Publications by authors named "Nathalie Poupin"

20 Publications

  • Page 1 of 1

Multiplatform metabolomics for an integrative exploration of metabolic syndrome in older men.

EBioMedicine 2021 Jun 19;69:103440. Epub 2021 Jun 19.

Université Clermont Auvergne, INRAE, UNH, Plateforme d'Exploration du Métabolisme, MetaboHUB Clermont, Clermont-Ferrand, France. Electronic address:

Background: Metabolic syndrome (MetS), a cluster of factors associated with risks of developing cardiovascular diseases, is a public health concern because of its growing prevalence. Considering the combination of concomitant components, their development and severity, MetS phenotypes are largely heterogeneous, inducing disparity in diagnosis.

Methods: A case/control study was designed within the NuAge longitudinal cohort on aging. From a 3-year follow-up of 123 stable individuals, we present a deep phenotyping approach based on a multiplatform metabolomics and lipidomics untargeted strategy to better characterize metabolic perturbations in MetS and define a comprehensive MetS signature stable over time in older men.

Findings: We characterize significant changes associated with MetS, involving modulations of 476 metabolites and lipids, and representing 16% of the detected serum metabolome/lipidome. These results revealed a systemic alteration of metabolism, involving various metabolic pathways (urea cycle, amino-acid, sphingo- and glycerophospholipid, and sugar metabolisms…) not only intrinsically interrelated, but also reflecting environmental factors (nutrition, microbiota, physical activity…).

Interpretation: These findings allowed identifying a comprehensive MetS signature, reduced to 26 metabolites for future translation into clinical applications for better diagnosing MetS.
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http://dx.doi.org/10.1016/j.ebiom.2021.103440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237302PMC
June 2021

Mitochondrial metabolism supports resistance to IDH mutant inhibitors in acute myeloid leukemia.

J Exp Med 2021 May;218(5)

Institut de Recherche en Cancérologie de Montpellier, Institut National de la Santé et de la Recherché Médicale, Université de Montpellier, Institut Régional du Cancer Montpellier, Montpellier, France.

Mutations in IDH induce epigenetic and transcriptional reprogramming, differentiation bias, and susceptibility to mitochondrial inhibitors in cancer cells. Here, we first show that cell lines, PDXs, and patients with acute myeloid leukemia (AML) harboring an IDH mutation displayed an enhanced mitochondrial oxidative metabolism. Along with an increase in TCA cycle intermediates, this AML-specific metabolic behavior mechanistically occurred through the increase in electron transport chain complex I activity, mitochondrial respiration, and methylation-driven CEBPα-induced fatty acid β-oxidation of IDH1 mutant cells. While IDH1 mutant inhibitor reduced 2-HG oncometabolite and CEBPα methylation, it failed to reverse FAO and OxPHOS. These mitochondrial activities were maintained through the inhibition of Akt and enhanced activation of peroxisome proliferator-activated receptor-γ coactivator-1 PGC1α upon IDH1 mutant inhibitor. Accordingly, OxPHOS inhibitors improved anti-AML efficacy of IDH mutant inhibitors in vivo. This work provides a scientific rationale for combinatory mitochondrial-targeted therapies to treat IDH mutant AML patients, especially those unresponsive to or relapsing from IDH mutant inhibitors.
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http://dx.doi.org/10.1084/jem.20200924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995203PMC
May 2021

DEXOM: Diversity-based enumeration of optimal context-specific metabolic networks.

PLoS Comput Biol 2021 02 11;17(2):e1008730. Epub 2021 Feb 11.

Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, Toulouse, France.

The correct identification of metabolic activity in tissues or cells under different conditions can be extremely elusive due to mechanisms such as post-transcriptional modification of enzymes or different rates in protein degradation, making difficult to perform predictions on the basis of gene expression alone. Context-specific metabolic network reconstruction can overcome some of these limitations by leveraging the integration of multi-omics data into genome-scale metabolic networks (GSMN). Using the experimental information, context-specific models are reconstructed by extracting from the generic GSMN the sub-network most consistent with the data, subject to biochemical constraints. One advantage is that these context-specific models have more predictive power since they are tailored to the specific tissue, cell or condition, containing only the reactions predicted to be active in such context. However, an important limitation is that there are usually many different sub-networks that optimally fit the experimental data. This set of optimal networks represent alternative explanations of the possible metabolic state. Ignoring the set of possible solutions reduces the ability to obtain relevant information about the metabolism and may bias the interpretation of the true metabolic states. In this work we formalize the problem of enumerating optimal metabolic networks and we introduce DEXOM, an unified approach for diversity-based enumeration of context-specific metabolic networks. We developed different strategies for this purpose and we performed an exhaustive analysis using simulated and real data. In order to analyze the extent to which these results are biologically meaningful, we used the alternative solutions obtained with the different methods to measure: 1) the improvement of in silico predictions of essential genes in Saccharomyces cerevisiae using ensembles of metabolic network; and 2) the detection of alternative enriched pathways in different human cancer cell lines. We also provide DEXOM as an open-source library compatible with COBRA Toolbox 3.0, available at https://github.com/MetExplore/dexom.
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http://dx.doi.org/10.1371/journal.pcbi.1008730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904180PMC
February 2021

An Integrated Analysis of miRNA and Gene Expression Changes in Response to an Obesogenic Diet to Explore the Impact of Transgenerational Supplementation with Omega 3 Fatty Acids.

Nutrients 2020 Dec 17;12(12). Epub 2020 Dec 17.

Unité de Nutrition Humaine (UNH), Université Clermont Auvergne, Institut National de Recherche pour L'agriculture, L'alimentation et L'environnement (INRAE), Faculté de Médecine, F-63000 Clermont-Ferrand, France.

Insulin resistance decreases the ability of insulin to inhibit hepatic gluconeogenesis, a key step in the development of metabolic syndrome. Metabolic alterations, fat accumulation, and fibrosis in the liver are closely related and contribute to the progression of comorbidities, such as hypertension, type 2 diabetes, or cancer. Omega 3 (-3) polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA), were identified as potent positive regulators of insulin sensitivity in vitro and in animal models. In the current study, we explored the effects of a transgenerational supplementation with EPA in mice exposed to an obesogenic diet on the regulation of microRNAs (miRNAs) and gene expression in the liver using high-throughput techniques. We implemented a comprehensive molecular systems biology approach, combining statistical tools, such as MicroRNA Master Regulator Analysis pipeline and Boolean modeling to integrate these biochemical processes. We demonstrated that EPA mediated molecular adaptations, leading to the inhibition of miR-34a-5p, a negative regulator of Irs2 as a master regulatory event leading to the inhibition of gluconeogenesis by insulin during the fasting-feeding transition. Omics data integration provided greater biological insight and a better understanding of the relationships between biological variables. Such an approach may be useful for deriving innovative data-driven hypotheses and for the discovery of molecular-biochemical mechanistic links.
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http://dx.doi.org/10.3390/nu12123864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765958PMC
December 2020

An Optimized Dual Extraction Method for the Simultaneous and Accurate Analysis of Polar Metabolites and Lipids Carried out on Single Biological Samples.

Metabolites 2020 Aug 19;10(9). Epub 2020 Aug 19.

MetaboHUB-MetaToul-Lipidomics Core Facility, Inserm U1048, 31432 Toulouse, France.

The functional understanding of metabolic changes requires both a significant investigation into metabolic pathways, as enabled by global metabolomics and lipidomics approaches, and the comprehensive and accurate exploration of specific key pathways. To answer this pivotal challenge, we propose an optimized approach, which combines an efficient sample preparation, aiming to reduce the variability, with a biphasic extraction method, where both the aqueous and organic phases of the same sample are used for mass spectrometry analyses. We demonstrated that this double extraction protocol allows working with one single sample without decreasing the metabolome and lipidome coverage. It enables the targeted analysis of 40 polar metabolites and 82 lipids, together with the absolute quantification of 32 polar metabolites, providing comprehensive coverage and quantitative measurement of the metabolites involved in central carbon energy pathways. With this method, we evidenced modulations of several lipids, amino acids, and energy metabolites in HepaRG cells exposed to fenofibrate, a model hepatic toxicant, and metabolic modulator. This new protocol is particularly relevant for experiments involving limited amounts of biological material and for functional metabolic explorations and is thus of particular interest for studies aiming to decipher the effects and modes of action of metabolic disrupting compounds.
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http://dx.doi.org/10.3390/metabo10090338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7570216PMC
August 2020

Postprandial NMR-Based Metabolic Exchanges Reflect Impaired Phenotypic Flexibility across Splanchnic Organs in the Obese Yucatan Mini-Pig.

Nutrients 2020 Aug 14;12(8). Epub 2020 Aug 14.

INRAE, Unité de Nutrition Humaine, Université Clermont Auvergne, 63000 Clermont-Ferrand, France.

The postprandial period represents one of the most challenging phenomena in whole-body metabolism, and it can be used as a unique window to evaluate the phenotypic flexibility of an individual in response to a given meal, which can be done by measuring the resilience of the metabolome. However, this exploration of the metabolism has never been applied to the arteriovenous (AV) exploration of organs metabolism. Here, we applied an AV metabolomics strategy to evaluate the postprandial flexibility across the liver and the intestine of mini-pigs subjected to a high fat-high sucrose (HFHS) diet for 2 months. We identified for the first time a postprandial signature associated to the insulin resistance and obesity outcomes, and we showed that the splanchnic postprandial metabolome was considerably affected by the meal and the obesity condition. Most of the changes induced by obesity were observed in the exchanges across the liver, where the metabolism was reorganized to maintain whole body glucose homeostasis by routing glucose formed de novo from a large variety of substrates into glycogen. Furthermore, metabolites related to lipid handling and energy metabolism showed a blunted postprandial response in the obese animals across organs. Finally, some of our results reflect a loss of flexibility in response to the HFHS meal challenge in unsuspected metabolic pathways that must be further explored as potential new events involved in early obesity and the onset of insulin resistance.
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http://dx.doi.org/10.3390/nu12082442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468879PMC
August 2020

Improving lipid mapping in Genome Scale Metabolic Networks using ontologies.

Metabolomics 2020 03 25;16(4):44. Epub 2020 Mar 25.

UMR1331, Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31300, Toulouse, France.

Introduction: To interpret metabolomic and lipidomic profiles, it is necessary to identify the metabolic reactions that connect the measured molecules. This can be achieved by putting them in the context of genome-scale metabolic network reconstructions. However, mapping experimentally measured molecules onto metabolic networks is challenging due to differences in identifiers and level of annotation between data and metabolic networks, especially for lipids.

Objectives: To help linking lipids from lipidomics datasets with lipids in metabolic networks, we developed a new matching method based on the ChEBI ontology. The implementation is freely available as a python library and in MetExplore webserver.

Methods: Our matching method is more flexible than an exact identifier-based correspondence since it allows establishing a link between molecules even if a different level of precision is provided in the dataset and in the metabolic network. For instance, it can associate a generic class of lipids present in the network with the molecular species detailed in the lipidomics dataset. This mapping is based on the computation of a distance between molecules in ChEBI ontology.

Results: We applied our method to a chemical library (968 lipids) and an experimental dataset (32 modulated lipids) and showed that using ontology-based mapping improves and facilitates the link with genome scale metabolic networks. Beyond network mapping, the results provide ways for improvements in terms of network curation and lipidomics data annotation.

Conclusion: This new method being generic, it can be applied to any metabolomics data and therefore improve our comprehension of metabolic modulations.
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http://dx.doi.org/10.1007/s11306-020-01663-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096385PMC
March 2020

Arterio-venous metabolomics exploration reveals major changes across liver and intestine in the obese Yucatan minipig.

Sci Rep 2019 08 29;9(1):12527. Epub 2019 Aug 29.

Université Clermont Auvergne, INRA, Unité de Nutrition Humaine, UMR1019, Clermont-Ferrand, France.

Blood circulation mainly aims at distributing the nutrients required for tissue metabolism and collecting safely the by-products of all tissues to be further metabolized or eliminated. The simultaneous study of arterial (A) and venous (V) specific metabolites therefore has appeared to be a more relevant approach to understand and study the metabolism of a given organ. We propose to implement this approach by applying a metabolomics (NMR) strategy on paired AV blood across the intestine and liver on high fat/high sugar (HFHS)-fed minipigs. Our objective was to unravel kinetically and sequentially the metabolic adaptations to early obesity/insulin resistance onset specifically on these two tissues. After two months of HFHS feeding our study of AV ratios of the metabolome highlighted three major features. First, the hepatic metabolism switched from carbohydrate to lipid utilization. Second, the energy demand of the intestine increased, resulting in an enhanced uptake of glutamine, glutamate, and the recruitment of novel energy substrates (choline and creatine). Third, the uptake of methionine and threonine was considered to be driven by an increased intestine turnover to cope with the new high-density diet. Finally, the unique combination of experimental data and modelling predictions suggested that HFHS feeding was associated with changes in tryptophan metabolism and fatty acid β-oxidation, which may play an important role in lipid hepatic accumulation and insulin sensitivity.
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http://dx.doi.org/10.1038/s41598-019-48997-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715693PMC
August 2019

Large-Scale Modeling Approach Reveals Functional Metabolic Shifts during Hepatic Differentiation.

J Proteome Res 2019 01 19;18(1):204-216. Epub 2018 Nov 19.

UMR1331 Toxalim (Research Centre in Food Toxicology) , Université de Toulouse, INRA, ENVT, INP-Purpan, UPS , 31027 Toulouse , France.

Being able to explore the metabolism of broad metabolizing cells is of critical importance in many research fields. This article presents an original modeling solution combining metabolic network and omics data to identify modulated metabolic pathways and changes in metabolic functions occurring during differentiation of a human hepatic cell line (HepaRG). Our results confirm the activation of hepato-specific functionalities and newly evidence modulation of other metabolic pathways, which could not be evidenced from transcriptomic data alone. Our method takes advantage of the network structure to detect changes in metabolic pathways that do not have gene annotations and exploits flux analyses techniques to identify activated metabolic functions. Compared to the usual cell-specific metabolic network reconstruction approaches, it limits false predictions by considering several possible network configurations to represent one phenotype rather than one arbitrarily selected network. Our approach significantly enhances the comprehensive and functional assessment of cell metabolism, opening further perspectives to investigate metabolic shifts occurring within various biological contexts.
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http://dx.doi.org/10.1021/acs.jproteome.8b00524DOI Listing
January 2019

An Untargeted Metabolomics Approach to Investigate the Metabolic Modulations of HepG2 Cells Exposed to Low Doses of Bisphenol A and 17β-Estradiol.

Front Endocrinol (Lausanne) 2018 25;9:571. Epub 2018 Sep 25.

Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France.

The model xeno-estrogen bisphenol A (BPA) has been extensively studied over the past two decades, contributing to major advances in the field of endocrine disrupting chemicals research. Besides its well documented adverse effects on reproduction and development observed in rodents, latest studies strongly suggest that BPA disrupts several endogenous metabolic pathways, with suspected steatogenic and obesogenic effects. BPA's adverse effects on reproduction are attributed to its ability to activate estrogen receptors (ERs), but its effects on metabolism and its mechanism(s) of action at low doses are so far only marginally understood. Metabolomics based approaches are increasingly used in toxicology to investigate the biological changes induced by model toxicants and chemical mixtures, to identify markers of toxicity and biological effects. In this study, we used proton nuclear magnetic resonance (H-NMR) based untargeted metabolite profiling, followed by multivariate statistics and computational analysis of metabolic networks to examine the metabolic modulation induced in human hepatic cells (HepG2) by an exposure to low and very low doses of BPA (10M, 10M, and 10M), vs. the female reference hormone 17β-estradiol (E2, 10M, 10M, and 10M). Metabolomic analysis combined to metabolic network reconstruction highlighted different mechanisms at lower doses of exposure. At the highest dose, our results evidence that BPA shares with E2 the capability to modulate several major metabolic routes that ensure cellular functions and detoxification processes, although the effects of the model xeno-estrogen and of the natural hormone can still be distinguished.
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http://dx.doi.org/10.3389/fendo.2018.00571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167423PMC
September 2018

Integrated transcriptomics and metabolomics reveal signatures of lipid metabolism dysregulation in HepaRG liver cells exposed to PCB 126.

Arch Toxicol 2018 08 14;92(8):2533-2547. Epub 2018 Jun 14.

Gene Expression and Therapy Group, King's College London, Faculty of Life Sciences and Medicine, Department of Medical and Molecular Genetics, 8th Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.

Chemical pollutant exposure is a risk factor contributing to the growing epidemic of non-alcoholic fatty liver disease (NAFLD) affecting human populations that consume a western diet. Although it is recognized that intoxication by chemical pollutants can lead to NAFLD, there is limited information available regarding the mechanism by which typical environmental levels of exposure can contribute to the onset of this disease. Here, we describe the alterations in gene expression profiles and metabolite levels in the human HepaRG liver cell line, a validated model for cellular steatosis, exposed to the polychlorinated biphenyl (PCB) 126, one of the most potent chemical pollutants that can induce NAFLD. Sparse partial least squares classification of the molecular profiles revealed that exposure to PCB 126 provoked a decrease in polyunsaturated fatty acids as well as an increase in sphingolipid levels, concomitant with a decrease in the activity of genes involved in lipid metabolism. This was associated with an increased oxidative stress reflected by marked disturbances in taurine metabolism. A gene ontology analysis showed hallmarks of an activation of the AhR receptor by dioxin-like compounds. These changes in metabolome and transcriptome profiles were observed even at the lowest concentration (100 pM) of PCB 126 tested. A decrease in docosatrienoate levels was the most sensitive biomarker. Overall, our integrated multi-omics analysis provides mechanistic insight into how this class of chemical pollutant can cause NAFLD. Our study lays the foundation for the development of molecular signatures of toxic effects of chemicals causing fatty liver diseases to move away from a chemical risk assessment based on in vivo animal experiments.
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http://dx.doi.org/10.1007/s00204-018-2235-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063328PMC
August 2018

MetExplore: collaborative edition and exploration of metabolic networks.

Nucleic Acids Res 2018 07;46(W1):W495-W502

INRA, UMR1331, Toxalim, F-31000 Toulouse, France.

Metabolism of an organism is composed of hundreds to thousands of interconnected biochemical reactions responding to environmental or genetic constraints. This metabolic network provides a rich knowledge to contextualize omics data and to elaborate hypotheses on metabolic modulations. Nevertheless, performing this kind of integrative analysis is challenging for end users with not sufficiently advanced computer skills since it requires the use of various tools and web servers. MetExplore offers an all-in-one online solution composed of interactive tools for metabolic network curation, network exploration and omics data analysis. In particular, it is possible to curate and annotate metabolic networks in a collaborative environment. The network exploration is also facilitated in MetExplore by a system of interactive tables connected to a powerful network visualization module. Finally, the contextualization of metabolic elements in the network and the calculation of over-representation statistics make it possible to interpret any kind of omics data. MetExplore is a sustainable project maintained since 2010 freely available at https://metexplore.toulouse.inra.fr/metexplore2/.
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http://dx.doi.org/10.1093/nar/gky301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030842PMC
July 2018

Early changes in tissue amino acid metabolism and nutrient routing in rats fed a high-fat diet: evidence from natural isotope abundances of nitrogen and carbon in tissue proteins.

Br J Nutr 2018 05 5;119(9):981-991. Epub 2018 Mar 5.

1UMR PNCA,AgroParisTech,INRA,Université Paris-Saclay,75005, Paris,France.

Little is known about how diet-induced obesity and insulin resistance affect protein and amino acid (AA) metabolism in tissues. The natural relative abundances of the heavy stable isotopes of C (δ 13C) and N (δ 15N) in tissue proteins offer novel and promising biomarkers of AA metabolism. They, respectively, reflect the use of dietary macronutrients for tissue AA synthesis and the relative metabolic use of tissue AA for oxidation v. protein synthesis. In this study, δ 13C and δ 15N were measured in the proteins of various tissues in young adult rats exposed perinatally and/or fed after weaning with a normal- or a high-fat (HF) diet, the aim being to characterise HF-induced tissue-specific changes in AA metabolism. HF feeding was shown to increase the routing of dietary fat to all tissue proteins via non-indispensable AA synthesis, but did not affect AA allocation between catabolic and anabolic processes in most tissues. However, the proportion of AA directed towards oxidation rather than protein synthesis was increased in the small intestine and decreased in the tibialis anterior muscle and adipose tissue. In adipose tissue, the AA reallocation was observed in the case of perinatal or post-weaning exposure to HF, whereas in the small intestine and tibialis anterior muscle the AA reallocation was only observed after HF exposure that covered both the perinatal and post-weaning periods. In conclusion, HF exposure induced an early reorganisation of AA metabolism involving tissue-specific effects, and in particular a decrease in the relative allocation of AA to oxidation in several peripheral tissues.
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http://dx.doi.org/10.1017/S0007114518000326DOI Listing
May 2018

MetExploreViz: web component for interactive metabolic network visualization.

Bioinformatics 2018 Jan;34(2):312-313

Toxalim, Université de Toulouse, INRA, Université de Toulouse 3 Paul Sabatier, Toulouse, France.

Summary: MetExploreViz is an open source web component that can be easily embedded in any web site. It provides features dedicated to the visualization of metabolic networks and pathways and thus offers a flexible solution to analyse omics data in a biochemical context.

Availability And Implementation: Documentation and link to GIT code repository (GPL 3.0 license) are available at this URL: http://metexplore.toulouse.inra.fr/metexploreViz/doc/.
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http://dx.doi.org/10.1093/bioinformatics/btx588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5860210PMC
January 2018

A Computational Solution to Automatically Map Metabolite Libraries in the Context of Genome Scale Metabolic Networks.

Front Mol Biosci 2016 16;3. Epub 2016 Feb 16.

TOXALIM (Research Centre in Food Toxicology), Institut National de la Recherche Agronomique, UMR1331, Université de Toulouse Toulouse, France.

This article describes a generic programmatic method for mapping chemical compound libraries on organism-specific metabolic networks from various databases (KEGG, BioCyc) and flat file formats (SBML and Matlab files). We show how this pipeline was successfully applied to decipher the coverage of chemical libraries set up by two metabolomics facilities MetaboHub (French National infrastructure for metabolomics and fluxomics) and Glasgow Polyomics (GP) on the metabolic networks available in the MetExplore web server. The present generic protocol is designed to formalize and reduce the volume of information transfer between the library and the network database. Matching of metabolites between libraries and metabolic networks is based on InChIs or InChIKeys and therefore requires that these identifiers are specified in both libraries and networks. In addition to providing covering statistics, this pipeline also allows the visualization of mapping results in the context of metabolic networks. In order to achieve this goal, we tackled issues on programmatic interaction between two servers, improvement of metabolite annotation in metabolic networks and automatic loading of a mapping in genome scale metabolic network analysis tool MetExplore. It is important to note that this mapping can also be performed on a single or a selection of organisms of interest and is thus not limited to large facilities.
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http://dx.doi.org/10.3389/fmolb.2016.00002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754433PMC
February 2016

Natural isotopic signatures of variations in body nitrogen fluxes: a compartmental model analysis.

PLoS Comput Biol 2014 Oct 2;10(10):e1003865. Epub 2014 Oct 2.

INRA, CRNH-IdF, UMR914 Nutrition Physiology and Ingestive Behavior, Paris, France; AgroParisTech, CRNH-IdF, UMR914 Nutrition Physiology and Ingestive Behavior, Paris, France.

Body tissues are generally 15N-enriched over the diet, with a discrimination factor (Δ15N) that varies among tissues and individuals as a function of their nutritional and physiopathological condition. However, both 15N bioaccumulation and intra- and inter-individual Δ15N variations are still poorly understood, so that theoretical models are required to understand their underlying mechanisms. Using experimental Δ15N measurements in rats, we developed a multi-compartmental model that provides the first detailed representation of the complex functioning of the body's Δ15N system, by explicitly linking the sizes and Δ15N values of 21 nitrogen pools to the rates and isotope effects of 49 nitrogen metabolic fluxes. We have shown that (i) besides urea production, several metabolic pathways (e.g., protein synthesis, amino acid intracellular metabolism, urea recycling and intestinal absorption or secretion) are most probably associated with isotope fractionation and together contribute to 15N accumulation in tissues, (ii) the Δ15N of a tissue at steady-state is not affected by variations of its P turnover rate, but can vary according to the relative orientation of tissue free amino acids towards oxidation vs. protein synthesis, (iii) at the whole-body level, Δ15N variations result from variations in the body partitioning of nitrogen fluxes (e.g., urea production, urea recycling and amino acid exchanges), with or without changes in nitrogen balance, (iv) any deviation from the optimal amino acid intake, in terms of both quality and quantity, causes a global rise in tissue Δ15N, and (v) Δ15N variations differ between tissues depending on the metabolic changes involved, which can therefore be identified using simultaneous multi-tissue Δ15N measurements. This work provides proof of concept that Δ15N measurements constitute a new promising tool to investigate how metabolic fluxes are nutritionally or physiopathologically reorganized or altered. The existence of such natural and interpretable isotopic biomarkers promises interesting applications in nutrition and health.
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http://dx.doi.org/10.1371/journal.pcbi.1003865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4183419PMC
October 2014

Effects of dark chocolate and cocoa consumption on endothelial function and arterial stiffness in overweight adults.

Br J Nutr 2014 Feb 25;111(4):653-61. Epub 2013 Nov 25.

Department of Nutritional Sciences, The Pennsylvania State University, 110 Chandlee Laboratory, University Park, PA 16802, USA.

The consumption of cocoa and dark chocolate is associated with a lower risk of CVD, and improvements in endothelial function may mediate this relationship. Less is known about the effects of cocoa/chocolate on the augmentation index (AI), a measure of vascular stiffness and vascular tone in the peripheral arterioles. We enrolled thirty middle-aged, overweight adults in a randomised, placebo-controlled, 4-week, cross-over study. During the active treatment (cocoa) period, the participants consumed 37 g/d of dark chocolate and a sugar-free cocoa beverage (total cocoa = 22 g/d, total flavanols (TF) = 814 mg/d). Colour-matched controls included a low-flavanol chocolate bar and a cocoa-free beverage with no added sugar (TF = 3 mg/d). Treatments were matched for total fat, saturated fat, carbohydrates and protein. The cocoa treatment significantly increased the basal diameter and peak diameter of the brachial artery by 6% (+2 mm) and basal blood flow volume by 22%. Substantial decreases in the AI, a measure of arterial stiffness, were observed in only women. Flow-mediated dilation and the reactive hyperaemia index remained unchanged. The consumption of cocoa had no effect on fasting blood measures, while the control treatment increased fasting insulin concentration and insulin resistance (P= 0·01). Fasting blood pressure (BP) remained unchanged, although the acute consumption of cocoa increased resting BP by 4 mmHg. In summary, the high-flavanol cocoa and dark chocolate treatment was associated with enhanced vasodilation in both conduit and resistance arteries and was accompanied by significant reductions in arterial stiffness in women.
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http://dx.doi.org/10.1017/S0007114513002912DOI Listing
February 2014

Isotopic and modeling investigation of long-term protein turnover in rat tissues.

Am J Physiol Regul Integr Comp Physiol 2013 Feb 7;304(3):R218-31. Epub 2012 Nov 7.

1INRA (Institut National de la Recherche Agronomique), CRNH-IdF (Centre de Recherche en Nutrition Humaine d’Ile de France), UMR914 Nutrition Physiology and Ingestive Behavior, Paris, France.

Fractional synthesis rates (FSR) of tissue proteins (P) are usually measured using labeled amino acid (AA) tracer methods over short periods of time under acute, particular conditions. By combining the long-term and non-steady-state (15)N labeling of AA and P tissue fractions with compartmental modeling, we have developed a new isotopic approach to investigate the degree of compartmentation of P turnover in tissues and to estimate long-term FSR values under sustained and averaged nutritional and physiological conditions. We measured the rise-to-plateau kinetics of nitrogen isotopic enrichments (δ(15)N) in the AA and P fractions of various tissues in rats for 2 mo following a slight increase in diet δ(15)N. Using these δ(15)N kinetics and a numerical method based on a two-compartment model, we determined reliable FSR estimates for tissues in which P turnover is adequately represented by such a simple precursor-product model. This was the case for kidney, liver, plasma, and muscle, where FSR estimates were 103, 101, 58, and 11%/day, respectively. Conversely, we identified tissues, namely, skin and small intestine, where P turnover proved to be too complex to be represented by a simple two-compartment model, evidencing the higher level of subcompartmentation of the P and/or AA metabolism in these tissues. The present results support the value of this new approach in gaining cognitive and practical insights into tissue P turnover and propose new and integrated FSR values over all individual precursor AA and all diurnal variations in P kinetics.
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http://dx.doi.org/10.1152/ajpregu.00310.2012DOI Listing
February 2013

Impact of the diet on net endogenous acid production and acid-base balance.

Clin Nutr 2012 Jun 18;31(3):313-21. Epub 2012 Feb 18.

AgroParisTech, CRNH-IdF, UMR914 Nutrition Physiology and Ingestive Behavior, 16 rue Claude Bernard, F-75005 Paris, France.

Net acid production, which is composed of volatile acids (15,000 mEq/day) and metabolic acids (70-100 mEq/day) is relatively small compared to whole-body H⁺ turnover (150,000 mEq/day). Metabolic acids are ingested from the diet or produced as intermediary or end products of endogenous metabolism. The three commonly reported sources of net acid production are the metabolism of sulphur amino acids, the metabolism or ingestion of organic acids, and the metabolism of phosphate esters or dietary phosphoproteins. Net base production occurs mainly as a result of absorption of organic anions from the diet. To maintain acid-base balance, ingested and endogenously produced acids are neutralized within the body by buffer systems or eliminated from the body through the respiratory (excretion of volatile acid in the form of CO₂) and urinary (excretion of fixed acids and remaining H⁺) pathways. Because of the many reactions involved in the acid-base balance, the direct determination of acid production is complex and is usually estimated through direct or indirect measurements of acid excretion. However, indirect approaches, which assess the acid-forming potential of the ingested diet based on its composition, do not take all the acid-producing reactions into account. Direct measurements therefore seem more reliable. Nevertheless, acid excretion does not truly provide information on the way acidity is dealt with in the plasma and this measurement should be interpreted with caution when assessing acid-base imbalance.
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http://dx.doi.org/10.1016/j.clnu.2012.01.006DOI Listing
June 2012

The nature of the dietary protein impacts the tissue-to-diet 15N discrimination factors in laboratory rats.

PLoS One 2011 22;6(11):e28046. Epub 2011 Nov 22.

INRA, CRNH-IdF, UMR914 Nutrition Physiology and Ingestive Behavior, Paris, France.

Due to the existence of isotope effects on some metabolic pathways of amino acid and protein metabolism, animal tissues are (15)N-enriched relative to their dietary nitrogen sources and this (15)N enrichment varies among different tissues and metabolic pools. The magnitude of the tissue-to-diet discrimination (Δ(15)N) has also been shown to depend on dietary factors. Since dietary protein sources affect amino acid and protein metabolism, we hypothesized that they would impact this discrimination factor, with selective effects at the tissue level. To test this hypothesis, we investigated in rats the influence of a milk or soy protein-based diet on Δ(15)N in various nitrogen fractions (urea, protein and non-protein fractions) of blood and tissues, focusing on visceral tissues. Regardless of the diet, the different protein fractions of blood and tissues were generally (15)N-enriched relative to their non-protein fraction and to the diet (Δ(15)N>0), with large variations in the Δ(15)N between tissue proteins. Δ(15)N values were markedly lower in tissue proteins of rats fed milk proteins compared to those fed soy proteins, in all sampled tissues except in the intestine, and the amplitude of Δ(15)N differences between diets differed between tissues. Both between-tissue and between-diet Δ(15)N differences are probably related to modulations of the relative orientation of dietary and endogenous amino acids in the different metabolic pathways. More specifically, the smaller Δ(15)N values observed in tissue proteins with milk than soy dietary protein may be due to a slightly more direct channeling of dietary amino acids for tissue protein renewal and to a lower recycling of amino acids through fractionating pathways. In conclusion, the present data indicate that natural Δ(15)N of tissue are sensitive markers of the specific subtle regional modifications of the protein and amino acid metabolism induced by the protein dietary source.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0028046PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3222673PMC
April 2012