Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 14 de 14
Filtrar
Mais filtros










Base de dados
Tipo de estudo
Intervalo de ano de publicação
1.
EBioMedicine ; 44: 476-488, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31153815

RESUMO

BACKGROUND: In brain, CREB-regulated transcription co-activator 1 (CRTC1) is involved in metabolic dysregulation. In humans a SNP in CRTC1 was associated to body fat percentage and two SNPs affected RNA Pol II binding and chromatin structure, implying epigenetic regulation of CRTC1. We sought to understand the relevance of CRTC1 SNPs, DNA methylation and expression in human eating behaviour and its relationship to clinical variables of obesity in blood and adipose tissue. METHODS: 13 CRTC1 SNPs were included to analyze eating behaviour. For rs7256986, follow up association analyses were applied on DNA methylation, CRTC1 expression and clinical parameters. Linear regression was used throughout the study adjusted for age, sex and BMI. Besides data extraction from previous work, rs7256986 was de-novo genotyped and DNA methylation was evaluated by using pyrosequencing. FINDINGS: We found several SNPs in the CRTC1 locus nominally associated with human eating behaviour or 2hr postprandial insulin levels and observed a correlation with alcohol and coffee intake (all P < 0.05). G-allele carriers of rs7256986 showed slightly increased hip circumference. We showed that rs7256986 represents a methylation quantitative trait locus (meQTL) in whole blood and adipose tissue. The presence of the SNP and/or DNA methylation correlated with CRTC1 gene expression which in turn, related to BMI and fat distribution. INTERPRETATION: Our data support the known role of CRCT1 regulating energy metabolism in brain. Here, we highlight relevance of CRTC1 regulation in blood and adipose tissue. FUND: IFB AdiposityDiseases (BMBF); n609020-Scientia Fellows; Helse-SørØst; DFG: CRC 1052/1 and/2; Kompetenznetz Adipositas, German Diabetes Association.

2.
Metabolism ; 2018 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-30399374

RESUMO

Obesity is among the most threatening health burdens worldwide and its prevalence has markedly increased over the last decades. Obesity maybe considered a heritable trait. Identifications of rare cases of monogenic obesity unveiled that hypothalamic circuits and the brain-adipose axis play an important role in the regulation of energy homeostasis, appetite, hunger and satiety. For example, mutations in the leptin gene cause obesity through almost unsuppressed overeating. Common (multifactorial) obesity, most likely resulting from a concerted interplay of genetic, epigenetic and environmental factors, is clearly linked to genetic predisposition by multiple risk variants, which, however only account for a minor part of the general BMI variability. Although GWAS opened new avenues in elucidating the complex genetics behind common obesity, understanding the biological mechanisms relative to the specific risk contributing to obesity remains poorly understood. Non-genetic factors such as eating behavior or physical activity strongly modulate the individual risk for developing obesity. These factors may interact with genetic predisposition for obesity through epigenetic mechanisms. Thus, here, we review the current knowledge about monogenic and common (multifactorial) obesity highlighting the important recent advances in our knowledge on how epigenetic regulation is involved in the etiology of obesity.

3.
FASEB J ; : fj201800528R, 2018 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-29932866

RESUMO

DNA methylation is a crucial epigenetic mechanism in obesity and fat distribution. We explored the Sarcospan ( SSPN) gene locus by using genome-wide data sets comprising methylation and expression data, pyrosequencing analysis in the promoter region, and genetic analysis of an SNP variant rs718314, which was previously reported to associate with waist-to-hip ratio. We found that DNA methylation influences several clinical variables related to fat distribution and glucose metabolism, while SSPN mRNA levels showed directionally opposite effects on these traits. Complete DNA methylation of the SSPN promoter construct suppressed the gene expression of firefly luciferase in MCF7 cells. Moreover, rs718314 was associated with waist and with DNA methylation at CpG sites. Our data strongly support the role of the SSPN locus in body fat composition and glucose homeostasis, and suggest that this is most likely the result of changes in DNA methylation of SSPN in adipose tissue.-Keller, M., Klös, M., Rohde, K., Krüger, J., Kurze, T., Dietrich, A., Schön, M. R., Gärtner, D., Lohmann, T., Dreßler, M., Stumvoll, M., Blüher, M., Kovacs, P., Böttcher, Y. DNA methylation of SSPN is linked to adipose tissue distribution and glucose metabolism.

4.
Sci Rep ; 7(1): 12369, 2017 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-28959056

RESUMO

The SNP variant rs2943650 near IRS1 gene locus was previously associated with decreased body fat and IRS1 gene expression as well as an adverse metabolic profile in humans. Here, we hypothesize that these effects may be mediated by an interplay with epigenetic alterations. We measured IRS1 promoter DNA methylation and mRNA expression in paired human subcutaneous and omental visceral adipose tissue samples (SAT and OVAT) from 146 and 41 individuals, respectively. Genotyping of rs2943650 was performed in all individuals (N = 146). We observed a significantly higher IRS1 promoter DNA methylation in OVAT compared to SAT (N = 146, P = 8.0 × 10-6), while expression levels show the opposite effect direction (N = 41, P = 0.011). OVAT and SAT methylation correlated negatively with IRS1 gene expression in obese subjects (N = 16, P = 0.007 and P = 0.010). The major T-allele is related to increased DNA methylation in OVAT (N = 146, P = 0.019). Finally, DNA methylation and gene expression in OVAT correlated with anthropometric traits (waist- circumference waist-to-hip ratio) and parameters of glucose metabolism in obese individuals. Our data suggest that the association between rs2943650 near the IRS1 gene locus with clinically relevant variables may at least be modulated by changes in DNA methylation that translates into altered IRS1 gene expression.

5.
Mol Metab ; 6(6): 482-493, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28580279

RESUMO

OBJECTIVE: Several studies have demonstrated anti-diabetic and anti-obesogenic properties of visceral adipose tissue-derived serine protease inhibitor (vaspin) and so evoked its potential use for treatment of obesity-related diseases. The aim of the study was to unravel physiological regulators of vaspin expression and secretion with a particular focus on its role in brown adipose tissue (BAT) biology. METHODS: We analyzed the effects of obesogenic diets and cold exposure on vaspin expression in liver and white and brown adipose tissue (AT) and plasma levels. Vaspin expression was analyzed in isolated white and brown adipocytes during adipogenesis and in response to adrenergic stimuli. DNA-methylation within the vaspin promoter was analyzed to investigate acute epigenetic changes after cold-exposure in BAT. RESULTS: Our results demonstrate a strong induction of vaspin mRNA and protein expression specifically in BAT of both cold-exposed and high-fat (HF) or high-sugar (HS) fed mice. While obesogenic diets also upregulated hepatic vaspin mRNA levels, cold exposure tended to increase vaspin gene expression of inguinal white adipose tissue (iWAT) depots. Concomitantly, vaspin plasma levels were decreased upon obesogenic or thermogenic triggers. Vaspin expression was increased during adipogenesis but unaffected by sympathetic activation in brown adipocytes. Analysis of vaspin promoter methylation in AT revealed lowest methylation levels in BAT, which were acutely reduced after cold exposure. CONCLUSIONS: Our data demonstrate a novel BAT-specific regulation of vaspin gene expression upon physiological stimuli in vivo with acute epigenetic changes that may contribute to cold-induced expression in BAT. We conclude that these findings indicate functional relevance and potentially beneficial effects of vaspin in BAT function.

6.
Mol Metab ; 6(1): 86-100, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-28123940

RESUMO

OBJECTIVE/METHODS: DNA methylation plays an important role in obesity and related metabolic complications. We examined genome-wide DNA promoter methylation along with mRNA profiles in paired samples of human subcutaneous adipose tissue (SAT) and omental visceral adipose tissue (OVAT) from non-obese vs. obese individuals. RESULTS: We identified negatively correlated methylation and expression of several obesity-associated genes in our discovery dataset and in silico replicated ETV6 in two independent cohorts. Further, we identified six adipose tissue depot-specific genes (HAND2, HOXC6, PPARG, SORBS2, CD36, and CLDN1). The effects were further supported in additional independent cohorts. Our top hits might play a role in adipogenesis and differentiation, obesity, lipid metabolism, and adipose tissue expandability. Finally, we show that in vitro methylation of SORBS2 directly represses gene expression. CONCLUSIONS: Taken together, our data show distinct tissue specific epigenetic alterations which associate with obesity.


Assuntos
Tecido Adiposo/metabolismo , Obesidade/genética , Adipogenia , Idoso , Ilhas de CpG/genética , Metilação de DNA/genética , Epigênese Genética/genética , Epigenômica , Feminino , Expressão Gênica , Perfilação da Expressão Gênica/métodos , Estudo de Associação Genômica Ampla , Humanos , Gordura Intra-Abdominal/metabolismo , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genética , RNA Mensageiro/genética , Gordura Subcutânea/metabolismo
7.
Epigenomics ; 7(6): 911-20, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26418625

RESUMO

BACKGROUND: A stable intermediate during DNA demethylation, 5-hydroxymethylcytosine (5-hmC), raises questions about its function and distribution. Therefore, we tested whether 5-hmC exists in human adipose tissue depots and correlates with clinical variables. MATERIALS & METHODS: We measured the % 5-hmC content in both subcutaneous adipose tissue and visceral adipose tissue (VAT) from 81 individuals by using ELISA technology. To test for associations with several clinical variables we used paired students t-tests and linear regression analyses. RESULTS: We observed an average % 5-hmC content of 0.47% ± 0.093 in subcutaneous adipose tissue, while VAT (0.51% ± 0.122) is higher hydroxymethylated (p = 0.005). In the total cohort we observed a positive association of % 5-hmC in VAT with age (p = 0.034) and a negative relationship with low density lipoprotein-cholesterol (p = 0.008). CONCLUSION: Our data suggest adipose tissue depot specific 5-hmC levels with higher levels in VAT.


Assuntos
Adiposidade/genética , Metilação de DNA , Gordura Intra-Abdominal/metabolismo , Gordura Subcutânea/metabolismo , 5-Metilcitosina/análogos & derivados , Adipócitos/citologia , Adipócitos/metabolismo , Idoso , Biomarcadores , Tamanho Celular , Citosina/análogos & derivados , Citosina/metabolismo , Feminino , Humanos , Gordura Intra-Abdominal/anatomia & histologia , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Gordura Subcutânea/anatomia & histologia , Tomografia Computadorizada por Raios X
8.
BMC Genet ; 16: 31, 2015 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-25887478

RESUMO

BACKGROUND: The human Aldoketoreductase 1B10 gene (AKR1B10) encodes one of the enzymes belonging to the family of aldoketoreductases and may be involved in detoxification of nutrients during digestion. Further, AKR1B10 mRNA (messenger ribonucleic acid) expression was diminished in brain regions potentially involved in the regulation of eating behavior in rats which are more sensitive to cocaine and alcohol. We hypothesized that the human AKR1B10 gene may also play a role in the regulation of human eating behavior. RESULTS: We investigated the effects of 5 genetic variants of AKR1B10 on human eating behavior among 548 subjects from a German self-contained population, the Sorbs, and in 350 subjects from another independent German cohort. Among the Sorbs, we observed nominal associations with disinhibition at the 5' untranslated region (5' UTR) variant rs10232478 and the intragenic variants rs1834150 and rs782881 (all P ≤ 0.05). Further, we detected a relationship of rs1834150 and rs782881 with waist, smoking consumption (rs782881) and coffee consumption (rs1834150) (all P ≤ 0.05). Albeit non-significant, replication analyses revealed similar effect directions for disinhibition at rs1834150 (combined P = 0.0096). Moreover, in the replication cohort we found rs1834150 related to increased restraint scores with a similar direction as in the Sorbs (combined P = 0.0072). CONCLUSION: Our data suggest that genetic variants in the AKR1B10 locus may influence human eating behavior.


Assuntos
Aldeído Redutase/genética , Comportamento Alimentar , Estudos de Associação Genética , Variação Genética , Adulto , Alelos , Estudos de Coortes , Genótipo , Alemanha , Humanos , Metanálise como Assunto , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Característica Quantitativa Herdável
9.
Ultrasound Med Biol ; 41(3): 858-70, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25619776

RESUMO

Calcaneal quantitative ultrasound can be used to predict osteoporotic fracture risk, but its ability to monitor therapy is unclear possibly because of its limited precision. We developed a quantitative ultrasound device (foot ultrasound scanner) that measures the speed of sound at the heel with the aim of minimizing common error sources like the position and penetration angle of the ultrasound beam, as well as the soft tissue temperature. To achieve these objectives, we used a receiver array, mechanics to adjust the beam direction and a foot temperature sensor. In a group of 60 volunteers, short-term precision was evaluated for the foot ultrasound scanner and a commercial device (Achilles Insight, GE Medical, Fairfield, CT, USA ). In a subgroup of 20 subjects, mid-term precision (1-mo follow-up) was obtained. Compared with measurement of the speed of sound with the Achilles Insight, measurement with the foot ultrasound scanner reduced precision errors by half (p < 0.05). The study indicates that improvement of the precision of calcaneal quantitative ultrasound measurements is feasible.


Assuntos
Calcâneo/diagnóstico por imagem , Calcanhar/diagnóstico por imagem , Osteoporose/diagnóstico por imagem , Densidade Óssea , Desenho de Equipamento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ultrassonografia
10.
Genes Nutr ; 10(1): 449, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25542302

RESUMO

The beneficial effects of adiponectin and its negative correlation with BMI are well described. Adiponectin serum levels are altered in eating disorders such as anorexia nervosa, bulimia nervosa or binge eating. Here, we tested the hypothesis that (1) adiponectin serum levels correlate with human eating behavior factors and (2) that genetic variants of the ADIPOQ locus influence both serum levels and eating behavior. We analyzed 11 SNPs within ADIPOQ and in the 5' UTR and measured serum adiponectin levels in 1,036 individuals from the German Sorbs population. The German version of the three-factor eating questionnaire (FEV) was completed by 548 Sorbs. For replication purposes, we included an independent replication cohort from Germany (N = 350). In the Sorbs, we observed positive correlations of restraint with adiponectin serum levels (P = 0.001; r = 0.148) which, however, did not withstand adjustment for covariates (P = 0.083; r = 0.077). In addition, four SNPs were nominally associated with serum adiponectin levels (all P < 0.05). Of these, two variants (rs3774261; rs1501229, all P < 0.05) were also related to disinhibition. Furthermore, three variants were exclusively associated with hunger (rs2036373, P = 0.049) and disinhibition (rs822396; rs864265, all P < 0.05). However, none of these associations withstood Bonferroni corrections for multiple testing (all P > 9.3 × 10(-4)). In our replication cohort, we observed similar effect directions at rs1501229 for disinhibition and hunger. A meta-analysis resulted in nominal statistical significance P = 0.036 (Z score 2.086) and P = 0.017 (Z score 2.366), respectively. Given the observed relationship of the SNPs with adiponectin levels and eating behavior, our data support a potential role of adiponectin in human eating behavior. Whether the relationship with eating behavior is mediated by the effects of circulating adiponectin warrants further investigations.

11.
Diabetologia ; 57(11): 2374-83, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25145546

RESUMO

AIMS/HYPOTHESIS: Epigenetic alterations may influence the metabolic pathways involved in human obesity. We hypothesised that global DNA methylation levels in adipose tissue might be associated with obesity and related phenotypes. METHODS: We measured global DNA methylation levels in paired samples of subcutaneous adipose tissue (SAT) and omental visceral adipose tissue (OVAT) from 51 individuals, and in leucocytes from 559 Sorbs, a population from Germany, using LUminometric Methylation Assay (LUMA). To further investigate the underlying mechanisms of the observed associations, we measured global methylation levels in 3T3-L1 adipocytes exposed to glucose, insulin and lipids. RESULTS: Global methylation levels (±SD) were significantly higher in OVAT (74.27% ± 2.2%) compared with SAT (71.97% ± 2.4%; paired t test, p < 1 × 10(-9)). Furthermore, global methylation levels in SAT were positive correlates of measures of fat distribution (waist measurement, WHR) and glucose homeostasis (HbA1c) (all p < 0.015 after accounting for multiple testing and covariates). Global methylation levels in the German Sorb cohort were associated with glucose homeostasis, but this association did not withstand adjustment for covariates. Exposure of 3T3-L1 adipocytes to insulin, palmitate and glucose decreased global methylation levels 1 h after treatment relative to controls. CONCLUSIONS/INTERPRETATION: Our data suggest that the variability in global methylation in adipose tissue might be related to alterations in glucose metabolism.


Assuntos
Tecido Adiposo/metabolismo , Metilação de DNA/fisiologia , Glucose/metabolismo , Células 3T3-L1 , Adulto , Idoso , Animais , Diferenciação Celular/fisiologia , Feminino , Humanos , Técnicas In Vitro , Gordura Intra-Abdominal/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade
12.
J Mol Med (Berl) ; 92(8): 881-8, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24763707

RESUMO

UNLABELLED: Epigenetic processes such as dynamic promoter methylation may play a role in obesity, fat distribution and its accompanied metabolic alterations. TMEM18 is a candidate gene for body mass index (BMI) comprising the second largest effect size among all loci identified so far via GWAS. We hypothesized that differential TMEM18 gene expression in visceral (VAT) and subcutaneous adipose tissue (SAT) may be a consequence of depot specific differential methylation at the TMEM18 promoter region. Differential methylation levels may confer fat depot specific correlations with measures of obesity and fat distribution. Here, we measured TMEM18 mRNA expression in VAT and SAT from 500 subjects. A total of 146 Caucasian individuals were investigated for differential methylation levels in VAT vs. SAT at three CpG sites. Subsequently, we tested for potential correlation of methylation levels with anthropometric and metabolic parameters. (1) In 500 individuals, we observed significantly decreased mRNA expression in SAT (paired t-test, P < 0.0001) compared to VAT with strongest effects in obese subjects. (2) We identified significantly higher methylation levels for the entire CpG locus in SAT (paired t-test, P = 0.00015). In 146 individuals, we detected positive correlations between CpG methylation levels in SAT with parameters of obesity and fat distribution (e.g., BMI, r = 0.173; P = 0.036; visceral fat area, r = 0.246; P = 0.004) and with metabolic traits (P ≤ 0.05). However, these correlations did not withstand adjustment for covariates. Our data suggest an adipose tissue depot specific TMEM18 promoter methylation that may mediate inter-depot specific variance in TMEM18 mRNA expression. KEY MESSAGES: Higher mean methylation across the entire CpG locus in SAT compared to VAT. Lower TMEM18 mRNA expression levels in SAT compared to VAT. TMEM18 mRNA expression levels are related to phenotypes of obesity and glucose metabolism.


Assuntos
Tecido Adiposo/metabolismo , Metilação de DNA , Proteínas de Membrana/genética , Regiões Promotoras Genéticas , Adulto , Idoso , Alelos , Ilhas de CpG , Feminino , Expressão Gênica , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Característica Quantitativa Herdável , RNA Mensageiro
13.
Artigo em Inglês | MEDLINE | ID: mdl-24474136

RESUMO

The femoral neck is a common fracture site in elderly people. The cortical shell is thought to be the major contributor to the mechanical competence of the femoral neck, but its microstructural parameters are not sufficiently accessible under in vivo conditions with current X-ray-based methods. To systematically investigate the influences of pore size, porosity, and thickness of the femoral neck cortex on the propagation of ultrasound, we developed 96 different bone models (combining 6 different pore sizes with 4 different porosities and 4 different thicknesses) and simulated the ultrasound propagation using a finite-difference time-domain algorithm. The simulated single-element emitter and receiver array consisting of 16 elements (8 inferior and 8 superior) were placed at anterior and posterior sides of the bone, respectively (transverse transmission). From each simulation, we analyzed the waveform collected by each of the inferior receiver elements for the one with the shortest time of flight. The first arriving signal of this waveform, which is associated with the wave traveling through the cortical shell, was then evaluated for its three different waveform characteristics (TOF: time point of the first point of inflection of the received signal, Δt: difference between the time point at which the signal first crosses the zero baseline and TOF, and A: amplitude of the first extreme of the first arriving signal). From the analyses of these waveform characteristics, we were able to develop multivariate models to predict pore size, porosity, and cortical thickness, corresponding to the 96 different bone models, with remaining errors in the range of 50 µm for pore size, 1.5% for porosity, and 0.17 mm for cortical thickness.


Assuntos
Algoritmos , Densidade Óssea/fisiologia , Colo do Fêmur/diagnóstico por imagem , Colo do Fêmur/fisiologia , Ondas de Choque de Alta Energia , Aumento da Imagem/métodos , Interpretação de Imagem Assistida por Computador/métodos , Modelos Biológicos , Simulação por Computador , Colo do Fêmur/ultraestrutura , Humanos , Porosidade , Reprodutibilidade dos Testes , Espalhamento de Radiação , Sensibilidade e Especificidade , Ultrassonografia
14.
PLoS One ; 8(12): e80512, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24312479

RESUMO

BACKGROUND: Genetic variants within the bitter taste receptor gene TAS2R38 are associated with sensitivity to bitter taste and are related to eating behavior in the Amish population. Sensitivity to bitter taste is further related to anthropometric traits in an genetically isolated Italian population. We tested whether the TAS2R38 variants (rs713598; rs1726866 and rs10246939) may be related to eating behavior, anthropometric parameters, metabolic traits and consumer goods intake in the German Sorbs. MATERIALS AND METHODS: The three SNPs were genotyped in a total cohort of 1007 individuals (male/female: 405/602). The German version of the three-factor eating questionnaire was completed by 548 individuals. Genetic association analyses for smoking behavior, alcohol and coffee intake, eating behavior factors (restraint, disinhibition and hunger) and other metabolic traits were analyzed. Further, by combining the three SNPs we applied comparative haplotype analyses categorizing PAV (proline-alanine-valine) carriers (tasters) vs. homozygous AVI (alanin-valine-isoleucine) carriers (non-tasters). RESULTS: Significant associations of genetic variants within TAS2R38 were identified with percentage of body fat, which were driven by associations in women. In men, we observed significant associations with 30 min plasma glucose, and area under the curve for plasma glucose (0-120 min) (all adjusted P≤0.05). Further, we found that carriers of at least one PAV allele show significantly lower cigarette smoking per day (P = 0.002) as well as, albeit non-significant, lower alcohol intake. We did not confirm previously reported associations between genetic variants of TAS2R38 and eating behavior. CONCLUSION: Our data suggest that genetic variation in TAS2R38 is related to individual body composition measures and may further influence consumer goods intake in the Sorbs possibly via individual sensitivity to bitter taste.


Assuntos
Glucose/metabolismo , Polimorfismo de Nucleotídeo Único , Receptores Acoplados a Proteínas-G/genética , Fumar , Adulto , Idoso , Feminino , Alemanha/etnologia , Humanos , Masculino , Pessoa de Meia-Idade , Fumar/etnologia , Fumar/genética , Fumar/metabolismo , Inquéritos e Questionários
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA