Direct quantitative trait locus mapping of mammalian metabolic phenotypes in diabetic and normoglycemic rat models

Dumas, Marc; Wilder, Steven P.; Bihoreau, Marie-Thérèse; Barton, Richard H.; Fearnside, Jane; Argoud, Karène; D’Amato, Lisa; Wallis, Robert H.; Blancher, Christine; Keun, Hector C.; Baunsgaard, Dorrit; Scott, James A.; Sidelmann, Ulla G.; Nicholson, Jeremy K.; Guyader, Dominique

doi:10.1038/ng2026

Cited by 137 publications

(130 citation statements)

References 29 publications

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“…With the emergence of transcriptomic data sets derived from NAFLD-susceptible strains [10,13,23], our results contribute to enrichment of the model proposed for disease pathogenesis [5] with novel insights into mechanisms regulating gene expression and novel diet-reactive molecular components, including predicted or poorly annotated genes. Further investigations in a genetic cross between 129S6 and a strain resistant to diet-induced NAFLD, obesity and diabetes are required to investigate causal relationships between altered transcriptomic and metabonomic patterns and disease traits [38].…”

Section: Discussionmentioning

confidence: 99%

Subtle metabolic and liver gene transcriptional changes underlie diet-induced fatty liver susceptibility in insulin-resistant mice

et al. 2007

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Aims/hypothesis Complex changes in gene expression are associated with insulin resistance and non-alcoholic fatty liver disease (NAFLD) promoted by feeding a high-fat diet (HFD). We used functional genomic technologies to document molecular mechanisms associated with dietinduced NAFLD. Materials and Methods Male 129S6 mice were fed a diet containing 40% fat (high-fat diet, HFD) for 15 weeks. Glucose tolerance, in vivo insulin secretion, plasma lipid profile and adiposity were determined. Plasma metabonomics and liver transcriptomics were used to identify changes in gene expression associated with HFD-induced NAFLD.Results In HFD-fed mice, NAFLD and impaired glucose and lipid homeostasis were associated with increased hepatic transcription of genes involved in fatty acid uptake, intracellular transport, modification and elongation, whilst genes involved in beta-oxidation and lipoprotein secretion were, paradoxically, also upregulated. NAFLD developed despite strong and sustained downregulation of transcription of the gene encoding stearoyl-coenzyme A desaturase 1 (Scd1) and uncoordinated regulation of transcription of Scd1 and the gene encoding sterol regulatory element binding factor 1c (Srebf1c) transcription. Inflammatory mechanisms appeared to be stimulated by HFD. Conclusions/interpretation Our results provide an accurate representation of subtle changes in metabolic and gene expression regulation underlying disease-promoting and compensatory mechanisms, collectively contributing to dietinduced insulin resistance and NAFLD. They suggest that proposed models of NAFLD pathogenesis can be enriched with novel diet-reactive genes and disease mechanisms.

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Section: Discussionmentioning

confidence: 99%

Subtle metabolic and liver gene transcriptional changes underlie diet-induced fatty liver susceptibility in insulin-resistant mice

et al. 2007

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“…plasma metabolites) and ''structural'' individual-linked parameters genotype, which better characterise the impact of gene-diet interactions and lead ''backwards'' to identification of candidate genes. As an example, this was studied using an NMR-based metabolomic approach linking variation in metabolite abundance to genetic polymorphisms in diabetic and normoglycemic rat models [13].…”

Section: Genetic Variation and Nutritionmentioning

confidence: 99%

“…However, because of the large scale of such studies, measures of dietary exposure are weak (mainly FFQs), thereby preventing definition of gene interactions at specific levels of dietary exposure. In such studies, most researchers have focused on the relationships between diet, genes, and risk markers of disease, not diet -genes and disease outcomes, although some studies have evaluated the interaction with early diagnostic markers such as carotid intima media thickness [13]. As with the candidate gene studies, results are varied and replication poor [14,24,54,56], but they are valuable in identifying putative diet-genotype interactions, which could be tested further in prospective intervention or in twin studies.…”

Section: Genetic Variation and Nutritionmentioning

confidence: 99%

The challenges for molecular nutrition research 1: linking genotype to healthy nutrition

Williams¹,

Ordovas

Lairon

et al. 2008

Genes Nutr

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Nutrition science finds itself at a major crossroad. On the one hand we can continue the current path, which has resulted in some substantial advances, but also many conflicting messages which impair the trust of the general population, especially those who are motivated to improve their health through diet. The other road is uncharted and is being built over the many exciting new developments in life sciences. This new era of nutrition recognizes the complex relation between the health of the individual, its genome, and the life-long dietary exposure, and has lead to the realisation that nutrition is essentially a gene-environment interaction science. This review on the relation between genotype, diet and health is the first of a series dealing with the major challenges in molecular nutrition, analyzing the foundations of nutrition research. With the unravelling of the human genome and the linking of its variability to a multitude of phenotypes from ''healthy'' to an enormously complex range of predispositions, the dietary modulation of these propensities has become an area of active research. Classical genetic approaches applied so far in medical genetics have steered away from incorporating dietary effects in their models and paradoxically, most genetic studies analyzing diet-associated phenotypes and diseases simply ignore diet. Yet, a modest but increasing number of studies are accounting for diet as a modulator of genetic associations. These range from observational cohorts to intervention studies with prospectively selected genotypes. New statistical and All authors are member of The European Nutrigenomics Organisation (http://www.nugo.org). bioinformatics approaches are becoming available to aid in design and evaluation of these studies. This review discusses the various approaches used and provides concrete recommendations for future research. C. M. Williams (&)Hugh

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“…Today, a range of molecular phenotyping tools is available to characterize mutations. Although gene expression and protein profiling are predominantly used (3)(4)(5), metabonomic and metabolomic strategies (6, 7) advantageously produce metabolic fingerprints that allow identification of variations in low-molecular-weight compounds in biofluids or organs in response to pathophysiological events (8), drug treatments (9), or genetic polymorphisms (10). It is therefore an attractive hypothesis-free approach for large-scale functional genomics in model organisms (11).…”

mentioning

confidence: 99%

Metabotyping of Caenorhabditis elegans reveals latent phenotypes

Blaise

Giacomotto

Elena

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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107

133

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Assigning functions to every gene in a living organism is the next challenge for functional genomics. In fact, 85-90% of the 19,000 genes of the nematode Caenorhabditis elegans genome do not produce any visible phenotype when inactivated, which hampers determining their function, especially when they do not belong to previously characterized gene families. We used 1 H high-resolution magic angle spinning NMR spectroscopy ( 1 H HRMAS-NMR) to reveal the latent phenotype associated to superoxide dismutase (sod-1) and catalase (ctl-1) C. elegans mutations, both involved in the elimination of radical oxidative species. These two silent mutations are significantly discriminated from the wild-type strain and from each other. We identify a metabotype significantly associated with these mutations involving a general reduction of fatty acyl resonances from triglycerides, unsaturated lipids being known targets of free radicals. This work opens up perspectives for the use of 1 H HRMAS-NMR as a molecular phenotyping device for model organisms. Because it is amenable to high throughput and is shown to be highly informative, this approach may rapidly lead to a functional and integrated metabonomic mapping of the C. elegans genome at the systems biology level.functional genomics ͉ metabolic profiling ͉ metabonomics ͉ nuclear magnetic resonance A ssigning functions to every gene in a living organism is the next challenge for functional genomics. However, only a small proportion of genes produce visible phenotypes when inactivated; for example, only 10-15% of the 19,000 genes of the nematode Caenorhabditis elegans produce a visible phenotype (1, 2). For the remaining ones, determining their function is more difficult, especially when they do not belong to previously characterized gene families.For example, oxidative stress is a key, yet subtle, biological process involved in aging, with long-term integration of many slow processes leading to irreversible cellular and molecular damage.Phenotyping plays a critical role in postgenomic sciences. Today, a range of molecular phenotyping tools is available to characterize mutations. Although gene expression and protein profiling are predominantly used (3-5), metabonomic and metabolomic strategies (6, 7) advantageously produce metabolic fingerprints that allow identification of variations in low-molecular-weight compounds in biofluids or organs in response to pathophysiological events (8), drug treatments (9), or genetic polymorphisms (10). It is therefore an attractive hypothesis-free approach for large-scale functional genomics in model organisms (11).Here we capitalize on recent developments in solid-state NMR that allow the acquisition of highly resolved 1 H spectra of metabolites from inhomogeneous materials such as biopsies (12) or food (13). As shown below, when applying 1 H high-resolution magic angle spinning NMR spectroscopy ( 1 H HRMAS-NMR), we provide complex metabolic phenotypes (6) or metabotypes (8) suitable for discriminating between C. elegans oxidative stress mutants, w...

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Direct quantitative trait locus mapping of mammalian metabolic phenotypes in diabetic and normoglycemic rat models

Cited by 137 publications

References 29 publications

Subtle metabolic and liver gene transcriptional changes underlie diet-induced fatty liver susceptibility in insulin-resistant mice

Subtle metabolic and liver gene transcriptional changes underlie diet-induced fatty liver susceptibility in insulin-resistant mice

The challenges for molecular nutrition research 1: linking genotype to healthy nutrition

Metabotyping of Caenorhabditis elegans reveals latent phenotypes

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