Broad-ranging natural metabotype variation drives physiological plasticity in healthy control inbred rat strains

Clément Pontoizeau, Jane F Fearnside, Vincent Navratil, Céline Domange, Jean-Baptiste Cazier, Cristina Fernández-Santamaría, Pamela J Kaisaki, Lyndon Emsley, Pierre Toulhoat, Marie-Thérèse Bihoreau, Jeremy K Nicholson, Dominique Gauguier, Marc E Dumas

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)


Maintaining homeostasis in higher organisms involves a complex interplay of multiple ubiquitous and organ-specific molecular mechanisms that can be characterized using functional genomics technologies such as transcriptomics, proteomics, and metabonomics and dissected out through genetic investigations in healthy and diseased individuals. We characterized the genomic, metabolic, and physiological divergence of several inbred rat strains--Brown Norway, Lewis, Wistar Kyoto, Fisher (F344)--frequently used as healthy controls in genetic studies of the cardiometabolic syndrome. Hierarchical clustering of (1)H NMR-based metabolic profiles (n = 20 for urine, n = 16 for plasma) identified metabolic phenotype (metabotype) divergence patterns similar to the phylogenetic variability based on single nucleotide polymorphisms. However, the observed urinary metabotype variation exceeded that explainable by genetic polymorphisms. To understand further this natural variation, we used an integrative, knowledge-based network biology metabolic pathway analysis approach, coined Metabolite-Set Enrichment Analysis (MSEA). MSEA reveals that homeostasis and physiological plasticity can be achieved despite widespread divergences in glucose, lipid, amino acid, and energy metabolism in the host, together with different gut microbiota contributions suggestive of strain-specific transgenomic interactions. This work illustrates the concept of natural metabolomic variation, leading to physiologically stable albeit diverse strategies within the range of normality, all of which are highly relevant to animal model physiology, genetical genomics, and patient stratification in personalized healthcare.

Original languageEnglish
Pages (from-to)1675-89
Number of pages15
JournalJournal of Proteome Research
Issue number4
Publication statusPublished - 1 Apr 2011


  • Animals
  • Cluster Analysis
  • Humans
  • Male
  • Metabolic Networks and Pathways
  • Metabolome
  • Metabolomics
  • Nuclear Magnetic Resonance, Biomolecular
  • Phenotype
  • Rats
  • Rats, Inbred Strains


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