Cell-autonomous programming of rat adipose tissue insulin signalling proteins by maternal nutrition.
Cell-autonomous programming of rat adipose tissue insulin signalling proteins by maternal nutrition.
复制标题
DOI：
10.1007/s00125-016-3905-8
复制
发表时间：
2016-06
期刊：
影响因子：
8.2
通讯作者：
Ozanne SE
中科院分区：
文献类型：
--
作者：
Martin-Gronert MS;Fernandez-Twinn DS;Bushell M;Siddle K;Ozanne SE
低出生体重的个体在成年后患2型糖尿病的风险增加。这与外周胰岛素抵抗有关。在这里，我们的目的是确定是否在白色脂肪组织（WAT）的胰岛素信号蛋白的变化可以检测到葡萄糖耐量受损的发病前，确定这些变化是否是细胞自主的，并确定相关的潜在机制。研究了在整个妊娠期和哺乳期内饲喂标准蛋白质（20%）饮食或低蛋白质（8%）饮食的母鼠所生的14个月大雄性大鼠后代。测定脂肪分布和脂肪细胞大小。蛋白质含量和关键胰岛素信号分子的mRNA表达进行了分析，在附睾WAT和前脂肪细胞，经历了体外分化。低蛋白喂养母鼠的后代（LP后代）内脏WAT质量降低，脂肪分布改变，附睾WAT中小脂肪细胞百分比较高。这与IRS 1、PI3K p110β、Akt1和PKC β蛋白以及磷酸化Akt Ser473水平降低有关。相应的mRNA转录水平不变。同样，LP后代的体外分化脂肪细胞显示IRβ、IRS 1、PI3K p85α和p110β亚基以及Akt1蛋白水平降低。Akt Ser473和IRS1 Tyr612磷酸化水平降低，而IRS1 Ser307磷酸化水平升高。妊娠期和哺乳期母体蛋白质限制改变了WAT的分布和形态，并降低了雄性后代中关键胰岛素信号蛋白的水平。这种表型保留在体外分化的脂肪细胞中，表明编程通过细胞自主机制发生。
Individuals with a low birthweight have an increased risk of developing type 2 diabetes mellitus in adulthood. This is associated with peripheral insulin resistance. Here, we aimed to determine whether changes in insulin signalling proteins in white adipose tissue (WAT) can be detected prior to the onset of impaired glucose tolerance, determine whether these changes are cell-autonomous and identify the underlying mechanisms involved. Fourteen-month-old male rat offspring born to dams fed a standard protein (20%) diet or a low (8%) protein diet throughout gestation and lactation were studied. Fat distribution and adipocyte size were determined. Protein content and mRNA expression of key insulin signalling molecules were analysed in epididymal WAT and in pre-adipocytes that had undergone in vitro differentiation. The offspring of low protein fed dams (LP offspring) had reduced visceral WAT mass, altered fat distribution and a higher percentage of small adipocytes in epididymal WAT. This was associated with reduced levels of IRS1, PI3K p110β, Akt1 and PKCζ proteins and of phospho-Akt Ser473. Corresponding mRNA transcript levels were unchanged. Similarly, in vitro differentiated adipocytes from LP offspring showed reduced protein levels of IRβ, IRS1, PI3K p85α and p110β subunits, and Akt1. Levels of Akt Ser473 and IRS1 Tyr612 phosphorylation were reduced, while IRS1 Ser307 phosphorylation was increased. Maternal protein restriction during gestation and lactation changes the distribution and morphology of WAT and reduces the levels of key insulin signalling proteins in the male offspring. This phenotype is retained in in vitro differentiated adipocytes, suggesting that programming occurs via cell-autonomous mechanism(s).