Modelling hepatic metabolic changes during the onset of obesity using NMR metabolomics arterio-venous blood exploration in minipigs
Résumé
Phenotypic alterations associated with obesity are well known, but metabolic adaptations occurring during its onset are poorly characterized. This study aims at understanding the hepatic metabolic processes modulated during the onset of obesity by combining paired arterial and venous metabolome analyses with computational modeling. It relies on the principle that differences in the metabolite composition of blood flowing in and out of the liver reflect its metabolic functioning. Blood samples were collected in a mini-pig model of obesity [1], consisting in over nutrition with a high-fat-high-sucrose (HFHS diet) for 60 days. Blood was sampled at the fasting state in 5 catheterized mini-pigs from incoming (abdominal artery and portal vein) and outgoing hepatic vessels at days 0 and 60 of HFHS feeding. From 1H-NMR analyses, we identified metabolites with significantly changed levels between arterious and venous blood. Calculated 1H-NMR integration ratios between arterious and venous blood allowed us to identify the metabolites with significant positive (resp. negative) balance between inflow and outflow, reflecting a release (resp. uptake) by the liver. These data were analyzed within the frame of an hepatic genome-scale metabolic network model using constraint-based modeling approaches to predict the changes in intra-tissular metabolic fluxes [2]. Constraints were set on exchange reactions in the metabolic model to enforce uptake and release of metabolites in accordance to experimental data and in silico flux balance analysis methods were used to predict possible flux ranges for hepatic metabolic reactions. We predicted that HFHS was associated with changes in the glucose metabolism and the sources of gluconeogenesis, but also in the catabolism of tryptophan and lysine, for which further support was found through complementary biochemical and molecular analyses.Polakof S, et al. Metabolic adaptations to HFHS overfeeding: how whole body and tissues postprandial metabolic flexibility adapt in Yucatan mini-pigs. Eur J Nutr. 2018;57(1):119-35.