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Diabetologia
Published in: Diabetologia 9/2007

01-09-2007 | Article

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

Authors: A. A. Toye, M. E. Dumas, C. Blancher, A. R. Rothwell, J. F. Fearnside, S. P. Wilder, M. T. Bihoreau, O. Cloarec, I. Azzouzi, S. Young, R. H. Barton, E. Holmes, M. I. McCarthy, R. Tatoud, J. K. Nicholson, J. Scott, D. Gauguier

Published in: Diabetologia | Issue 9/2007

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Abstract

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 diet-induced 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 diet-induced insulin resistance and NAFLD. They suggest that proposed models of NAFLD pathogenesis can be enriched with novel diet-reactive genes and disease mechanisms.
Appendix
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Metadata
Title
Subtle metabolic and liver gene transcriptional changes underlie diet-induced fatty liver susceptibility in insulin-resistant mice
Authors
A. A. Toye
M. E. Dumas
C. Blancher
A. R. Rothwell
J. F. Fearnside
S. P. Wilder
M. T. Bihoreau
O. Cloarec
I. Azzouzi
S. Young
R. H. Barton
E. Holmes
M. I. McCarthy
R. Tatoud
J. K. Nicholson
J. Scott
D. Gauguier
Publication date
01-09-2007
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 9/2007
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-007-0738-5

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