| 1. |
- Chorell, Elin, et al.
(författare)
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A Multivariate Screening Strategy for Investigating Metabolic Effects of Strenuous Physical Exercise in Human Serum
- 2007
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Ingår i: Journal of Proteome Research. - : American Chemical Society. - 1535-3893 .- 1535-3907. ; 6:6, s. 2113-2120
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Tidskriftsartikel (refereegranskat)abstract
- A novel hypothesis-free multivariate screening methodology for the study of human exercise metabolism in blood serum is presented. Serum gas chromatography/time-of-flight mass spectrometry (GC/TOFMS) data was processed using hierarchical multivariate curve resolution (H-MCR), and orthogonal partial least-squares discriminant analysis (OPLS-DA) was used to model the systematic variation related to the acute effect of strenuous exercise. Potential metabolic biomarkers were identified using data base comparisons. Extensive validation was carried out including predictive H-MCR, 7-fold full cross-validation, and predictions for the OPLS-DA model, variable permutation for highlighting interesting metabolites, and pairwise t tests for examining the significance of metabolites. The concentration changes of potential biomarkers were verified in the raw GC/TOFMS data. In total, 420 potential metabolites were resolved in the serum samples. On the basis of the relative concentrations of the 420 resolved metabolites, a valid multivariate model for the difference between pre- and post-exercise subjects was obtained. A total of 34 metabolites were highlighted as potential biomarkers, all statistically significant (p < 8.1E-05). As an example, two potential markers were identified as glycerol and asparagine. The concentration changes for these two metabolites were also verified in the raw GC/TOFMS data.The strategy was shown to facilitate interpretation and validation of metabolic interactions in human serum as well as revealing the identity of potential markers for known or novel mechanisms of human exercise physiology. The multivariate way of addressing metabolism studies can help to increase the understanding of the integrative biology behind, as well as unravel new mechanistic explanations in relation to, exercise physiology.
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| 2. |
- Chorell, Erik, et al.
(författare)
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Efficient Synthesis of 2-Substituted Phthalimides from Phthalic Acids in One Step
- 2013
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Ingår i: European Journal of Organic Chemistry. - : Wiley-VCH Verlagsgesellschaft. - 1434-193X .- 1099-0690. ; 2013:33, s. 7512-7516
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Tidskriftsartikel (refereegranskat)abstract
- Efficient procedures for synthesizing 2-substituted phthalimide (isoindole-1,3-dione) analogues starting from phthalic acids have been developed by using experimental design. The phthalimide central fragment frequently appears in biologically active compounds, materials, catalysts, and fluorescent probes, and therefore the development of general, fast, and convenient synthetic methods to this scaffold under neutral, acidic, and basic conditions would be attractive. After an initial screening, the use of acetonitrile, acetic acid, or pyridine in combination with microwave heating proved most promising. Experimental design was applied to these conditions to optimize the time, temperature, and concentration. This strategy has successfully generated synthetic methods that have been used to synthesize a series of phthalimides from phthalic acids and various amines or anilines in excellent yields. The developed methods have proven to be general, fast, convenient, and economic, and thus are expected to have broad utility to efficiently construct novel compounds for future biological and chemical applications.
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| 3. |
- Chorell, Elin, et al.
(författare)
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Statistical multivariate metabolite profiling for aiding biomarker pattern detection and mechanistic interpretations in GC/MS based metabolomics
- 2006
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Ingår i: Metabolomics. - : Springer Science and Business Media LLC. - 1573-3882 .- 1573-3890. ; 2:4, s. 257-68
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Tidskriftsartikel (refereegranskat)abstract
- A strategy for robust and reliable mechanistic statistical modelling of metabolic responses in relation to drug induced toxicity is presented. The suggested approach addresses two cases commonly occurring within metabonomic toxicology studies, namely; 1) A pre-defined hypothesis about the biological mechanism exists and 2) No such hypothesis exists. GC/MS data from a liver toxicity study consisting of rat urine from control rats and rats exposed to a proprietary AstraZeneca compound were resolved by means of hierarchical multivariate curve resolution (H-MCR) generating 287 resolved chromatographic profiles with corresponding mass spectra. Filtering according to significance in relation to drug exposure rendered in 210 compound profiles, which were subjected to further statistical analysis following correction to account for the control variation over time. These dose related metabolite traces were then used as new observations in the subsequent analyses. For case 1, a multivariate approach, named Target Batch Analysis, based on OPLS regression was applied to correlate all metabolite traces to one or more key metabolites involved in the pre-defined hypothesis. For case 2, principal component analysis (PCA) was combined with hierarchical cluster analysis (HCA) to create a robust and interpretable framework for unbiased mechanistic screening. Both the Target Batch Analysis and the unbiased approach were cross-verified using the other method to ensure that the results did match in terms of detected metabolite traces. This was also the case, implying that this is a working concept for clustering of metabolites in relation to their toxicity induced dynamic profiles regardless if there is a pre-existing hypothesis or not. For each of the methods the detected metabolites were subjected to identification by means of data base comparison as well as verification in the raw data. The proposed strategy should be seen as a general approach for facilitating mechanistic modelling and interpretations in metabolomic studies.
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| 4. |
- Jonsson, Pär, et al.
(författare)
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Constrained randomization and multivariate effect projections improve information extraction and biomarker pattern discovery in metabolomics studies involving dependent samples
- 2015
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Ingår i: Metabolomics. - : Springer. - 1573-3882 .- 1573-3890. ; 11:6, s. 1667-1678
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Tidskriftsartikel (refereegranskat)abstract
- Analytical drift is a major source of bias in mass spectrometry based metabolomics confounding interpretation and biomarker detection. So far, standard protocols for sample and data analysis have not been able to fully resolve this. We present a combined approach for minimizing the influence of analytical drift on multivariate comparisons of matched or dependent samples in mass spectrometry based metabolomics studies. The approach is building on a randomization procedure for sample run order, constrained to independent randomizations between and within dependent sample pairs (e.g. pre/post intervention). This is followed by a novel multivariate statistical analysis strategy allowing paired or dependent analyses of individual effects named OPLS-effect projections (OPLS-EP). We show, using simulated data that OPLS-EP gives improved interpretation over existing methods and that constrained randomization of sample run order in combination with an appropriate dependent statistical test increase the accuracy and sensitivity and decrease the false omission rate in biomarker detection. We verify these findings and prove the strength of the suggested approach in a clinical data set consisting of LC/MS data of blood plasma samples from patients before and after radical prostatectomy. Here OPLS-EP compared to traditional (independent) OPLS-discriminant analysis (OPLS-DA) on constrained randomized data gives a less complex model (3 versus 5 components) as well a higher predictive ability (Q2 = 0.80 versus Q2 = 0.55). We explain this by showing that paired statistical analysis detects 37 unique significant metabolites that were masked for the independent test due to bias, including analytical drift and inter-individual variation.
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| 5. |
- Kindahl, Tomas, et al.
(författare)
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Development and optimization of simple one-step methods for the synthesis of 4-amino-substituted 1,8-naphthalimides
- 2014
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Ingår i: European Journal of Organic Chemistry. - : Wiley. - 1434-193X .- 1099-0690. ; :28, s. 6175-6182
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Tidskriftsartikel (refereegranskat)abstract
- The 1,8-naphthalimide central fragment can be found in a vast number of bioactive compounds and drugs in clinical trials, and can be recognized from their use as fluorescent probes. Of key importance for the fluorescent properties of the scaffold is the 4-amino substituent, which has also proven to be critical in several other chemical and biological applications. Because of the great interest in 1,8-naphthalimides in general, and 4-amino-substituted 1,8-naphthalimides in particular, we have developed and optimized one-step procedures with which to access these derivatives by using an experimental design approach. The multivariate studies of temperature, reaction time, and equivalents of substrates identified conditions with close to quantitative yields that could be applied to generate a range of 4-amino-substituted 1,8-naphthalimides in high yields.
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| 6. |
- Thysell, Elin, et al.
(författare)
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Processing of mass spectrometry based metabolomics data for large scale screening studies and diagnostics
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- In mass spectrometry based metabolomics predictive data processing and sample classification based on representative sample subsets makes it possible to screen large sample banks or data sets in an efficient fashion regarding both data quality and processing time. This is a requirement for making use of high sensitivity and complexity metabolite data and to turn the metabolomics field into a competitive omics platform for biological interpretation and diagnostics. Predictive metabolomics by means of hierarchical multivariate curve resolution (H-MCR) followed by orthogonal partial least squares discriminant analysis (OPLS-DA) was used for the processing and classification of gas chromatography/time of flight mass spectrometry (GC/TOFMS) data characterizing human blood serum samples collected in a study of strenuous physical exercise. The efficiency of the predictive processing as a high throughput tool for generating high quality data is clearly proven and stated as a main benefit of the method. Extensive model validation schemes by means of cross validation and external predictions verified the robustness of the extracted systematic patterns in the data. Comparisons regarding the extracted metabolite patterns between models emphasized the reliability of the methodology in a biological information context. Furthermore, the high predictive power concerning longitudinal predictions provided proof for the diagnostic potential of the methodology. Finally, the predictive metabolite pattern was interpreted physiologically as well as verified in the literature, highlighting the biological relevance of the diagnostic pattern. The suggested approach makes it feasible to screen large data or sample sets with retained data quality and interpretation and to do this in a high throughput fashion. The method could be of value for sample bank mining, metabolome-wide association studies, verification of marker patterns and development of diagnostic systems.
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| 7. |
- Thysell, Elin, et al.
(författare)
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Validated and predictive processing of gas chromatography-mass spectra screening studies, diagnostics and metabolite pattern verification
- 2012
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Ingår i: Metabolites. - : M D P I AG. - 2218-1989 .- 2218-1989. ; 2:4, s. 796-817
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Tidskriftsartikel (refereegranskat)abstract
- The suggested approach makes it feasible to screen large metabolomics data, sample sets with retained data quality or to retrieve significant metabolic information from small sample sets that can be verified over multiple studies. Hierarchical multivariate curve resolution (H-MCR), followed by orthogonal partial least squares discriminant analysis (OPLS-DA) was used for processing and classification of gas chromatography/time of flight mass spectrometry (GC/TOFMS) data characterizing human serum samples collected in a study of strenuous physical exercise. The efficiency of predictive H-MCR processing of representative sample subsets, selected by chemometric approaches, for generating high quality data was proven. Extensive model validation by means of cross-validation and external predictions verified the robustness of the extracted metabolite patterns in the data. Comparisons of extracted metabolite patterns between models emphasized the reliability of the methodology in a biological information context. Furthermore, the high predictive power in longitudinal data provided proof for the potential use in clinical diagnosis. Finally, the predictive metabolite pattern was interpreted physiologically, highlighting the biological relevance of the diagnostic pattern.
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| 8. |
- Thysell, Elin, et al.
(författare)
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Validated and Predictive Processing of Gas Chromatography-Mass Spectrometry Based Metabolomics Data for Large Scale Screening Studies, Diagnostics and Metabolite Pattern Verification
- 2012
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Ingår i: Metabolites. - Basel : MDPI. - 2218-1989. ; 2, s. 796-817
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Tidskriftsartikel (refereegranskat)abstract
- The suggested approach makes it feasible to screen large metabolomics data, sample sets with retained data quality or to retrieve significant metabolic information from small sample sets that can be verified over multiple studies. Hierarchical multivariate curve resolution (H-MCR), followed by orthogonal partial least squares discriminant analysis (OPLS-DA) was used for processing and classification of gas chromatography/time of flight mass spectrometry (GC/TOFMS) data characterizing human serum samples collected in a study of strenuous physical exercise. The efficiency of predictive H-MCR processing of representative sample subsets, selected by chemometric approaches, for generating high quality data was proven. Extensive model validation by means of cross-validation and external predictions verified the robustness of the extracted metabolite patterns in the data. Comparisons of extracted metabolite patterns between models emphasized the reliability of the methodology in a biological information context. Furthermore, the high predictive power in longitudinal data provided proof for the potential use in clinical diagnosis. Finally, the predictive metabolite pattern was interpreted physiologically, highlighting the biological relevance of the diagnostic pattern. The suggested approach makes it feasible to screen large metabolomics data, sample sets with retained data quality or to retrieve significant metabolic information from small sample sets that can be verified over multiple studies. Hierarchical multivariate curve resolution (H-MCR), followed by orthogonal partial least squares discriminant analysis (OPLS-DA) was used for processing and classification of gas chromatography/time of flight mass spectrometry (GC/TOFMS) data characterizing human serum samples collected in a study of strenuous physical exercise. The efficiency of predictive H-MCR processing of representative sample subsets, selected by chemometric approaches, for generating high quality data was proven. Extensive model validation by means of cross-validation and external predictions verified the robustness of the extracted metabolite patterns in the data. Comparisons of extracted metabolite patterns between models emphasized the reliability of the methodology in a biological information context. Furthermore, the high predictive power in longitudinal data provided proof for the potential use in clinical diagnosis. Finally, the predictive metabolite pattern was interpreted physiologically, highlighting the biological relevance of the diagnostic pattern.
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| 9. |
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| 10. |
- Bergman, Frida, Medicine doktor, 1984-, et al.
(författare)
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Walking Time Is associated With Hippocampal Volume in Overweight and Obese Office Workers
- 2020
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Ingår i: Frontiers in Human Neuroscience. - : Frontiers Media S.A.. - 1662-5161. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To investigate the long-term effects on cognition and brain function after installing treadmill workstations in offices for 13 months.Methods: Eighty healthy overweight or obese office workers aged 40–67 years were individually randomized to an intervention group, receiving a treadmill workstation and encouraging emails, or to a control group, continuing to work as usual. Effects on cognitive function, hippocampal volume, prefrontal cortex (PFC) thickness, and circulating brain-derived neurotrophic factor (BDNF) were analyzed. Further, mediation analyses between changes in walking time and light-intensity physical activity (LPA) on changes in BDNF and hippocampal volume between baseline and 13 months, and multivariate analyses of the baseline data with percentage sitting time as the response variable, were performed.Results: No group by time interactions were observed for any of the outcomes. In the mediation analyses, positive associations between changes in walking time and LPA on changes in hippocampal volume were observed, although not mediated by changes in BDNF levels. In the multivariate analyses, a negative association between percentage sitting time and hippocampal volume was observed, however only among those older than 51 years of age.Conclusion: Although no group by time interactions were observed, our analyses suggest that increased walking and LPA may have positive effects on hippocampal volume and that sedentary behavior is associated with brain structures of importance for memory functions.Trial Registration: www.ClinicalTrials.gov as NCT01997970.
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| 11. |
- Blomquist, Caroline, et al.
(författare)
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Attenuated Low-Grade Inflammation Following Long-Term Dietary Intervention in Postmenopausal Women with Obesity
- 2017
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Ingår i: Obesity. - : Wiley. - 1930-7381 .- 1930-739X. ; 25:5, s. 892-900
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveAbdominal fat accumulation after menopause is associated with low-grade inflammation and increased risk of metabolic disorders. Effective long-term lifestyle treatment is therefore needed. MethodsSeventy healthy postmenopausal women (age 605.6 years) with BMI 32.55.5 were randomized to a Paleolithic-type diet (PD) or a prudent control diet (CD) for 24 months. Blood samples and fat biopsies were collected at baseline, 6 months, and 24 months to analyze inflammation-related parameters. ResultsAndroid fat decreased significantly more in the PD group (P=0.009) during the first 6 months with weight maintenance at 24 months in both groups. Long-term significant effects (P<0.001) on adipose gene expression were found for toll-like receptor 4 (decreased at 24 months) and macrophage migration inhibitory factor (increased at 24 months) in both groups. Serum interleukin 6 (IL-6) and tumor necrosis factor levels were decreased at 24 months in both groups (P<0.001) with a significant diet-by-time interaction for serum IL-6 (P=0.022). High-sensitivity C-reactive protein was decreased in the PD group at 24 months (P=0.001). ConclusionsA reduction of abdominal obesity in postmenopausal women is linked to specific changes in inflammation-related adipose gene expression.
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| 12. |
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| 13. |
- Blomquist, Caroline, et al.
(författare)
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Decreased lipogenesis-promoting factors in adipose tissue in postmenopausal women with overweight on a Paleolithic-type diet
- 2018
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Ingår i: European Journal of Nutrition. - : Springer. - 1436-6207 .- 1436-6215. ; 57:8, s. 2877-2886
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: We studied effects of diet-induced postmenopausal weight loss on gene expression and activity of proteins involved in lipogenesis and lipolysis in adipose tissue.Methods: Fifty-eight postmenopausal women with overweight (BMI 32.5 ± 5.5) were randomized to eat an ad libitum Paleolithic-type diet (PD) aiming for a high intake of protein and unsaturated fatty acids or a prudent control diet (CD) for 24 months. Anthropometry, plasma adipokines, gene expression of proteins involved in fat metabolism in subcutaneous adipose tissue (SAT) and lipoprotein lipase (LPL) activity and mass in SAT were measured at baseline and after 6 months. LPL mass and activity were also measured after 24 months.Results: The PD led to improved insulin sensitivity (P < 0.01) and decreased circulating triglycerides (P < 0.001), lipogenesis-related factors, including LPL mRNA (P < 0.05), mass (P < 0.01), and activity (P < 0.001); as well as gene expressions of CD36 (P < 0.05), fatty acid synthase, FAS (P < 0.001) and diglyceride acyltransferase 2, DGAT2 (P < 0.001). The LPL activity (P < 0.05) and gene expression of DGAT2 (P < 0.05) and FAS (P < 0.05) were significantly lowered in the PD group versus the CD group at 6 months and the LPL activity (P < 0.05) remained significantly lowered in the PD group compared to the CD group at 24 months.Conclusions: Compared to the CD, the PD led to a more pronounced reduction of lipogenesis-promoting factors in SAT among postmenopausal women with overweight. This could have mediated the favorable metabolic effects of the PD on triglyceride levels and insulin sensitivity.
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| 14. |
- Blomquist, Caroline, 1966-, et al.
(författare)
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Long-term effects of a Paleolithic diet on plasma fatty acid composition in postmenopausal women with obesity : a randomized trial
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: A Paleolithic-type diet (PD) can improve cardiometabolic risk factors, but its impact on plasma fatty acid (FA) composition is unknown. We hypothesized that a PD improves dietary fat quality and FA metabolism, which may help counteract obesity-related metabolic dysfunction. Objective: The current study investigated the impact of a PD on biomarkers of dietary fat quality and indices of FA desaturation and de novo lipogenesis compared with a prudent control diet (CD).Design: This randomized 2-year trial included 70 women (mean ± SD age 60 ± 5.6 years, BMI 33 ± 3.4). The PD was rich in fish and vegetable fats but devoid of dairy products and lower in carbohydrates than the CD advised to follow the Nordic Nutrition recommendations. FA composition of plasma cholesterol esters (CE) was assessed using gas chromatography, desaturase activities estimated by product-to-precursor FA ratios, and dietary intake measured by 4-day food records at baseline and after 6 and 24 months.Results: Saturated fat (P=0.009) and carbohydrate (P<0.001) intake was lower, whereas polyunsaturated (PUFA), monounsaturated FA, and protein intake were higher at 24 after PD versus CD (all P<0.001). Changes in plasma FA composition during PD compared to CD suggested that saturated FAs from dairy foods were partly replaced with PUFAs from fish and vegetable sources. Although comparable BMI, energy intake, and physical activity were found at 24 months with both diets, metabolic markers and desaturase activity indices, including 16:0 (P=0.005), 16:1n-7 (P=0.002), 20:3n-6 (P=0.004), stearoyl-CoA desaturase 1 (SCD-1) (P=0.006), lipogenic index (P<0.001), and the triglyceride/high-density lipoprotein cholesterol ratio (P=0.031), were lower after 24 months of PD versus CD.Conclusions: The PD had long-term effects on dietary fat quality intake and plasma FA composition, changes previously linked to improved cardiometabolic health. The results may suggest an anti-lipogenic effect of PD, possibly contributing to improved dyslipidemia.
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| 15. |
- Blomquist, Caroline, 1966-
(författare)
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Metabolic consequences of a Paleolithic diet in obese postmenopausal women
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundObesity, in particular abdominal adiposity, is associated with elevated fatty acids and pro-inflammatory adipokines, which are linked to ectopic fat storage and insulin resistance. During menopause, there is a redistribution of fat from the peripheral to abdominal depots. This transition is associated with an increased risk of type 2 diabetes and cardiovascular diseases. We hypothesized that a Paleolithic diet, with high proportions of lean meat, fish, vegetables, fruits, and oils, but devoid of dairy products and cereals, might have long-term beneficial effects on inflammation, fat metabolism, and circulating fatty acids. These effects might potentially reduce the risk of metabolic complications in postmenopausal women that are obese. MethodsPostmenopausal women with obesity were studied before, after six months, and after 24 months of one of two specified ad libitum diets. One diet was a Paleolithic diet, in which approximately 30% of the total energy (E%) was protein, 30 E% was fat, and 40 E% was carbohydrate. The other diet was a prudent control diet, consistent with Nordic Nutrition recommendations of 15 E% protein, 25 E% fat, and 55 E% carbohydrate. Dietary intakes of polyunsaturated fatty acids and protein were validated objectively by measuring circulating and urinary biomarkers. Anthropometrics and diet reports were analyzed, and abdominal subcutaneous fat samples were evaluated for the expression of proteins key in inflammation and fat metabolism and for lipoprotein lipase mass and activity. In addition, blood samples were analyzed to determine concentrations of specific serum proteins, serum lipids, and the fatty acids carried in cholesterol esters.ResultsThe Paleolithic diet group reported reduced intakes of saturated fatty acids and carbohydrates and elevated intakes of protein and unsaturated fatty acids, compared to baseline. The elevated intakes of polyunsaturated fatty acids and protein were objectively verified for this group. After 24 months, both diets were found to have beneficial effects on the expression of inflammation-related genes in adipose tissue and pro-inflammatory factors in the circulation. Compared to the control group, the Paleolithic diet group exhibited more pronounced reductions of circulating cardiometabolic risk factors, including the ratio of triglycerides to high density lipoprotein, lipogenic index, specific fatty acids, and indices of desaturase activities. After six months, the Paleolithic group also exhibited more pronounced reductions in lipogenesis-promoting factors, including the expression of key proteins in fat synthesis, the activity of lipoprotein lipase, and the activity of stearoyl-CoA desaturase 1, compared to the control group.ConclusionLong-term weight loss in postmenopausal obese women was accompanied by reductions in low-grade inflammation in adipose tissue and in the circulation. In addition, a Paleolithic diet, with a high content of unsaturated fatty acids and a low content of refined carbohydrates, appeared to provide greater reductions in cardiometabolic risk factors associated with insulin resistance and lipogenesis, compared to a prudent control diet.
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| 16. |
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| 17. |
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| 18. |
- Chorell, Elin, et al.
(författare)
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Impact of probiotic feeding during weaning on the serum lipid profile and plasma metabolome in infants
- 2013
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Ingår i: British Journal of Nutrition. - : Cambridge University Press. - 0007-1145 .- 1475-2662. ; 110:1, s. 116-126
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Tidskriftsartikel (refereegranskat)abstract
- The gut microbiome interacts with the host in the metabolic response to diet, and early microbial aberrancies may be linked to the development of obesity and metabolic disorders later in life. Probiotics have been proposed to affect metabolic programming and blood lipid levels, although studies are lacking in infants. Here, we report on the lipid profile and global metabolic response following daily feeding of probiotics during weaning. A total of 179 healthy, term infants were randomised to daily intake of cereals with (n 89) or without (n 90) the addition of Lactobacillus paracasei ssp. paracasei F19 (LF19) 108 colony-forming units per serving from 4 to 13 months of age. Weight, length and skinfold thickness were monitored. Venous blood was drawn at 5·5 and 13 months of age for analysis of the serum lipid profile. In a subsample, randomly selected from each group, GC-time-of-flight/MS was used to metabolically characterise plasma samples from thirty-seven infants. A combination of multi- and univariate analysis was applied to reveal differences related to LF19 treatment based on 228 putative metabolites, of which ninety-nine were identified or classified. We observed no effects of probiotic feeding on anthropometrics or the serum lipid profile. However, we detected significantly lower levels of palmitoleic acid (16 : 1) (P < 0·05) and significantly higher levels of putrescine (P < 0·01) in LF19-treated infants. Palmitoleic acid is a major MUFA strongly linked to visceral obesity, while putrescine is a polyamine with importance for gut integrity. Whether the observed differences will have long-term health consequences are being followed.
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| 19. |
- Chorell, Elin, 1981-, et al.
(författare)
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Improved peripheral and hepatic insulin sensitivity after lifestyle interventions in type 2 diabetes is associated with specific metabolomic and lipidomic signatures in skeletal muscle and plasma
- 2021
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Ingår i: Metabolites. - : MDPI. - 2218-1989 .- 2218-1989. ; 11:12
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Tidskriftsartikel (refereegranskat)abstract
- Lifestyle interventions with weight loss can improve insulin sensitivity in type 2 diabetes (T2D), but mechanisms are unclear. We explored circulating and skeletal muscle metabolite signatures of altered peripheral (pIS) and hepatic insulin sensitivity (hIS) in overweight and obese T2D individuals that were randomly assigned a 12-week Paleolithic-type diet with (diet-ex, n = 13) or without (diet, n = 13) supervised exercise. Baseline and post-intervention measures included: mass spectrometry-based metabolomics and lipidomics of skeletal muscle and plasma; pIS and hIS; ectopic lipid deposits in the liver and skeletal muscle; and skeletal muscle fat oxidation rate. Both groups lowered BMI and total % fat mass and increased their pIS. Only the diet-group improved hIS and reduced ectopic lipids in the liver and muscle. The combined improvement in pIS and hIS in the diet-group were associated with decreases in muscle and circulating branched-chain amino acid (BCAA) metabolites, specifically valine. Improved pIS with diet-ex was instead linked to increased diacylglycerol (34:2) and triacylglycerol (56:0) and decreased phosphatidylcholine (34:3) in muscle coupled with improved muscle fat oxidation rate. This suggests a tissue crosstalk involving BCAA-metabolites after diet intervention with improved pIS and hIS, reflecting reduced lipid influx. Increased skeletal muscle lipid utilization with exercise may prevent specific lipid accumulation at sites that perturb insulin signaling.
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| 20. |
- Chorell, Elin, 1981-, et al.
(författare)
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Lysophospholipids as Predictive Markers of ST-Elevation Myocardial Infarction (STEMI) and Non-ST-Elevation Myocardial Infarction (NSTEMI)
- 2021
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Ingår i: Metabolites. - : MDPI. - 2218-1989 .- 2218-1989. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- The present study explored patterns of circulating metabolites and proteins that can predict future risk for ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI). We conducted a prospective nested case-control study in northern Sweden in individuals who developed STEMI (N = 50) and NSTEMI (N = 50) within 5 years and individually matched controls (N = 100). Fasted plasma samples were subjected to multiplatform mass spectrometry-based metabolomics and multiplex protein analyses. Multivariate analyses were used to elucidate infarction-specific metabolite and protein risk profiles associated with future incident STEMI and NSTEMI. We found that altered lysophosphatidylcholine (LPC) to lysophosphatidylethanolamine (LPE) ratio predicted STEMI and NSTEMI events in different ways. In STEMI, lysophospholipids (mainly LPEs) were lower, whereas in NSTEMI, lysophospholipids (mainly LPEs) were higher. We found a similar response for all detected lysophospholipids but significant alterations only for those containing linoleic acid (C18:2, p < 0.05). Patients with STEMI had higher secretoglobin family 3A member 2 and tartrate-resistant acid phosphate type 5 and lower platelet-derived growth factor subunit A, which are proteins associated with atherosclerosis severity and plaque development mediated via altered phospholipid metabolism. In contrast, patients with NSTEMI had higher levels of proteins associated with inflammation and macrophage activation, including interleukin 6, C-reactive protein, chemerin, and cathepsin X and D. The STEMI risk marker profile includes factors closely related to the development of unstable plaque, including a higher LPC:LPE ratio, whereas NSTEMI is characterized by a lower LPC:LPE ratio and increased inflammation.
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| 21. |
- Chorell, Elin, 1981-
(författare)
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Mapping the consequenses of physical exercise and nutrition on human health : A predictive metabolomics approach
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Human health is a complex and wide-ranging subject far beyond nutrition and physical exercise. Still, these factors have a huge impact on global health by their ability to prevent diseases and thus promote health. Thus, to identify health risks and benefits, it is necessary to reveal the underlying mechanisms of nutrition and exercise, which in many cases follows a complex chain of events. As a consequence, current health research is generating massive amounts of data from anthropometric parameters, genes, proteins, small molecules (metabolites) et cetera, with the intent to understand these mechanisms. For the study of health responses, especially related to physical exercise and nutrition, alterations in small molecules (metabolites) are in most cases immediate and located close to the phenotypic level and could therefore provide early signs of metabolic imbalances. Since there are roughly as many different responses to exercise and nutrients as there are humans, this quest is highly multifaceted and will benefit from an interpretation of treatment effects on a general as well as on an individual level. This thesis involves the application of chemometric methods to the study of global metabolic reactions, i.e. metabolomics, in a strategy coined predictive metabolomics. Via the application of predictive metabolomics an extensive hypothesis-free biological interpretation has been carried out of metabolite patterns in blood, acquired using gas chromatography-mass spectrometry (GC-MS), related to physical exercise, nutrition and diet, all in the context of human health. In addition, the chemometrics methodology have computational benefits concerning the extraction of relevant information from information-rich data as well as for interpreting general treatment effects and individual responses, as exemplified throughout this work. Health concerns all lifestages, thus this thesis presents a strategic framework in combination with comprehensive interpretations of metabolite patterns throughout life. This includes a broad range of human studies revealing metabolic patterns related to the impact of physical exercise, macronutrient modulation and different fitness status in young healthy males, short and long term dietary treatments in overweight post menopausal women as well as metabolic responses related to probiotics treatment and early development in infants. As a result, the studies included in the thesis have revealed metabolic patterns potentially indicative of an anti-catabolic response to macronutrients in the early recovery phase following exercise. Moreover, moderate differences in the metabolome associated with cardiorespiratory fitness level were detected, which could be linked to variation in the inflammatory and antioxidaive defense system. This work also highlighted mechanistic information that could be connected to dietary related weight loss in overweight and obese postmenopausal women in relation to short as well as long term dietary effects based on different macronutrient compositions. Finally, alterations were observed in metabolic profiles in relation to probiotics treatment in the second half of infancy, suggesting possible health benefits of probiotics supplementation at an early age.
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| 22. |
- Chorell, Elin, 1981-, et al.
(författare)
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Physical fitness level is reflected by alterations in the human plasma metabolome
- 2012
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Ingår i: Molecular BioSystems. - : Royal Society of Chemistry. - 1742-206X. ; 8:4, s. 1187-1196
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Tidskriftsartikel (refereegranskat)abstract
- An excessive energy intake combined with a low level of physical activity induces detrimental processes involved in disease development, e.g. type 2 diabetes and cardiovascular disease. However the underlying mechanisms for regulation of metabolic capacity and fitness status remain unclear. Metabolomics involves global studies of the metabolic reactions in an organism or cell. Thus hypotheses regarding biochemical events can be generated to increase the understanding of disease development and thereby aid in the development of novel treatments or preventions. We present the first standardized intervention study focusing on characterizing the human metabolome in relation to moderate differences in cardiorespiratory fitness. Gas chromatography-time of flight/mass spectrometry (GC-TOF/MS) was used to characterize 460 plasma samples from 27 individuals divided into two groups based on physical fitness level (VO2max). Multi- and univariate between group comparisons based on 197 metabolites were carried out in samples collected at rest prior to any intervention, over time following a nutritional load or a standardized exercise scheme, with and without nutritional load. We detected decreased levels of gamma-tocopherol (GT), a vitamin E isomer, in response to a high fitness level, whereas the opposite was seen for the alpha isomer (AT). In addition, the high fitness level was associated with elevated ω3-PUFA (DHA, 22:6ω3) and a decrease in ω6-PUFA (18:2ω6) as well as in saturated (16:0, 18:0), monounsaturated (18:1) and trans (16:1) fatty acids. We thus hypothesize that high fitness status induces an increased cardiorespiratory inflammatory and antioxidant defense system, more prone to deal with the inflammatory response following exercise and nutrition intake.
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| 23. |
- Chorell, Elin, 1981-, et al.
(författare)
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Plasma metabolomic response to postmenopausal weight loss induced by different diets
- 2016
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Ingår i: Metabolomics. - : Springer Science and Business Media LLC. - 1573-3882 .- 1573-3890. ; 12:5
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Tidskriftsartikel (refereegranskat)abstract
- Background Menopause is associated with increased abdominal fat and increased risk of developing diabetes and cardiovascular disease. Objectives The present study evaluated the plasma metabolic response in relation to insulin sensitivity after weight loss via diet intervention. Methods This work includes two studies; i) Ten women on a 5 weeks Paleolithic-type diet (PD, 30 energy percent (E%) protein, 40 E% fat, 30 E% carbohydrates), ii) 55 women on 6 months of either PD or Nordic Nutrition Recommendations diet (NNR, 15 E% protein, 30 E% fat, and 55 E% carbohydrates). Plasma metabolic profiles were acquired at baseline and post diet using gas chromatography time-of-flight/mass spectrometry and investigated in relation to insulin sensitivity using multivariate bioinformatics. Results Both the PD and NNR diet resulted in significant weight loss, reduced waist circumference, improved serum lipid profiles, and improved insulin sensitivity. We detected a baseline metabolic profile that correlated significantly with insulin sensitivity, and of which components increased significantly in the PD group compared to NNR. Specifically, a significant increase in myo-inositol (MI), a second messenger of insulin action, and beta-hydroxybutyric acid (beta-HB)increased while dihomogamma-linoleic acid (DGLA) decreased in PD compared to NNR, which correlated with improved insulin sensitivity. We also detected a significant decrease in tyrosine and tryptophan, potential markers of insulin resistance when elevated in the circulation, with the PD but not the NNR. Conclusions Using metabolomics, we detected changes in the plasma metabolite profiles associated with weight loss in postmenopausal women by different diets. The metabolic profiles following 6 months of PD were linked to beneficial effects on insulin sensitivity compared to NNR.
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| 24. |
- Chorell, Elin, et al.
(författare)
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Predictive Metabolomics Evaluation of Nutrition-Modulated Metabolic Stress Responses in Human Blood Serum During the Early Recovery Phase of Strenuous Physical Exercise
- 2009
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Ingår i: Journal of Proteome Research. - Washington : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 8:6, s. 2966-2977
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Tidskriftsartikel (refereegranskat)abstract
- We have investigated whether postexercise ingestion of carbohydrates in combination with proteins generates a different systemic metabolic response, as compared to the sole ingestion of carbohydrate or water, in the early recovery phase following exercise. In addition, metabolic patterns related to fitness level were studied together with individual responses to nutritional modulation. Twenty-four male subjects were exposed to 90 min of ergometer-cycling. Each participant was subject to four identical test-sessions, including ingestion of one of four beverages (water, low-carbohydrate beverage, high-carbohydrate beverage, and low-carbohydrate-protein beverage (LCHO-P)) immediately after cycling. Blood was collected at six time points, one pre- and five postexercise. Extracted blood serum was subject to metabolomic characterization by gas chromatography/time-of-flight mass spectrometry (GC-TOF MS). Data was processed using hierarchical multivariate curve resolution (HMCR), and multivariate statistical analysis was carried out using orthogonal partial least-squares (OPLS). Predictive metabolomics, including predictive HMCR and OPLS classification, was applied to ensure efficient sample processing and validation of detected metabolic patterns. Separation of subjects in relation to ingested beverage was detected and interpreted. Pseudouridine was suggested as a novel marker for pro-anabolic effect following LCHO-P ingestion, which was supported by the detected decrease of the catabolic marker 3-methylhistidine. Separation of subjects according to fitness level was achieved, and nutritional modulation by LCHO-P was shown to improve the metabolic status of less fit subjects in the recovery phase. In addition, the potential of the methodology for detection of early signs of insulin resistance was also demonstrated.
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| 25. |
- Chorell, Elin, et al.
(författare)
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Pregnancy to postpartum transition of serum metabolites in women with gestational diabetes
- 2017
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Ingår i: Metabolism-Clinical and Experimental. - : Elsevier BV. - 0026-0495 .- 1532-8600. ; 72, s. 27-36
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Tidskriftsartikel (refereegranskat)abstract
- Context. Gestational diabetes is commonly linked to development of type 2 diabetes mellitus (T2DM). There is a need to characterize metabolic changes associated with gestational diabetes in order to find novel biomarkers for T2DM. Objective. To find potential pathophysiological mechanisms and markers for progression from gestational diabetes mellitus to T2DM by studying the metabolic transition from pregnancy to postpartum. Design. The metabolic transition profile from pregnancy to postpartum was characterized in 56 women by mass spectrometry-based metabolomics; 11 women had gestational diabetes mellitus, 24 had normal glucose tolerance, and 21 were normoglycaemic but at increased risk for gestational diabetes mellitus. Fasting serum samples collected during trimester 3 (gestational week 32 +/- 0.6) and postpartum (10.5 +/- 0.4 months) were compared in diagnosis-specific multivariate models (orthogonal partial least squares analysis). Clinical measurements (e.g., insulin, glucose, lipid levels) were compared and models of insulin sensitivity and resistance were calculated for the same time period. Results. Women with gestational diabetes had significantly increased postpartum levels of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine, and their circulating lipids did not return to normal levels after pregnancy. The increase in BCAAs occurred postpartum since the BCAAs did not differ during pregnancy, as compared to normoglycemic women. Conclusions. Postpartum levels of specific BCAAs, notably valine, are related to gestational diabetes during pregnancy. (C) 2017 Elsevier Inc. All rights reserved.
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