孕期肠胃外给予甲硫氨酰-甲硫氨酸二肽，通过激活蛋氨酸缺乏小鼠的PI3K-AKT信号通路，比游离蛋氨酸更能增强乳腺生成和泌乳性能。

Parenterally Delivered Methionyl-Methionine Dipeptide During Pregnancy Enhances Mammogenesis and Lactation Performance Over Free Methionine by Activating PI3K-AKT Signaling in Methionine-Deficient Mice.

作者信息

Chen Qiong, Zhao Feng-Qi, Ren Yifei, Han Jialiang, Liu Jianxin, Li Yang, Liu Hongyun

机构信息

College of Animal Sciences, Zhejiang University, Hangzhou, PR China.

Department of Animal and Veterinary Sciences, University of Vermont, Burlington, VT, USA.

出版信息

J Nutr. 2020 May 1;150(5):1186-1195. doi: 10.1093/jn/nxaa005.

DOI:10.1093/jn/nxaa005

PMID:32006013

Abstract

BACKGROUND

Pregnancy-induced hypoaminoacidemia, l-methionine (Met) included, disturbs embryogenesis and may also affect breast function. Supplementation with the dipeptide l-methionyl-Met (Met-Met) may improve lactation performance.

OBJECTIVE

We compared the effects of supplemental Met or Met-Met during pregnancy on mammogenesis and lactogenesis and investigated underlying mechanisms.

METHODS

In experiment 1, 9-wk-old ICR mice (n = 72, ∼30 g) were divided into 3 groups. During the first 17 days of pregnancy (DP), the Control group was fed a diet with Met (8.2 g/kg) and saline was intraperitoneally injected, the Met group was fed a Met-devoid diet and 35% of the Met (92-mmo l Met) as contained in the Control diet was intraperitoneally injected, and the Met-Met group was fed the same diet and 70-mmo l Met plus 11-mmo l Met-Met was intraperitoneally injected. All animals were fed the Control diet after DP17 and during lactation. Mammogenesis, lactogenesis, transcriptome at DP17, and milk performance during lactation were examined. In experiment 2, 9-wk-old ICR mice (n = 55, ∼30 g) at DP0 were injected through the teat with adeno-associated virus for overexpression/inhibition of phosphoinositide-3-kinase regulatory subunit 1 (Pik3r1), divided into the Control, Met, and Met-Met groups and received the same treatment as experiment 1 to examine mammogenesis and lactogenesis at DP17.

RESULTS

In experiment 1, compared with the Met group, the Met-Met group showed higher (P < 0.05) mammary epithelium percentage (42%) and αS1-casein expression (84%) at DP17, milk yield (34%) and energy concentrations (8.7%) during lactation; transcriptomic analysis illustrated activated phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT) signaling in the mammary glands of the Met-Met group (P-adj < 0.001). In experiment 2, overexpression of Pik3r1 enhanced (P < 0.05) the protective effect of Met-Met over Met on mammogenesis and β-casein expression.

CONCLUSION

Met-Met is more effective than Met in promoting mammogenesis and lactogenesis mainly by activation of PI3K-AKT signaling in Met-deficient mice.

摘要

背景

孕期诱发的低氨基酸血症，包括L-蛋氨酸（Met）缺乏，会干扰胚胎发育，还可能影响乳腺功能。补充二肽L-蛋氨酰-蛋氨酸（Met-Met）可能会改善泌乳性能。

目的

我们比较了孕期补充Met或Met-Met对乳腺生成和泌乳生成的影响，并研究其潜在机制。

方法

在实验1中，将9周龄的ICR小鼠（n = 72，约30 g）分为3组。在妊娠的前17天（DP），对照组喂食含Met（8.2 g/kg）的日粮，并腹腔注射生理盐水；Met组喂食不含Met的日粮，并腹腔注射对照组日粮中所含Met的35%（92 mmol Met）；Met-Met组喂食相同日粮，并腹腔注射70 mmol Met加11 mmol Met-Met。所有动物在DP17后及哺乳期均喂食对照日粮。检测DP17时的乳腺生成、泌乳生成、转录组以及哺乳期的乳汁性能。在实验2中，在DP0时通过乳头向9周龄的ICR小鼠（n = 55，约30 g）注射用于过表达/抑制磷酸肌醇-3-激酶调节亚基1（Pik3r1）的腺相关病毒，分为对照组、Met组和Met-Met组，并接受与实验1相同的处理，以检测DP17时的乳腺生成和泌乳生成。

结果

在实验1中，与Met组相比，Met-Met组在DP17时乳腺上皮百分比（42%）和αS1-酪蛋白表达（84%）更高（P < 0.05），哺乳期的产奶量（34%）和能量浓度（8.7%）更高；转录组分析表明Met-Met组乳腺中磷脂酰肌醇-3激酶（PI3K）/蛋白激酶B（AKT）信号通路被激活（P校正 < 0.001）。在实验2中，Pik3r1的过表达增强了（P < 0.05）Met-Met相对于Met对乳腺生成和β-酪蛋白表达的保护作用。