Objective

Individuals born with intrauterine growth retardation (IUGR) are more prone to cardio-metabolic diseases as adults, and environmental changes during the perinatal period have been identified as potentially crucial factors. We have studied in a preclinical model early-onset molecular alterations present before the development of a clinical phenotype.

Methods

We used a preclinical mouse model of induced IUGR, in which we modulated the nutrition of the pups during the suckling period, to modify their susceptibility to cardio-metabolic diseases in adulthood.

Results

Mice born with IUGR that were overfed (IUGR-O) during lactation rapidly developed obesity, hepatic steatosis and insulin resistance, by three months of age, whereas those subjected to nutrition restriction during lactation (IUGR-R) remained permanently thin and highly sensitive to insulin. Mice born with IUGR and fed normally during lactation (IUGR-N) presented an intermediate phenotype and developed insulin resistance by 12 months of age. Molecular alterations to the insulin signaling pathway with an early onset were observed in the livers of adult IUGR-N mice, nine months before the appearance of insulin resistance. The implication of epigenetic changes was revealed by ChIP sequencing, with both posttranslational H3K4me3 histone modifications and microRNAs involved.

Conclusions

These two changes lead to the coherent regulation of insulin signaling, with a decrease in Akt gene transcription associated with an increase in the translation of its inhibitor, Pten. Moreover, we found that the levels of the implicated miRNA19a-3p also decreased in the blood of young adult IUGR mice nine months before the appearance of insulin resistance, suggesting a possible role for this miRNA as an early circulating biomarker of metabolic fate of potential use for precision medicine.

中文翻译：

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循环 miRNA19a-3p 的变化先于小鼠子宫内生长迟缓编程的胰岛素抵抗。

客观的

出生时患有宫内发育迟缓 (IUGR) 的个体成年后更容易患心脏代谢疾病，围产期的环境变化已被确定为潜在的关键因素。我们在临床前模型中研究了临床表型发展之前存在的早发性分子改变。

方法

我们使用了诱导 IUGR 的临床前小鼠模型，在该模型中，我们在哺乳期调节幼崽的营养，以改变它们在成年期对心脏代谢疾病的易感性。

结果

出生时在哺乳期间过度喂养 (IUGR-O) 的 IUGR 小鼠在三个月大时迅速发展为肥胖、肝脂肪变性和胰岛素抵抗，而在哺乳期间受到营养限制 (IUGR-R) 的小鼠仍然永久消瘦，对胰岛素高度敏感。胰岛素。出生时具有 IUGR 并在哺乳期间正常喂养 (IUGR-N) 的小鼠呈现中间表型，并在 12 个月大时出现胰岛素抵抗。在胰岛素抵抗出现前 9 个月，在成年 IUGR-N 小鼠的肝脏中观察到胰岛素信号通路的分子改变，并且早发。ChIP 测序揭示了表观遗传变化的含义，其中涉及翻译后 H3K4me3 组蛋白修饰和 microRNA。

结论

这两个变化导致胰岛素信号的连贯调节，Akt基因转录的减少与其抑制剂 Pten 的翻译增加有关。此外，我们发现在出现胰岛素抵抗前 9 个月，年轻成年 IUGR 小鼠血液中相关 miRNA19a-3p 的水平也降低，表明该 miRNA 作为潜在用途代谢命运的早期循环生物标志物可能发挥作用用于精准医学。