Metabolic Research Laboratories, University of Cambridge, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, U.K.
Endocrinology. 2012 Dec;153(12):5961-71. doi: 10.1210/en.2012-1508. Epub 2012 Oct 15.
Human and animal studies suggest that suboptimal early nutrition during critical developmental periods impacts long-term health. For example, maternal overnutrition during pregnancy and lactation in mice programs insulin resistance, obesity, and endothelial dysfunction in the offspring. Here we investigated the effects of diet-induced maternal obesity on the offspring cardiac phenotype and explored potential underlying molecular mechanisms. Dams fed the obesogenic diet were heavier (P < 0.01) and fatter (P < 0.0001) than controls throughout pregnancy and lactation. There was no effect of maternal obesity on offspring body weight or body composition up to 8 wk of age. However, maternal obesity resulted in increased offspring cardiac mass (P < 0.05), increased heart-body weight (P < 0.01), heart weight-tibia length (P < 0.05), increased left ventricular free wall thickness and area (P < 0.01 and P < 0.05, respectively), and increased myocyte width (P < 0.001). Consistent with these structural changes, the expression of molecular markers of cardiac hypertrophy were also increased [Nppb(BNP), Myh7-Myh6(βMHC-αMHC) (both P < 0.05) and mir-133a (P < 0.01)]. Offspring were hyperinsulinemic and displayed increased insulin action through AKT (P < 0.01), ERK (P < 0.05), and mammalian target of rapamycin (P < 0.05). p38MAPK phosphorylation was also increased (P < 0.05), suggesting pathological remodeling. Increased Ncf2(p67(phox)) expression (P < 0.05) and impaired manganese superoxide dismutase levels (P < 0.01) suggested oxidative stress, which was consistent with an increase in levels of 4-hydroxy-2-trans-nonenal (a measure of lipid peroxidation). We propose that maternal diet-induced obesity leads to offspring cardiac hypertrophy, which is independent of offspring obesity but is associated with hyperinsulinemia-induced activation of AKT, mammalian target of rapamycin, ERK, and oxidative stress.
人体和动物研究表明，在关键发育阶段营养不足会影响长期健康。例如，母鼠妊娠和哺乳期营养过剩会导致后代胰岛素抵抗、肥胖和内皮功能障碍。在这里，我们研究了饮食诱导的母体肥胖对后代心脏表型的影响，并探讨了潜在的分子机制。在整个妊娠和哺乳期，给予肥胖饮食的母鼠体重（P < 0.01）和体脂（P < 0.0001）均高于对照组。母体肥胖对后代体重或体成分的影响直到 8 周龄时才显现。然而，母体肥胖导致后代心脏质量增加（P < 0.05），心脏-体重比增加（P < 0.01），心脏重-胫骨长比增加（P < 0.05），左心室游离壁厚度和面积增加（P < 0.01 和 P < 0.05），心肌细胞宽度增加（P < 0.001）。与这些结构变化一致，心脏肥大的分子标志物表达也增加[Nppb（BNP），Myh7-Myh6（βMHC-αMHC）（均 P < 0.05）和 mir-133a（P < 0.01）]。后代表现为高胰岛素血症，并通过 AKT（P < 0.01）、ERK（P < 0.05）和哺乳动物雷帕霉素靶蛋白（mTOR，P < 0.05）增加胰岛素作用。p38MAPK 磷酸化也增加（P < 0.05），表明存在病理性重塑。Ncf2（p67（phox））表达增加（P < 0.05）和锰超氧化物歧化酶水平降低（P < 0.01）表明存在氧化应激，这与 4-羟基-2-反式-壬烯醛水平升高（脂质过氧化的一种衡量标准）一致。我们提出，母体饮食诱导的肥胖导致后代心脏肥大，这种肥大与后代肥胖无关，但与高胰岛素血症诱导的 AKT、mTOR、ERK 和氧化应激的激活有关。
