RNA-seq reveals transcriptome changes which could be responsible to insulin in insulin resistance states
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE205460 | GEO | 2023/07/19
REPOSITORIES: GEO
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Project description:Objective: To study if diabetic and insulin-resistant states lead to mitochondrial dysfunction in the liver, or alternatively, if there is adaption of mitochondrial function to these states in the long-term range. Results: High-fat diet (HFD) caused insulin resistance and severe hepatic lipid accumulation, but respiratory chain parameters were unchanged. Livers from insulin-resistant IR/IRS-1+/- mice had normal lipid contents and normal respiratory chain parameters, however showed mitochondrial uncoupling. Livers from severely hyperglycemic and hypoinsulimic, streptozotocin (STZ)-treated mice had massively depleted lipid levels, but respiratory chain abundance was unchanged. However, their mitochondria showed increased abundance and activity of the respiratory chain, which was better coupled compared to controls. Conclusions: Insulin resistance, either induced by obesity or by genetic manipulation, does not cause mitochondrial dysfunction in the liver of mice. However, severe insulin deficiency and high blood glucose levels in mice cause an enhanced performance of the respiratory chain, probably in order to maintain the high energy requirement of the unsuppressed gluconeogenesis. We performed gene expression microarray analysis on liver tissue derived from mice treated with STZ or standard diet (control).
2013-12-10 | E-GEOD-39752 | biostudies-arrayexpress
Project description:Objective: To study if diabetic and insulin-resistant states lead to mitochondrial dysfunction in the liver, or alternatively, if there is adaption of mitochondrial function to these states in the long-term range. Results: High-fat diet (HFD) caused insulin resistance and severe hepatic lipid accumulation, but respiratory chain parameters were unchanged. Livers from insulin-resistant IR/IRS-1+/- mice had normal lipid contents and normal respiratory chain parameters, however showed mitochondrial uncoupling. Livers from severely hyperglycemic and hypoinsulimic, streptozotocin (STZ)-treated mice had massively depleted lipid levels, but respiratory chain abundance was unchanged. However, their mitochondria showed increased abundance and activity of the respiratory chain, which was better coupled compared to controls. Conclusions: Insulin resistance, either induced by obesity or by genetic manipulation, does not cause mitochondrial dysfunction in the liver of mice. However, severe insulin deficiency and high blood glucose levels in mice cause an enhanced performance of the respiratory chain, probably in order to maintain the high energy requirement of the unsuppressed gluconeogenesis.
2013-12-10 | GSE39752 | GEO
Project description:Recent discovery reveals HFD insult can cause insulin resistance very rapidly, but the underlying mechanism is still not well understood. We performed a short term experiment in a Diet Induced Insulin resistance mouse model. Objective: Insulin resistance (IR) is one of the earliest predictors of type 2 diabetes. However, diagnosis of IR is limited. High fat fed mouse models provide key insights into IR. We hypothesized that early features of IR are associated with persistent changes in gene expression (GE) and endeavoured to (a) develop novel methods for improving signal:noise in analysis of human GE using mouse models; (b) identify a GE motif that accurately diagnoses IR in humans; and (c) identify novel biology associated with IR in humans. Methods: We integrated human muscle GE data with longitudinal mouse GE data and developed an unbiased three-level cross-species analysis platform (single-gene, gene-set and networks) to generate a gene expression motif (GEM) indicative of IR. A logistic regression classification model validated GEM in 3 independent human datasets (n =115). Results: This GEM of 93 genes substantially improved diagnosis of IR compared to routine clinical measures across multiple independent datasets. Individuals misclassified by GEM possessed other metabolic features raising the possibility that they represent a separate metabolic subclass. The GEM was enriched in pathways previously implicated in insulin action and revealed novel associations between β-catenin and Jak1 and IR. Functional analyses using small molecule inhibitors showed an important role for these proteins in insulin action. Conclusions: This study shows that systems approaches for identifying molecular signatures provides a powerful way to stratify individuals into discrete metabolic groups. Moreover, we speculate that the β-catenin pathway may represent a novel biomarker for IR in humans that warrant future investigation. Comparison of gene expression in muscle tissue during High Fat Diet (HFD) time course (day 5 and day 42). Chow diet will serve as control for HFD. 4 samples per group serve as experimental replicates.
2015-12-07 | E-GEOD-73036 | biostudies-arrayexpress
Project description:Skeletal muscle insulin resistance is a prominent early feature in the pathogenesis of type 2 diabetes (T2D). In attempt to overcome this defect, we generated mice overexpressing insulin receptors (IR) specifically in skeletal muscle (IRMOE). On normal chow, IRMOE mice have similar body weight as controls, but an increase in lean mass and glycolytic muscle fibers and reduced fat mass. IRMOE mice also show higher basal phosphorylation of IR, IRS-1 and Akt in muscle and improved glucose tolerance compared to controls. When challenged with high fat diet (HFD), IRMOE mice are protected from diet-induced obesity. This is associated with reduced inflammation in fat and liver, improved glucose tolerance and improved systemic insulin sensitivity. Surprisingly, however, in both chow and HFD-fed mice, insulin stimulated Akt phosphorylation is significantly reduced in muscle of IRMOE mice, indicating post-receptor insulin resistance. RNA sequencing reveals downregulation of several post-receptor signaling proteins that contribute to this resistance. Thus, enhancing early insulin signaling in muscle by overexpression of the insulin receptor protects mice from diet-induced obesity and its effects on glucose metabolism. However, chronic overstimulation of this pathway leads to post-receptor desensitization, indicating the critical balance between normal signaling and hyperstimulation of the insulin signaling pathway.
2020-09-01 | GSE149662 | GEO
Project description:We developed a novel network inference approach, Biologically Anchored Knowledge Expansion (BAKE), to analyze large volume gene expression data obtained from a mouse model of insulin resistance progression. Both genetic aspects and dietary factors, specifically high caloric high-fat high-sugar diets, contribute to the progression of insulin resistance. To mimic genetic predisposition, we used a mouse model with double heterozygous deletion of early insulin signaling pathway intermediates, insulin receptor (IR) and insulin receptor substrate 1 (IRS1) genes. These mice were fed with high-fat (Western) or low-fat (Chow) diet for 8 and 16 weeks starting at 8 weeks of age. Gene expression data was collected from adipocytes isolated from these mice. Applying BAKE analysis to the adipocyte gene expression data, we demonstrate that we can accurately discover a novel regulatory gene in the insulin signaling pathway. The mouse model of double heterozygous deletion of insulin receptor (IR) and insulin receptor substrate 1 (IRS1) was originally introduced as a polygenic model to study the development of type 2 diabetes. This mouse model, on an atherosclerosis-prone ApoE null background (IR+/- IRS1+/- ApoE-/-), also shows increased atherosclerotic lesions due to impaired insulin signaling. For our study we used female double heterozygous mice (IR+/- IRS1+/-, 'Dhet' mice or 'Dâ mice) on an ApoE null background (ApoE-/-, âEâ) fed with a Western (high-fat) diet for 8 (DW8, n=5) and 16 (DW16, n=9) weeks starting at 8 weeks of age or with a Chow (low-fat) diet (DC8, n=7; DC16, n=5). There were also ApoE null mice (ApoE-/-, 'Eâ) fed either Western diet for 8 (EW8, n=6) and 16 (EW16, n=8) weeks or Chow diet for 16 weeks (EC16, n=5) starting at 8 weeks of age.
2015-12-31 | E-GEOD-76428 | biostudies-arrayexpress
Project description:Recent discovery reveals HFD insult can cause insulin resistance very rapidly, but the underlying mechanism is still not well understood. We performed a short term experiment in a Diet Induced Insulin resistance mouse model. Objective: Insulin resistance (IR) is one of the earliest predictors of type 2 diabetes. However, diagnosis of IR is limited. High fat fed mouse models provide key insights into IR. We hypothesized that early features of IR are associated with persistent changes in gene expression (GE) and endeavoured to (a) develop novel methods for improving signal:noise in analysis of human GE using mouse models; (b) identify a GE motif that accurately diagnoses IR in humans; and (c) identify novel biology associated with IR in humans. Methods: We integrated human muscle GE data with longitudinal mouse GE data and developed an unbiased three-level cross-species analysis platform (single-gene, gene-set and networks) to generate a gene expression motif (GEM) indicative of IR. A logistic regression classification model validated GEM in 3 independent human datasets (n =115). Results: This GEM of 93 genes substantially improved diagnosis of IR compared to routine clinical measures across multiple independent datasets. Individuals misclassified by GEM possessed other metabolic features raising the possibility that they represent a separate metabolic subclass. The GEM was enriched in pathways previously implicated in insulin action and revealed novel associations between β-catenin and Jak1 and IR. Functional analyses using small molecule inhibitors showed an important role for these proteins in insulin action. Conclusions: This study shows that systems approaches for identifying molecular signatures provides a powerful way to stratify individuals into discrete metabolic groups. Moreover, we speculate that the β-catenin pathway may represent a novel biomarker for IR in humans that warrant future investigation.
2015-12-07 | GSE73036 | GEO
Project description:We report that a high affinity, selective, small molecule Gpr120 agonist (cpdA), exerts potent anti-inflammatory effects on macrophages in vitro, and in obese mice in vivo. Gpr120 agonist treatment of high fat diet (HFD)/obese mice causes improved glucose tolerance, decreased hyperinsulinemia, increased insulin sensitivity and decreased hepatic steatosis. This suggests that Gpr120 agonists could become new insulin sensitizing drugs for the treatment of Type 2 diabetes and other human insulin resistant states in the future. Examination of effects of DHA and compound A on primary macrophages stimulated by LPS, 3 replicates for each condition
2014-06-07 | E-GEOD-58282 | biostudies-arrayexpress
Project description:We have performed gene expression microarray analysis to profile transcriptomic signatures between insulin resistance high risk subjects and insulin resistance low risk subjects Participants enrolled in this study were recruited in the overnight fasted state, then the collection and processing of glucose (fasting, 30, 60 and 120 minutes) and insulin from blood samples, hemoglobin A1c (HbA1c) , assessment of medical history, socio-demographic characteristics, lifestyle factors, blood pressure and anthropometric and body composition measurements were conducted. During baseline visit, participants were asked to refrain from eating, drinking and oral hygiene procedures for at least 1-hour prior to saliva collection.5 ml of unstimulated whole saliva samples were consistently collected, stabilized and preserved, the sample supernatants were reserved at -80°C prior to assay. Based on the homeostasis model assessment of insulin resistance (HOMA-IR), using the formula [HOMA-IR= (fasting glucose*fasting insulin)/405], participants were divided into 2 groups: IR high risk group (HOMA-IR value ?2.5) and IR low risk group (HOMA-IR value <2.5). Total RNA was extracted from saliva and subjected to gene expression microarray analysis using Affymetrix human genome 2.0 plus array
2015-04-10 | E-GEOD-67738 | biostudies-arrayexpress
Project description:The aim of this study is to define the molecular alterations occurring in human adipose tissue leading to its dysfunction. While obesity (defined by BMI>30) is strongly associated with insulin resistance and metabolic disorders, some individuals with obesity remain insulin sensitive. Therefore, in this study, we have considered a control group (lean, insuln sensitive: BMI<25, HOMA-IR<2), a group with overweight/obesity but without insulin resistance (BMI>25, HOMA-IR<2) and a group with overweight and insulin resistance (BMI>25, HOMA-IR>3) to dissect the transcriptional changes in viscreal adipose tissue due to increased fat mass, and those associated with metabolic disorder.
2021-02-28 | GSE165932 | GEO
Project description:Cyclic AMP-responsive element-binding protein H (CREBH, encoded by Creb3l3) is a transcription factor that regulates the expression of genes that control lipid and glucose metabolism, as well as inflammation. CREBH is upregulated in the liver under conditions of overnutrition, and mice globally lacking the gene (CREBH-/-) are highly susceptible to diet-induced obesity, insulin resistance (IR) and hepatic steatosis. The net protective effects of CREBH have been attributed in large part to the activities of Fibroblast growth factor (Fgf)-21 (Fgf21), a target gene that promotes weight loss, improves glucose homeostasis and reduces hepatic lipid accumulation. To explore the possibility that activation of the CREBH-Fgf21 axis could ameliorate established effects of high fat feeding, we generated an inducible transgenic hepatocyte-specific CREBH overexpression mouse model (Tg-rtTA). Acute overexpression of CREBH in livers of Tg-rtTA mice effectively reversed diet-induced obesity, IR and hepatic steatosis. These changes were associated with increased activities of thermogenic brown and beige adipose tissues in Tg-rtTA mice, leading to reductions in fat mass, along with enhanced insulin sensitivity and glucose tolerance. Genetically silencing of Fgf21 in Tg-rtTA mice abrogated the CREBH-mediated reductions in body weight loss, but only partially reversed the observed improvements in glucose metabolism. These findings reveal that the protective effects of CREBH activation may be leveraged to mitigate diet-induced obesity and associated metabolic abnormalities in both Fgf21-dependent and -independent pathways.
2021-04-30 | GSE173548 | GEO