Hepatic tissue expression profiles of insulin-sensitive obese mice, insulin-resistant mice and control mice
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1027791 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Male C57BL/6J mice were fed a high-fat diet (HFD, 60 kcal% fat, D12492, Research Diets, Inc) or normal standard chow diet with 10 kal% fat (ND, D09100304, Research Diets, Inc). Specifically, 6-week-old mice were fed a HFD for 12 weeks to induce insulin resistance (HFD-12w group); 14-week-old mice were fed a HFD for 4 weeks to induce obesity (HFD-4w group). Control mice were fed a ND continuously for 12 weeks starting at 6 weeks of age (ND group). All mice reached the experimental endpoint at 18 weeks of age. Insulin sensitivity was measured by glucose tolerance test and insulin tolerance test. Mice that developed insulin resistance in HFD-12w group and obese mice with normal insulin sensitivity in HFD-4w group were used for further experiments. Mice in ND group were used as controls. Upon reaching the experimental endpoint, livers from three insulin-resistant mice, three insulin-sensitive obese mice, and three control mice were removed for RNA sequencing.
2023-10-14 | GSE245301 | GEO
Project description:The obese people with abnormal BMI are predisposed to insulin resistance and diabetes. At the same time, human subjects with obesity and high BMI that are otherwise insulin sensitive are an interesting group to study the underlying gene expression patterns which provide them with such protective phenotype. 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. Gene expression from muscle biopsies of Lean, Obese insulin sensitive (OIS), Obese insulin resistant (OIR) and obese T2D patients (T2D) were compared for differential expression between the groups (n=7 in each group)
2015-12-15 | E-GEOD-73034 | biostudies-arrayexpress
Project description:Although aging is a physiological process to which all organisms are subject, the presence of obesity and type 2 diabetes accelerates biological aging. Recent studies have demonstrated the causal relationships between dietary interventions suppressing obesity and type 2 diabetes and delaying the onset of age-related endocrine changes. Curcumin, a natural antioxidant, has putative therapeutic properties such as reinstating insulin sensitivity in obese mice. However, how curcumin contributes to maintaining insulin homeostasis in aged organisms largely remains unclear. Thus, the objective of this study is to examine the pleiotropic effect of dietary curcumin on insulin homeostasis in a diet-induced obese (DIO) aged mouse model. Aged (18-20 months old) male mice given a high-fat high-sugar diet supplemented with curcumin displayed a different metabolic phenotype compared to mice given a high-fat high-sugar diet alone. Furthermore, curcumin supplementation altered hepatic gene expression profiling, especially insulin signaling and senescence pathways. We then mechanistically investigated how curcumin functions to fine-tune insulin sensitivity. We found that curcumin supplementation increased hepatic insulin degrading enzyme (IDE) expression levels and preserved islet integrity, both of which are beneficial during aging. Our findings suggest that the multifaceted therapeutic potential of curcumin can be used as a protective agent for age-induced metabolic diseases.
2021-11-04 | GSE186971 | GEO
Project description:The insulin inhibitory receptor (inceptor) was recently identified as a key terminator of insulin and insulin-like growth factor 1 receptor (INSR/IGF1R) signaling in pancreatic ?-cells12. Yet, the relevance of ?-cell inceptor for glucose regulation through the INS1R/IGF1R axis has only been demonstrated for normoglycemic and insulin sensitive lean mice, questioning whether inceptor regulation of INS1R/IGF1R action also plays a role in glucose metabolism under conditions of diet-induced obesity and insulin resistance. Here we demonstrate that whole-body germline loss of inceptor improves glucose metabolism in diet-induced obese mice with only minimal effects on weight and body composition. To assess the effect in different tissues we performed proteomics in the global, neuronal and beta cell specific mouse knock-outs.
2024-01-17 | PXD046256 | Pride
Project description:The obese people with abnormal BMI are predisposed to insulin resistance and diabetes. At the same time, human subjects with obesity and high BMI that are otherwise insulin sensitive are an interesting group to study the underlying gene expression patterns which provide them with such protective phenotype. 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.
2015-12-15 | GSE73034 | GEO
Project description:The flavonoid luteolin possess a variety of anti-inflammatory properties, but little has known about the detailed mechanisms linked to the anti-metabolic syndrome action of luteolin based on the integration of the transcriptional profile and the phenotype biomarkers. The aim of this study was to investigate the protective role of luteolin on inflammation-mediated metabolic diseases, focusing on its role in modulating toll-like receptor (TLR) signaling pathway triggered up-regulation of pro-inflammatory cytokines. Above all, it provides novel insights into the effect of luteolin on the link among adiposopathy, insulin resistance, hepatic steatosis and fibrosis. C57BL/6J mice were fed a normal, high-fat, and high-fat + 0.005% (w/w) luteolin diet for 16 weeks. In this study, (a) luteolin treatment resulted in an improvement in chronic low-grade inflammation by modulating TLR-signaling pathway resulting in reduced pro-inflammatory cytokines and macrophage accumulation; (b) there is a positive relationship of TLR5, MKK4/7, p38 and JNK-related gene expressions and lipogenesis in luteolin-treated obese mice, which is linked to an attenuation of hepatic lipotoxicity with an increased hepatic anti-oxidant system; (c) luteolin prevented hepatic and adipocyte fibrosis by decreasing ECM accumulation and cathepsin gene expressions; (d) Emr1 and Ccl7 genes, important markers inducing low-grade inflammation, are affected by advancing age as well as body weight, and luteolin treatment normalized those gene expressions; (e) luteolin treatment improved insulin resistance by normalizing pancreatic islet dysfunction, and differentially modulating the plasma GLP-1 and GIP levels. Taken together, luteolin ameliorates the deleterious effects of diet-induced obesity and its comorbidity.
2018-03-06 | GSE111412 | GEO
Project description:Tirzepatide (LY3298176), a dual GIP and GLP-1 receptor agonist, has been shown to deliver enhanced glycemic control and superior weight loss compared to a selective GLP-1 receptor (GLP-1R) agonist in patients with type 2 diabetes mellitus. However, the mechanism by which tirzepatide improves efficacy and how GIP receptor (GIPR) agonism contributes to the therapy is not fully understood. Here, hyperinsulinemic-euglycemic clamp studies were used to show that tirzepatide is a highly effective insulin sensitizer, improving insulin sensitivity in obese mice to a greater extent than GLP-1R agonism. To determine if GIPR agonism contributes to the insulin sensitization, we compared the effect of tirzepatide in obese wild-type and Glp-1r null mice. In the absence of GLP-1R induced weight loss, tirzepatide improved systemic insulin sensitivity by enhancing glucose disposal in WAT. To corroborate these results, chronic treatment with a long-acting GIPR agonist (LAGIPRA) was also found to enhance insulin sensitivity by increasing insulin stimulated glucose uptake in WAT. Interestingly, the effect of tirzepatide and LAGIPRA on insulin sensitivity was associated with reduced branched chain amino and keto acids in the circulation. Whole-body insulin sensitization was associated with pronounced upregulation of genes associated with the catabolism of glucose, lipid and BCAAs in brown adipose tissue. Together, our studies show that tirzepatide improved insulin sensitivity in a weight-dependent and -independent manner. These results highlight how GIPR agonism contributes to the therapeutic profile of dual GIP and GLP-1 receptor agonism, offering mechanistic insights into the clinical efficacy of tirzepatide.
2021-04-29 | GSE173522 | GEO
Project description:5 arrays from obese insulin-resistant and lean insulin-sensitive females adipose tissue at fasting and after 3h hyperinsulinemia 5 arrays from obese insulin-resistant and lean insulin-sensitive females adipose tissue at fasting and after 3h hyperinsulinemia FIR x 5, FIS x 5, HIR x 5, HIS x 5 F=fasting, H=hyperinsulinemia, IR=Insulin-resistant, IS=Insulin-sensitive (FIR, FIS, HIR, HIS)
2012-02-21 | E-GEOD-26637 | biostudies-arrayexpress
Project description:OC samples: muscle biopsy samples collected from insulin sensitive / insulin resistant obese indivduals before undergoing a hyperinsulinemic-euglycemic clamp. Subjects were previously categorized for the rate of fatty acid release from adipose tissue into the bloodstream as a measure of insuline resistance. Low-FA, Med-FA, and High-FA stand for low, medium, and high rate of release.
2017-08-02 | ST000841 | MetabolomicsWorkbench
Project description:Chronic GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese insulin resistant mice
| PRJNA725887 | ENA