title: Broad-ranging natural metabotype variation drives physiological plasticity in healthy control inbred rat strains.
abstract: 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.
authors.affiliation: Centre de Résonance Magnétique Nucléaire à Très Hauts Champs, FRE 3008, 5 rue de la Doua, 69100 Villeurbanne, France.
authors.forename: Clément
authors.initials: C
authors.lastname: Pontoizeau
authors.forename: Jane F
authors.initials: JF
authors.lastname: Fearnside
authors.forename: Vincent
authors.initials: V
authors.lastname: Navratil
authors.forename: Céline
authors.initials: C
authors.lastname: Domange
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Cazier
authors.forename: Cristina
authors.initials: C
authors.lastname: Fernández-Santamaría
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Kaisaki
authors.forename: Lyndon
authors.initials: L
authors.lastname: Emsley
authors.forename: Pierre
authors.initials: P
authors.lastname: Toulhoat
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Bihoreau
authors.forename: Jeremy K
authors.initials: JK
authors.lastname: Nicholson
authors.forename: Dominique
authors.initials: D
authors.lastname: Gauguier
authors.forename: Marc E
authors.initials: ME
authors.lastname: Dumas
mesh_terms: D000818:Animals; D016000:Cluster Analysis; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways / Q000502:physiology*; D055442:Metabolome; D055432:Metabolomics / Q000379:methods*; D019906:Nuclear Magnetic Resonance, Biomolecular; D010641:Phenotype; D051381:Rats / Q000378:metabolism* / Q000502:physiology*; D011919:Rats, Inbred Strains