Enhanced detoxification contributes to beneficial effects of dietary restriction in rat as revealed by systems biology

Abstract

Dietary restriction (DR) has many beneficial effects, but the detailed metabolic mechanism remains largely unresolved. For this, systems biology approach involving metabolomics and genomics was applied to identify molecular interaction networks related to effects of DR on multiple tissues. First, the metabolic profiles of urines from control and DR animals were investigated using NMR and LC-MS metabolomics approaches. Multivariate analysis presented distinctive metabolic profiles and marker signals from glucuronide and glycine conjugation pathways in the DR group. Broad profiling of the urine phase II metabolites with neutral loss scanning showed that glucuronide and glycine conjugation metabolites were generally higher in the DR group. The up-regulation of the phase II detoxifications in the DR group were confirmed by mRNA and protein expression levels of the UGT and GLYAT in actual liver tissue. In addition, the Nrf-2 signaling pathway was shown to be up-regulated, providing a mechanistic clue for the enhanced phase II detoxification in liver tissue. Next, metabolic and genomic profiles of multiple tissues from the control and DR rat were investigated using metabolomics and cDNA microarray. Multi-organ metabolomics markers indicated higher phase II detoxification and distinct energy metabolism in the DR group. Microarray analysis with gene, pathway enrichment, and gene ontology terms provided consistent results for the mechanism revealed by multi-organ metabolomics. In addition, pathway enrichment and gene ontology analysis gave evidence of enhanced phase I detoxification in the DR group as the beneficial effect of DR. Several other markers were also found related to age-associated diseases, such as diabetes, cancers, cardiovascular, neurodegenerative, hepatic, and renal diseases. These were consistent with the histopathology and serum biochemistry results that showed actual beneficial effects of DR in current experimental system. Taken together, metabolomics, microarray, and biochemical studies provide a possible metabolic and genomic perspective in understanding the complex mechanism of the beneficial effects of DR.