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。

• 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
• 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' 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

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，包括阿尔茨海默氏病（AD）， 血管认知障碍和血管痴呆。由于更年期导致进化的损失导致下降 能量消耗和葡萄糖稳态受损，导致2型DM的患病率增加。 下丘脑雌激素受体信号传导在能量体内平衡的中心调节中起作用 肝葡萄糖产生和组织葡萄糖摄取的调节。系统性葡萄糖稳态在很大程度上是 受中央自主通路的监管，如果自主功能障碍是 展示。自主功能障碍，包括抑制通过同情心完成的副交感神经语调 参与代谢自主神经控制的下丘脑回路的主要占主导地位和破坏一直是 在包括AD在内的几种形式的认知障碍患者中观察到。因此，确定 损害肝脏和葡萄糖稳态的自主调节的细胞机制，从而有助于 认知功能障碍。此外，虽然肥胖，但已知胰岛素抵抗和DM会损害海马 突触可塑性和认知功能，缺乏研究的研究 中雌性雌二醇对葡萄糖稳态中心调节的下丘脑神经元的治疗 以及在肥胖背景下的海马功能。我们的初步观察表明，雌二醇 治疗改善了卵巢切除（OVX）动物的葡萄糖水平。另外，在 高脂饮食（HFD）治疗的小鼠的室室核（PVN）更活跃，HFD干扰胰岛素 - 依赖性抑制兴奋性神经传递在交感前PVN神经元中。此外，雌二醇 增强了中年OVX动物海马神经元的长期增强（LTP）。这些发现引起了 在中心假设中，OVX小鼠中的中年雌二醇治疗提供了所需的有益影响 保持脑肝道途径的适当功能，海马LTP，一种与学习相关的细胞 记忆和海马依赖性的认知功能，但这些有益作用在小鼠上减弱 HFD由于胰岛素抵抗。拟议的研究将确定中年雌二醇治疗对1的影响） 预据自主PVN神经元的细胞特性，2）突触可塑性和细胞特性 海马，3）对照和HFD小鼠中的葡萄糖稳态和认知。这些研究可能导致 在认知障碍期间改善葡萄糖稳态的新策略以及更好的理解 雌二醇中期雌二醇对下丘脑和海马功能的影响。