Altered DNA methylation of glycolytic and lipogenic genes in liver from obese and type 2 diabetic patients
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PROVIDER: PRJNA272808 | ENA |
REPOSITORIES: ENA
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Project description:Type 2 diabetes is a complex disease associated with many underlying pathomechanisms. Epigenetic regulation of gene expression by DNA methylation has become increasingly recognized as an important component in the etiology of type 2 diabetes. We performed genome-wide methylome and transcriptome analysis in liver from severely obese patients with or without type 2 diabetes to discover aberrant pathways underlying the development of insulin resistance. We identified hypomethylation of five key genes involved in hepatic glycolysis, de novo lipogenesis and insulin resistance with concomitant increased mRNA expression and protein content. The CpG-site within the ATF-motif was hypomethylated in four of these genes in liver of non-diabetic and type 2 diabetic obese patients, suggesting epigenetic regulation of transcription by altered ATF-DNA binding. In conclusion, severely obese non-diabetic and type 2 diabetic patients have distinct alterations in the hepatic methylome and transcriptome and genes controlling glucose and lipid metabolism are hypomethylated at a regulatory site. Thus, obesity may epigenetically reprogram the liver towards increased lipid production and exacerbate the development of insulin resistance. To better understand the molecular mechanisms underlying the development of hepatic insulin resistance and type 2 diabetes at a molecular level, we performed a genome-wide methylome and transcriptome analysis of liver from non-obese metabolically healthy, obese non-diabetic and obese type 2 diabetic patients. Distinct DNA methylation and gene expression profiles were identified in liver from the obese and type 2 diabetic patients compared with the non-obese participants.
2016-03-08 | E-GEOD-64998 | biostudies-arrayexpress
Project description:Type 2 diabetes is a complex disease associated with many underlying pathomechanisms. Epigenetic regulation of gene expression by DNA methylation has become increasingly recognized as an important component in the etiology of type 2 diabetes. We performed genome-wide methylome and transcriptome analysis in liver from severely obese patients with or without type 2 diabetes to discover aberrant pathways underlying the development of insulin resistance. We identified hypomethylation of five key genes involved in hepatic glycolysis, de novo lipogenesis and insulin resistance with concomitant increased mRNA expression and protein content. The CpG-site within the ATF-motif was hypomethylated in four of these genes in liver of non-diabetic and type 2 diabetic obese patients, suggesting epigenetic regulation of transcription by altered ATF-DNA binding. In conclusion, severely obese non-diabetic and type 2 diabetic patients have distinct alterations in the hepatic methylome and transcriptome and genes controlling glucose and lipid metabolism are hypomethylated at a regulatory site. Thus, obesity may epigenetically reprogram the liver towards increased lipid production and exacerbate the development of insulin resistance.
2016-03-08 | GSE65057 | GEO
Project description:Type 2 diabetes is a complex disease associated with many underlying pathomechanisms. Epigenetic regulation of gene expression by DNA methylation has become increasingly recognized as an important component in the etiology of type 2 diabetes. We performed genome-wide methylome and transcriptome analysis in liver from severely obese patients with or without type 2 diabetes to discover aberrant pathways underlying the development of insulin resistance. We identified hypomethylation of five key genes involved in hepatic glycolysis, de novo lipogenesis and insulin resistance with concomitant increased mRNA expression and protein content. The CpG-site within the ATF-motif was hypomethylated in four of these genes in liver of non-diabetic and type 2 diabetic obese patients, suggesting epigenetic regulation of transcription by altered ATF-DNA binding. In conclusion, severely obese non-diabetic and type 2 diabetic patients have distinct alterations in the hepatic methylome and transcriptome and genes controlling glucose and lipid metabolism are hypomethylated at a regulatory site. Thus, obesity may epigenetically reprogram the liver towards increased lipid production and exacerbate the development of insulin resistance.
2016-03-08 | GSE64998 | GEO
Project description:Obesity is a strong risk factor for the development of type 2 diabetes. We have previously reported that in adipose tissue of obese (ob/ob) mice, the expression of adipogenic genes is decreased. When made genetically obese, the BTBR mouse strain is diabetes susceptible and the C57BL/6J (B6) strain is diabetes resistant. We used DNA microarrays and RT-PCR to compare the gene expression in BTBR-ob/ob versus B6-ob/ob mice in adipose tissue, liver, skeletal muscle, and pancreatic islets. Our results show: 1) there is an increased expression of genes involved in inflammation in adipose tissue of diabetic mice; 2) lipogenic gene expression was lower in adipose tissue of diabetes-susceptible mice, and it continued to decrease with the development of diabetes, compared with diabetes-resistant obese mice; 3) hepatic expression of lipogenic enzymes was increased and the hepatic triglyceride content was greatly elevated in diabetes-resistant obese mice; 4) hepatic expression of gluconeogenic genes was suppressed at the prediabetic stage but not at the onset of diabetes; and 5) genes normally not expressed in skeletal muscle and pancreatic islets were expressed in these tissues in the diabetic mice. We propose that increased hepatic lipogenic capacity protects the B6-ob/ob mice from the development of type 2 diabetes. Diabetes 52:688–700, 2003 Keywords: Genetic modifications
2005-07-12 | GSE2899 | GEO
Project description:ObjectiveEpigenetic modifications contribute to the etiology of type 2 diabetes.MethodWe performed genome-wide methylome and transcriptome analysis in liver from severely obese men with or without type 2 diabetes and non-obese men to discover aberrant pathways underlying the development of insulin resistance. Results were validated by pyrosequencing.ResultWe identified hypomethylation of genes involved in hepatic glycolysis and insulin resistance, concomitant with increased mRNA expression and protein levels. Pyrosequencing revealed the CpG-site within ATF-motifs was hypomethylated in four of these genes in liver of severely obese non-diabetic and type 2 diabetic patients, suggesting epigenetic regulation of transcription by altered ATF-DNA binding.ConclusionSeverely obese non-diabetic and type 2 diabetic patients have distinct alterations in the hepatic methylome and transcriptome, with hypomethylation of several genes controlling glucose metabolism within the ATF-motif regulatory site. Obesity appears to shift the epigenetic program of the liver towards increased glycolysis and lipogenesis, which may exacerbate the development of insulin resistance.
| S-EPMC4770265 | biostudies-literature
Project description:Type 2 diabetes mellitus (TM) is a severely metabolic disorder that affects above 10% worldwide population. Obesity is a major cause of insulin resistance and contributes to the development of TM. Liver is an essential metabolic organ that plays crucial roles in the pathogenesis of obesity and diabetes. However, the underlying mechanisms of liver in the transition of obesity to diabetes are not fully understood. Nonhuman primate (NHP) rhesus monkey is an appropriate animal for research of human diseases. Here, we first screened and selected three individual spontaneous and diabetic rhesus monkeys. Interestingly, the diabetic monkeys were obese with high BMI at beginning, but gradually lost their body weight during one-year observation. Furthermore, we performed a SILAC-based quantitative proteomics to identify proteins and signaling pathways with altered expression in the liver of obese and diabetic monkeys. Totally, 3509 proteins were identified and quantified, and of which 185 proteins displayed altered expression level. GO analysis revealed that the expression of proteins involved in fatty acids β-oxidation and galactose metabolism was increased in obese monkeys; while proteins involved in oxidative phosphorylation (OXPHOS) and branched chain amino acid (BCAA) degradation was upregulated in diabetic monkeys. In addition, we observed a mild impaired mitophagy and apoptosis in the liver of diabetic monkeys, suggesting a dysfunction of mitochondria and liver injury in the late onset of diabetics. Taken together, our liver proteomics may reveal a distinct metabolic transition from fatty acids β-oxidation in obese monkey to BCAA degradation in diabetic monkeys.
2019-08-26 | PXD008825 | Pride
Project description:Obesity is a strong risk factor for the development of type 2 diabetes. We have previously reported that in adipose tissue of obese (ob/ob) mice, the expression of adipogenic genes is decreased. When made genetically obese, the BTBR mouse strain is diabetes susceptible and the C57BL/6J (B6) strain is diabetes resistant. We used DNA microarrays and RT-PCR to compare the gene expression in BTBR-ob/ob versus B6-ob/ob mice in adipose tissue, liver, skeletal muscle, and pancreatic islets. Our results show: 1) there is an increased expression of genes involved in inflammation in adipose tissue of diabetic mice; 2) lipogenic gene expression was lower in adipose tissue of diabetes-susceptible mice, and it continued to decrease with the development of diabetes, compared with diabetes-resistant obese mice; 3) hepatic expression of lipogenic enzymes was increased and the hepatic triglyceride content was greatly elevated in diabetes-resistant obese mice; 4) hepatic expression of gluconeogenic genes was suppressed at the prediabetic stage but not at the onset of diabetes; and 5) genes normally not expressed in skeletal muscle and pancreatic islets were expressed in these tissues in the diabetic mice. We propose that increased hepatic lipogenic capacity protects the B6-ob/ob mice from the development of type 2 diabetes. Diabetes 52:688â700, 2003 Experiment Overall Design: Four B6-ob/ob and four BTBR-ob/ob male mice at 14 weeks of age were used in the microarray study. RNA samples from two individuals were pooled for each tissue, and each pooled RNA sample was applied to an Affymetrix MGU74AV2 array. Because of the scarcity of islets in the BTBR-ob/ob mice, 4 additional mice were pooled to obtain islet RNA from these animals. Sixteen MGU74Av2 arrays (2 strains X 4 tissues X 2 replicates = 16 arrays) were used to monitor the expression level of â12,000 genes or ESTs.
2007-08-31 | E-GEOD-2899 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below.
2016-03-08 | GSE65058 | GEO
Project description:The current project is within the range of molecular immunogenetic auto immune diseases and refers to the comparative study of promiscuous gene expression of tissue-specific antigens (TSAs) in the thymus of NOD mice line (non obese diabetic) who plays the auto-immune diabetes mellitus type 1, during the transition from state pre-diabetics to diabetics. Use the technology of oligo arrays to investigate the expression of miRNAs and cDNA microarrays to investigate the expression of genes encoding the messenger RNAs including TSAs (tissue specific antigens).
2009-10-10 | E-MEXP-2245 | biostudies-arrayexpress
Project description:The overall goal of this studyis to compare the transcription differences of epicardial adipose tissue between between lean and obese and Type 2 diabetic individuals
2021-07-30 | GSE179455 | GEO