely activate AMPK concurrently with mTOR. We show that AMPK under aa sufficiency acts to sustain autophagy. This may be required to maintain protein homoeostasis and deliver metabolite intermediates for biosynthetic processes.
2016-12-12 | PXD003073 | Pride
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.
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