Transcription profiling of Drosophila after fasting
Ontology highlight
ABSTRACT:
ORGANISM(S): Drosophila melanogaster
SUBMITTER: Biao Wang
PROVIDER: E-GEOD-10546 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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. Keywords: Fasting-induced gene expression
2008-07-04 | GSE10546 | GEO
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:Non-nutritive sweeteners like sucralose are consumed by billions of people. While animal and human studies have demonstrated a link between synthetic sweetener consumption and metabolic dysregulation, the mechanisms responsible remain unknown. Here we use a diet supplemented with sucralose to investigate the long-term effects of sweet/energy imbalance. In flies, chronic sweet/energy imbalance promoted hyperactivity, insomnia, glucose intolerance, enhanced sweet taste perception and a sustained increase in food and calories consumed, effects that are reversed upon sucralose removal. Mechanistically, this response was mapped to the ancient insulin, catecholamine, and NPF/NPY systems and the energy sensor AMPK, which together comprise a novel neuronal starvation response pathway. Interestingly, chronic sweet/energy imbalance promoted increased food intake in mammals as well, and this also occurs through an NPY-dependent mechanism. Together our data show that chronic consumption of a sweet/energy imbalanced diet triggers a conserved neuronal fasting response and increases the motivation to eat.
2016-07-10 | GSE73179 | GEO
Project description:Epilepsy is a disorder that affects around 1% of the population. Epilepsy is widely controlled by anti-convulsant drugs; however, approximately one third of patients do not respond to this treatment. In many cases of drug resistant epilepsy (DRE) surgical removal of the indicated tissue may be performed to decrease seizure burden. Mitochondrial damage and oxidative stress has been implicated in epilepsy suggesting that alternation in both energy metabolism and redox balance are critical to seizure onset. To understand the underlying biological processes involved in DRE, a combination of proteomics and metabolomics strategies together with oxidative damage assessment were used to compare molecular differences and enzymatic activities in tissue implicated in seizure onset to tissue with no abnormal activity within patients. Label free quantitation identified 17 proteins with altered abundance in the seizure onset zone as compared to tissue with normal activity. Assessment of oxidative protein damage by protein carbonylation identified additional 11 proteins with potentially altered function in the seizure onset zone. Pathway analysis revealed that most of the affected proteins are involved in energy metabolism and redox balance. Further enzymatic assays showed significantly decreased activity of transketolase (TKT) indicating a disruption of the Pentose Phosphate Pathway and diversion of intermediates into purine metabolic pathway, resulting in the generation of the potentially pro-convulsant metabolites. Altogether, these findings suggest that imbalance in energy metabolism and redox balance, pathways critical to proper neuronal function, play important roles in neuronal network hyperexcitability and can be used as a primary target for potential therapeutic strategies to combat DRE.
2022-03-07 | PXD010415 | Pride
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: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: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
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