Impact of estradiol on the central regulation of glucose homeostasis and subsequent implications for hippocampal function.

项目4摘要 中年肥胖和糖尿病(DM)是所有痴呆症的危险因素，包括阿尔茨海默病(AD)， 血管性认知障碍和血管性痴呆。绝经导致的雌激素丢失导致 能量消耗和糖平衡受损，导致2型糖尿病患病率增加。 下丘脑雌激素受体信号在能量稳态中枢调节中的作用 调节肝脏葡萄糖生成和组织葡萄糖摄取。全身性血糖稳态在很大程度上 受中枢自主神经回路调节，如果自主神经功能障碍，患2型糖尿病的风险很高 现在时。自主神经功能障碍，包括伴随交感神经的副交感神经张力抑制 参与新陈代谢自主神经控制的下丘脑回路的优势和干扰 在包括阿尔茨海默病在内的几种认知障碍患者中观察到。因此，关键是要确定 破坏肝脏自主调节和葡萄糖动态平衡的细胞机制 到认知功能障碍。此外，虽然肥胖、胰岛素抵抗和糖尿病已知会损害海马体 在突触可塑性和认知功能方面，目前还缺乏全面的研究来研究 中年雌二醇对参与葡萄糖稳态中枢调节的下丘脑神经元的作用 以及肥胖背景下的海马区功能。我们的初步观察显示，雌二醇 治疗可改善去卵巢(OVX)动物的血糖水平。此外，与肝脏相关的神经元在 高脂饮食(HFD)小鼠室旁核(PVN)更活跃，HFD干扰胰岛素分泌 交感神经前核神经元兴奋性神经传递的依赖性抑制。此外，雌二醇 增强中年去卵巢动物海马神经元的长时程增强(LTP)。这些发现导致了 对于中年雌激素治疗OVX小鼠提供有益效果的中心假设， 维持大脑-肝脏通路、海马LTP的正常功能，LTP是一种与学习和记忆相关的细胞 记忆和海马体依赖的认知功能，但这些有益的影响在小鼠身上减弱 因胰岛素抵抗引起的肾功能不全。拟议的研究将确定中年雌激素治疗对1)的影响 下丘脑室旁核前神经元的细胞特性，2)突触可塑性和细胞特性。 海马区，以及3)对照组和HFD小鼠的葡萄糖稳态和认知。这些研究可能会导致 认知障碍时改善血糖稳态的新策略以及更好的理解 中年雌激素治疗对下丘脑和海马体功能的影响。

Project 4 Summary Midlife obesity and diabetes mellitus (DM) are risk factors for all dementias including Alzheimer’s disease (AD), vascular cognitive impairment, and vascular dementia. Loss of estrogens due to menopause results in decreased energy expenditure and impaired glucose homeostasis, leading to increased prevalence of Type 2 DM. Hypothalamic estrogen receptor signaling plays a role in the central regulation of energy homeostasis via modulation of both liver glucose production and tissue glucose uptake. Systemic glucose homeostasis is largely regulated by central autonomic circuits, and the risk of developing Type 2 DM is high if autonomic dysfunction is present. Autonomic dysfunction, including suppression of parasympathetic tone accompanied by sympathetic predominance and disruption of hypothalamic circuits involved in autonomic control of metabolism, has been observed in patients with several forms of cognitive impairment including AD. It is therefore crucial to determine cellular mechanisms that impair autonomic regulation of the liver and glucose homeostasis, and thus contribute to cognitive dysfunction. In addition, while obesity, insulin resistance and DM are known to impair hippocampal synaptic plasticity and cognitive function, there is a lack of comprehensive studies investigating the effects of midlife estradiol treatment on hypothalamic neurons involved in the central regulation of glucose homeostasis and on hippocampal function in the context of obesity. Our preliminary observations have revealed that estradiol treatment improves glucose levels in ovariectomized (OVX) animals. In addition, liver-related neurons in the paraventricular nucleus (PVN) of high-fat diet (HFD) treated mice are more active and HFD interferes with insulin- dependent suppression of excitatory neurotransmission in pre-sympathetic PVN neurons. Furthermore, estradiol enhances long-term potentiation (LTP) in hippocampal neurons of middle-aged OVX animals. These findings led to the central hypothesis that midlife estradiol treatment in OVX mice provides beneficial effects required to maintain proper function of the brain-liver pathway, hippocampal LTP, a cellular correlate for learning and memory, and hippocampus-dependent cognitive function, but these beneficial effects are attenuated in mice on HFD due to insulin resistance. The proposed studies will determine the effect of midlife estradiol treatment on 1) the cellular properties of preautonomic PVN neurons, 2) synaptic plasticity and cellular properties in the hippocampus, and 3) glucose homeostasis and cognition in control and HFD mice. These studies may lead to new strategies to improve glucose homeostasis during cognitive impairment as well as to a better understanding of the effect of midlife estradiol treatment on hypothalamic and hippocampal function.