Objective

Perinatal exposure to maternal obesity results in predisposition of offspring to develop obesity later in life. Increased weight gain in offspring exposed to maternal obesity is usually associated with hyperphagia, implicating altered central regulation of food intake as a cause. We aimed to define how maternal obesity impacts early development of the hypothalamus to program lasting dysfunction in feeding regulatory pathways.

Methods

Mice offspring of diet-induced obese mothers were compared to the offspring of lean control mothers. We analysed gene expression in the fetal hypothalamus, alongside neurosphere assays to investigate the effects of maternal obesity on neural progenitor cell proliferation in vitro. Western blotting was used to investigate the insulin signalling pathway in the fetal hypothalamus. Characterisation of cell type and neuropeptide profile in adulthood was linked with analyses of feeding behaviour.

Results

There was a reduction in the expression of proliferative genes in the fetal hypothalamus of offspring exposed to maternal obesity. This reduction in proliferation was maintained in vitro when hypothalamic neural progenitor cells were grown as neurospheres. Hypothalamic fetal gene expression and neurosphere growth correlated with maternal body weight and insulin levels. Foetuses of obese mothers showed hypothalamic insulin resistance, which may be causative of reduced proliferation. Furthermore, maternal obesity activated the Notch signalling pathway in neonatal offspring hypothalamus, resulting in decreased neurogenesis. Adult offspring of obese mothers displayed an altered ratio of anorexigenic and orexigenic signals in the arcuate nucleus, associated with an inability to maintain energy homeostasis when metabolically challenged.

Conclusions

These findings show that maternal obesity alters the molecular signature in the developing hypothalamus, which is associated with disrupted growth and development of hypothalamic precursor cells and defective feeding regulation in adulthood. This is the first report of fetal hypothalamic insulin resistance in an obese pregnancy and suggests a mechanism by which maternal obesity causes permanent changes to hypothalamic structure and function.

中文翻译：

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母亲肥胖会导致胎儿下丘脑胰岛素抵抗并破坏下丘脑喂养途径的发育。

客观的

围产期暴露于母体肥胖会导致后代在以后的生活中易患肥胖症。暴露于母体肥胖的后代体重增加增加通常与摄食过多有关，这表明食物摄入的中枢调节改变是一个原因。我们旨在确定母体肥胖如何影响下丘脑的早期发育，从而对喂养调节途径中的持久功能障碍进行编程。

方法

将饮食诱导的肥胖母亲的小鼠后代与瘦对照母亲的后代进行比较。我们分析了胎儿下丘脑中的基因表达，以及神经球测定，以研究母体肥胖对体外神经祖细胞增殖的影响。Western印迹用于研究胎儿下丘脑中的胰岛素信号通路。成年期细胞类型和神经肽谱的表征与喂养行为分析有关。

结果

暴露于母体肥胖的后代的胎儿下丘脑中增殖基因的表达减少。这种增殖减少在体外得以维持当下丘脑神经祖细胞生长为神经球时。下丘脑胎儿基因表达和神经球生长与母体体重和胰岛素水平相关。肥胖母亲的胎儿表现出下丘脑胰岛素抵抗，这可能是增殖减少的原因。此外，母体肥胖激活了新生儿后代下丘脑中的 Notch 信号通路，导致神经发生减少。肥胖母亲的成年后代在弓状核中表现出厌食和厌食信号的比例发生变化，这与代谢受到挑战时无法维持能量稳态有关。

结论

这些研究结果表明，母体肥胖会改变发育中的下丘脑的分子特征，这与下丘脑前体细胞的生长和发育中断以及成年期的喂养调节缺陷有关。这是肥胖妊娠中胎儿下丘脑胰岛素抵抗的第一份报告，并提出了母体肥胖导致下丘脑结构和功能永久性改变的机制。