Characterization of transcriptome changes induced in 3T3L1 adipocytes by expression of Adenovirus subtype 5 protein E4-ORF1
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ORGANISM(S): Mus musculus
PROVIDER: GSE89621 | GEO | 2016/12/05
SECONDARY ACCESSION(S): PRJNA352729
REPOSITORIES: GEO
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Project description:This a model from the article:
A molecular mathematical model of glucose mobilization and uptake.
Liu W, Hsin C, Tang F. Math Biosci.
2009 Oct;221(2):121-9. 19651146
,
Abstract:
A new molecular mathematical model is developed by considering the kinetics of GLUT2, GLUT3, and GLUT4, the process of glucose mobilization by glycogen phosphorylase and glycogen synthase in liver, and the dynamics of the insulin signaling pathway. The new model can qualitatively reproduce the experimental glucose and insulin data. It also enables us to use the Bendixson criterion about the existence of periodic orbits of a two-dimensional dynamical system to mathematically predict that the oscillations of glucose and insulin are not caused by liver, instead they would be caused by the mechanism of insulin secretion from pancreatic beta cells. Furthermore it enables us to conduct a parametric sensitivity analysis. The analysis shows that both glucose and insulin are most sensitive to the rate constant for conversion of PI(3,4,5)P(3) to PI(4,5)P(2), the multiplicative factor modulating the rate constant for conversion of PI(3,4,5)P(3) to PI(4,5)P(2), the multiplicative factor that modulates insulin receptor dephosphorylation rate, and the maximum velocity of GLUT4. Moreover, the sensitivity analysis predicts that an increase of the apparent velocity of GLUT4, a combination of elevated mobilization rate of GLUT4 to the plasma membrane and an extended duration of GLUT4 on the plasma membrane, will result in a decrease in the needs of plasma insulin. On the other hand, an increase of the GLUT4 internalization rate results in an elevated demand of insulin to stimulate the mobilization of GLUT4 from the intracellular store to the plasma membrane.
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2005-01-01 | MODEL1112050001 | BioModels
Project description:Insulin action in adipocytes affects whole-body insulin sensitivity. Studies of adipose-specific Glut4 knockout mice have established that adipose Glut4 contributes to the control of systemic glucose homeostasis. Presumably, this reflects a role for Glut4-mediated glucose transport in the regulation of secreted adipokines. In cultured 3T3-L1 adipocytes, Rab10 GTPase is required for insulin-stimulated translocation of Glut4 (Sano et al., 2007). The physiological importance of adipose Rab10 and the significance of its role in the control of Glut4 vesicle trafficking in vivo are unknown. Here we report that adipocytes from adipose-specific Rab10 knockout mice have a ~50% reduction in glucose uptake and Glut4 translocation to the cell surface in response to insulin, demonstrating a role for Rab10 in Glut4 trafficking. Moreover, hyperinsulinemic-euglycemic clamp shows decreased whole-body glucose uptake as well as impaired suppression of hepatic glucose production in adipose Rab10 knockout mice. Thus, fully functional Glut4 vesicle trafficking in adipocytes is critical for maintaining insulin sensitivity. Comparative transcriptome analysis of perigonadal adipose tissue demonstrates significant transcriptional similarities between adipose Rab10 knockout mice and adipose Glut4 knockout mice, consistent with the notion that the phenotypic similarities between the two models are mediated by reduced insulin-stimulated glucose transport into adipocytes. Transcriptome sequencing of perigonadal white adipose tissue
2016-06-30 | E-GEOD-70123 | biostudies-arrayexpress
Project description:Insulin action in adipocytes affects whole-body insulin sensitivity. Studies of adipose-specific Glut4 knockout mice have established that adipose Glut4 contributes to the control of systemic glucose homeostasis. Presumably, this reflects a role for Glut4-mediated glucose transport in the regulation of secreted adipokines. In cultured 3T3-L1 adipocytes, Rab10 GTPase is required for insulin-stimulated translocation of Glut4 (Sano et al., 2007). The physiological importance of adipose Rab10 and the significance of its role in the control of Glut4 vesicle trafficking in vivo are unknown. Here we report that adipocytes from adipose-specific Rab10 knockout mice have a ~50% reduction in glucose uptake and Glut4 translocation to the cell surface in response to insulin, demonstrating a role for Rab10 in Glut4 trafficking. Moreover, hyperinsulinemic-euglycemic clamp shows decreased whole-body glucose uptake as well as impaired suppression of hepatic glucose production in adipose Rab10 knockout mice. Thus, fully functional Glut4 vesicle trafficking in adipocytes is critical for maintaining insulin sensitivity. Comparative transcriptome analysis of perigonadal adipose tissue demonstrates significant transcriptional similarities between adipose Rab10 knockout mice and adipose Glut4 knockout mice, consistent with the notion that the phenotypic similarities between the two models are mediated by reduced insulin-stimulated glucose transport into adipocytes.
2016-06-30 | GSE70123 | GEO
Project description:Type 2 diabetes (T2D) is major cause of mortality and morbidity. The key manifestations of this disease are insulin resistance (IR), hyperglycemia and hyperinsulinemia. Secretion of insulin from the endocrine pancreas is triggered by elevated circulating glucose and acts on skeletal muscle and adipose tissues to remove excess glucose from the blood (1). This is achieved through a series of intracellular events that trigger the translocation of vesicles containing the glucose transporter 4 (GLUT4) to the surface of skeletal muscle cells and adipocytes (2,3). This process is impaired in patients with IR or T2D and insulin fails to promote GLUT4 translocation, thus resulting in inefficient glucose uptake in storage tissue and hyperglycemia (4). Chronic hyperglycemic condition increases the risk of cardiovascular disease, stroke, neuropathy, and death (5). Previously developed insulin sensitizer like thiazolidinediones (TZDs) have proven effective in improving glycemic control, however, they significantly increase the risk of cardiovascular disease due to their agonist activity at PPAR(6-8). Consequently, identifying insulin sensitizers that restore insulin-stimulated GLUT4 translocation in diabetic patients without targeting PPAR is urgently needed. The discovery of such molecules has been challenging due to the lack of a GLUT4 translocation assay amenable to high throughput screening (HTS). For this reason, we have developed a new luminescence based HTS assay that allows real time monitoring of GLUT4 translocation in mammalian cells and further adapted the assay to measure GLUT4 translocation in live mice. Using this assay, we identified a new insulin sensitizer which greatly improves insulin-dependent glucose uptake in storage tissues and glucose tolerance in insulin resistant rodents. This new insulin sensitizers acts through interaction with the Unc119 family of proteins which are known to facilitate the transport of specific cargos (9) but had not yet been implicated in insulin action or GLUT4 translocation. This study identifies new PPAR-independent insulin sensitizers with in-vivo efficacy and identify Unc119 proteins as new targets for the treatment of T2D.
2024-07-03 | PXD034052 | Pride
Project description:Adenovirus infection leads to increased glycolytic metabolism in host cells. Expression of a single gene product encoded within the E4 early transcription region, E4ORF1, is sufficient to promote increased glycolytic flux in cultured epithelial cells. E4ORF1 reprograms cellular glucose metabolism by augmenting MYC-dependent transcription of metabolic genes. To gain insight into the mechanism by which E4ORF1 promotes increased glycolytic flux, we conducted a global microarray analysis of changes in RNA expression in MCF10A cells induced to accutely express ORF1 versus an empty vector.
2014-04-08 | E-GEOD-52998 | biostudies-arrayexpress
Project description:This experiment was conducted to identify target genes of the peroxisome proliferator-activated receptor alpha (PPARa) in skeletal muscle of transgenic mice that overexpressed PPARa. The following abstract from the published manuscript describes the major findings of this work. A potential link between muscle peroxisome proliferator- activated receptor-alpha signaling and obesity-related diabetes.Finck BN, Bernal-Mizrachi C, Han DH, Coleman T, Sambandam N, LaRiviere LL, Holloszy JO, Semenkovich CF, Kelly DP. The role of the peroxisome proliferator-activated receptor-alpha (PPARalpha) in the development of insulin-resistant diabetes was evaluated using gain- and loss-of-function approaches. Transgenic mice overexpressing PPARalpha in muscle (MCK-PPARalpha mice) developed glucose intolerance despite being protected from diet-induced obesity. Conversely, PPARalpha null mice were protected from diet-induced insulin resistance in the context of obesity. In skeletal muscle, MCK-PPARalpha mice exhibited increased fatty acid oxidation rates, diminished AMP-activated protein kinase activity, and reduced insulin-stimulated glucose uptake without alterations in the phosphorylation status of key insulin-signaling proteins. These effects on muscle glucose uptake involved transcriptional repression of the GLUT4 gene. Pharmacologic inhibition of fatty acid oxidation or mitochondrial respiratory coupling prevented the effects of PPARalpha on GLUT4 expression and glucose homeostasis. These results identify PPARalpha-driven alterations in muscle fatty acid oxidation and energetics as a potential link between obesity and the development of glucose intolerance and insulin resistance. Experiment Overall Design: RNA from two wild-type (non-transgenic (NTG)) and two PPARalpha overexpressing (MCK-PPARa) mice was analyzed. Two replicates of each are provided.
2008-06-14 | E-GEOD-5777 | biostudies-arrayexpress
Project description:Tankyrase1 and 2, members of the poly(ADP-ribose) polymerase family, play a role in multiple biological processes including Wnt signalling and glucose uptake. However, their role in glucose uptake remains elusive, particularly in skeletal muscle cells. Treatment of differentiated L6 myotubes with the small molecule tankyrase inhibitor XAV939 resulted in insulin resistance as determined by impaired insulin-stimulated glucose uptake. Proteomic analysis identified 109 proteins that were down-regulated and 109 proteins that were up-regulated in response to XAV939. Among the down-regulated proteins there were several glucose transporter GLUT4 storage vesicle (GSV) proteins including RAB10, VAMP8, SORT1 as well as GLUT4 itself. Knock down of tankyrase1 in L6 myotubes also led to a reduction in the level of GSV proteins and impaired insulin-mediated glucose uptake. Inhibition of the proteasome rescued protein levels of GSV proteins as well as insulin-stimulated glucose uptake in XAV939-treated L6 myotubes. These studies reveal an important role for tankyrase in maintaining the stability of key GLUT4 regulatory proteins that in turn plays a role in regulating cellular insulin sensitivity.
2018-04-17 | PXD007182 | Pride
Project description:One major effect of PI3-kinase activation downstream of the serine/threonine kinase Akt is the phosphorylation of the transcription factor FOXO1 and its neutralization. FOXO1 has several ubiquitous targets genes in many cell types that control cell quiescence, oxydative stress or apoptosis. However, it has been demonstrated that FOXO1 also has specific targets depending of the cellular context. The role of FOXO1 to regulate specific genes in T lymphocytes has not been investigated yet. To examine this point, we used the CD4+ leukemia Jurkat T-cell line, in which the PI3K pathway is constitutively turned-on and FOXO1 transcriptional activity strongly repressed. These cells were transduced with lentiviruses coding for a constitutively active form of FOXO1 fused to GFP and having the three AKT phosphorylation sites mutated to alanine (FOXO1-AAA-GFP) to restore its transcriptional activity. GFP-transduced cells were used as a control and the gene activation levels in the two cell populations analyzed 48 hours post-infection.
2008-12-01 | E-TABM-391 | biostudies-arrayexpress
Project description:This experiment was conducted to identify target genes of the peroxisome proliferator-activated receptor alpha (PPARa) in skeletal muscle of transgenic mice that overexpressed PPARa. The following abstract from the published manuscript describes the major findings of this work. A potential link between muscle peroxisome proliferator- activated receptor-alpha signaling and obesity-related diabetes.Finck BN, Bernal-Mizrachi C, Han DH, Coleman T, Sambandam N, LaRiviere LL, Holloszy JO, Semenkovich CF, Kelly DP. The role of the peroxisome proliferator-activated receptor-alpha (PPARalpha) in the development of insulin-resistant diabetes was evaluated using gain- and loss-of-function approaches. Transgenic mice overexpressing PPARalpha in muscle (MCK-PPARalpha mice) developed glucose intolerance despite being protected from diet-induced obesity. Conversely, PPARalpha null mice were protected from diet-induced insulin resistance in the context of obesity. In skeletal muscle, MCK-PPARalpha mice exhibited increased fatty acid oxidation rates, diminished AMP-activated protein kinase activity, and reduced insulin-stimulated glucose uptake without alterations in the phosphorylation status of key insulin-signaling proteins. These effects on muscle glucose uptake involved transcriptional repression of the GLUT4 gene. Pharmacologic inhibition of fatty acid oxidation or mitochondrial respiratory coupling prevented the effects of PPARalpha on GLUT4 expression and glucose homeostasis. These results identify PPARalpha-driven alterations in muscle fatty acid oxidation and energetics as a potential link between obesity and the development of glucose intolerance and insulin resistance. Keywords: genetic modification
2006-09-08 | GSE5777 | GEO
Project description:Prospective epidemiological studies have consistently supported that pancreatic cancer associated new-onset diabetes mellitus (PC-DM) is probably an important clue for early diagnosis of pancreatic cancer (PC). However, the mechanism underlying remains fragmentary. In this study, two types of exosomes released by murine pancreatic cancer cells and murine pancreatic ductal epithelial cells were isolated，and their effects on skeletal muscle cells were invested. The results showed that PC-derived exosomes can readily enter C2C12 myotubes, and then induce lipidosis, glucose intake inhibition. We also found that PC-derived exosomes can inhibit Insulin and PI3K/Akt signaling, in which insulin-induced FoxO1 nuclear exclusion is preserved while Glut4 trafficking is impaired. In addition, further microarray and Kyoto encyclopedia of genes and genomes (KEGG) analysis prompted that exosomal microRNAs (miRNAs) probably play an critical role in this process, which also has been preliminarily demonstrated in vitro. Taking together, these results suggest that PC-derived exosomes induce insulin resistance (IR) of skeletal muscle cells through Insulin and PI3K/Akt/FoxO1 signaling pathway, and exosomal miRNAs are probably involved. The novel findings also support the theories of cancer “metabolic reprogramming” and “metabolic crosstalk”.
2017-08-11 | GSE95741 | GEO