“Multiomics Assessment of Dietary Protein Titration Reveals Altered Hepatic Glucose Usage”, Michael R. MacArthur, Sarah J. Mitchell, Katia S. Chadaideh, J. Humberto Treviño-Villarreal, Jonathan Jung, Krystle C. Kalafut, Justin S. Reynolds, Charlotte G. Mann, Kaspar M. Trocha, Ming Tao, Tay-Zar Aye Cho, Anantawat Koontanatechanon, Vladimir Yeliseyev, Lynn Bry, Alban Longchamp, C. Keith Ozaki, Caroline A. Lewis, Rachel N. Carmody, James R. Mitchell2022 (exercise)⁠:

Dietary protein restriction (PR) has rapid effects on metabolism including improved glucose and lipid homeostasis, via multiple mechanisms. Here, we investigate responses of fecal microbiome, hepatic transcriptome, and hepatic metabolome to 6 diets with protein 35.9%–59.4% of energy in mice.

PR alters fecal microbial composition, but metabolic effects are not transferable via fecal transplantation. Liver transcriptome and metabolome are statistically-significantly altered in diets with lower than 10% energy from protein. Changes upon PR correlate with calorie restriction but with a larger magnitude and specific changes in amino acid (AA) metabolism.

PR increases steady-state aspartate, serine, and glutamate and decreases glucose and gluconeogenic intermediates. 13C6 glucose and glycerol tracing reveal increased fractional enrichment in aspartate, serine, and glutamate. Changes remain intact in hepatic ATF4 knockout mice.

Together, this demonstrates an ATF4-independent shift in gluconeogenic substrate usage toward specific AAs, with compensation from glycerol to promote a protein-sparing response.

…Titration of protein produced a non-linear response in body mass with 0% and 2% groups losing body mass, 10% and 14% groups tending to gain body mass, and the 6% group remaining unchanged versus the 18% control group (Figures 1A and ​& 1C). The 0% and 2% groups also consumed statistically-significantly less food, and the 14% group consumed statistically-significantly more food, than the 18% control group on a gram-per-mouse basis (Figures 1B & S1C). Reduced food intake in the 0% and 2% groups was largely explained by a transient decrease during the first 3 days (Figures S1A & S1B), and intake between groups was not statistically-significantly different when normalized to body weight (Figure S1D). Similar non-linear changes in fat mass and lean mass were observed with the 0% and 2% groups having statistically-significantly less lean mass, fat mass, and lower body fat percent versus the 18% group (Figures 1D, ​1E, & S1E).