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Nutritional Systems Biology Modeling: From Molecular Mechanisms to Physiology

By Matthias Heinemann, Neema Jamshidi, Baukje de Roos, Andreas P. Freidig, Albert A. de Graaf, Ben van Ommen, Martin Adiels, Kevin D. Hall and Johan A.C. Rullmann


The use of computational modeling and simulation has increased in many biological fields, but despite their potential these techniques are only marginally applied in nutritional sciences. Nevertheless, recent applications of modeling have been instrumental in answering important nutritional questions from the cellular up to the physiological levels. Capturing the complexity of today’s important nutritional research questions poses a challenge for modeling to become truly integrative in the consideration and interpretation of experimental data at widely differing scales of space and time. In this review, we discuss a selection of available modeling approaches and applications relevant for nutrition. We then put these models into perspective by categorizing them according to their space and time domain. Through this categorization process, we identified a dearth of models that consider processes occurring between the microscopic and macroscopic scale. We propose a ‘‘middle-out’’ strategy to develop the required full-scale, multilevel computational models. Exhaustive and accurate phenotyping, the use of the virtual patient concept, and the development of biomarkers from ‘‘-omics’’ signatures are identified as key elements of a successful systems biology modeling approach in nutrition research—one that integrates physiological mechanisms and data at multiple space and time scales.

Year: 2009
DOI identifier: 10.1371/journal.pcbi.1000554
OAI identifier: oai:ub.rug.nl:dbi/4c909286565b5

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  1. (2008). A doi
  2. (2006). A comprehensive map of the toll-like receptor signaling network. doi
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  5. (2002). A mathematical model of metabolic insulin signaling pathways.
  6. (2004). A multi-scale approach for the predictive modeling of metabolic regulation.
  7. (1988). A multicompartment model of vitamin B6 metabolism.
  8. (2005). A new combined multicompartmental model for apolipoprotein B-100 and triglyceride metabolism in VLDL subfractions. doi
  9. (2009). A viscerally driven cachexia syndrome in patients with advanced colorectal cancer: contributions of organ and tumor mass to whole-body energy demands. doi
  10. (2007). Acute suppression of VLDL1 secretion rate by insulin is associated with hepatic fat content and insulin resistance. doi
  11. (2008). Allometric relationship between changes of visceral fat and total fat mass. doi
  12. (2005). Application of predictive biosimulation within pharmaceutical clinical development: examples of significance for translational medicine and clinical trial design. doi
  13. (2005). Approaches to the analysis of cell signaling networks and their application in drug discovery.
  14. (1997). Bidirectional reaction steps in metabolic networks: I. Modeling and simulation of carbon isotope labeling experiments. doi
  15. (1999). Bidirectional reaction steps in metabolic networks: III. Explicit solution and analysis of isotopomer labeling systems. doi
  16. (2008). Bioinformatics, multiscale modeling and the IUPS Physiome Project. doi
  17. (2002). Biosimulation: dynamic modelling of biological systems. doi
  18. (2007). Body fat and fat-free mass inter-relationships: Forbes’s theory revisited. doi
  19. (2008). Boolean network models of cellular regulation: prospects and limitations. doi
  20. (2001). Brown adipose tissue-specific insulin receptor knockout shows diabetic phenotype without insulin resistance. doi
  21. (2008). Computational lipidology: predicting lipoprotein density profiles in human blood plasma. doi
  22. (2006). Computational model of in vivo human energy metabolism during semistarvation and refeeding. doi
  23. (2008). Computational modeling of cancer cachexia. doi
  24. (2008). Computational models of the heart and their use in assessing the actions of drugs. doi
  25. (2006). Computational tools for isotopically instationary 13C labeling experiments under metabolic steady state conditions. doi
  26. de Graaf AA (2005) Metabolic flux analysis in Corynebacterium glutamicum. Eggeling doi
  27. (2004). Decomposition of metabolic network into functional modules based on the global connectivity structure of reaction graph. doi
  28. (1992). Development of a model for selenite metabolism in humans.
  29. (2006). Diabetic dyslipidaemia. doi
  30. (2008). Dynamic coordination of macronutrient balance during infant growth: insights from a mathematical model.
  31. (2001). Dynamic simulation of the human red blood cell metabolic network. doi
  32. (2002). Effect of atorvastatin and fish oil on plasma high-sensitivity C-reactive protein concentrations in individuals with visceral obesity.
  33. (1998). Effects of fish oil supplementation on apolipoprotein B100 production and lipoprotein metabolism in normolipidaemic males. doi
  34. (2002). Energy balance for analysis of complex metabolic networks. doi
  35. (2007). Ensemble modeling for analysis of cell signaling dynamics. doi
  36. (2008). Extracting global system dynamics of corticosteroid genomic effects in rat liver. doi
  37. (2008). Formulating genome-scale kinetic models in the post-genome era. doi
  38. (2006). From in vivo to in silico biology and back. doi
  39. (2008). Gaining insight into microbial physiology in the large intestine: a special role for stable isotopes. doi
  40. (2006). Garg A doi
  41. (2004). Genome-scale models of microbial cells: evaluating the consequences of constraints. doi
  42. (2003). Genome-scale reconstruction of the Saccharomyces cerevisiae metabolic network. doi
  43. (2007). Global reconstruction of the human metabolic network based on genomic and bibliomic data. doi
  44. (2007). How adaptations of substrate utilization regulate body composition. doi
  45. (2009). Improved cholesterol phenotype analysis by a model relating lipoprotein lifecycle processes to particle size. J Lipid Res. doi
  46. (2008). Increasing weight loss attenuates the preferential loss of visceral compared with subcutaneous fat: a predicted result of an allometric model. doi
  47. (1982). Integrated regulation of very low density lipoprotein triglyceride and apolipoprotein-B kinetics in noninsulin-dependent diabetes mellitus. doi
  48. (2005). Integrative model of the response of yeast to osmotic shock. doi
  49. (2007). Intracellular crowding defines the mode and sequence of substrate uptake by Escherichia coli and constrains its metabolic activity. doi
  50. (1987). Lean body mass-body fat interrelationships in humans. doi
  51. (2004). Lipoprotein transport in the metabolic syndrome: pathophysiological and interventional studies employing stable isotopy and modelling methods. doi
  52. (2008). Liver X receptor alpha is a transcriptional repressor of the uncoupling protein 1 gene and the brown fat phenotype. doi
  53. MaH,S o r o k i nA ,M a z e i nA ,S e l k o vA ,S e l k o vE ,e ta l
  54. (2009). Mathematical modelling of competitive LDL/VLDL binding and uptake by hepatocytes. doi
  55. (2008). Mechanisms of disease: using genetically altered mice to study concepts of type 2 diabetes. doi
  56. (2000). Metabolic abnormalities of apolipoprotein B-containing lipoproteins in noninsulin-dependent diabetes: a stable isotope kinetic study. doi
  57. (1992). Metabolic control analysis: a survey of its theoretical and experimental development.
  58. (2006). Methods of robustness analysis for Boolean models of gene control networks. doi
  59. (2005). Modeling hybridoma cell metabolism using a generic genome-scale metabolic model of Mus musculus. doi
  60. (2008). Modeling weight-loss maintenance to help prevent body weight regain. doi
  61. (2008). Multi-scale computational modelling in biology and physiology. doi
  62. (1991). Network rigidity and metabolic engineering in metabolite overproduction. Science 252: 1675–1681. PLoS doi
  63. (2003). New insights into cardiovascular disease risk in subjects with visceral obesity.
  64. (2004). New stable isotope-mass spectrometric techniques for measuring fluxes through intact metabolic pathways in mammalian systems: introduction of moving pictures into functional genomics and biochemical phenotyping. doi
  65. (1927). Nutrition and diet in health and disease. doi
  66. (2006). Oncogenic pathway signatures in human cancers as a guide to targeted therapies. doi
  67. (2006). Overproduction of large VLDL particles is driven by increased liver fat content in man. doi
  68. (2005). Overproduction of VLDL1 driven by hyperglycemia is a dominant feature of diabetic dyslipidemia. doi
  69. (1981). Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell glucose sensitivity from the response to intravenous glucose. doi
  70. (2006). Putative regulatory sites unraveled by network-embedded thermodynamic analysis of metabolome data. doi
  71. (2001). Quantitative aspects of metabolic organization: a discussion of concepts. doi
  72. (1999). Reduction in visceral adipose tissue is associated with improvement in apolipoprotein B-100 metabolism in obese men. doi
  73. (2002). Regulatory effects of HMG CoA reductase inhibitor and fish oils on apolipoprotein B-100 kinetics in insulin-resistant obese male subjects with dyslipidemia. doi
  74. (2007). Something from nothing: bridging the gap between constraint-based and kinetic modelling. doi
  75. (2006). Systematic assignment of thermodynamic constraints in metabolic network models.
  76. (1990). The application of compartmental analysis to research in nutrition. doi
  77. (2006). The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. doi
  78. (2008). The dynamics of human body weight change. doi
  79. (2008). The role of exercise and PGC1alpha in inflammation and chronic disease. doi
  80. (2004). The statistical mechanics of complex signaling networks: nerve growth factor signaling. doi
  81. (2006). Thematic review series: patient-oriented research. What we have learned about VLDL and LDL metabolism from human kinetics studies. doi
  82. (2006). Towards multidimensional genome annotation. doi
  83. (2005). Uncovering transcriptional regulation of metabolism by using metabolic network topology. doi
  84. (2007). Universally sloppy parameter sensitivities in systems biology models. doi
  85. (2002). Use of stable isotopically labeled tracers to measure very low density lipoproteintriglyceride turnover.
  86. (2008). What is the required energy deficit per unit weight loss? doi
  87. (1979). Zinc metabolism in humans: a kinetic model.

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