Interventionsstudie zur Rolle von Isoflavonen im Fettstoffwechsel gesunder postmenopausaler Frauen

In postmenopausalen Frauen (PMF) gehen hormonelle Veränderungen mit charakteristischen Wechseljahrsbeschwerden und Veränderungen der Körperfettverteilung sowie der Lipoprotein- und Serumlipidkonzentrationen einher und stehen in Zusammenhang mit einem gesteigerten Risiko für kardiovaskuläre Erkrankungen (KVE). Epidemiologische- und Querschnittsstudien deuten auf ein niedrigeres Risiko für u. a. KVE in PMF aus asiatischen Ländern hin, was mit einem höheren Konsum an Soja und Sojaisoflavonen (IF) in Zusammenhang gebracht wird. IF werden in westlichen Ländern als Nahrungsergänzungsmittel für PMF als Alternative zu einer Hormonersatztherapie postuliert und von vielen Frauen konsumiert. Allerdings sind Studienergebnisse zu Wirkungen der IF z. B. auf die Lipoprotein- oder Serumlipidkonzentrationen oder weitere Risikofaktoren für KVE uneinheitlich. Modulierende Faktoren auf die Wirkungen der IF sind denkbar, welche ursächlich für diese uneinheitlichen Studienergebnisse sein könnten. So erfolgt der Transport der IF zu ca. 50 % an Lipoproteine assoziiert und Lipoproteinprofile können sich in Abhängigkeit des Körperfettgehaltes- bzw. der Körperfettverteilung unterscheiden, sodass ein Zusammenhang zwischen Körperfettgehalt- bzw. Verteilung und IF-Wirkungen angenommen wurde. Ziel der Arbeit war es, einen umfassenden Überblick über die Rolle der IF im Fettstoffwechsel der PMF zu geben. Die 12 wöchige, randomisierte, doppelblinde und Placebo-kontrollierte Studie im Paralleldesign wurde mit 179 gesunden PMF durchgeführt, die 117,4 mg/d IF-Extrakt konsumierten. Untersucht wurde einerseits der Einfluss der Inter-vention auf Serumlipidkonzentrationen und die Expression des LDLR und Scavenger-rezeptors CD36 (CD36) auf den Leukozyten und andererseits, ob modulierende Einflüsse durch den Körperfettgehalt bzw. die Viszeralfettmenge (VAT) oder den Equolbildnerstatus (EBS) auf die Intervention mit IF bestehen. Eine Genexpressionsanalyse in Biopsaten des subkutanen Bauchfettgewebes (SAT) wurde durchgeführt, um differentiell exprimierte Gene des Energie- und Fettstoffwechsels in diesem aufzuzeigen. Zudem wurde untersucht, ob die Intervention sich auf die Körperfettverteilung auswirkt und ob IF und IF-Metabolite im SAT nachgewiesen werden können. Die Intervention erhöhte die LDL-Cholesterolkonzentrationen (LDL-Chol) um ca. 3,4 %. Die weiteren Serumlipidkonzentrationen, die LDLR- und CD36-Expression auf den Leukozyten sowie die Parameter der Körperzusammensetzung wurden durch die Intervention nicht verändert. Ein Effekt des Körperfettanteils- bzw. der Menge an VAT oder des EBS auf die Intervention hinsichtlich der Serumlipidkonzentrationen und der LDLR- und CD36-Expression konnte ebenfalls nicht festgestellt werden. Im SAT waren keine Gene differentiell zwischen der Placebo- und IF-Gruppe exprimiert, auch wenn hier nach der Intervention IF nachzuweisen waren. Interventionsunabhängig kam es durch die Durchführung der Studie in zwei unterschiedlichen Jahreszeiten u. a. zu einem Anstieg der LDL Chol um 3,5 %. Die 12-wöchige Intervention mit IF-Extrakt hatte somit, mit Ausnahme des moderaten Anstiegs der LDL-Chol, keinen Einfluss auf Parameter des Fettstoffwechsels gesunder PMF. Dieser leichte Anstieg kann jedoch dadurch relativiert werden, dass ein Anstieg der LDL-Chol in vergleichbarer Höhe interventionsunabhängig auch allein durch die Durchführung der Studie in einer bestimmten Jahreszeit hätte auftreten können. Auch modulierende Effekte durch den Körperfettgehalt, die Viszeralfettmenge oder den EBS lagen nicht vor. Die Ergebnisse dieser randomisierten, doppelblinden und Placebo-kontrollierten Studie lassen den Schluss zu, dass IF im Fettstoffwechsel PMF eher eine untergeordnete Rolle spielen.The role of isoflavones in lipid metabolism of healthy postmenopausal women - an intervention study Menopause is accompanied by hormonal alterations as well as changes in lipid and lipoprotein metabolism and is furthermore associated with alterations in body fat distribution. These alterations lead to an increased risk of cardiovascular diseases (CVD) in postmenopausal women (PMW). Epidemiological and cross sectional studies indicate lower incidence of CVD and menopausal symptoms in PMW in Asian countries. This is assumed to be associated with a higher amount of soy and soy isoflavones (IF) in Asian diets. In Western countries, IF are over-the–counter supplements and represent a potential alternative to hormone replacement therapies for PMW suffering from menopausal symptoms. However, studies regarding the effects of IF on e.g. lipoprotein or serum lipid concentrations or other risk factors concerning CVD show heterogeneous results. It is conceivable that modulating factors exist, which are responsible for these disparate results. It is known that approx. 50 % of the IF transport is associated with lipoproteins. Lipoprotein profiles can vary due to different body fat contents or body fat compositions. Therefore, a direct interaction between body fat content or the amount of visceral adipose tissue and effects of IF can be assumed. The objective of the presented work was to give a comprehensive overview about the role of IF in the lipid metabolism of PMW. A randomized, double-blind and placebo-controlled study with 179 healthy PMW was conducted over a period of 12 weeks. An over-the-counter IF extract was used as the intervention product with a daily dose of 117.4 mg. Effects of IF on serum lipid concentrations and the expression of LDLR and CD36 receptors on leukocytes were examined. Moreover, a modulating effect of body fat content or rather the amount of visceral adipose tissue (VAT) or the ability to produce equol on effects of IF was investigated. Biopsies of subcutaneous adipose tissue (SAT) were used to perform a gene expression analysis to show differentially expressed genes of lipid and energy metabolism due to the intervention. Furthermore, IF and their metabolites were determined in these samples. Effects of IF on body fat content and body composition were also investigated. An effect of IF on serum lipid concentrations was only shown for LDL-cholesterol concentrations (LDL-chol), which rose around 3.4 % after 12 weeks of IF intervention. No effects were shown for total cholesterol and HDL-cholesterol concentrations. Expression of LDLR and CD36 receptors as well as body composition parameters were not affected through the intervention. The postulated effect of body fat content or rather the amount of VAT on IF effects on serum lipid concentrations and receptor expressions could not be proved. The ability to produce equol did not contribute to potential IF effects in these women compared to women not able to produce equol. In subcutaneous adipose tissue, genes of lipid or energy metabolism were not differentially expressed between the placebo and IF group. However, IF could be found in this tissue after 12 weeks of intervention. As the study was conducted during two different seasons, effects on e. g. LDL-chol occurred independently of the intervention with IF. This seasonal effect increased LDL-chol by 3.5 %. Summarizing the aforementioned results, the intervention with 117.4 mg IF extract per day for 12 weeks did not affect parameters of lipid metabolism in healthy PMW, except for a moderate rise in LDL-chol. A similar increase of LDL-chol can also occur independently of the IF intervention by simply conducting a study in a particular season. Therefore, the moderate effect of IF on LDL-chol can be qualified. A modulating effect of body fat content or rather the amount of VAT regarding IF effects was not observed. It can be concluded that IF only play a minor role in the lipid metabolism of healthy PMW

Microbial Metabolism of the Soy Isoflavones Daidzein and Genistein in Postmenopausal Women: Human Intervention Study Reveals New Metabotypes

Background: Soy isoflavones belong to the group of phytoestrogens and are associated with beneficial health effects but are also discussed to have adverse effects. Isoflavones are intensively metabolized by the gut microbiota leading to metabolites with altered estrogenic potency. The population is classified into different isoflavone metabotypes based on individual metabolite profiles. So far, this classification was based on the capacity to metabolize daidzein and did not reflect genistein metabolism. We investigated the microbial metabolite profile of isoflavones considering daidzein and genistein. Methods: Isoflavones and metabolites were quantified in the urine of postmenopausal women receiving a soy isoflavone extract for 12 weeks. Based on these data, women were clustered in different isoflavone metabotypes. Further, the estrogenic potency of these metabotypes was estimated. Results: Based on the excreted urinary amounts of isoflavones and metabolites, the metabolite profiles could be calculated, resulting in 5 metabotypes applying a hierarchical cluster analysis. The metabotypes differed in part strongly regarding their metabolite profile and their estimated estrogenic potency

Image3_Acute effects of moderate vs. vigorous endurance exercise on urinary metabolites in healthy, young, physically active men—A multi-platform metabolomics approach.JPEG

Introduction: Endurance exercise alters whole-body as well as skeletal muscle metabolism and physiology, leading to improvements in performance and health. However, biological mechanisms underlying the body’s adaptations to different endurance exercise protocols are not entirely understood.Methods: We applied a multi-platform metabolomics approach to identify urinary metabolites and associated metabolic pathways that distinguish the acute metabolic response to two endurance exercise interventions at distinct intensities. In our randomized crossover study, 16 healthy, young, and physically active men performed 30 min of continuous moderate exercise (CME) and continuous vigorous exercise (CVE). Urine was collected during three post-exercise sampling phases (U01/U02/U03: until 45/105/195 min post-exercise), providing detailed temporal information on the response of the urinary metabolome to CME and CVE. Also, fasting spot urine samples were collected pre-exercise (U00) and on the following day (U04). While untargeted two-dimensional gas chromatography-mass spectrometry (GC×GC-MS) led to the detection of 608 spectral features, 44 metabolites were identified and quantified by targeted nuclear magnetic resonance (NMR) spectroscopy or liquid chromatography-mass spectrometry (LC-MS).Results: 104 urinary metabolites showed at least one significant difference for selected comparisons of sampling time points within or between exercise trials as well as a relevant median fold change >1.5 or 2.0 or Discussion: To conclude, this study provided first evidence of specific urinary metabolites as potential metabolic markers of endurance exercise intensity. Future studies are needed to validate our results and to examine whether acute metabolite changes in urine might also be partly reflective of mechanisms underlying the health- or performance-enhancing effects of endurance exercise, particularly if performed at high intensities.</p

DataSheet1_Acute effects of moderate vs. vigorous endurance exercise on urinary metabolites in healthy, young, physically active men—A multi-platform metabolomics approach.PDF

Introduction: Endurance exercise alters whole-body as well as skeletal muscle metabolism and physiology, leading to improvements in performance and health. However, biological mechanisms underlying the body’s adaptations to different endurance exercise protocols are not entirely understood.Methods: We applied a multi-platform metabolomics approach to identify urinary metabolites and associated metabolic pathways that distinguish the acute metabolic response to two endurance exercise interventions at distinct intensities. In our randomized crossover study, 16 healthy, young, and physically active men performed 30 min of continuous moderate exercise (CME) and continuous vigorous exercise (CVE). Urine was collected during three post-exercise sampling phases (U01/U02/U03: until 45/105/195 min post-exercise), providing detailed temporal information on the response of the urinary metabolome to CME and CVE. Also, fasting spot urine samples were collected pre-exercise (U00) and on the following day (U04). While untargeted two-dimensional gas chromatography-mass spectrometry (GC×GC-MS) led to the detection of 608 spectral features, 44 metabolites were identified and quantified by targeted nuclear magnetic resonance (NMR) spectroscopy or liquid chromatography-mass spectrometry (LC-MS).Results: 104 urinary metabolites showed at least one significant difference for selected comparisons of sampling time points within or between exercise trials as well as a relevant median fold change >1.5 or 2.0 or Discussion: To conclude, this study provided first evidence of specific urinary metabolites as potential metabolic markers of endurance exercise intensity. Future studies are needed to validate our results and to examine whether acute metabolite changes in urine might also be partly reflective of mechanisms underlying the health- or performance-enhancing effects of endurance exercise, particularly if performed at high intensities.</p

Table4_Acute effects of moderate vs. vigorous endurance exercise on urinary metabolites in healthy, young, physically active men—A multi-platform metabolomics approach.XLSX

Introduction: Endurance exercise alters whole-body as well as skeletal muscle metabolism and physiology, leading to improvements in performance and health. However, biological mechanisms underlying the body’s adaptations to different endurance exercise protocols are not entirely understood.Methods: We applied a multi-platform metabolomics approach to identify urinary metabolites and associated metabolic pathways that distinguish the acute metabolic response to two endurance exercise interventions at distinct intensities. In our randomized crossover study, 16 healthy, young, and physically active men performed 30 min of continuous moderate exercise (CME) and continuous vigorous exercise (CVE). Urine was collected during three post-exercise sampling phases (U01/U02/U03: until 45/105/195 min post-exercise), providing detailed temporal information on the response of the urinary metabolome to CME and CVE. Also, fasting spot urine samples were collected pre-exercise (U00) and on the following day (U04). While untargeted two-dimensional gas chromatography-mass spectrometry (GC×GC-MS) led to the detection of 608 spectral features, 44 metabolites were identified and quantified by targeted nuclear magnetic resonance (NMR) spectroscopy or liquid chromatography-mass spectrometry (LC-MS).Results: 104 urinary metabolites showed at least one significant difference for selected comparisons of sampling time points within or between exercise trials as well as a relevant median fold change >1.5 or 2.0 or Discussion: To conclude, this study provided first evidence of specific urinary metabolites as potential metabolic markers of endurance exercise intensity. Future studies are needed to validate our results and to examine whether acute metabolite changes in urine might also be partly reflective of mechanisms underlying the health- or performance-enhancing effects of endurance exercise, particularly if performed at high intensities.</p

Table6_Acute effects of moderate vs. vigorous endurance exercise on urinary metabolites in healthy, young, physically active men—A multi-platform metabolomics approach.DOCX

Introduction: Endurance exercise alters whole-body as well as skeletal muscle metabolism and physiology, leading to improvements in performance and health. However, biological mechanisms underlying the body’s adaptations to different endurance exercise protocols are not entirely understood.Methods: We applied a multi-platform metabolomics approach to identify urinary metabolites and associated metabolic pathways that distinguish the acute metabolic response to two endurance exercise interventions at distinct intensities. In our randomized crossover study, 16 healthy, young, and physically active men performed 30 min of continuous moderate exercise (CME) and continuous vigorous exercise (CVE). Urine was collected during three post-exercise sampling phases (U01/U02/U03: until 45/105/195 min post-exercise), providing detailed temporal information on the response of the urinary metabolome to CME and CVE. Also, fasting spot urine samples were collected pre-exercise (U00) and on the following day (U04). While untargeted two-dimensional gas chromatography-mass spectrometry (GC×GC-MS) led to the detection of 608 spectral features, 44 metabolites were identified and quantified by targeted nuclear magnetic resonance (NMR) spectroscopy or liquid chromatography-mass spectrometry (LC-MS).Results: 104 urinary metabolites showed at least one significant difference for selected comparisons of sampling time points within or between exercise trials as well as a relevant median fold change >1.5 or 2.0 or Discussion: To conclude, this study provided first evidence of specific urinary metabolites as potential metabolic markers of endurance exercise intensity. Future studies are needed to validate our results and to examine whether acute metabolite changes in urine might also be partly reflective of mechanisms underlying the health- or performance-enhancing effects of endurance exercise, particularly if performed at high intensities.</p

Image6_Acute effects of moderate vs. vigorous endurance exercise on urinary metabolites in healthy, young, physically active men—A multi-platform metabolomics approach.JPEG

Introduction: Endurance exercise alters whole-body as well as skeletal muscle metabolism and physiology, leading to improvements in performance and health. However, biological mechanisms underlying the body’s adaptations to different endurance exercise protocols are not entirely understood.Methods: We applied a multi-platform metabolomics approach to identify urinary metabolites and associated metabolic pathways that distinguish the acute metabolic response to two endurance exercise interventions at distinct intensities. In our randomized crossover study, 16 healthy, young, and physically active men performed 30 min of continuous moderate exercise (CME) and continuous vigorous exercise (CVE). Urine was collected during three post-exercise sampling phases (U01/U02/U03: until 45/105/195 min post-exercise), providing detailed temporal information on the response of the urinary metabolome to CME and CVE. Also, fasting spot urine samples were collected pre-exercise (U00) and on the following day (U04). While untargeted two-dimensional gas chromatography-mass spectrometry (GC×GC-MS) led to the detection of 608 spectral features, 44 metabolites were identified and quantified by targeted nuclear magnetic resonance (NMR) spectroscopy or liquid chromatography-mass spectrometry (LC-MS).Results: 104 urinary metabolites showed at least one significant difference for selected comparisons of sampling time points within or between exercise trials as well as a relevant median fold change >1.5 or 2.0 or Discussion: To conclude, this study provided first evidence of specific urinary metabolites as potential metabolic markers of endurance exercise intensity. Future studies are needed to validate our results and to examine whether acute metabolite changes in urine might also be partly reflective of mechanisms underlying the health- or performance-enhancing effects of endurance exercise, particularly if performed at high intensities.</p

Image7_Acute effects of moderate vs. vigorous endurance exercise on urinary metabolites in healthy, young, physically active men—A multi-platform metabolomics approach.JPEG

Introduction: Endurance exercise alters whole-body as well as skeletal muscle metabolism and physiology, leading to improvements in performance and health. However, biological mechanisms underlying the body’s adaptations to different endurance exercise protocols are not entirely understood.Methods: We applied a multi-platform metabolomics approach to identify urinary metabolites and associated metabolic pathways that distinguish the acute metabolic response to two endurance exercise interventions at distinct intensities. In our randomized crossover study, 16 healthy, young, and physically active men performed 30 min of continuous moderate exercise (CME) and continuous vigorous exercise (CVE). Urine was collected during three post-exercise sampling phases (U01/U02/U03: until 45/105/195 min post-exercise), providing detailed temporal information on the response of the urinary metabolome to CME and CVE. Also, fasting spot urine samples were collected pre-exercise (U00) and on the following day (U04). While untargeted two-dimensional gas chromatography-mass spectrometry (GC×GC-MS) led to the detection of 608 spectral features, 44 metabolites were identified and quantified by targeted nuclear magnetic resonance (NMR) spectroscopy or liquid chromatography-mass spectrometry (LC-MS).Results: 104 urinary metabolites showed at least one significant difference for selected comparisons of sampling time points within or between exercise trials as well as a relevant median fold change >1.5 or 2.0 or Discussion: To conclude, this study provided first evidence of specific urinary metabolites as potential metabolic markers of endurance exercise intensity. Future studies are needed to validate our results and to examine whether acute metabolite changes in urine might also be partly reflective of mechanisms underlying the health- or performance-enhancing effects of endurance exercise, particularly if performed at high intensities.</p

Image4_Acute effects of moderate vs. vigorous endurance exercise on urinary metabolites in healthy, young, physically active men—A multi-platform metabolomics approach.JPEG

Introduction: Endurance exercise alters whole-body as well as skeletal muscle metabolism and physiology, leading to improvements in performance and health. However, biological mechanisms underlying the body’s adaptations to different endurance exercise protocols are not entirely understood.Methods: We applied a multi-platform metabolomics approach to identify urinary metabolites and associated metabolic pathways that distinguish the acute metabolic response to two endurance exercise interventions at distinct intensities. In our randomized crossover study, 16 healthy, young, and physically active men performed 30 min of continuous moderate exercise (CME) and continuous vigorous exercise (CVE). Urine was collected during three post-exercise sampling phases (U01/U02/U03: until 45/105/195 min post-exercise), providing detailed temporal information on the response of the urinary metabolome to CME and CVE. Also, fasting spot urine samples were collected pre-exercise (U00) and on the following day (U04). While untargeted two-dimensional gas chromatography-mass spectrometry (GC×GC-MS) led to the detection of 608 spectral features, 44 metabolites were identified and quantified by targeted nuclear magnetic resonance (NMR) spectroscopy or liquid chromatography-mass spectrometry (LC-MS).Results: 104 urinary metabolites showed at least one significant difference for selected comparisons of sampling time points within or between exercise trials as well as a relevant median fold change >1.5 or 2.0 or Discussion: To conclude, this study provided first evidence of specific urinary metabolites as potential metabolic markers of endurance exercise intensity. Future studies are needed to validate our results and to examine whether acute metabolite changes in urine might also be partly reflective of mechanisms underlying the health- or performance-enhancing effects of endurance exercise, particularly if performed at high intensities.</p