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

雌二醇对葡萄糖稳态中枢调节的影响以及随后对海马功能的影响。

基本信息

批准号：
10334235
负责人：
Andrea Zsombok
金额：
$ 51.14万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10334235
关键词：
1-Phosphatidylinositol 3-Kinase Address Age Alzheimer&apos s Disease Animal Model Animals Attenuated Autonomic Dysfunction Blood Pressure Body Composition Body Weight Brain Cells Clinical Trials Cognition Cognitive Cognitive aging Data Dementia Dementia with Lewy Bodies Diabetes Mellitus Energy Metabolism Estradiol Estrogen Receptors Estrogen Therapy Estrogens Failure Female Glucose Health High Fat Diet Hippocampus (Brain)Homeostasis Hormones Hypothalamic structure Impaired cognition Impairment Insulin Insulin Resistance Lead Learning Link Liver Long-Term Potentiation Memory Menopause Metabolic Metabolism Mus Neurons Non-Insulin-Dependent Diabetes Mellitus Obesity Ovary Pathway interactions Patients Play Prevalence Property Receptor Signaling Regulation Risk Risk Factors Rodent Role Signal Pathway Sympathetic Nervous System Synapses Synaptic plasticity Testing Tissues Tracer Vascular Cognitive Impairment Vascular Dementia Viral Woman behavior test blood glucose regulation cardiometabolism cognitive function dietary control glucose production glucose tolerance glucose uptake glycemic control hippocampal pyramidal neuron hormone therapy improved insulin sensitivity insulin tolerance middle age mild cognitive impairment mouse model neurotransmission paraventricular nucleus patch clamp spatial memory treatment comparison vascular cognitive impairment and dementia

项目摘要

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.

项目4总结中年肥胖和糖尿病 (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由于更年期导致雌激素减少。能量消耗和葡萄糖稳态受损，导致 2 型糖尿病患病率增加。下丘脑雌激素受体信号通过以下途径在能量稳态的中枢调节中发挥作用肝脏葡萄糖产生和组织葡萄糖摄取的调节很大程度上取决于全身葡萄糖稳态。受中枢自主神经回路调节，如果自主神经功能失调，患 2 型糖尿病的风险很高存在自主神经功能障碍，包括伴随交感神经张力的副交感神经张力抑制。参与代谢自主控制的下丘脑回路的优势和破坏已被证实在患有包括 AD 在内的多种认知障碍的患者中观察到的结果至关重要。损害肝脏自主调节和葡萄糖稳态的细胞机制，从而有助于此外，肥胖、胰岛素抵抗和糖尿病也会损害海马体。突触可塑性和认知功能，缺乏全面的研究来调查突触可塑性和认知功能的影响中年雌二醇治疗参与葡萄糖稳态中枢调节的下丘脑神经元我们的初步观察表明，雌二醇对肥胖背景下的海马功能有影响。治疗可改善卵巢切除（OVX）动物的血糖水平，此外，还可以改善肝脏相关神经元的水平。高脂饮食（HFD）治疗小鼠的室旁核（PVN）更加活跃，并且 HFD 会干扰胰岛素交感神经前PVN神经元兴奋性神经传递的依赖性抑制。增强中年 OVX 动物海马神经元的长时程增强 (LTP)。中心假设是，OVX 小鼠的中年雌二醇治疗提供了所需的有益效果维持脑肝通路、海马 LTP 的正常功能，这是学习和学习的细胞相关因素记忆和海马依赖性认知功能，但这些有益作用在小鼠中减弱由于胰岛素抵抗而导致的 HFD。拟议的研究将确定中年雌二醇治疗对 1) 的影响。前自主神经 PVN 神经元的细胞特性，2）突触可塑性和细胞特性海马体，以及 3) 对照小鼠和 HFD 小鼠的葡萄糖稳态和认知。改善认知障碍期间葡萄糖稳态以及更好理解的新策略中年雌二醇治疗对下丘脑和海马功能的影响。