{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T03:06:59Z","timestamp":1774926419852,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1009522","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T00:00:00Z","timestamp":1637193600000}}],"reference-count":41,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2021,11,8]],"date-time":"2021-11-08T00:00:00Z","timestamp":1636329600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Dutch Provincie Limburg"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Genome-scale metabolic models (GEMs) are comprehensive knowledge bases of cellular metabolism and serve as mathematical tools for studying biological phenotypes and metabolic states or conditions in various organisms and cell types. Given the sheer size and complexity of human metabolism, selecting parameters for existing analysis methods such as metabolic objective functions and model constraints is not straightforward in human GEMs. In particular, comparing several conditions in large GEMs to identify condition- or disease-specific metabolic features is challenging. In this study, we showcase a scalable, model-driven approach for an in-depth investigation and comparison of metabolic states in large GEMs which enables identifying the underlying functional differences. Using a combination of flux space sampling and network analysis, our approach enables extraction and visualisation of metabolically distinct network modules. Importantly, it does not rely on known or assumed objective functions. We apply this novel approach to extract the biochemical differences in adipocytes arising due to unlimited vs blocked uptake of branched-chain amino acids (BCAAs, considered as biomarkers in obesity) using a human adipocyte GEM (iAdipocytes1809). The biological significance of our approach is corroborated by literature reports confirming our identified metabolic processes (TCA cycle and Fatty acid metabolism) to be functionally related to BCAA metabolism. Additionally, our analysis predicts a specific altered uptake and secretion profile indicating a compensation for the unavailability of BCAAs. Taken together, our approach facilitates determining functional differences between any metabolic conditions of interest by offering a versatile platform for analysing and comparing flux spaces of large metabolic networks.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1009522","type":"journal-article","created":{"date-parts":[[2021,11,8]],"date-time":"2021-11-08T18:43:35Z","timestamp":1636397015000},"page":"e1009522","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":10,"title":["Comparison of metabolic states using genome-scale metabolic models"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1115-4323","authenticated-orcid":true,"given":"Chaitra","family":"Sarathy","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0529-4031","authenticated-orcid":true,"given":"Marian","family":"Breuer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7699-8191","authenticated-orcid":true,"given":"Martina","family":"Kutmon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4472-7119","authenticated-orcid":true,"given":"Michiel E.","family":"Adriaens","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5301-3142","authenticated-orcid":true,"given":"Chris T.","family":"Evelo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6462-6692","authenticated-orcid":true,"given":"Ilja C. W.","family":"Arts","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,11,8]]},"reference":[{"issue":"7121","key":"pcbi.1009522.ref001","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1038\/nature05485","article-title":"Inflammation and metabolic disorders","volume":"444","author":"GS Hotamisligil","year":"2006","journal-title":"Nature"},{"issue":"1","key":"pcbi.1009522.ref002","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.ajpath.2013.07.035","article-title":"Is Cancer a Metabolic Disease?","volume":"184","author":"HA Coller","year":"2014","journal-title":"The American Journal of Pathology"},{"key":"pcbi.1009522.ref003","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-662-49771-5","volume-title":"Inborn Metabolic Diseases: Diagnosis and Treatment","author":"JM Saudubray","year":"2016"},{"issue":"10","key":"pcbi.1009522.ref004","doi-asserted-by":"crossref","first-page":"2953","DOI":"10.1039\/C6MB00476H","article-title":"Integrative analysis of human omics data using biomolecular networks","volume":"12","author":"JL Robinson","year":"2016","journal-title":"Molecular BioSystems"},{"issue":"1","key":"pcbi.1009522.ref005","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1038\/msb.2011.35","article-title":"Predicting selective drug targets in cancer through metabolic networks","volume":"7","author":"O Folger","year":"2011","journal-title":"Molecular Systems Biology"},{"issue":"5","key":"pcbi.1009522.ref006","doi-asserted-by":"crossref","first-page":"e1002518","DOI":"10.1371\/journal.pcbi.1002518","article-title":"Reconstruction of Genome-Scale Active Metabolic Networks for 69 Human Cell Types and 16 Cancer Types Using INIT","volume":"8","author":"R Agren","year":"2012","journal-title":"PLoS Computational Biology"},{"issue":"8","key":"pcbi.1009522.ref007","doi-asserted-by":"crossref","first-page":"744","DOI":"10.15252\/msb.20134993","article-title":"A computational study of the Warburg effect identifies metabolic targets inhibiting cancer migration","volume":"10","author":"K Yizhak","year":"2014","journal-title":"Molecular Systems Biology"},{"issue":"6","key":"pcbi.1009522.ref008","doi-asserted-by":"crossref","first-page":"817","DOI":"10.15252\/msb.20145307","article-title":"Modeling cancer metabolism on a genome scale","volume":"11","author":"K Yizhak","year":"2015","journal-title":"Molecular Systems Biology"},{"issue":"1","key":"pcbi.1009522.ref009","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1038\/msb.2013.5","article-title":"Integration of clinical data with a genome-scale metabolic model of the human adipocyte","volume":"9","author":"A Mardinoglu","year":"2013","journal-title":"Molecular Systems Biology"},{"issue":"1","key":"pcbi.1009522.ref010","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms4083","article-title":"Genome-scale metabolic modelling of hepatocytes reveals serine deficiency in patients with non-alcoholic fatty liver disease","volume":"5","author":"A Mardinoglu","year":"2014","journal-title":"Nature Communications"},{"issue":"3","key":"pcbi.1009522.ref011","doi-asserted-by":"crossref","first-page":"916","DOI":"10.15252\/msb.20167422","article-title":"Personal model-assisted identification of NAD+ and glutathione metabolism as intervention target in NAFLD","volume":"13","author":"A Mardinoglu","year":"2017","journal-title":"Molecular Systems Biology"},{"issue":"4","key":"pcbi.1009522.ref012","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1038\/nrmicro2737","article-title":"Constraining the metabolic genotype\u2013phenotype relationship using a phylogeny of in silico methods","volume":"10","author":"NE Lewis","year":"2012","journal-title":"Nature Reviews Microbiology"},{"issue":"3","key":"pcbi.1009522.ref013","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/nbt.1614","article-title":"What is flux balance analysis?","volume":"28","author":"JD Orth","year":"2010","journal-title":"Nature Biotechnology"},{"issue":"02","key":"pcbi.1009522.ref014","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1142\/S0218339094000131","article-title":"On Elementary Flux Modes in biochemical reaction systems at steady state","volume":"02","author":"S Schuster","year":"1994","journal-title":"Journal of Biological Systems"},{"issue":"9","key":"pcbi.1009522.ref015","doi-asserted-by":"crossref","first-page":"5457","DOI":"10.1074\/jbc.R800048200","article-title":"Use of Randomized Sampling for Analysis of Metabolic Networks","volume":"284","author":"J Schellenberger","year":"2008","journal-title":"Journal of Biological Chemistry"},{"issue":"1\/2","key":"pcbi.1009522.ref016","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1023\/A:1020390132244","article-title":"Combinatorial complexity of pathway analysis in metabolic networks","volume":"29","author":"S Klamt","year":"2002","journal-title":"Molecular Biology Reports"},{"issue":"110","key":"pcbi.1009522.ref017","doi-asserted-by":"crossref","first-page":"20150543","DOI":"10.1098\/rsif.2015.0543","article-title":"Mapping high-growth phenotypes in the flux space of microbial metabolism","volume":"12","author":"O G\u00fcell","year":"2015","journal-title":"Journal of The Royal Society Interface"},{"issue":"4","key":"pcbi.1009522.ref018","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/j.jtbi.2004.02.006","article-title":"Monte Carlo sampling can be used to determine the size and shape of the steady-state flux space","volume":"228","author":"SJ Wiback","year":"2004","journal-title":"Journal of Theoretical Biology"},{"issue":"1","key":"pcbi.1009522.ref019","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms14915","article-title":"An analytic approximation of the feasible space of metabolic networks","volume":"8","author":"A Braunstein","year":"2017","journal-title":"Nature Communications"},{"issue":"1","key":"pcbi.1009522.ref020","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/1752-0509-3-30","article-title":"Decomposing complex reaction networks using random sampling, principal component analysis, and basis rotation","volume":"3","author":"CL Barrett","year":"2009","journal-title":"BMC Systems Biology"},{"issue":"15","key":"pcbi.1009522.ref021","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1056\/NEJM196910092811503","article-title":"Plasma Amino Acid Levels and Insulin Secretion in Obesity","volume":"281","author":"P Felig","year":"1969","journal-title":"New England Journal of Medicine"},{"issue":"4","key":"pcbi.1009522.ref022","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.cmet.2009.02.002","article-title":"A Branched-Chain Amino Acid-Related Metabolic Signature that Differentiates Obese and Lean Humans and Contributes to Insulin Resistance","volume":"9","author":"CB Newgard","year":"2009","journal-title":"Cell Metabolism"},{"issue":"15","key":"pcbi.1009522.ref023","doi-asserted-by":"crossref","first-page":"11348","DOI":"10.1074\/jbc.M109.075184","article-title":"Adipose Tissue Branched Chain Amino Acid (BCAA) Metabolism Modulates Circulating BCAA Levels","volume":"285","author":"MA Herman","year":"2010","journal-title":"Journal of Biological Chemistry"},{"issue":"1","key":"pcbi.1009522.ref024","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1038\/nchembio.1961","article-title":"Branched-chain amino acid catabolism fuels adipocyte differentiation and lipogenesis","volume":"12","author":"CR Green","year":"2015","journal-title":"Nature Chemical Biology"},{"key":"pcbi.1009522.ref025","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.jnutbio.2018.05.011","article-title":"Interaction between leucine and palmitate catabolism in 3T3-L1 adipocytes and primary adipocytes from control and obese rats","volume":"59","author":"D Salinas-Rubio","year":"2018","journal-title":"The Journal of Nutritional Biochemistry"},{"issue":"17","key":"pcbi.1009522.ref026","doi-asserted-by":"crossref","first-page":"8074","DOI":"10.1016\/S0021-9258(19)70609-7","article-title":"Leucine degradation and release of glutamine and alanine by adipose tissue","volume":"255","author":"ME Tischler","year":"1980","journal-title":"Journal of Biological Chemistry"},{"issue":"3","key":"pcbi.1009522.ref027","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1016\/S0006-291X(77)80066-1","article-title":"Alanine release by rat adipose tissue in vitro","volume":"77","author":"K Snell","year":"1977","journal-title":"Biochemical and Biophysical Research Communications"},{"issue":"6","key":"pcbi.1009522.ref028","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.3390\/nu11061356","article-title":"Glycine Metabolism and Its Alterations in Obesity and Metabolic Diseases","volume":"11","author":"A Alves","year":"2019","journal-title":"Nutrients"},{"key":"pcbi.1009522.ref029","unstructured":"MATLAB. version 9.3.0.713579 (R2017b); 2017."},{"issue":"11","key":"pcbi.1009522.ref030","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction Networks","volume":"13","author":"P Shannon","year":"2003","journal-title":"Genome Research"},{"issue":"10","key":"pcbi.1009522.ref031","doi-asserted-by":"crossref","first-page":"e1006541","DOI":"10.1371\/journal.pcbi.1006541","article-title":"RAVEN 2.0: A versatile toolbox for metabolic network reconstruction and a case study on Streptomyces coelicolor","volume":"14","author":"H Wang","year":"2018","journal-title":"PLOS Computational Biology"},{"issue":"3","key":"pcbi.1009522.ref032","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1038\/s41596-018-0098-2","article-title":"Creation and analysis of biochemical constraint-based models using the COBRA Toolbox v.3.0","volume":"14","author":"L Heirendt","year":"2019","journal-title":"Nature Protocols"},{"key":"pcbi.1009522.ref033","unstructured":"Gurobi Optimization L. Gurobi Optimizer Reference Manual; 2021. Available from: https:\/\/www.gurobi.com."},{"issue":"7","key":"pcbi.1009522.ref034","doi-asserted-by":"crossref","first-page":"e1000859","DOI":"10.1371\/journal.pcbi.1000859","article-title":"Sampling the Solution Space in Genome-Scale Metabolic Networks Reveals Transcriptional Regulation in Key Enzymes","volume":"6","author":"S Bordel","year":"2010","journal-title":"PLoS Computational Biology"},{"key":"pcbi.1009522.ref035","unstructured":"Himberg J, Hyvarinen A. Icasso: software for investigating the reliability of ICA estimates by clustering and visualization. In: 2003 IEEE XIII Workshop on Neural Networks for Signal Processing (IEEE Cat. No.03TH8718). IEEE; 2003."},{"issue":"1","key":"pcbi.1009522.ref036","doi-asserted-by":"crossref","DOI":"10.1186\/s12864-017-4112-9","article-title":"Determining the optimal number of independent components for reproducible transcriptomic data analysis","volume":"18","author":"U Kairov","year":"2017","journal-title":"BMC Genomics"},{"key":"pcbi.1009522.ref037","unstructured":"Kairov U, Zinovyev A, Molkenov A. BIODICA GitHub page (https:\/\/github.com\/LabBandSB\/BIODICA\/); 2017."},{"key":"pcbi.1009522.ref038","unstructured":"Kaplan D. Knee Point. MATLAB Central File Exchange (https:\/\/wwwmathworkscom\/matlabcentral\/fileexchange\/35094-knee-point). 2020;."},{"issue":"2","key":"pcbi.1009522.ref039","doi-asserted-by":"crossref","first-page":"66","DOI":"10.3390\/metabo10020066","article-title":"EFMviz: A COBRA Toolbox Extension to Visualize Elementary Flux Modes in Genome-Scale Metabolic Models","volume":"10","author":"C Sarathy","year":"2020","journal-title":"Metabolites"},{"key":"pcbi.1009522.ref040","doi-asserted-by":"crossref","first-page":"478","DOI":"10.12688\/f1000research.6767.1","article-title":"CyREST: Turbocharging Cytoscape Access for External Tools via a RESTful API","volume":"4","author":"K Ono","year":"2015","journal-title":"F1000Research"},{"issue":"4","key":"pcbi.1009522.ref041","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.cels.2015.10.001","article-title":"NDEx, the Network Data Exchange","volume":"1","author":"D Pratt","year":"2015","journal-title":"Cell Systems"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1009522","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T00:00:00Z","timestamp":1637193600000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1009522","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T19:15:29Z","timestamp":1637262929000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1009522"}},"subtitle":[],"editor":[{"given":"Balazs","family":"Papp","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2021,11,8]]},"references-count":41,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11,8]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1009522","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pcbi.1009522","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,8]]}}}