Department of Health Sciences and Technology, ETH Zürich, 8603 Schwerzenbach, Switzerland.
Department of Health Sciences and Technology, ETH Zürich, 8603 Schwerzenbach, Switzerland.
Cell Rep. 2022 Aug 16;40(7):111187. doi: 10.1016/j.celrep.2022.111187.
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 six diets with protein from 18% to 0% of energy in mice. PR alters fecal microbial composition, but metabolic effects are not transferable via fecal transplantation. Hepatic transcriptome and metabolome are 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. C6 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 utilization toward specific AAs, with compensation from glycerol to promote a protein-sparing response.
饮食蛋白质限制（PR）通过多种机制对代谢产生快速影响，包括改善葡萄糖和脂质稳态。在这里，我们研究了粪便微生物组、肝转录组和肝代谢组对六组能量蛋白分别为 18%到 0%的饮食的反应。PR 改变了粪便微生物组成，但代谢效应不能通过粪便移植传递。低于 10%能量蛋白的饮食显著改变了肝转录组和代谢组。PR 引起的变化与热量限制相关，但幅度更大，并且在氨基酸（AA）代谢方面存在特定变化。PR 增加天冬氨酸、丝氨酸和谷氨酸的稳态水平，降低葡萄糖和糖异生中间产物的水平。C6 葡萄糖和甘油示踪显示，天冬氨酸、丝氨酸和谷氨酸的分数富集增加。在肝 ATF4 敲除小鼠中，这些变化仍然完整。总之，这表明 ATF4 独立的糖异生底物利用向特定氨基酸的转变，甘油代偿性增加以促进蛋白保护反应。
