TY  - JOUR
AB  - The aim was to characterise associations between circulating thyroid hormones-free thyroxine (FT4) and thyrotropin (TSH)-and the metabolite profiles in serum samples from participants of the German population-based KORA F4 study. Analyses were based on the metabolite profile of 1463 euthyroid subjects. In serum samples, obtained after overnight fasting (≥8), 151 different metabolites were quantified in a targeted approach including amino acids, acylcarnitines (ACs), and phosphatidylcholines (PCs). Associations between metabolites and thyroid hormone concentrations were analysed using adjusted linear regression models. To draw conclusions on thyroid hormone related pathways, intra-class metabolite ratios were additionally explored. We discovered 154 significant associations (Bonferroni p < 1.75 × 10-04) between FT4 and various metabolites and metabolite ratios belonging to AC and PC groups. Significant associations with TSH were lacking. High FT4 levels were associated with increased concentrations of many ACs and various sums of ACs of different chain length, and the ratio of C2 by C0. The inverse associations observed between FT4 and many serum PCs reflected the general decrease in PC concentrations. Similar results were found in subgroup analyses, e.g., in weight-stable subjects or in obese subjects. Further, results were independent of different parameters for liver or kidney function, or inflammation, which supports the notion of an independent FT4 effect. In fasting euthyroid adults, higher serum FT4 levels are associated with increased serum AC concentrations and an increased ratio of C2 by C0 which is indicative of an overall enhanced fatty acyl mitochondrial transport and β-oxidation of fatty acids.
AU  - Jourdan, C.
AU  - Linseisen, J.
AU  - Meisinger, C.
AU  - Petersen, A.-K.
AU  - Gieger, C.
AU  - Rawal, R.
AU  - Illig, T.
AU  - Heier, M.
AU  - Peters, A.
AU  - Wallaschofski, H.*
AU  - Nauck, M.*
AU  - Kastenmüller, G.
AU  - Suhre, K.
AU  - Prehn, C.
AU  - Adamski, J.
AU  - Koenig, W.*
AU  - Roden, M.*
AU  - Wichmann, H.-E.
AU  - Völzke, H.*
C1  - 25964
C2  - 32009
CY  - New York
SP  - 152-164
TI  - Associations between thyroid hormones and serum metabolite profiles in an euthyroid population.
JO  - Catal. Lett.
VL  - 10
IS  - 1
PB  - Springer
PY  - 2014
SN  - 1011-372X
ER  - 

TY  - JOUR
AB  - The Berlin Fat Mouse Inbred (BFMI) line harbors a major recessive gene defect on chromosome 3 (jobes1) leading to juvenile obesity and metabolic syndrome. The present study aimed at the identification of metabolites that might be linked to recessively acting genes in the obesity locus. Firstly, serum metabolites were analyzed between obese BFMI and lean B6 and BFMI × B6 F1 mice to identify metabolites that are different. In a second step, a metabolite-protein network analysis was performed linking metabolites typical for BFMI mice with genes of the jobes1 region. The levels of 22 diacyl-phosphatidylcholines (PC aa), two lyso-PC and three carnitines were found to be significantly lower in obese mice compared with lean mice, while serine, glycine, arginine and hydroxysphingomyelin were higher for the same comparison. The network analysis identified PC aa C42:1 as functionally linked with the genes Ccna2 and Trpc3 via the enzymes choline kinase alpha and phospholipase A2 group 1B (PLA2G1B), respectively. Gene expression analysis revealed elevated Ccna2 expression in adipose tissue of BFMI mice. Furthermore, unique mutations were found in the Ccna2 promoter of BFMI mice which are located in binding sites for transcription factors or micro RNAs and could cause differential Ccna2 mRNA levels between BFMI and B6 mice. Increased expression of Ccna2 was consistent with higher mitotic activity of adipose tissue in BFMI mice. Therefore, we suggest a higher demand for PC necessary for adipose tissue growth and remodeling. This study highlights the relationship between metabolite profiles and the underlying genetics of obesity in the BFMI line.
AU  - Schäfer, N.*
AU  - Yu, Z.
AU  - Wagener, A.*
AU  - Millrose, M.K.*
AU  - Reissmann, M.*
AU  - Bortfeldt, R.*
AU  - Dieterich, C.*
AU  - Adamski, J.
AU  - Wang-Sattler, R.
AU  - Illig, T.
AU  - Brockmann, G.A.*
C1  - 27933
C2  - 32865
CY  - New York
SP  - 461-472
TI  - Changes in metabolite profiles caused by genetically determined obesity in mice.
JO  - Catal. Lett.
VL  - 10
IS  - 3
PB  - Springer
PY  - 2014
SN  - 1011-372X
ER  - 

TY  - JOUR
AB  - The measurement of metabolites during intravenous or nutritional challenges may improve the identification of novel metabolic signatures which are not detectable in the fasting state. Here, we comprehensively characterized the plasma metabolomics response to five defined challenge tests and explored their use to identify interactions with the FTO rs9939609 obesity risk genotype. Fifty-six non-diabetic male participants of the KORA S4/F4 cohort, including 25 homozygous carriers of the FTO risk allele (AA genotype) and 31 carriers of the TT genotype were recruited. Challenges comprised an oral glucose tolerance test, a standardized high-fat high-carbohydrate meal and a lipid tolerance test, as well as an intravenous glucose tolerance test and a euglycemic hyperinsulinemic clamp. Blood was sampled for biochemical and metabolomics measurement before and during the challenges. Plasma samples were analyzed using a mass spectrometry-based metabolomics approach targeting 163 metabolites. Linear mixed-effects models and cluster analysis were performed. In both genotype groups, we observed significant challenge-induced changes for all major metabolite classes (amino acids, hexose, acylcarnitines, phosphatidylcholines, lysophosphatidylcholines and sphingomyelins, with corrected p-values ranging from 0.05 to 6.7E-37), which clustered in five distinct metabolic response profiles. Our data contribute to the understanding of plasma metabolomics response to diverse metabolic challenges, including previously unreported metabolite changes in response to intravenous challenges. The FTO genotype had only minor effects on the metabolite fluxes after standardized metabolic challenges.
AU  - Wahl, S.
AU  - Krug, S.
AU  - Then, C.
AU  - Kirchhofer, A.
AU  - Kastenmüller, G.
AU  - Brand, T.
AU  - Skurk, T.*
AU  - Claussnitzer, M.*
AU  - Huth, C.
AU  - Heier, M.
AU  - Meisinger, C.
AU  - Peters, A.
AU  - Thorand, B.
AU  - Gieger, C.
AU  - Prehn, C.
AU  - Römisch-Margl, W.
AU  - Adamski, J.
AU  - Suhre, K.
AU  - Illig, T.
AU  - Grallert, H.
AU  - Laumen, H.
AU  - Seissler, J.
AU  - Hauner, H.
C1  - 28084
C2  - 32921
CY  - New York
SP  - 386-401
TI  - Comparative analysis of plasma metabolomics response to metabolic challenge tests in healthy subjects and influence of the FTO obesity risk allele.
JO  - Catal. Lett.
VL  - 10
IS  - 3
PB  - Springer
PY  - 2014
SN  - 1011-372X
ER  - 

TY  - JOUR
AB  - Changes in an individual's human metabolic phenotype (metabotype) over time can be indicative of disorder-related modifications. Studies covering several months to a few years have shown that metabolic profiles are often specific for an individual. This "metabolic individuality" and detected changes may contribute to personalized approaches in human health care. However, it is not clear whether such individual metabotypes persist over longer time periods. Here we investigate the conservation of metabotypes characterized by 212 different metabolites of 818 participants from the Cooperative Health Research in the Region of Augsburg; Germany population, taken within a 7-year time interval. For replication, we used paired samples from 83 non-related individuals from the TwinsUK study. Results indicated that over 40 % of all study participants could be uniquely identified after 7 years based on their metabolic profiles alone. Moreover, 95 % of the study participants showed a high degree of metabotype conservation (>70 %) whereas the remaining 5 % displayed major changes in their metabolic profiles over time. These latter individuals were likely to have undergone important biochemical changes between the two time points. We further show that metabolite conservation was positively associated with heritability (rank correlation 0.74), although there were some notable exceptions. Our results suggest that monitoring changes in metabotypes over several years can trace changes in health status and may provide indications for disease onset. Moreover, our study findings provide a general reference for metabotype conservation over longer time periods that can be used in biomarker discovery studies.
AU  - Yousri, N.A.*
AU  - Kastenmüller, G.
AU  - Gieger, C.
AU  - Shin, S.-Y.*
AU  - Erte, I.*
AU  - Menni, C.*
AU  - Peters, A.
AU  - Meisinger, C.
AU  - Mohney, R.P.*
AU  - Illig, T.*
AU  - Adamski, J.
AU  - Soranzo, N.*
AU  - Spector, T.D.*
AU  - Suhre, K.
C1  - 30697
C2  - 33823
CY  - New York
SP  - 1005-1017
TI  - Long term conservation of human metabolic phenotypes and link to heritability.
JO  - Catal. Lett.
VL  - 10
IS  - 5
PB  - Springer
PY  - 2014
SN  - 1011-372X
ER  - 

TY  - JOUR
AB  - Nutrition plays an important role in human metabolism and health. Metabolomics is a promising tool for clinical, genetic and nutritional studies. A key question is to what extent metabolomic profiles reflect nutritional patterns in an epidemiological setting. We assessed the relationship between metabolomic profiles and nutritional intake in women from a large cross-sectional community study. Food frequency questionnaires (FFQs) were applied to 1,003 women from the TwinsUK cohort with targeted metabolomic analyses of serum samples using the Biocrates Absolute-IDQ (TM) Kit p150 (163 metabolites). We analyzed seven nutritional parameters: coffee intake, garlic intake and nutritional scores derived from the FFQs summarizing fruit and vegetable intake, alcohol intake, meat intake, hypo-caloric dieting and a "traditional English" diet. We studied the correlation between metabolite levels and dietary intake patterns in the larger population and identified for each trait between 14 and 20 independent monozygotic twins pairs discordant for nutritional intake and replicated results in this set. Results from both analyses were then meta-analyzed. For the metabolites associated with nutritional patterns, we calculated heritability using structural equation modelling. 42 metabolite nutrient intake associations were statistically significant in the discovery samples (Bonferroni P < 4 x 10(-5)) and 11 metabolite nutrient intake associations remained significant after validation. We found the strongest associations for fruit and vegetables intake and a glycerophospholipid (Phosphatidylcholine diacyl C38:6, P = 1.39 x 10(-9)) and a sphingolipid (Sphingomyeline C26:1, P = 6.95 x 10(-13)). We also found significant associations for coffee (confirming a previous association with C10 reported in an independent study), garlic intake and hypo-caloric dieting. Using the twin study design we find that two thirds the metabolites associated with nutritional patterns have a significant genetic contribution, and the remaining third are solely environmentally determined. Our data confirm the value of metabolomic studies for nutritional epidemiologic research.
AU  - Menni, C.*
AU  - Zhai, G.
AU  - MacGregor, A.*
AU  - Prehn, C.
AU  - Römisch-Margl, W.
AU  - Suhre, K.
AU  - Adamski, J.
AU  - Cassidy, A.*
AU  - Illig, T.
AU  - Spector, T.D.*
AU  - Valdes, A.M.*
C1  - 11312
C2  - 30606
SP  - 506-514
TI  - Targeted metabolomics profiles are strongly correlated with nutritional patterns in women.
JO  - Catal. Lett.
VL  - 9
IS  - 2
PB  - Springer
PY  - 2013
SN  - 1011-372X
ER  - 

TY  - JOUR
AB  - The amount of weight loss in obese children during lifestyle intervention differs strongly between individuals. The metabolic processes underlying this variability are largely unknown. We hypothesize that metabolomics analyses of serum samples might help to identify metabolic predictors of weight loss. In this study, we investigated 80 obese children aged 6-15 years having completed the one-year lifestyle intervention program 'Obeldicks', 40 that achieved a substantial reduction of their body mass index standard deviation score (BMI-SDS) during this intervention (defined as BMI-SDS reduction ≥ 0.5), and 40 that did not improve their overweight status (BMI-SDS reduction < 0.1). Anthropometric and clinical parameters were measured and baseline fasting serum samples of all children were analyzed with a mass spectrometry-based metabolomics approach targeting 163 metabolites. Both univariate regression models and a multivariate least absolute shrinkage and selection operator (LASSO) approach identified lower serum concentrations of long-chain unsaturated phosphatidylcholines as well as smaller waist circumference as significant predictors of BMI-SDS reduction during intervention (p-values univariate models: 5.3E-03 to 1.0E-04). A permutation test showed that the LASSO model explained a significant part of BMI-SDS change (p = 4.6E-03). Our results suggest a role of phosphatidylcholine metabolism and abdominal obesity in body weight regulation. These findings might lead to a better understanding of the mechanisms behind the large inter-individual variation in response to lifestyle interventions, which is a prerequisite for the development of individualized intervention programs.
AU  - Wahl, S.
AU  - Holzapfel, C.
AU  - Yu, Z.
AU  - Breier, M.
AU  - Kondofersky, I.
AU  - Fuchs, C.
AU  - Singmann, P.
AU  - Prehn, C.
AU  - Adamski, J.
AU  - Grallert, H.
AU  - Illig, T.
AU  - Wang-Sattler, R.
AU  - Reinehr, T.*
C1  - 26270
C2  - 32154
SP  - 1157-1167
TI  - Metabolomics reveals determinants of weight loss during lifestyle intervention in obese children.
JO  - Catal. Lett.
VL  - 9
IS  - 6
PB  - Springer
PY  - 2013
SN  - 1011-372X
ER  - 

TY  - JOUR
AB  - Volatile breath constituents such as acetone and ammonia have been linked to dextrose, fat, and protein metabolism. Non-invasive breath analysis, therefore, may be used for metabolic monitoring, identification of fuel sources actually used for energy production and determination of the anaerobic threshold (AT). This study was intended to assess correlations between exhaled volatile organic compound (VOC) concentrations, metabolism, and physiological parameters. In addition, we tried to find out whether AT could be determined by means of non-invasive analysis of VOCs in breath. Exhaled concentrations of acetone, ammonia, and isoprene were determined in 21 healthy volunteers under controlled ergometric exercise by means of continuous real time Proton Transfer Reaction Mass Spectrometry (PTR-MS). In parallel, spiro-ergometric parameters (O-2, CO2, respiratory rate and minute ventilation) and hemodynamic data such as heart rate were recorded. AT was determined from serum lactate, by means of respiratory exchange rate and by means of exhaled acetone concentrations. Exhaled acetone concentrations mirrored exercise induced changes of dextrose metabolism and lipolysis. Bland-Altman statistics showed good agreement between lactate threshold, respiratory compensation point (RCP), and determination of AT by means of exhaled acetone. Exhaled ammonia concentration seemed to be linked to protein metabolism and changes of pH under exercise. Isoprene concentrations showed a close correlation to cardiac output and minute ventilation. Breath biomarkers represent a promising alternative for metabolic monitoring under exercise as they can be determined non-invasively and continuously. In addition, these markers may add complementary information on biochemistry, energy production and fuel consumption.
AU  - Schubert, R.*
AU  - Schwoebel, H.
AU  - Mau-Moeller, A.*
AU  - Behrens, M.*
AU  - Fuchs, P.*
AU  - Sklorz, M.
AU  - Schubert, J.K.*
AU  - Bruhn, S.*
AU  - Miekisch, W.*
C1  - 11095
C2  - 30566
SP  - 1069-1080
TI  - Metabolic monitoring and assessment of anaerobic threshold by means of breath biomarkers.
JO  - Catal. Lett.
VL  - 8
IS  - 6
PB  - Springer
PY  - 2012
SN  - 1011-372X
ER  - 

TY  - JOUR
AB  - Impaired glucose tolerance (IGT) which precedes overt type 2 diabetes (T2DM) for decades is associated with multiple metabolic alterations in insulin sensitive tissues. In an UPLC-qTOF-mass spectrometry-driven non-targeted metabonomics approach we investigated plasma as well as spot urine of 51 non-diabetic, overnight fasted individuals aiming to separate subjects with IGT from controls thereby identify pathways affected by the pre-diabetic metabolic state. We could clearly demonstrate that normal glucose tolerant (NGT) and IGT subjects clustered in two distinct groups independent of the investigated metabonome. These findings reflect considerable differences in individual metabolite fingerprints, both in plasma and urine. Pre-diabetes associated alterations in fatty acid-, tryptophan-, uric acid-, bile acid-, and lysophosphatidylcholine-metabolism, as well as the TCA cycle were identified. Of note, individuals with IGT also showed decreased levels of gut flora-associated metabolites namely hippuric acid, methylxanthine, methyluric acid, and 3-hydroxyhippuric acid. The findings of our non-targeted UPLC-qTOF-MS metabonomics analysis in plasma and spot urine of individuals with IGT vs NGT offers novel insights into the metabolic alterations occurring in the long, asymptomatic period preceding the manifestation of T2DM thereby giving prospects for new intervention targets.
AU  - Zhao, X.*
AU  - Fritsche, J.*
AU  - Wang, J.*
AU  - Chen, J.*
AU  - Rittig, K.*
AU  - Schmitt-Kopplin, P.
AU  - Fritsche, A.*
AU  - Häring, H.-U.*
AU  - Schleicher, E.D.*
AU  - Xu, G.*
AU  - Lehmann, R.*
C1  - 1569
C2  - 27272
SP  - 362-374
TI  - Metabonomic fingerprints of fasting plasma and spot urine reveal human pre-diabetic metabolic traits.
JO  - Catal. Lett.
VL  - 6
IS  - 3
PB  - Springer
PY  - 2010
SN  - 1011-372X
ER  - 

TY  - JOUR
AU  - Welthagen, W.
AU  - Shellie, R.A.*
AU  - Spranger, J.*
AU  - Ristow, M.*
AU  - Zimmermann, R.
AU  - Fiehn, O.*
C1  - 1213
C2  - 22631
SP  - 65-73
TI  - Comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry (GC x GC-TOF) for high resolution metabolomics: Biomarker discovery on spleen tissue extracts of obese NZO compared to lean C57BL/6 mice.
JO  - Catal. Lett.
VL  - 1
PY  - 2005
SN  - 1011-372X
ER  -