ISL1 Regulates Peroxisome Proliferator-Activated Receptor γ Activation and Early Adipogenesis via Bone Morphogenetic Protein 4-Dependent and -Independent Mechanisms

Ma, Xiuquan; Yang, Pengyi; Kaplan, Warren; Lee, Bon Hyang; Wu, Lindsay E.; Yang, Jean Yee-Hwa; Yasunaga, Mayu; Sato, Kei; Chisholm, Donald J.; James, David E.

doi:10.1128/mcb.00583-14

Cited by 11 publications

(9 citation statements)

References 58 publications

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“…In adipocytes, ETS2 has been shown to be essential for adipogenesis 44 . Indeed, ETS2 expression increases under early adipogenesis 18 , 44 , 45 and in every 3T3-L1 insulin resistance model (Fazakerley et al ., unpublished data). Interestingly, there is also evidence that ETS2 is regulated by insulin-stimulated kinase signalling 46 and mediates insulin-responsive gene expression 47 .…”

Section: Resultsmentioning

confidence: 99%

The transcriptional response to oxidative stress is part of, but not sufficient for, insulin resistance in adipocytes

Chaudhuri

Krycer

Fazakerley

et al. 2018

Sci Rep

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Insulin resistance is a major risk factor for metabolic diseases such as Type 2 diabetes. Although the underlying mechanisms of insulin resistance remain elusive, oxidative stress is a unifying driver by which numerous extrinsic signals and cellular stresses trigger insulin resistance. Consequently, we sought to understand the cellular response to oxidative stress and its role in insulin resistance. Using cultured 3T3-L1 adipocytes, we established a model of physiologically-derived oxidative stress by inhibiting the cycling of glutathione and thioredoxin, which induced insulin resistance as measured by impaired insulin-stimulated 2-deoxyglucose uptake. Using time-resolved transcriptomics, we found > 2000 genes differentially-expressed over 24 hours, with specific metabolic and signalling pathways enriched at different times. We explored this coordination using a knowledge-based hierarchical-clustering approach to generate a temporal transcriptional cascade and identify key transcription factors responding to oxidative stress. This response shared many similarities with changes observed in distinct insulin resistance models. However, an anti-oxidant reversed insulin resistance phenotypically but not transcriptionally, implying that the transcriptional response to oxidative stress is insufficient for insulin resistance. This suggests that the primary site by which oxidative stress impairs insulin action occurs post-transcriptionally, warranting a multi-level 'trans-omic' approach when studying time-resolved responses to cellular perturbations.Insulin resistance is a major risk factor for various metabolic diseases, such as type 2 diabetes, cardiovascular disease, and some cancers. Although its underlying mechanisms are elusive, insulin-responsive tissues such as adipose tissue undergo oxidative stress during insulin resistance 1,2 . Indeed, we have previously shown that oxidative stress unifies numerous triggers of insulin resistance in adipocytes and myotubes 3 . These include hyperinsulinaemia, inflammation, and glucocorticoids in vitro, as well as nutrient oversupply in vivo 3 . Thus, oxidative stress is an etiological component of insulin resistance 4,5 , yet how it impairs insulin action remains elusive.Oxidative stress arises from the aberrant production or defective scavenging of reactive oxygen or nitrogen species. These species can react with a range of macromolecules -in particular, they can oxidise exposed cysteine residues within proteins 6 , altering signalling and cellular physiology. To protect the cell from oxidative stress, the cell has two major redox buffering pools, governed by glutathione and thioredoxin. Although both thiol antioxidants, they are not redundant, serving to regulate distinct cellular signalling and metabolic pathways 7 . Inhibiting

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Section: Resultsmentioning

confidence: 99%

The transcriptional response to oxidative stress is part of, but not sufficient for, insulin resistance in adipocytes

Chaudhuri

Krycer

Fazakerley

et al. 2018

Sci Rep

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“…We have reported the presence of the transcription factor Islet1 (important for development of islets, cardiac tissue, and neurons) in the stromovascular (preadipocyte-containing) fraction of VAT but not SAT and its expression is correlated in animals and humans with leanness ( 54 ). We have also recently demonstrated the ability of Islet1 to inhibit 3T3-L1 preadipocyte differentiation in vitro at least in part via downregulation of bone morphogenic protein 4 (BMP4) ( 55 ). Further work will be needed to determine whether Islet1 is a significant regulator of visceral adiposity in humans.…”

Section: Regulation Of Adipose Tissue Expansion In Different Fat Depomentioning

confidence: 99%

Control of Adipocyte Differentiation in Different Fat Depots; Implications for Pathophysiology or Therapy

et al. 2015

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Adipocyte differentiation and its impact on restriction or expansion of particular adipose tissue depots have physiological and pathophysiological significance in view of the different functions of these depots. Brown or “beige” fat [brown adipose tissue (BAT)] expansion can enhance thermogenesis, lipid oxidation, insulin sensitivity, and glucose tolerance; conversely expanded visceral fat [visceral white adipose tissue (VAT)] is associated with insulin resistance, low grade inflammation, dyslipidemia, and cardiometabolic risk. The largest depot, subcutaneous white fat [subcutaneous white adipose tissue (SAT)], has important beneficial characteristics including storage of lipid “out of harms way” and secretion of adipokines, especially leptin and adiponectin, with positive metabolic effects including lipid oxidation, energy utilization, enhanced insulin action, and an anti-inflammatory role. The absence of these functions in lipodystrophies leads to major metabolic disturbances. An ability to expand white adipose tissue adipocyte differentiation would seem an important defense mechanism against the detrimental effects of energy excess and limit harmful accumulation of lipid in “ectopic” sites, such as liver and muscle. Adipocyte differentiation involves a transcriptional cascade with PPARγ being most important in SAT but less so in VAT, with increased angiogenesis also critical. The transcription factor, Islet1, is fairly specific to VAT and in vitro inhibits adipocyte differentiation. The physiological importance of Islet1 requires further study. Basic control of differentiation is similar in BAT but important differences include the effect of PGC-1α on mitochondrial biosynthesis and upregulation of UCP1; also PRDM16 plays a pivotal role in expression of the BAT phenotype. Modulation of the capacity or function of these different adipose tissue depots, by altering adipocyte differentiation or other means, holds promise for interventions that can be helpful in human disease, particularly cardiometabolic disorders associated with the world wide explosion of obesity.

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“…The differentially expressed genes in these cases were obtained from the original papers. Next, we considered a study where a global stress was applied, in this case the induction of adipogenesis [ 17 ]. In this case, the raw data was acquired, and differentially expressed genes were identified according to the workflow depicted in Fig A of S3 File .…”

Section: Resultsmentioning

confidence: 99%

“…Next, we used the adipogenesis time-course data [ 17 ] to elucidate temporal changes in transcriptional network during early adipogenesis. This biological process is driven by transcriptional cascades, whereby one TF regulates the expression of another TF, influencing other TFs downstream [ 18 ].…”

Section: Resultsmentioning

confidence: 99%

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ORTI: An Open-Access Repository of Transcriptional Interactions for Interrogating Mammalian Gene Expression Data

Vafaee

Krycer

et al. 2016

PLoS ONE

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Transcription factors (TFs) play a fundamental role in coordinating biological processes in response to stimuli. Consequently, we often seek to determine the key TFs and their regulated target genes (TGs) amidst gene expression data. This requires a knowledge-base of TF-TG interactions, which would enable us to determine the topology of the transcriptional network and predict novel regulatory interactions. To address this, we generated an Open-access Repository of Transcriptional Interactions, ORTI, by integrating available TF-TG interaction databases. These databases rely on different types of experimental evidence, including low-throughput assays, high-throughput screens, and bioinformatics predictions. We have subsequently categorised TF-TG interactions in ORTI according to the quality of this evidence. To demonstrate its capabilities, we applied ORTI to gene expression data and identified modulated TFs using an enrichment analysis. Combining this with pairwise TF-TG interactions enabled us to visualise temporal regulation of a transcriptional network. Additionally, ORTI enables the prediction of novel TF-TG interactions, based on how well candidate genes co-express with known TGs of the target TF. By filtering out known TF-TG interactions that are unlikely to occur within the experimental context, this analysis predicts context-specific TF-TG interactions. We show that this can be applied to experimental designs of varying complexities. In conclusion, ORTI is a rich and publicly available database of experimentally validated mammalian transcriptional interactions which is accompanied with tools that can identify and predict transcriptional interactions, serving as a useful resource for unravelling the topology of transcriptional networks.

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ISL1 Regulates Peroxisome Proliferator-Activated Receptor γ Activation and Early Adipogenesis via Bone Morphogenetic Protein 4-Dependent and -Independent Mechanisms

Cited by 11 publications

References 58 publications

The transcriptional response to oxidative stress is part of, but not sufficient for, insulin resistance in adipocytes

The transcriptional response to oxidative stress is part of, but not sufficient for, insulin resistance in adipocytes

Control of Adipocyte Differentiation in Different Fat Depots; Implications for Pathophysiology or Therapy

ORTI: An Open-Access Repository of Transcriptional Interactions for Interrogating Mammalian Gene Expression Data

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