MTORC2/Akt Activation in Adipocytes is Required for Mycobacterium tuberculosis Derived Inflammation in Adipose Tissue
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA417450 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The association between type 2 DM (T2DM) and susceptibility to tuberculosis (TB) is well recognized. Patients with DM have 2-3 fold increased susceptibility to TB, treatment is longer and the outcome is worse than in non-diabetic TB patients. Here, we report that aerosol infection with M. tuberculosis is followed by leukocyte infiltration and proliferation, and expression of inflammatory markers in adipose tissue of lean mice leading to disrupted lipid metabolism and the induction of adipocyte hypertrophy. RNA-sequencing (RNAseq) in whole pgWAT adipose tissue at 8 wk after aerosol challenge revealed an upregulation of genes that were associated with antigen presentation, Th1 and type-1 interferon response, indicated the induction of T cell activation. This was found to be due to activated mTORC2/Akt signaling. By depleting Rictor (mTORC2 subunit) in adipocytes we noticed the restoration of inflammation and cell hypertrophy. Our study suggests that TB-induced inflammation in the adipose tissue is associated with improved glucose tolerance and is mediated by mTORC2/Akt pathway.
2019-01-01 | GSE106611 | GEO
Project description:mTOR complex 2 (mTORC2) phosphorylates AKT in a hydrophobic motif site that is a biomarker of insulin sensitivity. In adipocytes, mTORC2 regulates glucose and lipid metabolism; however, the mechanism has been unclear because downstream AKT signaling appears unaffected by mTORC2 loss. Here, by applying immunoblotting, targeted phosphoproteomics and metabolite profiling in brown preadipocytes, we identify ATP-citrate lyase (ACLY) as a distinctly mTORC2-sensitive AKT substrate. mTORC2 appears dispensable for most other AKT actions examined indicating a previously unappreciated selectivity in mTORC2-AKT signaling. Rescue experiments show brown preadipocytes require the mTORC2/AKT/ACLY pathway to induce PPAR-gamma and establish the epigenetic landscape during differentiation. mTORC2 also acts through ACLY in mature brown adipocytes to increase ChREBP activity, histone acetylation, and gluco-lipogenic gene expression. Substrate utilization studies additionally implicate mTORC2 in promoting acetyl-CoA synthesis from acetate through acetyl-CoA synthetase 2 (ACSS2). These data suggest that a principal mTORC2 action is controlling nuclear-cytoplasmic acetyl-CoA synthesis.
| MSV000084309 | MassIVE
Project description: Not available
| S-EPMC6642333 | biostudies-literature
Project description:Sestrins represent a family of stress-inducible proteins that prevent the progression of many age- and obesity-associated disorders. Endogenous Sestrins maintain insulin-dependent AKT Ser/Thr kinase (AKT) activation during high-fat diet (HFD)-induced obesity, and overexpressed Sestrins activate AKT in various cell types, including liver and skeletal muscle cells. Although Sestrin-mediated AKT activation improves metabolic parameters, the mechanistic details underlying such improvement remain elusive. Here, we investigated how Sestrin2, the Sestrin homolog highly expressed in liver, induces strong AKT activation. We found that two known targets of Sestrin2, mTOR complex 1 (mTORC1) and AMP-activated protein kinase (AMPK), are not required for Sestrin2-induced AKT activation. Rather, phosphoinositol-3-kinase (PI3K) and mTORC2, kinases upstream of AKT and important for its activation, were essential for Sestrin2-induced AKT activation. Among these kinases, mTORC2 catalytic activity was strongly up-regulated upon Sestrin2 overexpression in an in vitro kinase assay, indicating that mTORC2 may represent the major link between Sestrin2 and AKT. As reported previously, Sestrin2 interacted with mTORC2; however, we found here that this interaction occurs indirectly through GATOR2, a pentameric protein complex that directly interacts with Sestrin2. Deleting or silencing WD repeat domain 24 (WDR24), the GATOR2 component essential for the Sestrin2–GATOR2 interaction, or WDR59, the GATOR2 component essential for the GATOR2–mTORC2 interaction, completely ablated Sestrin2’s effect on AKT activation. We also noted that Sestrin2 directly binds to the pleckstrin homology (PH) domain of AKT and induces AKT translocation to the plasma membrane. These results uncover a signaling mechanism whereby Sestrin2 activates AKT through GATOR2 and mTORC2.
2020-01-15 | PXD015824 | Pride
Project description:Stimulating brown adipose tissue (BAT) activity represents a promising therapy for overcoming metabolic diseases. mTORC2 has been shown to be important for regulating BAT metabolism, yet its mechanism of activation is not known, nor are the identities of its downstream effectors. In this study, we apply proteomics to investigate the role of mTORC2 in brown adipocytes. To assess the role of mTORC2 in brown adipocytes, we compare wild-type controls to isogenic cells with an induced knockout of the mTORC2-specific subunit RICTOR (Rictor-iKO) by stimulating each with insulin for a 30 minute time course, and measuring the proteomes and phosphoproteomes. In Rictor-iKO cells, we identify decreases to the abundance of glycolytic and de novo lipogenesis enzymes, and increases to mitochondrial proteins as well as a set of proteins known to increase upon interferon stimulation, suggesting increased interferon-like signaling. We observe significant differences to basal phosphorylation including decreased phosphorylation of the lipid droplet protein perilipin-1 in Rictor-iKO cells and Rictor-null mouse BAT, suggesting that RICTOR could be involved with regulating basal lipolysis or droplet dynamics. And finally, we observe a general dampening of the insulin signaling response in Rictor-iKO cells. Some sites exhibit significant dependence on RICTOR, including an AKT substrate site on ATP citrate lyase, which could partially explain the previously-observed RICTOR dependence of de novo lipogenesis from glucose in BAT.
| MSV000084310 | MassIVE
Project description:DallePezze2012 - TSC-independent mTORC2
regulation
This model is described in the article:
A dynamic network model of
mTOR signaling reveals TSC-independent mTORC2 regulation.
Dalle Pezze P, Sonntag AG, Thien A,
Prentzell MT, Gödel M, Fischer S, Neumann-Haefelin E, Huber
TB, Baumeister R, Shanley DP, Thedieck K.
Sci Signal 2012 Mar; 5(217): ra25
Abstract:
The kinase mammalian target of rapamycin (mTOR) exists in
two multiprotein complexes (mTORC1 and mTORC2) and is a central
regulator of growth and metabolism. Insulin activation of
mTORC1, mediated by phosphoinositide 3-kinase (PI3K), Akt, and
the inhibitory tuberous sclerosis complex 1/2 (TSC1-TSC2),
initiates a negative feedback loop that ultimately inhibits
PI3K. We present a data-driven dynamic insulin-mTOR network
model that integrates the entire core network and used this
model to investigate the less well understood mechanisms by
which insulin regulates mTORC2. By analyzing the effects of
perturbations targeting several levels within the network in
silico and experimentally, we found that, in contrast to
current hypotheses, the TSC1-TSC2 complex was not a direct or
indirect (acting through the negative feedback loop) regulator
of mTORC2. Although mTORC2 activation required active PI3K,
this was not affected by the negative feedback loop. Therefore,
we propose an mTORC2 activation pathway through a PI3K variant
that is insensitive to the negative feedback loop that
regulates mTORC1. This putative pathway predicts that mTORC2
would be refractory to Akt, which inhibits TSC1-TSC2, and,
indeed, we found that mTORC2 was insensitive to constitutive
Akt activation in several cell types. Our results suggest that
a previously unknown network structure connects mTORC2 to its
upstream cues and clarifies which molecular connectors
contribute to mTORC2 activation.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000581.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2015-08-12 | BIOMD0000000581 | BioModels
Project description:Obesity causes type 2 diabetes, cardiovascular diseases, NAFLD, and cancer, but all fat is not equal as subcutaneous white adipose tissue (SWAT) is more metabolically favorable than visceral fat. Here, we investigate mTORC2 function in SWAT growth by deleting its essential subunit Rictor in SWAT precursor cells and examining its effect on adipocyte differentiation and tissue development. We found that Rictor/mTORC2 is not required for SWAT preadipocyte differentiation per se; however, SWAT preadipocytes differentiating without Rictor cannot fully induce the lipid storage transcriptional program. In vivo, this results in smaller adipocytes, reduced SWAT size, lipid re-distribution to visceral and brown fat, and gender-distinct effects on systemic metabolic fitness. Mechanistically, mTORC2 promotes PPARg activity towards specific lipid metabolism genes independently of ChREBP, but in coordination, to set the lipid handling capacity of SWAT. Further exploring this pathway may uncover new strategies to stimulate lipid storage in more metabolically favorable SWAT.
2020-10-06 | GSE146470 | GEO
Project description:Transmembrane B cell lymphoma 2-associated X protein inhibitor motif-containing (TMBIM) 6, a Ca2+ channel-like protein, is highly upregulated in several cancer types. Here, we show that TMBIM6 is closely associated with survival in patients with cervical, breast, lung, and prostate cancer. TMBIM6 deletion or knockdown suppressed primary tumor growth. Further, mTORC2 activation was up-regulated by TMBIM6 and stimulated glycolysis, protein synthesis, and the expression of lipid synthesis genes and glycosylated proteins. Moreover, ER-leaky Ca2+ from TMBIM6, a unique characteristic, was shown to affect mTORC2 assembly and its association with ribosomes. In addition, we identified that BIA compound, a suggestive TMBIM6 antagonist, prevented TMBIM6 binding to mTORC2, decreased mTORC2 activity, and also regulated TMBIM6-leaky Ca2+, further suppressing tumor formation and progression in cancer xenograft models. This previously unknown signaling cascade in which mTORC2 activity is enhanced via the interaction with TMBIM6 provides effective therapeutic targets for various malignancies. We used microarrays to detail the global of gene expression and identified that most of the differentially expressed genes related to apoptotic process, migration, proliferation, and metabolic pathways were decreased in TMBIM6 KO HT1080 cells
2020-07-15 | GSE153716 | GEO
Project description:Primary glioblastoma, representing over 90% of adult glioblastoma, develop rapidly without preexisting lower-grade glioma. We have generated a mouse model of primary glioblastoma driven by a single p53 mutation. These p53-mutant gliomas lose the syntenic region of human chromosome 10q, which is mapped to mouse chr19 and chr7. Loss of mouse chr19, containing Pten, activates PI3K/Akt signaling. Rictor/mTORC2 deletion inhibits Akt signaling, causing a significant delay in p53-mutant driven glioma formation. Unexpectedly, Rictor/mTORC2 loss promotes p53-mutant driven medulloblastomas with unique features of pediatric SHH medulloblastoma. Mechanistically, Rictor/mTORC2 loss inhibits the generation of glioma precursor cells from neural stem/progenitor cells in the adult brain, while causing a delay in differentiation of granule cell precursors in the developing brain, a cell-of-origin of SHH medulloblastoma.
2018-06-01 | GSE78895 | GEO
Project description:Most human cancers arise from stem/progenitor cells by sequential accumulation of genetic/epigenetic alterations, while cancer modeling typically requires simultaneous multiple oncogenic events. Here we show that a single p53 mutation, despite causing no defect in mouse brain, promoted neural stem/progenitor cells to spontaneously accumulate oncogenic alterations, including loss of multiple chromosomal (chr) regions syntenic to human chr10 containing Pten, forming malignant gliomas/glioblastomas with PI3K/Akt activation. Rictor/mTORC2 loss inhibited Akt signaling, greatly delaying and reducing glioma formation by suppressing glioma precursors within the subventricular zone stem-cell niche. Unexpectedly, Rictor/mTORC2 loss delayed timely differentiation of granule cell precursors (GCPs) during cerebellar development, promoting sustained GCP proliferation and medulloblastoma formation, which recapitulated critical features of TP53-mutant Sonic Hedgehog (SHH) medulloblastomas with GLI2 and/or N-MYC amplification. Our study demonstrates that Rictor/mTORC2 has opposing functions in neural stem cells and GCPs in the adult and developing brain, promoting malignant gliomas/glioblastoma and suppressing SHH-medulloblastoma formation, respectively.
2021-06-15 | GSE115840 | GEO