Municipal Clinic Dresden Neustadt

Dresden, Germany

Municipal Clinic Dresden Neustadt

Dresden, Germany
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Pfeiffer S.,University of Leipzig | Kruger J.,University of Leipzig | Maierhofer A.,University of Leipzig | Bottcher Y.,University of Leipzig | And 12 more authors.
Scientific Reports | Year: 2016

Recently, a genome-wide analysis identified DNA methylation of the HIF3A (hypoxia-inducible factor 3A) as strongest correlate of BMI. Here we tested the hypothesis that HIF3A mRNA expression and CpG-sites methylation in adipose tissue (AT) and genetic variants in HIF3A are related to parameters of AT distribution and function. In paired samples of subcutaneous AT (SAT) and visceral AT (VAT) from 603 individuals, we measured HIF3A mRNA expression and analyzed its correlation with obesity and related traits. In subgroups of individuals, we investigated the effects on HIF3A genetic variants on its AT expression (N = 603) and methylation of CpG-sites (N = 87). HIF3A expression was significantly higher in SAT compared to VAT and correlated with obesity and parameters of AT dysfunction (including CRP and leucocytes count). HIF3A methylation at cg22891070 was significantly higher in VAT compared to SAT and correlated with BMI, abdominal SAT and VAT area. Rs8102595 showed a nominal significant association with AT HIF3A methylation levels as well as with obesity and fat distribution. HIF3A expression and methylation in AT are fat depot specific, related to obesity and AT dysfunction. Our data support the hypothesis that HIF pathways may play an important role in the development of AT dysfunction in obesity.


Keller M.,University of Leipzig | Kralisch S.,University of Leipzig | Rohde K.,University of Leipzig | Schleinitz D.,University of Leipzig | And 11 more authors.
Diabetologia | Year: 2014

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. © 2014 Springer-Verlag Berlin Heidelberg.


Rohde K.,University of Leipzig | Keller M.,University of Leipzig | Klos M.,University of Leipzig | Schleinitz D.,University of Leipzig | And 9 more authors.
Journal of Molecular Medicine | Year: 2014

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. 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. © 2014 Springer-Verlag.


Krist J.,University of Leipzig | Wieder K.,University of Leipzig | Kloting N.,University of Leipzig | Oberbach A.,University of Leipzig | And 11 more authors.
Obesity Facts | Year: 2013

Objective: Apelin is an adipokine which plays a role in the regulation of glucose homeostasis and may contribute to the link between increased adipose tissue mass and obesity related metabolic diseases. Here we investigate the role of omental and subcutaneous (SC) adipose tissue apelin and its receptor APJ mRNA expression in human obesity and test the hypothesis that changes in circulating apelin are associated with reduced fat mass in three weight loss intervention studies. Methods: Apelin serum concentration was measured in 740 individuals in a cross-sectional (n = 629) study including a subgroup (n = 161) for which omental and SC apelin mRNA expression has been analyzed and in three interventions: 12 weeks exercise (n = 60), 6 months calorie-restricted diet (n = 19), 12 months after bariatric surgery (n = 32). Results: Apelin mRNA is significantly higher expressed in adipose tissue of patients with type 2 diabetes and correlates with circulating apelin, BMI, body fat, C-reactive protein, and insulin sensitivity. Obesity surgery-induced weight loss causes a significant reduction in omental and SC apelin expression. All interventions led to significantly reduced apelin serum concentrations which significantly correlate with improved insulin sensitivity, independently of changes in BMI. Conclusions: Reduced apelin expression and serum concentration may contribute to improved insulin sensitivity beyond significant weight loss. © 2013 S. Karger GmbH, Freiburg.


PubMed | University of Leipzig, Clinic of Visceral Surgery and Municipal Clinic Dresden Neustadt
Type: Journal Article | Journal: PloS one | Year: 2015

Genome wide association studies revealed an association of the single nucleotide polymorphism rs11708067 within the ADCY5 gene--encoding adenylate cyclase 5--with increased type 2 diabetes (T2D) risk and higher fasting glucose. However, it remains unclear whether the association between ADCY5 variants and glycemic traits may involve adipose tissue (AT) related mechanisms. We therefore tested the hypothesis that ADCY5 mRNA expression in human and mouse AT is related to obesity, fat distribution, T2D in humans and high fat diet (HFD) in mice. We measured ADCY5 mRNA expression in paired samples of visceral and subcutaneous adipose tissue from 244 individuals with a wide range of body weight and parameters of hyperglycemia, which have been genotyped for rs11708067. In addition, AT ADCY5 mRNA was assessed in C57BL/6NTac which underwent a 10 weeks standard chow (n = 6) or high fat diet (HFD, n = 6). In humans, visceral ADCY5 expression is significantly higher in obese compared to lean individuals. ADCY5 expression correlates with BMI, body fat mass, circulating leptin, fat distribution, waist and hip circumference, but not with fasting plasma glucose and HbA1c. Adcy5 expression in mouse AT is significantly higher after a HFD compared to chow (p<0.05). Importantly, rs11708067 is not associated with ADCY5 mRNA expression levels in either fat depot in any of the genetic models tested. Our results suggest that changes in AT ADCY5 expression are related to obesity and fat distribution, but not with impaired glucose metabolism and T2D. However, altered ADCY5 expression in AT does not seem to be the mechanism underlying the association between rs11708067 and increased T2D risk.


Chakaroun R.,University of Leipzig | Raschpichler M.,University of Leipzig | Kloting N.,University of Leipzig | Oberbach A.,University of Leipzig | And 9 more authors.
Metabolism: Clinical and Experimental | Year: 2012

Chemerin is a chemoattractant adipokine that regulates adipogenesis and may induce insulin resistance. Chemerin serum concentrations are elevated in obese, insulin-resistant, and inflammatory states in vivo. Here we investigate the role of omental (OM) and subcutaneous (SC) adipose tissue chemerin and CMKLR1 messenger RNA (mRNA) expression in human obesity. In addition, we test the hypothesis that changes in chemerin serum concentrations are primarily associated with reduced body fat mass in the context of 3 weight loss intervention studies. Chemerin serum concentration was measured in 740 individuals in a cross-sectional (n = 629) study including a subgroup (n = 161) for which OM and SC chemerin mRNA expression has been analyzed as well as in 3 interventions including 12 weeks of exercise (n = 60), 6 months of calorie-restricted diet (n = 19) studies, and 12 months after bariatric surgery (n = 32). Chemerin mRNA is significantly higher expressed in adipose tissue of patients with type 2 diabetes mellitus and correlates with circulating chemerin, body mass index (BMI), percentage body fat, C-reactive protein, homeostasis model assessment of insulin resistance, and glucose infusion rate in euglycemic-hyperinsulinemic clamps. CMKLR1 mRNA expression was not significantly different between the 2 fat depots. Obesity surgery-induced weight loss causes a significant reduction on both OM and SC chemerin expression. All interventions led to significantly reduced chemerin serum concentrations. Decreased chemerin serum concentrations significantly correlate with improved glucose infusion rate and reduced C-reactive protein levels independently of changes in BMI. Insulin resistance and inflammation are BMI-independent predictors of elevated chemerin serum concentrations. Reduced chemerin expression and serum concentration may contribute to improved insulin sensitivity and subclinical inflammation beyond significant weight loss. © 2012 Elsevier Inc.


Brune J.E.,University of Leipzig | Kern M.,University of Leipzig | Kunath A.,University of Leipzig | Kunath A.,German Center for Diabetes Research | And 11 more authors.
Obesity | Year: 2016

Objective Independent previous studies in both rodents and humans suggest a role of developmental genes in the origin of obesity and body fat distribution. Here, the hypothesis that human adipose tissue (AT) expression of the developmental genes homeobox transcription factors C9 (HOXC9) and C10 (HOXC10) is fat depot-specific and related to obesity-related traits was tested. Methods In 636 individuals, HOXC9 and HOXC10 mRNA expression was investigated in paired abdominal subcutaneous (SC) and omental AT samples in relation to a wide range of age, BMI, fat distribution, and metabolic parameters and in subfractions of isolated adipocytes and cells of the stromal vascular fraction (SVF). Results HOXC9 and HOXC10 mRNA expression is significantly higher in SC compared to omental AT. HOXC9 and HOXC10 mRNA expression significantly correlates with body fat mass, even after adjustment for age and gender. In smaller subgroups (depending on the availability of data), fat depot-related significant gender- and BMI-independent associations between HOXC9 and HOXC10 gene expression and parameters of glucose metabolism and AT biology were found (e.g., adipocyte size). Conclusions Taken together, these data suggest that HOXC9 and HOXC10 may play an important role in the development of obesity, adverse fat distribution, and subsequent alterations in whole-body metabolism and AT function. © 2015 The Obesity Society.


Lakowa N.,University of Leipzig | Trieu N.,University of Leipzig | Flehmig G.,University of Leipzig | Lohmann T.,Municipal Clinic Dresden Neustadt | And 7 more authors.
Biochemical and Biophysical Research Communications | Year: 2015

Adipocyte hypertrophy and hyperplasia have been shown to be associated with shorter telomere length, which may reflect aging, altered cell proliferation and adipose tissue (AT) dysfunction. In individuals with obesity, differences in fat distribution and AT cellular composition may contribute to obesity related metabolic diseases. Here, we tested the hypotheses that telomere lengths (TL) are different between: (1) abdominal subcutaneous and omental fat depots, (2) superficial and deep abdominal subcutaneous AT (SAT), and (3) adipocytes and cells of the stromal vascular fraction (SVF). We further asked whether AT TL is related to age, anthropometric and metabolic traits. TL was analyzed by quantitative PCR in total human genomic DNA isolated from paired subcutaneous and visceral AT of 47 lean and 50 obese individuals. In subgroups, we analyzed TL in isolated small and large adipocytes and SVF cells. We find significantly shorter TL in subcutaneous compared to visceral AT (P < 0.001) which is consistent in men and subgroups of lean and obese, and individuals with or without type 2 diabetes (T2D). Shorter TL in SAT is entirely due to shorter TL in the SVF compared to visceral AT (P < 0.01). SAT TL is most strongly correlated with age (r = -0.205, P < 0.05) and independently of age with HbA1c (r = -0.5, P < 0.05). We found significant TL differences between superficial SAT of lean and obese as well as between individuals with our without T2D, but not between the two layers of SAT. Our data indicate that fat depot differences in TL mainly reflect shorter TL of SVF cells. In addition, we found an age and BMI-independent relationship between shorter TL and HbA1c suggesting that chronic hyperglycemia may impair the regenerative capacity of AT more strongly than obesity alone. © 2015 Elsevier Inc. All rights reserved.


Heiker J.T.,University of Leipzig | Kern M.,University of Leipzig | Kosacka J.,University of Leipzig | Flehmig G.,University of Leipzig | And 7 more authors.
Obesity | Year: 2013

Objective: A spontaneous deletion in the nicotinamide nucleotide transhydrogenase (Nnt) gene eliminating exons 7-11 in C57BL/6J (B6J) mice is associated with reduced glucose-stimulated insulin secretion in vitro, impaired glucose tolerance, higher epigonadal fat mass, and altered susceptibility to diet induced obesity of male B6J mice was proposed. A potential implication for NNT in human adipose tissue distribution has not been investigated so far. Design and Methods: Therefore, NNT mRNA expression in paired human samples of visceral (vis) and subcutaneous (sc) adipose tissue from 221 subjects with a wide range of body mass index (BMI), insulin sensitivity, and glucose tolerance was analyzed. Results: NNT mRNA expression is significantly higher in visceral fat of obese patients and correlates with body weight, BMI, % body fat, visceral and sc fat area, waist and hip circumference, and fasting plasma insulin (FPI). Multivariate linear regression analysis revealed visceral NNT expression as age and gender independent predictor of BMI, waist circumference, visceral fat area, and % body fat, but not FPI and 2 h OGTT glucose. Conclusion: In conclusion, a functional relevance of NNT in the development of human obesity and visceral fat distribution was suggested here. Copyright © 2013 The Obesity Society.


PubMed | University of Leipzig, Municipal Clinic Dresden Neustadt and Stadtisches Klinikum Karlsruhe
Type: Journal Article | Journal: Obesity (Silver Spring, Md.) | Year: 2015

Independent previous studies in both rodents and humans suggest a role of developmental genes in the origin of obesity and body fat distribution. Here, the hypothesis that human adipose tissue (AT) expression of the developmental genes homeobox transcription factors C9 (HOXC9) and C10 (HOXC10) is fat depot-specific and related to obesity-related traits was tested.In 636 individuals, HOXC9 and HOXC10 mRNA expression was investigated in paired abdominal subcutaneous (SC) and omental AT samples in relation to a wide range of age, BMI, fat distribution, and metabolic parameters and in subfractions of isolated adipocytes and cells of the stromal vascular fraction (SVF).HOXC9 and HOXC10 mRNA expression is significantly higher in SC compared to omental AT. HOXC9 and HOXC10 mRNA expression significantly correlates with body fat mass, even after adjustment for age and gender. In smaller subgroups (depending on the availability of data), fat depot-related significant gender- and BMI-independent associations between HOXC9 and HOXC10 gene expression and parameters of glucose metabolism and AT biology were found (e.g., adipocyte size).Taken together, these data suggest that HOXC9 and HOXC10 may play an important role in the development of obesity, adverse fat distribution, and subsequent alterations in whole-body metabolism and AT function.

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