scholarly journals Altered Transcription Factor Expression Responses to Exercise in Insulin Resistance

2021 ◽  
Vol 12 ◽  
Author(s):  
Rocio Zapata-Bustos ◽  
Jean Finlayson ◽  
Paul R. Langlais ◽  
Dawn K. Coletta ◽  
Moulun Luo ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Growth Factors ◽  
Enrichment Analysis ◽  
Rt Pcr ◽  
Post Exercise ◽  
Insulin Resistant ◽  
Exercise Muscle ◽  
Muscle Biopsies

PurposeInsulin resistant muscle is resistant to gene expression changes induced by acute exercise. This study was undertaken to identify transcription factors that differentially respond to exercise in insulin resistance. Candidate transcription factors were identified from analysis of 5′-untranslated regions (5′-UTRs) of exercise responsive genes and from analysis of the 5′-UTRs of genes coding for proteins that differ in abundance in insulin resistance.Research Design and MethodsTwenty participants took part in this study. Insulin sensitivity was assessed by an euglycemic clamp. Participants were matched for aerobic capacity and performed a single 48 min bout of exercise with sets at 70 and 90% of maximum heart rate. Muscle biopsies were obtained at resting conditions, 30 min and 24 h after exercise. Global proteomics analysis identified differentially abundant proteins in muscle. The 5′-UTRs of genes coding for significant proteins were subjected to transcription factor enrichment analysis to identify candidate transcription factors. Q-rt-PCR to determine expression of candidate transcription factors was performed on RNA from resting and post-exercise muscle biopsies; immunoblots quantified protein abundance.ResultsProteins involved in mitochondrial function, protein targeting and translation, and metabolism were among those significantly different between lean and obese groups. Transcription factor enrichment analysis of genes coding for these proteins revealed new candidate transcription factors to be evaluated along the previously identified factors. Q-rt-PCR analysis of RNA and immunoblot analysis from pre- and post-exercise muscle biopsies revealed several transcription and growth factors that had altered responses to exercise in insulin resistant participants. A significant increase (EGR3 and CTGF) and decrease (RELA and ATF2) in the mRNA expression of transcription and growth factors was found after exercise in the lean group, but not in the obese participants.ConclusionsThese results confirm findings of an association between insulin sensitivity and transcription factor mRNA response to exercise and show that obesity also may be a sufficient prerequisite for exercise resistance. Analysis of the muscle proteome together with determination of effects of exercise on expression of transcription factors suggests that abnormal responses of transcription factors to exercise may be responsible for differences in protein abundances in insulin resistant muscle.

Insulin receptor autophosphorylation in cultured myoblasts correlates to glucose disposal in Pima Indians

1999 ◽  
Vol 276 (5) ◽  
pp. E990-E994 ◽  
Author(s):  
Jack F. Youngren ◽  
Ira D. Goldfine ◽  
Richard E. Pratley
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Glucose Disposal ◽  
Pima Indians ◽  
Insulin Resistant ◽  
Highly Sensitive ◽  
Fasting Plasma Insulin ◽  
The Relationship ◽  
Muscle Biopsies

In a previous study [Youngren, J. F., I. D. Goldfire, and R. E. Pratley. Am. J. Physiol. 273 ( Endocrinol. Metab. 36): E276–E283, 1997] of skeletal muscle biopsies from insulin-resistant, nondiabetic Pima Indians, we demonstrated that diminished insulin receptor (IR) autophosphorylation correlated with in vivo insulin resistance. In the present study, to determine whether decreased IR function is a primary trait of muscle, and not secondary to an altered in vivo environment, we cultured myoblasts from 17 nondiabetic Pima Indians in whom insulin-stimulated glucose disposal (M) was measured during hyperinsulinemic-euglycemic glucose clamps. Myoblast IR autophosphorylation was determined by a highly sensitive ELISA. IR autophosphorylation directly correlated with M ( r = 0.56, P = 0.02) and inversely correlated with the fasting plasma insulin ( r = −0.58, P < 0.05). The relationship between M and IR autophosphorylation remained significant after M was adjusted for the effects of percent body fat (partial r = 0.53, P < 0.04). The relationship between insulin resistance and the capacity for myoblast IR autophosphorylation in nondiabetic Pima Indians suggests that variations in IR-signaling capacity may be intrinsic characteristics of muscle that contribute to the genetic component determining insulin action in this population.

scholarly journals Cardiac Development and Transcription Factors: Insulin Signalling, Insulin Resistance, and Intrauterine Nutritional Programming of Cardiovascular Disease

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Annelene Govindsamy ◽  
Strinivasen Naidoo ◽  
Marlon E. Cerf
Keyword(s):  
Insulin Resistance ◽  
Cardiovascular Disease ◽  
Transcription Factors ◽  
Cardiac Development ◽  
Insulin Signalling ◽  
Life Stages ◽  
Sequential Process ◽  
Insulin Resistant ◽  
Sensitive Organ ◽  
And Function

Programming with an insult or stimulus during critical developmental life stages shapes metabolic disease through divergent mechanisms. Cardiovascular disease increasingly contributes to global morbidity and mortality, and the heart as an insulin-sensitive organ may become insulin resistant, which manifests as micro- and/or macrovascular complications due to diabetic complications. Cardiogenesis is a sequential process during which the heart develops into a mature organ and is regulated by several cardiac-specific transcription factors. Disrupted cardiac insulin signalling contributes to cardiac insulin resistance. Intrauterine under- or overnutrition alters offspring cardiac structure and function, notably cardiac hypertrophy, systolic and diastolic dysfunction, and hypertension that precede the onset of cardiovascular disease. Optimal intrauterine nutrition and oxygen saturation are required for normal cardiac development in offspring and the maintenance of their cardiovascular physiology.

The effect of magnesium oxide supplementation on muscle glycogen metabolism before and after exercise and at slaughter in sheep

2001 ◽  
Vol 52 (7) ◽  
pp. 723 ◽  
Author(s):  
G. E. Gardner ◽  
R. H. Jacob ◽  
D. W. Pethick
Keyword(s):  
Magnesium Oxide ◽  
Muscle Glycogen ◽  
Glycogen Metabolism ◽  
Post Exercise ◽  
Exercise Regimen ◽  
Before And After ◽  
Series Of Experiments ◽  
Glycogen Repletion ◽  
Exercise Muscle ◽  
Muscle Biopsies

This study was a series of experiments designed to test the influence of supplemental magnesium oxide (MgO) on muscle glycogen concentration in sheep exposed to stress (exercise) and the commercial slaughter process, and to test the effectiveness of this supplement in the commercial scenario. In Expt 1, Merino wethers maintained on a mixed ration (metabolisable energy 11 MJ/kg and crude protein 16.3% in DM) were supplemented with MgO at the rate of 0%, 0.5%, or 1% of their ration for 10 days prior to a single bout of exercise and for 10 days prior to slaughter at a commercial abattoir. The exercise regimen consisted of 4 intervals of 15 min, with muscle biopsies taken by biopsy drill from the m. semimembranosis (SM) and m. semitendinosis (ST) pre-exercise and immediately post-exercise, and at 36 and 72 h post-exercise. Muscle biopsies were also taken 1 week prior to slaughter from the SM and ST, with further samples taken approximately 30 min post-slaughter. Ultimate pH (pHu) of the SM, ST, and m. longissimus dorsi (LD) was measured 48 h after slaughter. Sheep supplemented with MgO lost less muscle glycogen in the ST during exercise, and repleted more muscle glycogen in the SM during the post-exercise repletion phase, than unsupplemented sheep. The supplemented animals also had higher muscle glycogen concentrations in the ST at slaughter. In Expt 2, MgO was administered to Merino wether lambs for 4 days prior to slaughter in the form of a water-borne slurry at a rate equivalent to 1% of their ration. This treatment resulted in significantly reduced muscle glycogen concentrations in both the SM and ST at slaughter. In Expts 3–5, MgO was used as an ‘in-feed’ supplement in the commercial scenario. In each case, slaughter-weight Merino lambs were supplemented with MgO at the rate of 1% of their ration for 4 days prior to commercial slaughter. Positive responses were seen in 2 of the 3 experiments, with increased glycogen concentrations and a reduced pHu. The animals that demonstrated no response to MgO had the lowest pHu after slaughter, suggesting a minimal stress load, thus providing very little scope for an effect of the MgO supplement. We conclude that MgO can reduce the effects of exercise, leading to a subsequent reduction in glycogen loss, and an increase in the rate of glycogen repletion in skeletal muscle following exercise. The results support MgO supplementation as a viable option for reducing the stress associated with commercial slaughter.

scholarly journals Transcriptome profilings reveal the candidate genes, pathways and transcription factors related to nitrogen utilization and excessive nitrogen stress in perennial ryegrass.

2020 ◽  
Author(s):  
Yinruizhi Li ◽  
Mengdi Wang ◽  
Ke Teng ◽  
Di Dong ◽  
Zhuocheng Liu ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Perennial Ryegrass ◽  
Expression Patterns ◽  
Enrichment Analysis ◽  
Nitrogen Utilization ◽  
Utilization Rate ◽  
Nitrogen Stress ◽  
Molecular Response ◽  
Stress Effect

Abstract Background：Lolium perenne L. is a kind of high quality forage grass, which can provide a good nutritional basis for herbivorous livestock. However, how to improve the nitrogen utilization rate of ryegrass and avoid the nitrate toxicity caused by excessive nitrogen has been troubling people for a long time. Up to now, the molecular response mechanism of ryegrass to nitrogen is not clear, especially under the condition of excessive nitrogen. Based on this, we tried to obtain a new insight into molecular response of ryegrass in nitrogen utilization and excessive nitrogen stress, providing the molecular theoretical basis for solving this problem.Results: In this study, the transcription of perennial ryegrass at different nitrogen levels was identified by high-throughput next-generation DNA sequencing. Phenotypic characterizations investigated that ryegrass in treatment N0.5 has a better growth state than the other three groups. The treatment N1 and N10 contained excessive nitrogen, which had a stress effect on plant growth. Analysis of differentially expressed genes indicated that 345, 105 genes are considered to involve in the regulation of nitrogen utilization and excessive nitrogen stress, respectively. GO enrichment analysis revealed that plant response to nitrogen mainly enrich in two categories, including “biological process” and “molecular function”. KEGG enrichment analysis suggested that “Photosynthesis-antenna proteins” may respond positively to nitrogen under appropriate nitrogen conditions, whereas “steroid biosynthesis”, “carotenoid biosynthesis” and “C5-branched dibasic acid metabolism” had been identified as top significant enrichment pathways response to excessive nitrogen. Transcription factors analysis showed that 21 TFs related to nitrogen utilization were classified into 10 transcription factor families, especially AP2-EREBP and MYB TF families. 4 TFs related to excessive nitrogen stress were identified, which belonged to 4 transcription factor families including LOB, NAC, AP2-EREBP and HB. The expression patterns of these selected genes above were also analyzed. Conclusions: These results made a contribution to comprehend the molecular mechanism of perennial ryegrass response to nitrogen. It provides new ideas for guiding the production practice and variety improvement of forage and even food crops from the perspective of molecular biology.

scholarly journals Transcription factor enrichment analysis (TFEA): Quantifying the activity of hundreds of transcription factors from a single experiment

2020 ◽  
Author(s):  
Jonathan D. Rubin ◽  
Jacob T. Stanley ◽  
Rutendo F. Sigauke ◽  
Cecilia B. Levandowski ◽  
Zachary L. Maas ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Regulatory Networks ◽  
Time Series Data ◽  
Effective Means ◽  
Enrichment Analysis ◽  
Cost Effective ◽  
Computational Method ◽  
Series Data ◽  
Single Experiment

1AbstractDetecting differential activation of transcription factors (TFs) in response to perturbation provides insight into cellular processes. Transcription Factor Enrichment Analysis (TFEA) is a robust and reliable computational method that detects differential activity of hundreds of TFs given any set of perturbation data. TFEA draws inspiration from GSEA and detects positional motif enrichment within a list of ranked regions of interest (ROIs). As ROIs are typically inferred from the data, we also introduce muMerge, a statistically principled method of generating a consensus list of ROIs from multiple replicates and conditions. TFEA is broadly applicable to data that informs on transcriptional regulation including nascent (eg. PRO-Seq), CAGE, ChIP-Seq, and accessibility (e.g. ATAC-Seq). TFEA not only identifies the key regulators responding to a perturbation, but also temporally unravels regulatory networks with time series data. Consequently, TFEA serves as a hypothesis-generating tool that provides an easy, rigorous, and cost-effective means to broadly assess TF activity yielding new biological insights.

scholarly journals Characteristics of the New Insulin-Resistant Zebrafish Model

2021 ◽  
Vol 14 (7) ◽  
pp. 642
Author(s):  
Youn-Hee Nam ◽  
Isabel Rodriguez ◽  
Sung-Woo Shin ◽  
Ji-Heon Shim ◽  
Na-Woo Kim ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Drug Discovery ◽  
Pancreatic Islets ◽  
Drug Testing ◽  
Enrichment Analysis ◽  
Mapk Signaling ◽  
Pathway Enrichment Analysis ◽  
Rodent Models ◽  
Zebrafish Model ◽  
Insulin Resistant

Insulin resistance, which occurs when insulin levels are sufficiently high over a prolonged period, causing the cells to fail to respond normally to the hormone. As a system for insulin resistance and diabetes drug development, insulin-resistant rodent models have been clearly established, but there is a limitation to high-throughput drug screening. Recently, zebrafish have been identified as an excellent system for drug discovery and identification of therapeutic targets, but studies on insulin resistance models have not been extensively performed. Therefore, we aimed to make a rapid insulin-resistant zebrafish model that complements the existing rodent models. To establish this model, zebrafish were treated with 10 μM insulin for 48 h. This model showed characteristics of insulin-resistant disease such as damaged pancreatic islets. Then we confirmed the recovery of the pancreatic islets after pioglitazone treatment. In addition, it was found that insulin-resistant drugs have as significant an effect in zebrafish as in humans, and these results proved the value of the zebrafish insulin resistance model for drug selection. In addition, RNA sequencing was performed to elucidate the mechanism involved. KEGG pathway enrichment analysis of differentially expressed genes showed that insulin resistance altered gene expression due to the MAPK signaling and calcium signaling pathways. This model demonstrates the utility of the zebrafish model for drug testing and drug discovery in insulin resistance and diabetes.

scholarly journals Information-dependent Enrichment Analysis Reveals Time-dependent Transcriptional Regulation of the Estrogen Pathway of Toxicity

2016 ◽  
Author(s):  
Salil N. Pendse ◽  
Alexandra Maertens ◽  
Michael Rosenberg ◽  
Dipanwita Roy ◽  
Rick A. Fasani ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Expression Patterns ◽  
Enrichment Analysis ◽  
Fold Change ◽  
Gene Set Enrichment Analysis ◽  
High Dose ◽  
Functional Responses ◽  
Pathways Of Toxicity

The twenty-first century vision for toxicology involves a transition away from high-dose animal studies and into in vitro and computational models. This movement requires mapping pathways of toxicity through an understanding of how in vitro systems respond to chemical perturbation. Uncovering transcription factors responsible for gene expression patterns is essential for defining pathways of toxicity, and ultimately, for determining chemical mode of action, through which a toxicant acts. Traditionally this is achieved via chromatin immunoprecipitation studies and summarized by calculating, which transcription factors are statistically associated with the up- and down-regulated genes. These lists are commonly determined via statistical or fold-change cutoffs, a procedure that is sensitive to statistical power and may not be relevant to determining transcription factor associations. To move away from an arbitrary statistical or fold-change based cutoffs, we have developed in the context of the Mapping the Human Toxome project, a novel enrichment paradigm called Information Dependent Enrichment Analysis (IDEA) to guide identification of the transcription factor network. We used the test case of endocrine disruption of MCF-7 cells activated by 17β estradiol (E2). Using this new approach, we were able to establish a time course for transcriptional and functional responses to E2. ERα and ERβ are associated with short-term transcriptional changes in response to E2. Sustained exposure leads to the recruitment of an additional ensemble of transcription factors and alteration of cell-cycle machinery. TFAP2C and SOX2 were the transcription factors most highly correlated with dose. E2F7, E2F1 and Foxm1, which are involved in cell proliferation, were enriched only at 24h. IDEA is, therefore, a novel tool to identify candidate pathways of toxicity, clearly outperforming Gene-set Enrichment Analysis but with similar results as Weighted Gene Correlation Network Analysis, which helps to identify genes not annotated to pathways.

Inhibition of FOXO1 transcription factor in primary human adipocytes mimics the insulin-resistant state of type 2 diabetes

2018 ◽  
Vol 475 (10) ◽  
pp. 1807-1820 ◽  
Author(s):  
Meenu R. Rajan ◽  
Elin Nyman ◽  
Cecilia Brännmark ◽  
Charlotta S. Olofsson ◽  
Peter Strålfors
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Transcription Factor ◽  
Insulin Signalling ◽  
Regulation Of Transcription ◽  
Human Adipocytes ◽  
Insulin Resistant ◽  
Resistant State ◽  
Insulin Resistant State

Type 2 diabetes is characterized by insulin resistance in the expanding adipose tissue of obesity. The insulin resistance manifests in human adipocytes as system-wide impairment of insulin signalling. An exception is the regulation of transcription factor FOXO1 (forkhead box protein O1), which is phosphorylated downstream of mTORC2 (mammalian/mechanistic target of rapamycin in complex with raptor) and is therefore not exhibiting impaired response to insulin. However, the abundance, and activity, of FOXO1 is reduced by half in adipocytes from patients with diabetes. To elucidate the effect of reduced FOXO1 activity, we here transduced human adipocytes with a dominant-negative construct of FOXO1 (DN-FOXO1). Inhibition of FOXO1 reduced the abundance of insulin receptor, glucose transporter-4, ribosomal protein S6, mTOR and raptor. Functionally, inhibition of FOXO1 induced an insulin-resistant state network-wide, a state that qualitatively and quantitatively mimicked adipocytes from patients with type 2 diabetes. In contrast, and in accordance with these effects of DN-FOXO1, overexpression of wild-type FOXO1 appeared to augment insulin signalling. We combined experimental data with mathematical modelling to show that the impaired insulin signalling in FOXO1-inhibited cells to a large extent can be explained by reduced mTORC1 activity — a mechanism that defines much of the diabetic state in human adipocytes. Our findings demonstrate that FOXO1 is critical for maintaining normal insulin signalling of human adipocytes.

scholarly journals Calcium activates serum response factor-dependent transcription by a Ras- and Elk-1-independent mechanism that involves a Ca2+/calmodulin-dependent kinase.

1995 ◽  
Vol 15 (7) ◽  
pp. 3672-3684 ◽  
Author(s):  
C K Miranti ◽  
D D Ginty ◽  
G Huang ◽  
T Chatila ◽  
M E Greenberg
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Growth Factors ◽  
Serum Response Factor ◽  
Active Form ◽  
Response Factor ◽  
Transcriptional Responses ◽  
Pheochromocytoma Cell ◽  
Independent Mechanism ◽  
Serum Response

Enhanced levels of cytoplasmic Ca2+ due to membrane depolarization with elevated levels of KCl or exposure to the Ca2+ ionophore ionomycin stimulate serum response element (SRE)-dependent transcription in the pheochromocytoma cell line PC12. By using altered binding specificity mutants of transcription factors that bind to the SRE, it was demonstrated that in contrast to treatment with purified growth factors, such as nerve growth factor, the serum response factor (SRF), but not Elk-1, mediates Ca(2+)-regulated SRE-dependent transcription. Enhanced levels of cytoplasmic Ca2+ were found to trigger SRE-dependent transcription via a Ras-independent signaling pathway that appears to involve a Ca2+/calmodulin-dependent kinase (CaMK). Overexpression of a constitutively active form of CaMKIV stimulated SRF-dependent transcription. Taken together, these findings indicate that SRF is a versatile transcription factor that, when bound to the SRE, can function by distinct mechanisms and can mediate transcriptional responses to both CaMK- and Ras-dependent signaling pathways.

scholarly journals Identification of a Transcription Factor-microRNA-Gene Coregulation Network in Meningioma through a Bioinformatic Analysis

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Juan Wang ◽  
Yan Liang ◽  
Hui Yang ◽  
Jian-Huang Wu
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Differentially Expressed Genes ◽  
Mirna Gene ◽  
Control Sample ◽  
Interaction Network ◽  
Enrichment Analysis ◽  
Differentially Expressed ◽  
Pathway Enrichment Analysis ◽  
Ontology Term

Background. Meningioma is a prevalent type of brain tumor. However, the initiation and progression mechanisms involved in the meningioma are mostly unknown. This study aimed at exploring the potential transcription factors/micro(mi)RNAs/genes and biological pathways associated with meningioma. Methods. mRNA expressions from GSE88720, GSE43290, and GSE54934 datasets, containing data from 83 meningioma samples and eight control samples, along with miRNA expression dataset GSE88721, which had 14 meningioma samples and one control sample, were integrated analyzed. The bioinformatics approaches were used for identifying differentially expressed genes and miRNAs, as well as predicting transcription factor targets related to the differentially expressed genes. The approaches were also used for gene ontology term analysis and biological pathway enrichment analysis, construction, and analysis of protein-protein interaction network, and transcription factor-miRNA-gene coregulation network construction. Results. Fifty-six upregulated and 179 downregulated genes were identified. Thirty transcription factors able to target the differentially expressed genes were predicted and selected based on public databases. One hundred seventeen overlapping genes were identified from the differentially expressed genes and the miRNAs predicted by miRWalk. Furthermore, NF-κB/IL6, PTGS2, MYC/hsa-miR-574-5p, hsa-miR-26b-5p, hsa-miR-335-5p, and hsa-miR-98-5p, which are involved in the transcription factor-miRNA-mRNA coregulation network, were found to be associated with meningioma. Conclusion. The bioinformatics analysis identified several potential molecules and relevant pathways that may represent critical mechanisms involved in the progression and development of meningioma. This work provides new insights into meningioma pathogenesis and treatments.

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