Understanding the mechanisms of N utilization for lactation can lead to improved requirement estimates and increased efficiency, which modern dairy diets currently fail to maximize. The mechanistic target of rapamycin complex 1 (mTORC1) is a central hub of translation regulation, processing extra- and intra-cellular signals of nutrient availability and physiological state, such as amino acids and energy. We hypothesized that dietary amino acids regulate lactation through mTORC1, such that inhibition of mTORC1 will lead to decreased lactation performance when amino acids are not limiting. Our objectives were to assess lactation performance in lactating mice undergoing dietary and pharmacologic interventions designed to alter mTORC1 activity. First lactation mice (N = 18; n = 6/treatment) were fed an adequate protein diet (18% crude protein), or an isocaloric protein-restricted diet (9% crude protein) from the day after parturition until lactation day 13. A third group of mice was fed an adequate protein diet and treated with the mTORC1 inhibitor rapamycin (4 mg/kg every other day) intraperitoneally, with the first two groups treated with vehicle as control. Dams and pups were weighed daily, and feed intake was recorded every other day. Milk production was measured every other day beginning on lactation day 4 by the weigh-suckle-weigh method. Tissues were collected after fasting and refeeding. Milk production and pup weight were similarly decreased by both protein restriction and rapamycin treatment, with final production at 50% of control (P = 0.008) and final pup weight at 85% of control (P < 0.001). Mammary phosphorylation of mTORC1’s downstream targets were decreased by protein restriction and rapamycin treatment (P < 0.05), while very little effect was observed in the liver of rapamycin treated mice, and none by protein restriction. Overall, sufficient supply of dietary amino acids was unable to maintain lactation performance status in mice with pharmacologically reduced mammary mTORC1 activity, as evidenced by diminished pup growth and milk production, supporting the concept that mTORC1 activation rather than substrate supply is the primary route by which amino acids regulate synthesis of milk components.

中文翻译：

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mTORC1 的药理学抑制模拟了哺乳期小鼠模型中的饮食蛋白质限制。

了解哺乳期氮利用的机制可以改善需求估计并提高效率，而现代乳制品日粮目前未能最大限度地提高这一点。雷帕霉素复合物 1 (mTORC1) 的机械靶点是翻译调节的中心枢纽，处理营养物质可用性和生理状态（如氨基酸和能量）的细胞外和细胞内信号。我们假设膳食氨基酸通过 mTORC1 调节泌乳，因此当氨基酸不受限制时，抑制 mTORC1 会导致泌乳性能下降。我们的目标是评估接受旨在改变 mTORC1 活性的饮食和药物干预的哺乳期小鼠的泌乳性能。第一次哺乳小鼠（N = 18；n = 6/治疗）喂食足够的蛋白质饮食（18% 粗蛋白），或从分娩后的第二天到哺乳第 13 天的等热量蛋白质限制饮食（9% 粗蛋白）。第三组小鼠喂食足够的蛋白质饮食，并用 mTORC1 抑制剂雷帕霉素（每隔一天 4 mg/kg）治疗腹腔内，前两组用载体作为对照。每天对母鼠和幼崽称重，每隔一天记录一次采食量。从泌乳第 4 天开始，每隔一天通过称重-哺乳-称重法测量产奶量。在禁食和再喂食后收集组织。蛋白质限制和雷帕霉素处理同样降低了产奶量和幼犬体重，最终产量为对照的 50%（P = 0.008），最终幼犬体重为对照的 85%（P < 0.001）。蛋白质限制和雷帕霉素处理降低了 mTORC1 下游靶标的乳腺磷酸化 (P < 0.05)，而在雷帕霉素处理的小鼠的肝脏中观察到的影响很小，而蛋白质限制则没有。总体而言，充足的膳食氨基酸供应无法维持乳腺 mTORC1 活性药理学降低的小鼠的泌乳性能状态，幼崽生长和产奶量减少就证明了这一点，这支持了 mTORC1 激活而不是底物供应是主要途径的概念氨基酸调节乳成分的合成。