Improved perinatal glucose metabolism and the effect on the offspring's hippocampus in the mouse

在全球超重和肥胖率稳步上升的情况下，怀孕前和怀孕期间的母亲肥胖正变得越来越普遍。不幸的是，母亲和孩子都面临着许多风险。除了儿童易患心血管和代谢性疾病，如动脉高血压、2型糖尿病或肥胖症外，母亲妊娠期肥胖还会增加神经认知发育障碍和精神疾病的发生率。基于动物模型的初步工作，我们能够证明，母亲肥胖会在出生前后和后代出生的头几周导致葡萄糖代谢紊乱。成年后，后代的海马体表现出对胰岛素的抵抗和神经元可塑性的改变。这些海马体变化的功能后果还没有被研究。此外，尚不清楚围产期葡萄糖代谢的改善是否有可能预防海马体胰岛素抵抗和神经元可塑性改变。这两个问题都将在所要求的项目中得到解决。在出生后56天(青春期)，正常体重和超重母亲的后代将接受焦虑、学习、社交和抑郁行为的测试，并将同时调查海马体中的分子过程(胰岛素敏感性、神经元可塑性标志和蛋白质组筛选分析)。此外，还将测试两种完善的改善围产期葡萄糖代谢的措施(母亲跑步训练或怀孕期间使用胰岛素增敏剂二甲双胍治疗)是否能够减少母亲肥胖对后代海马体和行为的影响。最后，动物实验的结果将被用来制定一种具体的策略，以调查可通过合作者获得的人类母子队列。总而言之，该项目旨在更好地了解母亲肥胖对后代的神经认知和行为后果，并将有助于制定预防和治疗战略。

Maternal obesity before and during pregnancy is becoming more common in the face of a steadily increasing global prevalence of overweight and obesity. Unfortunately, there are many risks to both, the mother and the child. In addition to the predisposition of the child for cardiovascular and metabolic diseases, such as arterial hypertension, type 2 diabetes or obesity, maternal periconceptual obesity also causes an increased occurrence of neurocognitive developmental disorders and mental illnesses. Based on preliminary work in the animal model we were able to show that maternal obesity leads to a disturbed glucose metabolism around birth and during the first weeks of life of the offspring. In adulthood, the offspring’s hippocampus shows resistance to insulin and altered neuronal plasticity. The functional consequences of these hippocampal changes have not yet been investigated. Furthermore, it is unclear whether an improvement in perinatal glucose metabolism has the potential to prevent hippocampal insulin resistance and altered neuronal plasticity. Both questions will be addressed in the requested project. The offspring of normal-weight and overweight dams will be tested with regard to anxiety, learning, social and depressive behaviour at postnatal days 56 (adolescence) and molecular processes in the hippocampus (insulin sensitivity, markers of neuronal plasticity and proteomic screening analysis) will be investigated in parallel. In addition, it will be tested whether two well-established measures to improve perinatal glucose metabolism (maternal running-wheel training or treatment with the insulin sensitizer metformin during pregnancy) are able to reduce the consequences of maternal obesity in the offspring's hippocampus and behaviour. Finally, the findings of the animal experiments will be used to develop a specific strategy for the investigation of a human mother-child cohort that is accessible via a collaborator. In summary, the project aims at a better understanding of the neurocognitive and behavioural consequences of maternal obesity for the offspring and will help to develop prevention and treatment strategies.