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1.
Mol Metab ; 75: 101774, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37429525

RESUMO

OBJECTIVES: Better disease management can be achieved with earlier detection through robust, sensitive, and easily accessible biomarkers. The aim of the current study was to identify novel epigenetic biomarkers determining the risk of type 2 diabetes (T2D). METHODS: Livers of 10-week-old female New Zealand Obese (NZO) mice, slightly differing in their degree of hyperglycemia and liver fat content and thereby in their diabetes susceptibility were used for expression and methylation profiling. We screened for differences in hepatic expression and DNA methylation in diabetes-prone and -resistant mice, and verified a candidate (HAMP) in human livers and blood cells. Hamp expression was manipulated in primary hepatocytes and insulin-stimulated pAKT was detected. Luciferase reporter assays were conducted in a murine liver cell line to test the impact of DNA methylation on promoter activity. RESULTS: In livers of NZO mice, the overlap of methylome and transcriptome analyses revealed a potential transcriptional dysregulation of 12 hepatokines. The strongest effect with a 52% decreased expression in livers of diabetes-prone mice was detected for the Hamp gene, mediated by elevated DNA methylation of two CpG sites located in the promoter. Hamp encodes the iron-regulatory hormone hepcidin, which had a lower abundance in the livers of mice prone to developing diabetes. Suppression of Hamp reduces the levels of pAKT in insulin-treated hepatocytes. In liver biopsies of obese insulin-resistant women, HAMP expression was significantly downregulated along with increased DNA methylation of a homologous CpG site. In blood cells of incident T2D cases from the prospective EPIC-Potsdam cohort, higher DNA methylation of two CpG sites was related to increased risk of incident diabetes. CONCLUSIONS: We identified epigenetic changes in the HAMP gene which may be used as an early marker preceding T2D.


Assuntos
Diabetes Mellitus Tipo 2 , Hepcidinas , Humanos , Feminino , Camundongos , Animais , Hepcidinas/genética , Hepcidinas/metabolismo , Metilação de DNA , Diabetes Mellitus Tipo 2/metabolismo , Estudos Prospectivos , Insulina/metabolismo , Obesidade/genética , Biomarcadores/metabolismo , Células Sanguíneas/metabolismo
2.
Nat Commun ; 14(1): 3312, 2023 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-37286550

RESUMO

Mutations in thyroid hormone receptor α1 (TRα1) cause Resistance to Thyroid Hormone α (RTHα), a disorder characterized by hypothyroidism in TRα1-expressing tissues including the heart. Surprisingly, we report that treatment of RTHα patients with thyroxine to overcome tissue hormone resistance does not elevate their heart rate. Cardiac telemetry in male, TRα1 mutant, mice indicates that such persistent bradycardia is caused by an intrinsic cardiac defect and not due to altered autonomic control. Transcriptomic analyses show preserved, thyroid hormone (T3)-dependent upregulation of pacemaker channels (Hcn2, Hcn4), but irreversibly reduced expression of several ion channel genes controlling heart rate. Exposure of TRα1 mutant male mice to higher maternal T3 concentrations in utero, restores altered expression and DNA methylation of ion channels, including Ryr2. Our findings indicate that target genes other than Hcn2 and Hcn4 mediate T3-induced tachycardia and suggest that treatment of RTHα patients with thyroxine in high dosage without concomitant tachycardia, is possible.


Assuntos
Síndrome da Resistência aos Hormônios Tireóideos , Tiroxina , Masculino , Animais , Camundongos , Tiroxina/uso terapêutico , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética , Síndrome da Resistência aos Hormônios Tireóideos/genética , Hormônios Tireóideos , Receptores alfa dos Hormônios Tireóideos/genética , Receptores alfa dos Hormônios Tireóideos/metabolismo , Mutação , Taquicardia/genética
3.
Int J Mol Sci ; 24(7)2023 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-37047391

RESUMO

De novo lipogenesis (DNL) in visceral adipose tissue (VAT) is associated with systemic insulin sensitivity. DNL in VAT is regulated through ChREBP activity and glucose uptake through Glut4 (encoded by Slc2a4). Slc2a4 expression, ChREBP activity, and DNL are decreased in obesity, the underlying cause however remains unidentified. We hypothesize that increased DNA methylation in an enhancer region of Slc2a4 decreases Slc2a4 expression in obesity and insulin resistance. We found that SLC2A4 expression in VAT of morbidly obese subjects with high HbA1c (>6.5%, n = 35) is decreased, whereas DNA methylation is concomitantly increased compared to morbidly obese subjects with low HbA1c (≤6.5%, n = 65). In diet-induced obese (DIO) mice, DNA methylation of Slc2a4 persistently increases with the onset of obesity and insulin resistance, while gene expression progressively decreases. The regulatory impact of DNA methylation in the investigated enhancer region on SLC2A4 gene expression was validated with a reporter gene assay. Additionally, treatment of 3T3 pre-adipocytes with palmitate/oleate during differentiation decreased DNA methylation and increased Slc2a4 expression. These findings highlight a potential regulation of Slc2a4 by DNA methylation in VAT, which is induced by fatty acids and may play a role in the progression of obesity and insulin resistance in humans.


Assuntos
Resistência à Insulina , Insulinas , Obesidade Mórbida , Camundongos , Animais , Humanos , Resistência à Insulina/genética , Ácidos Graxos/metabolismo , Metilação de DNA , Obesidade Mórbida/metabolismo , Gordura Intra-Abdominal/metabolismo , Hemoglobinas Glicadas , Fatores de Transcrição/metabolismo , Insulinas/genética , Tecido Adiposo/metabolismo , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo
4.
J Nutr Biochem ; 100: 108907, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34801693

RESUMO

DNA methylation is dynamically regulated in metabolic diseases, but it remains unclear whether the changes are causal or consequential. Therefore, we used a longitudinal approach to refine the onset of metabolic and DNA methylation changes at high temporal resolution. Male C57BL/6N mice were fed with 60 % high-fat diet (HFD) for up to 12 weeks and metabolically characterized weekly. Liver was collected after 1, 2, 4, 5, 6, 7, 8, and 12 weeks and hepatic DNA methylation and gene expression were analyzed. A subset of obese mice underwent vertical sleeve gastrectomy (VSG) or metformin treatment and livers were studied. Distinct hepatic gene expression patterns developed upon feeding HFD, with genes from the fatty acid metabolism pathway being predominantly altered. When comparing metabolic data with gene expression and DNA methylation, in particular Fgf21 DNA methylation decreased before the onset of increased Fgf21 expression and metabolic changes. Neither weight loss induced by VSG nor improved glucose tolerance by metformin treatment could revert hepatic Fgf21 DNA methylation or expression. Our data emphasize the dynamic induction of DNA methylation upon metabolic stimuli. Reduced Fgf21 DNA methylation established before massive overexpression of Fgf21, which is likely an adaptive effort of the liver to maintain glucose homeostasis despite the developing insulin resistance and steatosis. Fgf21 DNA methylation resisted reversion by intervention strategies, illustrating the long-term effects of unhealthy lifestyle. Our data provide a temporal roadmap to the development of hepatic insulin resistance, comprehensively linking DNA methylation with gene expression and metabolic data.


Assuntos
Metilação de DNA , Fatores de Crescimento de Fibroblastos/genética , Resistência à Insulina , Fígado/metabolismo , Obesidade/metabolismo , Animais , Dieta Hiperlipídica , Ácidos Graxos/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Glucose/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/genética , Transcriptoma , Redução de Peso
5.
Exp Clin Endocrinol Diabetes ; 129(9): 674-682, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32434239

RESUMO

OBJECTIVE: The risk to develop type 2 diabetes increases with the amount of visceral adiposity presumably due to increased lipolysis and subsequent lipid accumulation in visceral organs. However, data describing the molecular regulation of these pathways in humans are rare. We tested if genes of the lipogenic and lipolytic pathways are associated with glucose intolerance independently of obesity in visceral adipose tissue (VAT) of obese subjects. Moreover, we studied DNA methylation of FASN (fatty acid synthase), that catalyses the synthesis of long-chain fatty acids, in VAT of the same subjects and whether it is associated with metabolic traits. SUBJECTS AND METHODS: Visceral adipose tissue biopsies and blood samples were taken from 93 severely obese subjects undergoing bariatric surgery. Subjects were grouped in low HbA1c (L-HbA1c, HbA1c<6.5 %) and high HbA1c (H-HbA1c, HbA1c≥6.5 %) groups and expression of genes from the lipogenic and lipolytic pathways was analysed by TaqMan qPCR. DNA methylation of FASN was quantified by bisulfite-pyrosequencing. RESULTS: FASN expression was downregulated in visceral fat from subjects with high HbA1c (p = 0.00009). Expression of other lipogenetic (SCD, ELOVL6) or lipolytic genes (ADRB3, PNPLA2) and FABP4 was not changed. DNA methylation of FASN was increased at a regulatory ChoRE recognition site in the H-HbA1c-subgroup and correlated negatively with FASN mRNA (r = - 0.302, p = 0.0034) and positively with HbA1c (r = 0.296, p = 0.0040) and blood glucose (r = 0.363, p = 0.0005). CONCLUSIONS: Epigenetic downregulation of FASN in visceral adipose tissue of obese subjects might contribute to limited de novo lipogenesis of important insulin sensitizing fatty acids and could thereby contribute to glucose intolerance and the development of type 2 diabetes independently of obesity.


Assuntos
Epigênese Genética/fisiologia , Ácido Graxo Sintase Tipo I/metabolismo , Intolerância à Glucose/metabolismo , Resistência à Insulina/fisiologia , Gordura Intra-Abdominal/metabolismo , Obesidade Mórbida/metabolismo , Adulto , Metilação de DNA/fisiologia , Regulação para Baixo , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/sangue
6.
Cell Rep ; 33(5): 108351, 2020 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-33147454

RESUMO

Environmental temperature is a driving factor in evolution, and it is commonly assumed that metabolic adaptations to cold climates are the result of transgenerational selection. Here, we show in mice that even minor changes in maternal thermogenesis alter the metabolic phenotype already in the next generation. Male offspring of mothers genetically lacking brown adipose tissue (BAT) thermogenesis display increased lean mass and improved glucose tolerance as adults, while females are unaffected. The phenotype is replicated in offspring of mothers kept at thermoneutrality; conversely, mothers with higher gestational BAT thermogenesis produce male offspring with reduced lean mass and impaired glucose tolerance. Running-wheel exercise reverses the offspring's metabolic impairments, pointing to the muscle as target of these fetal programming effects. Our data demonstrate that gestational BAT activation negatively affects metabolic health of the male offspring; however, these unfavorable fetal programming effects may be negated by active lifestyle.


Assuntos
Tecido Adiposo Marrom/fisiologia , Glucose/metabolismo , Termogênese/fisiologia , Animais , Metabolismo Energético/fisiologia , Feminino , Homeostase , Humanos , Masculino , Metabolômica , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Condicionamento Físico Animal , Gravidez , Temperatura , Proteína Desacopladora 1/deficiência , Proteína Desacopladora 1/metabolismo
7.
Mov Disord ; 35(12): 2220-2229, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32914507

RESUMO

BACKGROUND: X-linked dystonia-parkinsonism is a neurodegenerative movement disorder. The underlying molecular basis has still not been completely elucidated, but likely involves dysregulation of TAF1 expression. In X-linked dystonia-parkinsonism, 3 disease-specific single-nucleotide changes (DSCs) introduce (DSC12) or abolish (DSC2 and DSC3) CpG dinucleotides and consequently sites of putative DNA methylation. Because transcriptional regulation tightly correlates with specific epigenetic marks, we investigated the role of DNA methylation in the pathogenesis of X-linked dystonia-parkinsonism. METHODS: DNA methylation at DSC12, DSC3, and DSC2 was quantified by bisulfite pyrosequencing in DNA from peripheral blood leukocytes, fibroblasts, induced pluripotent stem cell-derived cortical neurons and brain tissue from X-linked dystonia-parkinsonism patients and age- and sex-matched healthy Filipino controls in a prospective study. RESULTS: Compared with controls, X-linked dystonia-parkinsonism patients showed striking differences in DNA methylation at the 3 investigated CpG sites. Using methylation-sensitive luciferase reporter gene assays and immunoprecipitation, we demonstrated (1) that lack of DNA methylation because of DSC2 and DSC3 affects gene promoter activity and (2) that methylation at all 3 investigated CpG sites alters DNA-protein interaction. Interestingly, DSC3 decreased promoter activity per se compared with wild type, and promoter activity further decreased when methylation was present. Moreover, we identified specific binding of proteins to the investigated DSCs that are associated with splicing and RNA and DNA binding. CONCLUSIONS: We identified altered DNA methylation in X-linked dystonia-parkinsonism patients as a possible additional mechanism modulating TAF1 expression and putative novel targets for future therapies using DNA methylation-modifying agents. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Fatores Associados à Proteína de Ligação a TATA , Fator de Transcrição TFIID , Metilação de DNA/genética , Distúrbios Distônicos , Doenças Genéticas Ligadas ao Cromossomo X , Histona Acetiltransferases/metabolismo , Humanos , Estudos Prospectivos , Fatores Associados à Proteína de Ligação a TATA/genética , Fatores Associados à Proteína de Ligação a TATA/metabolismo , Fator de Transcrição TFIID/genética , Fator de Transcrição TFIID/metabolismo
8.
Diabetologia ; 63(10): 2182-2193, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32710190

RESUMO

AIMS/HYPOTHESIS: IRS2 is an important molecular switch that mediates insulin signalling in the liver. IRS2 dysregulation is responsible for the phenomenon of selective insulin resistance that is observed in type 2 diabetes. We hypothesise that epigenetic mechanisms are involved in the regulation of IRS2 in the liver of obese and type 2 diabetic individuals. METHODS: DNA methylation of seven CpG sites was studied by bisulphite pyrosequencing and mRNA and microRNA (miRNA) expression was assessed by quantitative real-time PCR in liver biopsies of 50 obese non-diabetic and 31 obese type 2 diabetic participants, in a cross-sectional setting. Methylation-sensitive luciferase assays and electrophoretic mobility shift assays were performed. Furthermore, HepG2 cells were treated with insulin and high glucose concentrations to induce miRNA expression and IRS2 downregulation. RESULTS: We found a significant downregulation of IRS2 expression in the liver of obese individuals with type 2 diabetes (0.84 ± 0.08-fold change; p = 0.0833; adjusted p value [pa] = 0.0417; n = 31) in comparison with non-diabetic obese participants (n = 50). This downregulation correlated with hepatic IRS2 DNA methylation at CpG5. Additionally, CpG6, which is located in intron 1 of IRS2, was hypomethylated in type 2 diabetes; this site spans the sterol regulatory element binding transcription factor 1 (SREBF1) recognition motif, which likely acts as transcriptional repressor. The adjacent polymorphism rs4547213 (G>A) was significantly associated with DNA methylation at a specificity-protein-1 (SP1) binding site (CpG3). Moreover, DNA methylation of cg25924746, a CpG site located in the shore region of the IRS2 promoter-associated CpG island, was increased in the liver of individuals with type 2 diabetes, as compared with those without diabetes. A second epigenetic mechanism, upregulation of hepatic miRNA hsa-let-7e-5p (let-7e-5p) in obese individuals with type 2 diabetes (n = 29) vs non-diabetic obese individuals (n = 49) (1.2 ± 0.08-fold change; p = 0.0332; pa = 0.0450), is likely to act synergistically with altered IRS2 DNA methylation to decrease IRS2 expression. Mechanistic in vitro experiments demonstrated an acute upregulation of let-7e-5p expression and simultaneous IRS2 downregulation in a liver (HepG2) cell line upon hyperinsulinaemic and hyperglycaemic conditions. CONCLUSIONS/INTERPRETATION: Our study highlights a new multi-layered epigenetic network that could be involved in subtle dysregulation of IRS2 in the liver of individuals with type 2 diabetes. This might lead to fine-tuning of IRS2 expression and is likely to be supplementary to the already known factors regulating IRS2 expression. Thereby, our findings could support the discovery of new diagnostic and therapeutic strategies for type 2 diabetes. Graphical abstract.


Assuntos
Diabetes Mellitus Tipo 2/genética , Proteínas Substratos do Receptor de Insulina/genética , Fígado/metabolismo , Obesidade/genética , Adulto , Estudos de Casos e Controles , Metilação de DNA , Diabetes Mellitus Tipo 2/complicações , Regulação para Baixo , Epigênese Genética , Repressão Epigenética , Feminino , Células Hep G2 , Humanos , Resistência à Insulina/genética , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/complicações , RNA Mensageiro/metabolismo
9.
Epigenomics ; 11(8): 885-897, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31169416

RESUMO

Aim: Validation of epigenome-wide association studies is sparse. Therefore, we evaluated the methylation markers cg06500161 (ABCG1) and cg11024682 (SREBF1) as classifiers for diabetes stratification. Patients & methods: DNA methylation was measured in blood (n = 167), liver (n = 99) and visceral adipose tissue (n = 99) of nondiabetic or Type 2 diabetic subjects by bisulfite pyrosequencing. Results: DNA methylation at cg11024682 in blood and liver correlated with BMI. Methylation at cg06500161 was influenced by the adjacent SNP rs9982016. Insulin-resistant and sensitive subjects could be stratified by DNA methylation status in blood or visceral adipose tissue. Conclusion: DNA methylation at both loci in blood presents a promising approach for risk group stratification and could be valuable for personalized Type 2 diabetes risk prediction in the future.


Assuntos
Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Diabetes Mellitus Tipo 2/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Metilação de DNA , Diabetes Mellitus Tipo 2/sangue , Marcadores Genéticos/genética , Humanos , Insulina/metabolismo
10.
Endocr Connect ; 7(12): 1448-1456, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30496129

RESUMO

Hepatic thyroid hormone signaling has an important role in the development and progression of nonalcoholic steatohepatitis (NASH). While the systemic levels of thyroid hormone might remain stable, there is evidence that the intracellular signaling machinery consisting of transporters, deiodinases and receptors could be altered in NASH. However, clinical material from human liver biopsies of individuals with NASH has not been studied to date. In a cross-sectional study, we analyzed 85 liver biopsies from patients with different stages of NASH that underwent bariatric surgery. Using qPCR, we analyzed gene expression of thyroid hormone transporters NTCP (SLC10A1), MCT8 (SLC16A2) and OATP1C1 (SLCO1C1), thyroid hormone receptor α and ß (THRA and THRB) and deiodinase type I, II and III (DIO1, DIO2, DIO3). The expression was correlated with serum TSH, triglyceride, HbA1c and NASH score and corrected for age or gender if required. While DIO2, DIO3 and SLCO1C1 were not expressed in human liver, we observed a significant negative correlation of THRB and DIO1 with age, and SLC16A2 with gender. THRB expression was also negatively associated with serum triglyceride levels and HbA1c. More importantly, its expression was inversely correlated with NASH score and further declined with age. Our data provide unique insight into the mRNA expression of thyroid hormone transporters, deiodinases and receptors in the human liver. The findings allow important conclusions on the intrahepatic mechanisms governing thyroid hormone action, indicating a possible tissue resistance to the circulating hormone in NASH, which becomes more prominent in advanced age.

11.
J Relig Health ; 54(6): 2142-54, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25204789

RESUMO

Little research has been done on comparing confessions regarding mental health. In the present study, 320 people (78 Buddhists, 77 Catholics, 89 Protestants and 79 Muslims) were compared in terms of their symptom severity. Buddhists and Protestants had lower scores than Catholics and Muslims for obsessive-compulsive behavior and hostility. Muslim group had the highest comparative scores for psychoticism. Buddhists and Protestants had comparatively low scores for paranoid ideation and overall symptom severity, with Catholics and Muslims having high ones. Results reveal that confession should be taken in account in psychological research and diagnosis, since it is explicitly associated with psychological well-being.


Assuntos
Revelação , Transtornos Mentais/psicologia , Religião e Psicologia , Adaptação Psicológica , Adolescente , Adulto , Idoso , Budismo/psicologia , Catolicismo/psicologia , Feminino , Humanos , Islamismo/psicologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Protestantismo/psicologia , Índice de Gravidade de Doença , Adulto Jovem
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