Erhuma Aml, Salter Andrew M, Sculley Dean V, Langley-Evans Simon C, Bennett Andrew J
School of Biosciences, University of Nottingham, Queens Medical Centre, Nottingham, UK.
Am J Physiol Endocrinol Metab. 2007 Jun;292(6):E1702-14. doi: 10.1152/ajpendo.00605.2006. Epub 2007 Feb 13.
The nutritional environment encountered during fetal life is strongly implicated as a determinant of lifelong metabolic capacity and risk of disease. Pregnant rats were fed a control or low-protein (LP) diet, targeted to early (LPE), mid-(LPM), or late (LPL) pregnancy, or throughout gestation (LPA). The offspring were studied at 1, 9, and 18 mo of age. All LP-exposed groups had similar plasma triglyceride, cholesterol, glucose, and insulin concentrations to those of controls at 1 and 9 mo of age, but by 18 mo there was evidence of LP-programmed hypertriglyceridemia and insulin resistance. All LP-exposed groups exhibited histological evidence of hepatic steatosis and were found to have two- to threefold more hepatic triglyceride than control animals. These phenotypic changes were accompanied by age-related changes in mRNA and protein expression of the transcription factors SREBP-1c, ChREBP, PPARgamma, and PPARalpha and their respective downstream target genes ACC1, FAS, L-PK, and MCAD. At 9 mo of age, the LP groups exhibited suppression of the SREBP-1c-related lipogenic pathway but between 9 and 18 mo underwent a switch to increased lipogenic capacity with a lower expression of PPARgamma and MCAD, consistent with reduced lipid oxidation. The findings indicate that prenatal protein restriction programs development of a metabolic syndrome-like phenotype that develops only with senescence. The data implicate altered expression of SREBP-1c and ChREBP as key mediators of the programmed phenotype, but the basis of the switch in metabolic status that occurred between 9 and 18 mo of age is, as yet, unidentified.
胎儿期所遭遇的营养环境被强烈认为是终身代谢能力和疾病风险的一个决定因素。给怀孕大鼠喂食对照饮食或低蛋白（LP）饮食，分别针对妊娠早期（LPE）、中期（LPM）、晚期（LPL），或整个妊娠期（LPA）。在子代1、9和18月龄时对其进行研究。所有暴露于LP的组在1和9月龄时血浆甘油三酯、胆固醇、葡萄糖和胰岛素浓度与对照组相似，但到18月龄时，有证据表明存在LP编程性高甘油三酯血症和胰岛素抵抗。所有暴露于LP的组均表现出肝脂肪变性的组织学证据，且发现其肝脏甘油三酯比对照动物多两到三倍。这些表型变化伴随着转录因子SREBP-1c、ChREBP、PPARγ和PPARα及其各自下游靶基因ACC1、FAS、L-PK和MCAD的mRNA和蛋白质表达的年龄相关变化。在9月龄时，LP组表现出SREBP-1c相关脂肪生成途径的抑制，但在9至18月龄之间转变为脂肪生成能力增加，同时PPARγ和MCAD表达降低，这与脂质氧化减少一致。这些发现表明，产前蛋白质限制编程了一种仅在衰老时才出现的代谢综合征样表型的发展。数据表明SREBP-1c和ChREBP表达改变是编程表型的关键介质，但9至18月龄之间发生的代谢状态转变的基础尚未明确。
