Transition to dietary plant-based proteins requires functional liver GDH for proper control of ammonia and energy homeostasis.

Plant-based diet is growingly recommended, although switching the source of proteins from animal to plant regimen requires metabolic adaptations. According to its pivotal function in bridging amino acids and glucose homeostasis, we investigated the role of liver GDH in short-term adaptation to plant versus animal dietary proteins keeping the same spectrum of macronutrients. Control and Hep-Glud1-/- mice lacking liver GDH were fed for 4 days with either animal- or plant-based diets. Hepatic GDH was upregulated in control mice eating animal proteins compared to mice under the plant regimen. Glycemia of ad libitum fed control mice were lower under plant-based regimen compared to animal-based diet; not further changed in Hep-Glud1-/- mice. After 6h of fasting, glycemia remained within the physiological range but mice under the plant-based diet engaged a more robust fasting response versus animal protein regimen. In Hep-Glud1-/- mice, exhibiting impaired endogenous glucose production evoked by amino acids, plant-based diet was associated with reduced plasma concentrations of gluconeogenic alanine and L-carnitine precursor lysine, underscoring limited fasting adaptation. Liver in situ high-resolution metabolomics revealed higher pyruvate levels in periportal regions of mice fed the animal-based diet and the knockout of liver GDH induced elevated aspartate, while urea production was impaired. This resulted in high plasma ammonia concentrations in Hep-Glud1-/- mice, causing severe hyperammonemia in GDH null mice under plant-based diet. These mice exhibited reduced voluntary physical activity, an effect absent in Hep-Glud1-/- mice under animal-based proteins. Overall, dietary source of proteins shapes energy partitioning according to the respective amino acid availability.