Couteur D, Solon-Biet S, Parker B, Pulpitel T, Brandon A, Hunt N, Wali J, Gokarn R, Senior A, Cooney G, Raubenheimer D, Cogger V, James D, Simpson S (2021) Cell Metabolism doi: 10.1016/j.cmet.2021.10.016
Dietary energy intake has a negative correlation with abundance of spliceosome proteins
Protein intake correlates with abundance of mitochondrial proteins and oxidative stress
Metformin, rapamycin, and resveratrol dampen responses to nutrients
Abundance of SLC25A51, the mitochondrial NAD transporter increased with protein intake
Nutrient sensing pathways influence metabolic health and aging, offering the possibility that diet might be used therapeutically, alone or with drugs targeting these pathways. We used the Geometric Framework for Nutrition to study interactive and comparative effects of diet and drugs on the hepatic proteome in mice across 40 dietary treatments differing in macronutrient ratios, energy density, and drug treatment (metformin, rapamycin, resveratrol). There was a strong negative correlation between dietary energy and the spliceosome and a strong positive correlation between dietary protein and mitochondria, generating oxidative stress at high protein intake. Metformin, rapamycin, and resveratrol had lesser effects than and dampened responses to diet. Rapamycin and metformin reduced mitochondrial responses to dietary protein while the effects of carbohydrates and fat were downregulated by resveratrol. Dietary composition has a powerful impact on the hepatic proteome, not just on metabolic pathways but fundamental processes such as mitochondrial function and RNA splicing.