INRA, UMR1280, Physiopathologie des Adaptations Nutritionnelles, Institut des maladies de l'appareil digestif (IMAD), Centre de Recherche en Nutrition Humaine Ouest (CRNH), Nantes, France; LUNAM, Institut des maladies de l'appareil digestif (IMAD), Centre de Recherche en Nutrition Humaine Ouest (CRNH), Nantes, France.
Nantes University, House of the Human Sciences-USR3491, Nantes, F-44021, France.
J Nutr Biochem. 2018 May;55:124-141. doi: 10.1016/j.jnutbio.2017.11.009. Epub 2017 Dec 10.
Perinatal undernutrition affects not only fetal and neonatal growth but also adult health outcome, as suggested by the metabolic imprinting concept. However, the exact mechanisms underlying offspring metabolic adaptations are not yet fully understood. Specifically, it remains unclear whether the gestation or the lactation is the more vulnerable period to modify offspring metabolic flexibility. We investigated in a rodent model of intrauterine growth restriction (IUGR) induced by maternal protein restriction (R) during gestation which time window of maternal undernutrition (gestation, lactation or gestation-lactation) has more impact on the male offspring metabolomics phenotype. Plasma metabolome and hepatic lipidome of offspring were characterized through suckling period and at adulthood using liquid chromatography-high-resolution mass spectrometry. Multivariate analysis of these fingerprints highlighted a persistent metabolomics signature in rats suckled by R dams, with a clear-cut discrimination from offspring fed by control (C) dams. Pups submitted to a nutritional switch at birth presented a metabolomics signature clearly distinct from that of pups nursed by dams maintained on a consistent perinatal diet. Control rats suckled by R dams presented transiently higher branched-chain amino acid (BCAA) oxidation during lactation besides increased fatty acid (FA) β-oxidation, associated with preserved insulin sensitivity and lesser fat accretion that persisted throughout their life. In contrast, IUGR rats displayed permanently impaired β-oxidation, associated to increased glucose or BCAA oxidation at adulthood, depending on the fact that pups experienced slow postnatal or catch-up growth, as suckled by R or C dams, respectively. Taken together, these findings provide evidence for a significant contribution of the lactation period in metabolic programming.
围产期营养不良不仅影响胎儿和新生儿的生长，还影响成年后的健康结果，这一概念被称为代谢印迹。然而，后代代谢适应的具体机制尚不完全清楚。具体来说，尚不清楚是妊娠还是哺乳期更易改变后代的代谢灵活性。我们在由母体蛋白质限制（R）引起的宫内生长受限（IUGR）的啮齿动物模型中进行了研究，即母体营养不足（妊娠、哺乳期或妊娠-哺乳期）的哪个时间窗口对雄性后代的代谢组学表型影响更大。通过哺乳期和成年期使用液相色谱-高分辨率质谱法，对后代的血浆代谢组和肝脂代谢组进行了特征描述。对这些指纹图谱进行多元分析，突出了 R 代哺乳大鼠的持续代谢组学特征，与由对照（C）代哺乳的后代明显区分开来。在出生时进行营养转换的幼崽表现出与哺乳期由 R 代哺乳的幼崽明显不同的代谢组学特征。由 R 代哺乳的对照大鼠在哺乳期会短暂地增加支链氨基酸（BCAA）氧化，同时增加脂肪酸（FA）β氧化，这与胰岛素敏感性的保持和脂肪堆积的减少有关，这种情况会持续到它们的一生。相比之下，IUGR 大鼠的β氧化永久受损，与成年后葡萄糖或 BCAA 氧化增加有关，这取决于幼崽在哺乳期由 R 代或 C 代哺乳的情况下经历了缓慢的产后或追赶生长。总的来说，这些发现为哺乳期在代谢编程中的重要贡献提供了证据。
