The Children's Health Research Institute and the Lawson Health Research Institute, Department of Obstetrics and Gynecology and Physiology and Pharmacology, The University of Western Ontario, London, Ontario, Canada N6A 5C1.
Metabolism. 2013 Oct;62(10):1367-74. doi: 10.1016/j.metabol.2013.05.002. Epub 2013 Jun 13.
Epidemiological studies have established that low birth weight offspring, when faced with a nutritional mismatch in postnatal life, have an increased risk of developing the metabolic syndrome. Our laboratory and others have demonstrated that maternal protein restriction (MPR) leads to high cholesterol and insulin resistance in the offspring due to impaired liver function, though the underlying molecular mechanisms remain elusive. Recent in vitro studies have associated decreased phosphorylation of Akt1 (Serine 473), a marker of insulin sensitivity, with increased phosphorylation of eukaryotic initiation factor (eIF)-2α (Serine 51), a key regulator of protein translation attenuation. The main aim of the study was to determine whether nutritional mismatch in MPR offspring leads to elevated phospho-eIF2α (Ser51) levels in the liver.
MATERIALS/METHODS: To investigate if this occurs long-term in MPR offspring, pregnant Wistar rats were fed a control (20%) protein diet (control) or a low (8%) protein diet during pregnancy and postnatal life (LP1), or during pregnancy and lactation (LP2).
At postnatal day 130, LP2 offspring exhibited increases in hepatic phosphorylation of eIF2α (Ser51) concomitant with decreases in the phosphorylation of Akt1 (Ser473), while LP1 offspring exhibited the converse relationship. Interestingly, in embryonic day 19 livers derived from control or MPR pregnancy, no changes in eIF2α (Ser51) or Ak1 (Ser473) phosphorylation were observed.
Collectively, our data provide robust evidence that phosphorylation of eIF2α (Ser51) is inversely correlated with phosphorylated Akt1 (Ser473) in vivo. Moreover, this study demonstrates that this inverse relationship is adversely influenced in these MPR offspring by a mismatch in the postnatal nutritional environment.
流行病学研究已经证实，出生体重较低的后代在出生后生活中面临营养不匹配时，患代谢综合征的风险增加。我们的实验室和其他实验室已经证明，由于肝功能受损，母体蛋白质限制（MPR）会导致后代胆固醇升高和胰岛素抵抗，尽管潜在的分子机制仍不清楚。最近的体外研究表明，胰岛素敏感性的标志 Akt1（丝氨酸 473）的磷酸化减少与真核起始因子（eIF）-2α（丝氨酸 51）的磷酸化增加有关，eIF-2α（丝氨酸 51）是蛋白质翻译衰减的关键调节剂。该研究的主要目的是确定 MPR 后代的营养不匹配是否会导致肝脏中磷酸化 eIF2α（Ser51）水平升高。
材料/方法：为了研究这种情况是否长期存在于 MPR 后代中，我们在妊娠和产后（LP1）或妊娠和哺乳期（LP2）期间用对照（20％）蛋白质饮食（对照）或低（8％）蛋白质饮食喂养怀孕的 Wistar 大鼠。
在出生后第 130 天，LP2 后代的肝脏 eIF2α（Ser51）磷酸化增加，同时 Akt1（Ser473）磷酸化减少，而 LP1 后代则表现出相反的关系。有趣的是，在源自对照或 MPR 妊娠的胚胎第 19 天肝脏中，未观察到 eIF2α（Ser51）或 Ak1（Ser473）磷酸化的变化。
总之，我们的数据提供了有力的证据，表明 eIF2α（Ser51）的磷酸化与体内磷酸化 Akt1（Ser473）呈负相关。此外，这项研究表明，这种负相关关系在这些 MPR 后代中受到出生后营养环境不匹配的不利影响。
