Department of Pediatrics and Adolescent Medicine, University Hospital of Cologne, Kerpener Str. 62, Cologne, 50924, Germany.
Max Planck Institute for Biology of Ageing, Phenotyping Core Facility, Joseph-Stelzmann-Str. 9b, Cologne, 50931, Germany.
Psychoneuroendocrinology. 2018 Mar;89:46-52. doi: 10.1016/j.psyneuen.2017.12.023. Epub 2017 Dec 28.
Maternal obesity and a disturbed metabolic environment during pregnancy and lactation have been shown to result in many long-term health consequences for the offspring. Among them, impairments in neurocognitive development and performance belong to the most dreaded ones. So far, very few mechanistic approaches have aimed to determine the responsible molecular events.
In a mouse model of maternal diet-induced obesity and perinatal hyperinsulinemia, we assessed adult offspring's hippocampal insulin signaling as well as concurrent effects on markers of hippocampal neurogenesis, synaptic plasticity and function using western blotting and immunohistochemistry. In search for a potential link between neuronal insulin resistance and hippocampal plasticity, we additionally quantified protein expression of key molecules of synaptic plasticity in an in vitro model of acute neuronal insulin resistance.
Maternal obesity and perinatal hyperinsulinemia result in adult hippocampal insulin resistance with subsequently reduced hippocampal mTor signaling and altered expression of markers of neurogenesis (doublecortin), synaptic plasticity (FoxO1, pSynapsin) and function (vGlut, vGAT) in the offspring. The observed effects are independent of the offspring's adult metabolic phenotype and can be associated with multiple previously reported behavioral abnormalities. Additionally, we demonstrate that induction of insulin resistance in cultured hippocampal neurons reduces mTor signaling, doublecortin and vGAT protein expression.
Hippocampal insulin resistance might play a key role in mediating the long-term effects of maternal obesity and perinatal hyperinsulinemia on hippocampal plasticity and the offspring's neurocognitive outcome.
孕期和哺乳期母体肥胖和代谢环境紊乱会导致后代出现许多长期健康问题。其中，神经认知发育和表现受损属于最可怕的问题之一。到目前为止，很少有机制方法旨在确定负责的分子事件。
在母体饮食诱导肥胖和围产期高胰岛素血症的小鼠模型中，我们使用 Western blot 和免疫组织化学评估了成年后代海马胰岛素信号以及对海马神经发生、突触可塑性和功能标志物的并发影响。为了寻找神经元胰岛素抵抗和海马可塑性之间的潜在联系，我们还在急性神经元胰岛素抵抗的体外模型中定量了突触可塑性关键分子的蛋白表达。
母体肥胖和围产期高胰岛素血症导致成年海马胰岛素抵抗，随后海马 mTor 信号降低，以及后代神经发生标志物（双皮质素）、突触可塑性标志物（FoxO1、pSynapsin）和功能标志物（vGlut、vGAT）的表达改变。观察到的影响与后代的成年代谢表型无关，并且可能与先前报道的多种行为异常有关。此外，我们证明培养的海马神经元中胰岛素抵抗的诱导会降低 mTor 信号、双皮质素和 vGAT 蛋白的表达。
海马胰岛素抵抗可能在介导母体肥胖和围产期高胰岛素血症对海马可塑性和后代神经认知结果的长期影响方面发挥关键作用。
