Altered DNA methylation of glycolytic and lipogenic genes in liver from obese and type 2 diabetic patients
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE65058 | GEO | 2016/03/08
SECONDARY ACCESSION(S): PRJNA272808
REPOSITORIES: GEO
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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 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. 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 | GSE64998 | GEO
Project description:Altered DNA methylation of glycolytic and lipogenic genes in liver from obese and type 2 diabetic patients
| PRJNA272808 | ENA
Project description:Type 2 diabetes mellitus (T2DM) is associated with a high incidence of non-alcoholic fatty liver disease (NAFLD) related to obesity and insulin resistance. Currently, medical interventions for NAFLD have focused on diet control and exercise to reduce body weight, and there is a requirement for effective pharmacological therapies. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are oral antidiabetic drugs that promote the urinary excretion of glucose by blocking its reabsorption in renal proximal tubules. SGLT2 inhibitors lower blood glucose independent of insulin action and are expected to reduce body weight because of urinary calorie loss. Here we show that an SGLT2 inhibitor ipragliflozin improves hepatic steatosis in high-fat diet-induced and leptin-deficient (ob/ob) obese mice irrespective of body weight reduction. In the obese mice, ipragliflozin-induced hyperphagia occurred to increase energy intake, attenuating body weight reduction with increased epididymal fat mass. There is an inverse correlation between weights of liver and epididymal fat in ipragliflozin-treated obese mice, suggesting that ipragliflozin treatment promotes normotopic fat accumulation in the epididymal fat and prevents ectopic fat accumulation in the liver. Despite increased adiposity, ipragliflozin ameliorates obesity-associated inflammation and insulin resistance in epididymal fat. Clinically, ipragliflozin improves liver dysfunction in patients with T2DM irrespective of body weight reduction. These findings provide new insight into the effects of SGLT2 inhibitors on energy homeostasis and fat accumulation and indicate their potential therapeutic efficacy in T2DM-associated hepatic steatosis.
| S-EPMC4792392 | biostudies-literature
Project description:Macrophages have been recognized as key players in non-alcoholic fatty liver disease (NAFLD). Our aim was to assess whether pharmacological attenuation of macrophages can be achieved by imatinib, an anti-leukemia drug with known anti-inflammatory and anti-diabetic properties, and how this impacts on NAFLD. We analyzed the pro- and anti-inflammatory gene expression of murine macrophages and human monocytes in vitro in the presence or absence of imatinib. In a time-resolved study, we characterized metabolic disease manifestations such as hepatic steatosis, systemic and adipose tissue inflammation as well as lipid and glucose metabolism in obese mice at one and three months of imatinib treatment. Our results showed that imatinib lowered pro-inflammatory markers in murine macrophages and human monocytes in vitro. In obese mice, imatinib reduced TNFα-gene expression in peritoneal and liver macrophages and systemic lipid levels at one month. This was followed by decreased hepatic steatosis, systemic and adipose tissue inflammation and increased insulin sensitivity after three months. As the transcription factor sterol regulatory element-binding protein (SREBP) links lipid metabolism to the innate immune response, we assessed the gene expression of SREBPs and their target genes, which was indeed downregulated in the liver and partially in peritoneal macrophages. In conclusion, targeting both inflammatory and lipogenic pathways in macrophages and liver as shown by imatinib could represent an attractive novel therapeutic strategy for patients with NAFLD.
| S-EPMC6193017 | biostudies-literature
Project description:Obesity and type 2 diabetes (T2D) are associated with low-grade inflammation, activation of immune cells, and alterations of the gut microbiota. Mucosal-associated invariant T (MAIT) cells, which are innate-like T cells that recognize bacterial ligands, are present in blood and enriched in mucosal and inflamed tissues. Here, we analyzed MAIT cells in the blood and adipose tissues of patients with T2D and/or severe obesity. We determined that circulating MAIT cell frequency was dramatically decreased in both patient groups, and this population was even undetectable in some obese patients. Moreover, in both patient groups, circulating MAIT cells displayed an activated phenotype that was associated with elevated Th1 and Th17 cytokine production. In obese patients, MAIT cells were more abundant in adipose tissue than in the blood and exhibited a striking IL-17 profile. Bariatric surgery in obese patients not only improved their metabolic parameters but also increased circulating MAIT cell frequency at 3 months after surgery. Similarly, cytokine production by blood MAIT cells was strongly decreased after surgery. This study reveals profound MAIT cell abnormalities in patients harboring metabolic disorders, suggesting their potential role in these pathologies.
| S-EPMC4396481 | biostudies-literature
Project description:To address the possible involvement of VGF peptides in obesity and diabetes, we studied type 2 diabetes (T2D) and obese patients, and high-fat diet induced obese mice. Two VGF peptides (NAPP-19 and QQET-30) were identified in human plasma by HPLC-ESI-MS. The VGF C-terminus, the above two cleaved peptides, and the TLQP-21 related peptide/s were studied using ELISA and immunohistochemistry. In euglycemic patients, plasma NAPPE and TLQP like peptides were significantly reduced with obesity (74±10 vs. 167±28, and 92±10 vs. 191±19 pmol/ml, mean+SEM, n = 10 and 6, obese vs. normal BMI, respectively, p<0.03). Upon a standard glucose load, a distinct response was shown for VGF C-terminus, TLQP and QQET-like (ERVW immunoreactive) peptides in euglycemic normal BMI patients, but was virtually abolished in euglycemic obese, and in T2D patients independently of BMI. High-fat diet induced obese mice showed reduced plasma VGF C-terminus, NAPPE and QQET-like (ERVW) peptide/s (3±0.2 vs. 4.6±0.3, 22±3.5 vs. 34±1.3, and 48±7 vs. 100±7 pmol/ml, mean+SEM, n = 8/group, obese vs. slim, respectively, p<0.03), with a loss of the response to glucose for all VGF peptides studied. In immunohistochemistry, TLQP and/or VGF C-terminus antibodies labelled VGF containing perikarya in mouse celiac ganglia, pancreatic islet cells and thin beaded nerve fibres in brown adipose tissues, with fewer in white adipose tissue. Upon the glucose load, tyrosine hydroxylase and VGF C-terminus immunoreactive axons became apparent in pancreatic islets of slim animals, but not in obese animals. Alltogether, a significant loss of VGF peptide immunoreactivity and/or their response to glucose was demonstrated in obese patients, with or without T2D, in parallel with a similar loss in high-fat diet induced obese mice. An involvement of VGF in metabolic regulations, including those of brown and/or white adipose tissues is underlined, and may point out specific VGF peptides as potential targets for diagnosis and/or treatment.
| S-EPMC4643017 | biostudies-literature
Project description:BackgroundNon-obese non-alcoholic fatty liver disease (NAFLD) has been reported to share clinical outcomes with its obese counterpart in the general population. However, conflicting results have been observed regarding the cardio-metabolic risk profile of non-obese NAFLD as compared to obese NAFLD. Moreover, in the context of type 2 diabetes mellitus (T2DM), this issue has been even less addressed. We hence aimed to examine the association of NAFLD with the cardio-metabolic risk profile in patients with T2DM according to their obesity status.MethodsA total of 2,708 patients with T2DM who were hospitalized between June 2018 and May 2021 were cross-sectionally assessed.ResultsThe prevalence of NAFLD was 49.3%. NAFLD was found in 34.1% of non-obese patients and 66.0% of obese patients. Non-obese NAFLD patients had more and worse metabolic disorders than obese patients without NAFLD in both men and women. Comparable cardio-metabolic risk profiles were noted between non-obese and obese NAFLD subjects. The associations of worse cardio-metabolic risk profiles with NAFLD were overall stronger in non-obese than in obese subjects among women with T2DM, while more pronounced in obese than in non-obese subjects among men with T2DM.ConclusionIn patients with T2DM, non-obese NAFLD had no better cardio-metabolic risk profile than obese NAFLD. The associations of metabolic disorders with NAFLD were stronger in non-obese than in obese patients in women patients with T2DM.
| S-EPMC9569122 | biostudies-literature