Theys Nicolas, Bouckenooghe Thomas, Ahn Marie-Thérèse, Remacle Claude, Reusens Brigitte
Laboratory of Cell Biology, Institute of Life Sciences, Université catholique de Louvain, Louvain-la-Neuve, Belgium.
Am J Physiol Regul Integr Comp Physiol. 2009 Nov;297(5):R1516-25. doi: 10.1152/ajpregu.00280.2009. Epub 2009 Sep 16.
Mitochondrial dysfunction may be a long-term consequence of a poor nutritional environment during early life. Our aim was to investigate whether a maternal low-protein (LP) diet may program mitochondrial dysfunction in islets of adult progeny before glucose intolerance ensues. To address this, pregnant Wistar rats were fed isocaloric diets containing either 20% protein (control) or 8% protein (LP diet) throughout gestation. From birth, offspring received the control diet. The mitochondrial function was analyzed in islets of 3-mo-old offspring. Related to their basal insulin release, cultured islets from both male and female LP offspring presented a lower response to glucose challenge and a blunted ATP production compared with control offspring. The expression of malate dehydrogenase as well as the subunit 6 of the ATP synthase encoded by mitochondrial genome (mtDNA) was lower in these islets, reducing the capacity of ATP production through the Krebs cycle and oxidative phosphorylation. However, mtDNA content was unchanged in LP islets compared with control. Several consequences of protein restriction during fetal life were more marked in male offspring. Only LP males showed an increased reactive oxygen species production associated with a higher expression of mitochondrial subunits of the electron transport chain NADH-ubiquinone oxireductase subunit 4L, an overexpression of peroxisome proliferator-activated receptor-gamma and uncoupling protein-2, and a strongly reduced beta-cell mass. In conclusion, mitochondrial function is clearly altered in islets from LP adult offspring in a sex-specific manner. That may provide a cellular explanation for the earlier development of glucose intolerance in male than in female offspring of dams fed an LP diet.
线粒体功能障碍可能是生命早期不良营养环境的长期后果。我们的目的是研究母体低蛋白（LP）饮食是否会在成年后代的胰岛出现葡萄糖不耐受之前就使其发生线粒体功能障碍。为了解决这个问题，在整个妊娠期，给怀孕的Wistar大鼠喂食等热量饮食，其中一种含有20%蛋白质（对照），另一种含有8%蛋白质（LP饮食）。从出生起，后代接受对照饮食。对3月龄后代的胰岛进行线粒体功能分析。与基础胰岛素释放相关，与对照后代相比，来自雄性和雌性LP后代的培养胰岛对葡萄糖刺激的反应较低，ATP生成减少。这些胰岛中苹果酸脱氢酶的表达以及线粒体基因组（mtDNA）编码的ATP合酶亚基6的表达较低，降低了通过三羧酸循环和氧化磷酸化产生ATP的能力。然而，与对照相比，LP胰岛中的mtDNA含量没有变化。胎儿期蛋白质限制的一些后果在雄性后代中更为明显。只有LP雄性表现出活性氧产生增加，这与电子传递链NADH-泛醌氧化还原酶亚基4L的线粒体亚基表达增加、过氧化物酶体增殖物激活受体-γ和解偶联蛋白-2的过表达以及β细胞量显著减少有关。总之，LP成年后代的胰岛线粒体功能明显以性别特异性方式改变。这可能为喂食LP饮食的母鼠雄性后代比雌性后代更早出现葡萄糖不耐受提供细胞层面的解释。
