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Hepatic gene expression profiles after long-term high-fat diet feeding in wild type and Nrf2 knock-out mice.

ABSTRACT: To assess the role of the transcription factor NFE2 related factor 2 like 2 ( Nrf2) in the development of high-fat diet (HFD)-induced obesity and non-alcoholic HFD-induced fatty liver disease, 8 wild type (WT) and 8 Nrf2 knock-out (Nrf2-KO) C57BL6J male mice (obtained from Riken BRC, Tsukuba, Japan and originally developed by Prof. M. Yamamoto) were fed an HFD (60 kcal % fat) for 180 days. Whole genome microarray expression profiling was performed in pooled liver samples of WT and Nrf2-KO mice to identify genes that are differentially expressed between WT and Nrf2-KO mice under the stress conditions of HFD-induced obesity.

ORGANISM(S): Mus musculus

PROVIDER: GSE33575 | GEO | 2011/11/30

SECONDARY ACCESSION(S): PRJNA148571

REPOSITORIES: GEO

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Project description:Maternal obesity can program metabolic syndrome in offspring but the mechanisms are not well characterized. Moreover, the consequences of maternal overnutrition in the absence of frank obesity remain poorly understood. This study aimed to determine the effects of maternal consumption of a high fat-sucrose diet on the skeletal muscle metabolic and transcriptional profiles of adult offspring. Female Sprague Dawley rats were fed either a diet rich in saturated fat and sucrose (HFD, 23.5% fat, 20% sucrose wt/wt) or a standard chow diet (NFD, 7% fat, 10% sucrose w/w) for the 3 weeks prior to mating and throughout pregnancy and lactation. Although maternal weights were not different between groups at conception or weaning, HFD dams were ~22% heavier than chow fed dams from mid-pregnancy until 4 days post-partum. Adult male offspring of HFD dams were not heavier than controls but demonstrated features of insulin resistance including elevated plasma insulin concentration (+40%, P<0.05). Next Generation mRNA Sequencing was used to identify differentially expressed genes in the soleus muscle of offspring, and Gene Set Enrichment Analysis (GSEA) to detect coordinated changes that are characteristic of a biological function. GSEA identified 15 pathways enriched for up-regulated genes, including cytokine signaling (P<0.005), starch and sucrose metabolism (P<0.017), and inflammatory response (P<0.024). A further 8 pathways were significantly enriched for down-regulated genes including oxidative phosphorylation (P<0.004) and electron transport (P<0.022). Western blots confirmed a ~60% reduction in the phosphorylation of the insulin signaling protein Akt (P<0.05) and ~70% reduction in mitochondrial complexes II (P<0.05) and V expression (P<0.05). On a normal diet, offspring of HFD dams developed an insulin resistant phenotype, with transcriptional evidence of muscle cytokine activation, inflammation and mitochondrial dysfunction. These data indicate that maternal overnutrition, even in the absence of pre-pregnancy obesity can promote metabolic dysregulation and predispose offspring to type 2 diabetes. Messenger RNA profile of skeletal muscle of male offspring from female Sprague Dawley rats fed either a diet rich in saturated fat and sucrose (HFD, 23.5% fat, 20% sucrose wt/wt) or a standard chow diet (NFD, 7% fat, 10% sucrose w/w) for the 3 weeks prior to mating and throughout pregnancy and lactation. There were 5 HFD samples compared to 6 NFD control samples.

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Hepatic gene expression profiles after long-term high-fat diet feeding in wild type and Nrf2 knock-out mice.

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