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Comprehensive analysis of different in vitro insulin resistance models

ABSTRACT: Diet-induced obesity (DIO) predisposes individuals to insulin resistance, and adipose tissue has a major role in the disease. Insulin resistance can be induced in cultured adipocytes by a variety of treatments, but what aspects of the in vivo responses are captured by these models remains unknown. We use global RNA sequencing to investigate changes induced by TNF-a, hypoxia, dexamethasone, high insulin, and a combination of TNF-a and hypoxia, comparing the results to the changes in white adipose tissue from DIO mice. We found that different in vitro models capture distinct features of DIO adipose insulin resistance, and a combined treatment of TNF-a and hypoxia is most able to mimic the in vivo changes. Using genome-wide DNase I hypersensitivity followed by sequencing, we further examined the transcriptional regulation of TNF-a-induced insulin resistance, and we found that C/EPBß key regulator of adipose insulin resistance.

ORGANISM(S): Mus musculus

PROVIDER: GSE35724 | GEO | 2013/10/18

SECONDARY ACCESSION(S): PRJNA152127

REPOSITORIES: GEO

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Comprehensive analysis of different in vitro insulin resistance models

Project description:Diet-induced obesity (DIO) predisposes individuals to insulin resistance, and adipose tissue has a major role in the disease. Insulin resistance can be induced in cultured adipocytes by a variety of treatments, but what aspects of the in vivo responses are captured by these models remains unknown. We use global RNA sequencing to investigate changes induced by TNF-a, hypoxia, dexamethasone, high insulin, and a combination of TNF-a and hypoxia, comparing the results to the changes in white adipose tissue from DIO mice. We found that different in vitro models capture distinct features of DIO adipose insulin resistance, and a combined treatment of TNF-a and hypoxia is most able to mimic the in vivo changes. Using genome-wide DNase I hypersensitivity followed by sequencing, we further examined the transcriptional regulation of TNF-a-induced insulin resistance, and we found that C/EPBM-CM-^_ key regulator of adipose insulin resistance. RNA-seq for 6 insulin resistance conditions and 2 control conditions, Dnase hypersensitivity-seq of 4 conditions and 1 control condition, ChIP-seq on p65 after TNFa treatment.

2013-10-18 | E-GEOD-35724 | biostudies-arrayexpress

Cx3cl1 expression in the adipose tissue is downregulated during development of obesity

Project description:To assess changes in expression level of various chemokines and their receptors on diet-induced obesity, we analysed gene expression in adipose tissue of C56BL/6J mice fed a high-fat (HF) diet or normal chow diet for 8 weeks. HF diet-induced obese (DIO) mice showed adipose tissue inflammation and insulin resistance. Comprehensive gene expression analysis showed that MCP-1–CCR2 and CCL5–CCR5 signalling in epididymal white adipose tissue (eWAT) were enhanced during the development of obesity. Surprisingly, the gene expression of Cx3cl1 was decreased in the eWAT of DIO mice compared with lean mice. While Cx3cr1 expression showed no significant difference between DIO and lean mice. Decreased CX3CL1-CX3CR1 signalling in adipose tissue may also be involved in the development of obesity-induced adipose tissue inflammation and insulin resistance.

2021-04-01 | GSE167311 | GEO

Proteomic analysis of adipocyte insulin resistance

Project description:Insulin resistance is a major risk factor for human metabolic diseases including type 2 diabetes, cardiovascular diseases and some cancers. We analysed the proteome analyses across in vitro and in vivo models of insulin resistance to find common features of insulin resistance and identified lower expression of enzymes within the mevalonate pathway. mitochondrial CoQ was lower in all models of insulin resistance. Specifically, the coenzyme Q (CoQ) biosynthetic proteins Coq 7 and 9 were decreased in adipose tissue from a mouse model of diet-induced obesity, and mitochondrial CoQ was lower in all models of insulin resistance. Moreover, the mitochondrial content of CoQ in adipose tissue correlated positively with insulin sensitivity in obese humans. Inhibition of CoQ biosynthesis induced insulin resistance, while replenishment of CoQ restored insulin sensitivity in cell culture models and in animals, demonstrating that loss of CoQ is both necessary and sufficient for adipocyte insulin resistance. Mechanistically, loss of CoQ increased mitochondrial peroxides. These findings place defective mitochondrial CoQ homeostasis upstream of increased mitochondrial oxidants in the induction of insulin resistance in adipocytes and highlight the CoQ biosynthetic pathway as an appealing therapeutic target to combat insulin resistance.

2018-02-07 | PXD005128 | Pride

Quantitative proteomics and phosphoproteomics reveal TNF-alpha mediated downstream protein functions in hepatocytes

Project description:The increased secretion of pro-inflammatory cytokines, such as tumor necrosis factor-alpha, is often associated with adipose tissue dysregulation, which often accompanies obesity. High levels of TNF-alpha have been linked to development of insulin resistance in several tissues and organs, including skeletal muscle and the liver. In this study, we examined the complex regulatory roles of TNF-alpha in murine hepatocytes utilizing a combination of global proteomics and phosphoproteomics analyses. Our results show that TNF-alpha promotes extensive, dynamic changes not only of protein levels, but also the dynamics of their downstream phosphorylation signaling states. We provide evidence that TNF-alpha likely induces DNA replication, and promotes G1/S transition through the activation of the MAPK pathway. Our data also highlights several other novel proteins, many of which are regulated by phosphorylation and that play a role in the progression and development of insulin resistance in hepatocytes.

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Metabolic effects of cesarean section induced gut microbial dysbiosis in high-fat diet induced obese mice

Project description:The aim of this study was to investigate the causative effect of CS induced dysbiosis on obesity and insulin resistance in a high-fat diet induced obese (DIO) mouse model. Male germ-free BALB/c mice were humanized by fecal microbiota transfer using samples from children born by CS or VD and fed HFD for 16 weeks. Adipose tissue was sampled for RNAseq at study termination.

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Transcriptional responses of mouse adipocytes during insulin resistance

Project description:Insulin resistance is a sine qua non of Type 2 diabetes (T2D) and a frequent complication of multiple clinical conditions, including obesity, aging, and steroid use, among others. How such a panoply of insults can result in a common phenotype is incompletely understood. Furthermore, very little is known about the transcriptional and epigenetic basis of this disorder, despite evidence that such pathways are likely to play a fundamental role. Here, we compare cell autonomous models of insulin resistance induced by the cytokine tumor necrosis factor-a (TNF) or by the steroid dexamethasone (Dex) to construct detailed transcriptional profiles associated with cellular insulin resistance. Gene expression data from mouse adipocyte, with TNF or Dex treatments at different time points. Murine 3T3-L1 adipocytes were treated separately with dexamethasone (Dex; 20nM) or tumor necrosis factor-alpha. To comprehensively assess gene expression changes caused by Dex and TNF in a time-dependent manner, we profiled cells at early (2 hours), intermediate (24 hours), and late (6 days) points in the development of insulin resistance.

2014-12-23 | E-GEOD-62635 | biostudies-arrayexpress

Characterizing the profiles of histone markers in mouse adipocytes during insulin resistance

Project description:Insulin resistance is a sine qua non of Type 2 diabetes (T2D) and a frequent complication of multiple clinical conditions, including obesity, aging, and steroid use, among others. How such a panoply of insults can result in a common phenotype is incompletely understood. Furthermore, very little is known about the transcriptional and epigenetic basis of this disorder, despite evidence that such pathways are likely to play a fundamental role. Here, we compare cell autonomous models of insulin resistance induced by the cytokine tumor necrosis factor-a (TNF) or by the steroid dexamethasone (Dex) to construct detailed epigenomic maps associated with cellular insulin resistance. Murine 3T3-L1 adipocytes were treated separately with dexamethasone (Dex; 20nM) or tumor necrosis factor-alpha. To comprehensively assess epigenomic changes caused by Dex and TNF in a time-dependent manner, we profiled cells at early (2 hours), intermediate (24 hours), and late (6 days) points in the development of insulin resistance.

2014-12-23 | E-GEOD-58491 | biostudies-arrayexpress

Hypoxia-induced modulation of gene expression in human adipocytes - A microarray study

Project description:Obesity is characterised by expansion of white adipose tissue, accompanied by an inflamatory response. It has been proposed that the inflammatory state observed may be linked to relative hypoxia in clusters of adipocytes distant from vasculature. Adipose tissue hypoxia has been observed in both animal models and human studies in obesity, and has been linked to insulin resistance. This study has used Agilent whole-genome microarrays to examine the effects of acute hypoxia on the global gene expression in human adipocytes.

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Insulin resistance in 3T3-L1 adipose cells

Project description:3T3-L1 adipose cells were grown, differentiated and insulin resistance was stimulated by addition of TNF or treatment inlcuding chronic insulin and dexamethasone.

2018-01-31 | GSE87853 | GEO

Transcriptomic profiling of diabetic rats treated with peripherical focused ultrasound (pFUS)

Project description:To better characterize the systemic response of diabetic rats to daily hepatoportal pFUS stimulation, we conducted transcriptomic profiling of different metabolic tissues by RNAseq. For this purpose, we included samples from liver, intestines, kidney, adipose, muscle, pancreas, hypothalamus and blood in the Zucker diabetic fatty (ZDF) and diet induced obese (DIO) rodent models. ZDF rats spontaneously develop type 2 diabetes (T2D) as a result of a missense mutation (fatty, fa) in the leptin receptor gene and develop moderate hyperglycemia spontaneously as a result of the insulin resistance and pancreatic insufficiency. DIO model uses a high fat/high carbohydrate diet to induce obesity and insulin resistance. Following development of obesity low dose streptozotocin (STZ) is used to induce a moderate level of pancreatic beta cell death which impairs insulin secretion similar to that seen in later stage T2D. Tissue samples were processed and analyzed after 3 days, 4 weeks, and 7 weeks of 3 minute per day pFUS treatments. All procedures performed were done in accordance with the National Institutes of Health (NIH) Guidelines under protocols approved by the Institutional Animal Care and Use Committee (IACUC) of GE Global Research.

2022-03-31 | GSE197097 | GEO

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