DTORC gene profiling
Ontology highlight
ABSTRACT:
ORGANISM(S): Drosophila melanogaster
PROVIDER: GSE10546 | GEO | 2008/07/04
SECONDARY ACCESSION(S): PRJNA107909
REPOSITORIES: GEO
Similar Datasets
Project description:In fasted mammals, glucose homeostasis is maintained through activation of the cAMP responsive CREB coactivator TORC2, which stimulates the gluconeogenic program in concert with the forkhead transcription factor FOXO1. Here we show that starvation also triggers TORC activation in Drosophila, where it maintains energy balance by promoting the expression of CREB target genes in the brain. TORC mutant flies have reduced glycogen and lipid stores, and they are sensitive to starvation as well as oxidative stress. Neuronal TORC expression rescued starvation and oxidative stress sensitivity as well as CREB target gene expression in TORC mutants. During refeeding, increases in insulin signaling inhibited TORC activity in wild type flies by stimulating the Salt Inducible Kinase 2 (SIK2)-mediated phosphorylation and subsequent degradation of TORC. Depletion of neuronal SIK2 increased TORC activity and enhanced resistance to starvation and oxidative stress in adult flies. As disruption of insulin signaling, either by ablation of insulin-producing cells (IPCs) or by mutation of the insulin receptor adaptor gene chico, also increased TORC activity, our results illustrate the importance of an insulin-regulated pathway in brain that promotes energy balance in Drosophila. Experiment Overall Design: Male fly heads were collected after 24h fasting, and RNA was extracted using RNAeasy kit.
2008-10-20 | E-GEOD-10546 | biostudies-arrayexpress
Project description:dFOXO targets in adult Drosophila melanogaster females, and the effect of insulin signalling and stress on binding. The experimets determined the binding locations of dFOXO in the whole adult female fly using ChIP-chip. The protocol was validated using mock conditions: pre-immune serum or IP on chromatin from foxo null flies. The response of this binding to stress induced by treatment of flies with paraquat or by their exposure to starvation, as well as the response to an insulin-signalling-reducing genetic manipulation (over-expression of dominant negative form of the insulin receptor), was determined.
2011-06-18 | E-TABM-751 | biostudies-arrayexpress
Project description:Obesity stimulates the infiltration of adipose tissue by innate immune cells, which in turn promote insulin resistance via the NFkB mediated induction of pro-inflammatory cytokines, which interfere with triglyceride metabolism. The cAMP responsive factor CREB has also been implicated in adipose tissue inflammation and insulin resistance, although the underlying mechanism is unclear. Here, we show that high fat diet (HFD) feeding triggers activation of the CREB cofactors CRTC2 and CRTC3, which bind to CREB and mediate induction of CXCL1 and other cytokine genes in cooperation with NFkB. HFD feeding reduced adipocyte C/EBPa expression in adipose, leading to decreases in the expression of Salt Inducible Kinase 2 (SIK2), which otherwise phosphorylates and sequesters CRTCs in the cytoplasm. Depletion of SIK2 in adipose led to dephosphorylation of CRTC2 and CRTC3 (CRTC2/3) and to the induction of CXCL1 and other cytokine genes in adipocytes. Indeed, CRTC2/3 were found to stimulate the expression of a subset of cellular genes cooperatively with NF-kB in adipocytes. Knockout of both CRTC2 and CRTC3 in adipose decreased the expression of CXCL1/2 and thereby reduced neutrophil and macrophage infiltration. As depletion of CXCL1/2, with neutralizing antiserum or by KO of the CXCL1 gene restored glucose tolerance and insulin sensitivity in the setting of diet induced obesity, our results demonstrate that NF-kB and CREB/CRTC pathways modulate adipose tissue function in part via cooperative effects on target gene expression.
2021-10-27 | GSE160597 | GEO
Project description:Lipins are eukaryotic proteins with functions in lipid synthesis and the homeostatic control of energy balance. They execute these functions by acting as phosphatidate phosphatase enzymes in the cytoplasm and by changing gene expression after translocation into the cell nucleus, in particular under fasting conditions. Here, we asked how gene expression changes, under both fed and fasting conditions, when nuclear translocation of Lipin is impaired. To address this question, we created a Drosophila mutant expressing Lipin lacking a nuclear localization signal (LipinDNLS). Notably, adult LipinDNLS flies were not only viable but also exhibited improved life expectancy. In contrast, they were highly susceptible to starvation. To examine how these phenotypes correlate with changes in gene expression, we carried out an RNA-seq analysis with mRNA from female and male LipinDNLS and control flies that had been kept under fed or fasting conditions. We found that genes involved in metabolism, feeding behavior, and the immune response were mis-regulated in LipinDNLS flies. The changed expression of these genes supports hypotheses explaining improved life expectancy under fed and decreased life expectancy under fasting conditions. For instance, metabolic rate measurements confirmed the prediction based on the RNA-seq data that energy production by oxidative phosphorylation is reduced in fed LipinDNLS flies.
2020-09-19 | GSE158189 | GEO
Project description:It is well appreciated that reactive oxygen species (ROS) are deleterious to mammals, including humans, especially when generated in abnormally large quantities from cellular metabolism. Whereas the mechanisms leading to the production of ROS are rather well delineated, the mechanisms underlying tissue susceptibility or tolerance to oxidant stress remain elusive. Through an experimental selection over many generations, we have previously generated Drosophila melanogaster flies that tolerate tremendous oxidant stress and have shown that the family of antimicrobial peptides (AMP) is over-represented in these tolerant flies. Furthermore, we have also demonstrated that overexpression of even one AMP at a time (e.g. Diptericin) allows wild type flies to survive much better in hyperoxia. In the current study, we used a number of experimental approaches to investigate the potential mechanisms underlying hyperoxia tolerance in flies with antimicrobial peptide overexpression. We demonstrate that flies with Diptericin overexpression resist oxidative stress by increasing antioxidant enzyme activities and preventing an increase in ROS level after hyperoxia. Depleting the GSH pool using buthionine sulfoximine limits fly survival, thus confirming that enhanced survival observed in these flies is related to improved redox homeostasis. We conclude that a) AMPs play an important role in tolerance to oxidant stress; b) overexpression of Diptericin changes the cellular redox balance between oxidant and antioxidant, and c) this change in redox balance plays an important role in survival in hyperoxia. Expression profiles of Drosophila melanogaster with anti-microbial peptide over-expression (experimental sample; n=3) and controls (UAS-AMP alone not crossed to da-GAL4; n=3) were determined using Affymetrix Drosophila Genome 2.0 Arrays.
2010-12-21 | E-GEOD-23902 | biostudies-arrayexpress
Project description:Smith2013 - Regulation of Insulin Signalling by Oxidative Stress
The model describes insulin signalling (in rodent adipocytes), which includes in addition to the core pathway, the transcriptional feedback through the Forkhead box type O (FOXO) transcription factor and interaction with oxidative stress.
This model is described in the article:
Computational modelling of the regulation of Insulin signalling by oxidative stress.
Smith GR, Shanley DP.
BMC Syst Biol. 2013 May 24;7:41.
Abstract:
BACKGROUND:
Existing models of insulin signalling focus on short term dynamics, rather than the longer term dynamics necessary to understand many physiologically relevant behaviours. We have developed a model of insulin signalling in rodent adipocytes that includes both transcriptional feedback through the Forkhead box type O (FOXO) transcription factor, and interaction with oxidative stress, in addition to the core pathway. In the model Reactive Oxygen Species are both generated endogenously and can be applied externally. They regulate signalling though inhibition of phosphatases and induction of the activity of Stress Activated Protein Kinases, which themselves modulate feedbacks to insulin signalling and FOXO.
RESULTS:
Insulin and oxidative stress combined produce a lower degree of activation of insulin signalling than insulin alone. Fasting (nutrient withdrawal) and weak oxidative stress upregulate antioxidant defences while stronger oxidative stress leads to a short term activation of insulin signalling but if prolonged can have other effects including degradation of the insulin receptor substrate (IRS1) and FOXO. At high insulin the protective effect of moderate oxidative stress may disappear.
CONCLUSION:
Our model is consistent with a wide range of experimental data, some of which is difficult to explain. Oxidative stress can have effects that are both up- and down-regulatory on insulin signalling. Our model therefore shows the complexity of the interaction between the two pathways and highlights the need for such integrated computational models to give insight into the dysregulation of insulin signalling along with more data at the individual level.A complete SBML model file can be downloaded from BIOMODELS (https://www.ebi.ac.uk/biomodels-main) with unique identifier MODEL1212210000.Other files and scripts are available as additional files with this journal article and can be downloaded from https://github.com/graham1034/Smith2012_insulin_signalling.
This model is hosted on BioModels Database
and identified
by: BIOMD0000000474
.
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.
2013-09-06 | BIOMD0000000474 | BioModels
Project description:Gamma-aminobutyric acid-containing (GABAergic) interneurons are the major source of inhibition in the mammalian brain. They control the output of principal neurons, shaping brain oscillations and maintaining excitation/inhibition balance. PV+ interneurons play a major role in the regulation of the excitatory/inhibitory balance in the cortex. One gene of the oxidative phosphorylation machinery shows particularly specific expression in PV+ interneurons, Cox6a2. The gene codes for the isoform 2 of the subunit Cox6a in cytochrome c oxidase, also known as complex IV (CIV), of oxidative phosphorylation. Cox6a2 had been shown to regulate the generation of energy in the heart and skeletal muscle to meet the high energy demands. To unravel the molecular signaling that contributes to the increase in oxidative stress and metabolic dysregulation following Cox6a2 knockout, we sorted PV+ interneurons from wild-type and Cox6a2-/- mice using the PV-EGFP transgenic mouse line and compared the neuronal transcriptome between the two phenotypes by RNA sequencing. We noted significant transcriptional changes in Cox6a2-/- PV+ interneurons relative to WT. Thus, we found deregulated expression of a number of genes that are involved in synaptic transmission and cellular metabolism.
2020-01-01 | E-MTAB-7879 | biostudies-arrayexpress
Project description:We investigate whether lower weight gain with insulin detemir is due to a decrease in energy intake or an increase in energy output and whether any change in energy balance is accompanied by changes in hormones, lipid metabolism and muscle gene expression.
2018-04-20 | GSE37785 | GEO
Project description:Although persistent elevations in circulating glucose concentrations promote compensatory increases in pancreatic islet mass, unremitting insulin resistance causes a deterioration in beta cell function that disrupts glucose balance and signals the progression to diabetes 1. Glucagon like Peptide 1 (GLP1) agonists improve glucose tolerance in insulin resistance, although some individuals are unresponsive to treatment. Here we show that increases in GLP1 during feeding promote beta cell function in part through the PKA-mediated activation of CREB and its coactivator CRTC2 2. Mice with a knockout of CRTC2 in beta cells have impaired oral glucose tolerance due to decreases in circulating insulin concentrations. CRTC2 was found to promote beta cell function in part by stimulating the expression of the transcription factor MafA. Chronic hyperglycemia associated with high fat or high carbohydrate diet feeding disrupted cAMP signaling in pancreatic islets. Indeed, prolonged elevations in circulating glucose concentrations interfered with CREB signaling by activating the mTOR pathway and triggering the hypoxia inducible factor (HIF1)-dependent induction of the Protein Kinase A Inhibitor beta (PKIB), a potent inhibitor of PKA catalytic activity 3. As disruption of the PKIB gene restored glucose tolerance and insulin secretion in obesity, our results demonstrate how cross-talk between nutrient and hormonal pathways contributes to loss of pancreatic islet function in insulin resistance. Rat insulinoma cells were used to interrogate the impact of glucose exposure and CREB activity on cAMP dependent gene regulation in the pancreatic beta cells
2015-02-23 | E-GEOD-60158 | biostudies-arrayexpress
Project description:The hypothalamus is a key site for the integration of the response to nutrient deprivation in higher organisms. Transcripts that are dynamically regulated in the hypothalamus by feeding and fasting are likely to play a regulatory role in energy balance. In order to identify hypothalamic genes whose expression is altered by fasting, we compared the transcriptomes of hypothalamic blocks from freely feeding vs overnight fasted mice using whole genome oligonucleotide arrays. In order to exclude changes due to non-specific neuronal stress responses to energy deprivation we simultaneously profiled the cerebellum, a brain site with no known regulatory role in energy balance. The power of this approach was illustrated by the fact that while we confirmed previous observations that the Sulfotransferase family 1A gene is upregulated by fasting in the hypothalamus, we showed that it was similarly upregulated in the cerebellum and is therefore unlikely to be specifically involved in the regulation of energy balance. In contrast, using three different methods of pathway enrichment analysis, multiple genes involved in mitochondrial oxidative phosphorylation were found to be co-ordinately downregulated by fasting in the hypothalamus but not in the cerebellum. These findings suggest that a switch from oxidative to non-oxidative metabolism in the hypothalamus may be an important element of the homeostatic response to nutrient deprivation. Keywords: hypothalamus, cerebellum, fasting, appetite, obesity
2007-02-09 | GSE4221 | GEO