Hepatic metabolomics and transcriptomics provide valuable insights on inflammatory and metabolic features in rats fed on a high fat diet but showing similar clinical phenotyping alterations

The complex processes of obesity development involve genetic and environmental factors. Genetic factors are considered to account for only a small fraction of the overall susceptibility to high fat (HF) induced obesity. Under certain conditions, foetal environment can trigger an adaptive response. This involves the further onset of insulin resistance to optimize the development of key organs (brain, heart...), to the detriment of others organs such as the liver. We studied the impact of a perinatal exposure to a HF diet on rats liver metabolome and transcriptome. Pregnant rats were fed with a normal fat (NF) or a HF diet during gestation and lactation. After weaning, males from the F1 generation were fed either the NF or the HF diet, until PND142, resulting in 4 groups depending on perinatal and post-weaning diet, respectively (NFxNF, NFxHF, HFxNF and HFxHF). H-NMR spectroscopy and mRNA (TLDA) analyses were performed on male livers extracts. Clinical phenotyping were different according to post-weaning diet but not according to maternal diet. The multivariate OPLSDA models discriminated F1-animals based on F1 diet (NFxNF and HFxNF vs NFxHF and HFxHF). When dams were fed on a standard diet (NFxNF vs NFxHF) HF-fed F1 animals showed an increased expression of genes participating to hepatic inflammation and a reduction in oxidative stress protectors (lower glutathione in the metabolome). In contrast, feeding dams and pups with a HF diet (HFxNF vs HFxHF) resulted in major changes at the metabolic level, including a reduced expression of lipogenic genes and several actors involved in branched-chain amino acid metabolism. The latter result was further supported by the increased hepatic levels of leucine (metabolome). The most extreme scenario compared to the control one (NFxNF vs. HFxHF) resulted in a more deleterious phenotype, which is the consequence of the combination of the inflammatory and metabolic features described above. In conclusion, despite the fact that HF feeding at the F1 level induced similar changes in clinical phenotyping, metabolomics and transcriptomics analyses at the liver level were able to discriminate between animals, providing valuable information on the underlying inflammatory and metabolic processes specifically signing the consequence of different maternal feeding.