The developmental and metabolic roles of the diabetes candidate gene TCF7L2 in adipose tissue
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE95029 | GEO | 2018/02/07
REPOSITORIES: GEO
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Project description:TCF7L2 is one of the strongest type 2 diabetes (T2DM) candidate genes to emerge from GWAS studies, but the mechanisms by which it regulates the pathways which are important in the pathogenesis of type 2 diabetes are unknown. Previous in vitro and in vivo studies have focused on the link between TCF7L2 and insulin secretion as an explanation for the association between TCF7L2 and T2DM. However, TCF7L2 and the Wnt/β-catenin pathway are important for metabolic zonation in the liver. This raises the interesting possibility that TCF7L2 may influence glucose homeostasis by regulating hepatic glucose production (HGP). To examine this question, we utilized the H4IIE cell as a model of HGP. Inhibition of HGP in H4IIE cells from lactate and pyruvate was highly sensitive to physiological concentrations of insulin and metformin. Silencing of TCF7L2 protein expression induced a 5-fold increase in basal HGP (P<0.0001), and this was accompanied by marked increase in the expression of several key gluconeogenic genes. FBPase, PEPCK and G6Pase mRNA were up-regulated 2.5-fold (P<0.0001), 1.4-fold (P<0.01) and 2.3-fold (P<0.0001), respectively, compared to scramble siRNA. Compared to their respective baseline values, insulin and metformin suppressed HGP equally in the scramble and TCF7L2 siRNA cells, but HGP remained elevated in TCF7L2 silenced cells due to the increased baseline HGP. Using chromatin immunoprecipitation sequencing (ChIP-Seq), we investigated the direct transcriptional targets of TCF7L2 in hepatocytes. A total of 2119 ChIP peaks were detected, of which 36% were located inside gene boundaries and, overall, a total of 65% of all binding events were within 50 Kb of a gene. De novo motif analysis revealed remarkable conservation of the long and short TCF7L2 consensus binding sites in the rat hepatocytes. Pathway analysis showed that the top two disease categories over-represented in our dataset were “non-insulin dependent diabetes” (155 genes; P = 1.63 x 10-10) and “diabetes mellitus” (245 genes; P = 7.4 x 10-12). Inspection of genes in these categories revealed that TCF7L2 directly binds to multiple genes important in the regulation of glucose metabolism in the liver, including PEPCK, FBP1, IRS1, IRS2, AKT2 ADIPOR1, PDK4 and CPT1A. Our findings suggest a novel mechanism for the regulation of HGP by TCF7L2, and provide a possible explanation for the association of TCF7L2 polymorphisms with the incidence of T2DM. two samples: TCF7L2 ChIP-Seq and Input DNA
2011-09-12 | E-GEOD-28782 | biostudies-arrayexpress
Project description:Development of insulin resistance is a key pathogenic component underlying metabolic syndrome and Type 2 diabetes (T2DM). Despite its importance, the molecular mechanisms underlying insulin resistance are poorly understood. Genome-wide association studies for T2DM and other metabolic traits have led to the identification of many candidate SNPs, but the majority of these SNPs are noncoding and determination of associated causal genes and/or specific tissue sites of action have been difficult. Adipocytes are critical regulators of mammalian metabolic homeostasis, with important effects on appetite, satiety, glucose and lipid homeostasis, energy expenditure, blood pressure, and immune function. Although insulin resistance (IR) in skeletal muscle, the major source of glucose disposal, is responsible for the bulk of the hyperglycemia observed in T2DM, muscle IR KO mice are generally healthy, IR also occurs in adipocytes, and inflammation within adipose tissue has been proposed as a primary mediator of IR, resulting in excess release of free fatty acids as well as alterations in adipokine release. Absence of adipose tissue, as observed in various lipodystrophies, or adipocyte-specific knockout of genes such as GLUT4 or insulin receptor, also alter systemic IR and T2DM risk. Transcriptional changes in adipocytes associated with metabolic disease. Despite the importance of adipocytes to metabolic disease, we have a poor understanding of how the adipocyte transcriptome changes in the disease state. Studies investigating transcriptional changes in whole adipose tissue have shown decreases in genes involved in adipogenesis, as well as alterations in inflammation, mitochondrial metabolism, lipid metabolism, detoxification, and insulin signaling. However, the vast majority of these studies use total adipose tissue samples, which does not allow for the exclusive evaluation of gene expression in mature adipocytes due to the substantial number of nonadipocyte cells (immune cells, fibroblasts, endothelial cells, pre-adipocytes, and mesenchymal cells) that also reside in adipose tissue. This is particularly relevant when studying metabolic disorders related to obesity-associated insulin resistance because these conditions are characterized by an increased influx of inflammatory cells into the adipose tissue.
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Project description:TCF7L2 is one of the strongest type 2 diabetes (T2DM) candidate genes to emerge from GWAS studies, but the mechanisms by which it regulates the pathways which are important in the pathogenesis of type 2 diabetes are unknown. Previous in vitro and in vivo studies have focused on the link between TCF7L2 and insulin secretion as an explanation for the association between TCF7L2 and T2DM. However, TCF7L2 and the Wnt/β-catenin pathway are important for metabolic zonation in the liver. This raises the interesting possibility that TCF7L2 may influence glucose homeostasis by regulating hepatic glucose production (HGP). To examine this question, we utilized the H4IIE cell as a model of HGP. Inhibition of HGP in H4IIE cells from lactate and pyruvate was highly sensitive to physiological concentrations of insulin and metformin. Silencing of TCF7L2 protein expression induced a 5-fold increase in basal HGP (P<0.0001), and this was accompanied by marked increase in the expression of several key gluconeogenic genes. FBPase, PEPCK and G6Pase mRNA were up-regulated 2.5-fold (P<0.0001), 1.4-fold (P<0.01) and 2.3-fold (P<0.0001), respectively, compared to scramble siRNA. Compared to their respective baseline values, insulin and metformin suppressed HGP equally in the scramble and TCF7L2 siRNA cells, but HGP remained elevated in TCF7L2 silenced cells due to the increased baseline HGP. Using chromatin immunoprecipitation sequencing (ChIP-Seq), we investigated the direct transcriptional targets of TCF7L2 in hepatocytes. A total of 2119 ChIP peaks were detected, of which 36% were located inside gene boundaries and, overall, a total of 65% of all binding events were within 50 Kb of a gene. De novo motif analysis revealed remarkable conservation of the long and short TCF7L2 consensus binding sites in the rat hepatocytes. Pathway analysis showed that the top two disease categories over-represented in our dataset were “non-insulin dependent diabetes” (155 genes; P = 1.63 x 10-10) and “diabetes mellitus” (245 genes; P = 7.4 x 10-12). Inspection of genes in these categories revealed that TCF7L2 directly binds to multiple genes important in the regulation of glucose metabolism in the liver, including PEPCK, FBP1, IRS1, IRS2, AKT2 ADIPOR1, PDK4 and CPT1A. Our findings suggest a novel mechanism for the regulation of HGP by TCF7L2, and provide a possible explanation for the association of TCF7L2 polymorphisms with the incidence of T2DM.
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2012-08-06 | E-GEOD-39534 | biostudies-arrayexpress
Project description:The association between central obesity and insulin resistance reflects the properties of visceral adipose tissue. Our aim was to gain further insight into this association by analysing the lipid composition of subcutaneous and omental adipose tissue in obese women with and without insulin resistance. Subcutaneous and omental adipose tissue and serum were obtained from 29 obese nondiabetic women, 13 of whom were hyperinsulinemic. Histology, and lipid and gene profiling were performed. In omental adipose tissue of obese, insulin-resistant women, adipocyte hypertrophy and macrophage infiltration were accompanied by an increase in GM3 ganglioside and its synthesis enzyme ST3GAL5; in addition, phosphatidylethanolamine (PE) lipids were increased and their degradation enzyme, PEMT, decreased. ST3GAL5 was expressed predominantly in adipose stromovascular cells and PEMT in adipocytes. Insulin resistance was also associated with an increase in PE lipids in serum. Total RNA was isolated and up to 400 ng of total RNA per sample was labelled and hybridized to Illumina HumanHT-12_V4 expression BeadChip platform. Paired subcutaneous and omental samples from 6 women were analysed.
2015-12-07 | E-GEOD-73108 | biostudies-arrayexpress
Project description:The association between central obesity and insulin resistance reflects the properties of visceral adipose tissue. Our aim was to gain further insight into this association by analysing the lipid composition of subcutaneous and omental adipose tissue in obese women with and without insulin resistance. Subcutaneous and omental adipose tissue and serum were obtained from 29 obese nondiabetic women, 13 of whom were hyperinsulinemic. Histology, and lipid and gene profiling were performed. In omental adipose tissue of obese, insulin-resistant women, adipocyte hypertrophy and macrophage infiltration were accompanied by an increase in GM3 ganglioside and its synthesis enzyme ST3GAL5; in addition, phosphatidylethanolamine (PE) lipids were increased and their degradation enzyme, PEMT, decreased. ST3GAL5 was expressed predominantly in adipose stromovascular cells and PEMT in adipocytes. Insulin resistance was also associated with an increase in PE lipids in serum.
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Project description:Lipid overload and adipocyte dysfunction are key to the development of insulin resistance and can be induced by a high-fat diet. CD1d-restricted invariant natural killer T (iNKT) cells have been proposed as mediators between lipid overload and insulin resistance, but recent studies found decreased iNKT cell numbers and marginal effects of iNKT cell depletion on insulin resistance under high-fat diet conditions. Here, we focused on the role of iNKT cells under normal conditions. We showed that iNKT cell–deficient mice on a low-fat diet, considered a normal diet for mice, displayed a distinctive insulin resistance phenotype without overt adipose tissue inflammation. Insulin resistance was characterized by adipocyte dysfunction, including adipocyte hypertrophy, increased leptin, and decreased adiponectin levels. The lack of liver abnormalities in CD1d-null mice together with the enrichment of CD1d-restricted iNKT cells in both mouse and human adipose tissue indicated a specific role for adipose tissue–resident iNKT cells in the development of insulin resistance. Strikingly, iNKT cell function was directly modulated by adipocytes, which acted as lipid antigen-presenting cells in a CD1d-mediated fashion. Based on these findings, we propose that, especially under low-fat diet conditions, adipose tissue–resident iNKT cells maintain healthy adipose tissue through direct interplay with adipocytes and prevent insulin resistance.
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2017-03-29 | MSV000080798 | MassIVE
Project description:Gestational diabetes mellitus (GDM) is considered as the early stage of type 2 diabetes mellitus. In this study, we compared the demographic and clinical data between six GDM and six NGT (healthy controls) and found the HOMA-IR was increased in GDM. Previously, many researches had proved that omental adipose tissues dysfunction could induce insulin resistance. Thus, in order to investigate the cause of the insulin resistance in GDM, label-free proteomics was used to discover differentially expressed proteins in omental adipose tissues between GDM and NGT. A total of 3529 proteins identified, including 66 significantly changed proteins. Adipocyte plasma membrane associated protein (APMAP also called C20orf3) was one of changed proteins and down regulated in GDM omental adipose tissues. Further, mature 3T3-L1 adipocytes were used to simulate omental adipocytes and we found that inhibited the expression of APMAP by RNAi would impaired the insulin signaling and activated the NFkB signaling in adipocytes. These results indicated that the decreased of APMAP in mental adipose tissues may be important in process of the insulin resistance in GDM.
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