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: 10579251
• 负责人: Andrea Zsombok
• 金额: $ 51.44万
• 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/10579251
• 关键词: Address; Age; Alzheimer' s Disease; Alzheimer' s disease patient; 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; Diabetes prevention; Energy Metabolism; Estradiol; Estrogen Receptors; Estrogen Therapy; Estrogens; Failure; Female; Glucose; Health; High Fat Diet; Hippocampus; Homeostasis; Hypothalamic structure; Impaired cognition; Impairment; Insulin; Insulin Resistance; Learning; Link; Liver; Long-Term Potentiation; Memory; Menopause; Metabolic; Metabolism; Mus; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Ovary; PIK3CG gene; Pathway interactions; Patients; Play; Postmenopause; 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; menopausal hormone therapy; 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（包括阿尔茨海默病（AD））的危险因素， 血管性认知障碍和血管性痴呆。由于绝经导致的雌激素的损失减少 能量消耗和葡萄糖稳态受损，导致2型DM患病率增加。 下丘脑雌激素受体信号转导在能量稳态的中枢调节中起作用， 调节肝脏葡萄糖产生和组织葡萄糖摄取。全身葡萄糖稳态主要是 2型糖尿病的发病风险是高的，如果自主神经功能紊乱， 礼物自主神经功能障碍，包括副交感神经张力抑制，伴有交感神经张力 下丘脑回路参与代谢的自主控制， 在包括AD在内的几种形式的认知障碍患者中观察到。因此，至关重要的是， 损害肝脏和葡萄糖稳态的自主调节的细胞机制， 认知功能障碍此外，虽然肥胖，胰岛素抵抗和糖尿病是众所周知的损害海马 突触可塑性和认知功能，缺乏全面的研究调查的影响， 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 以及肥胖情况下海马体功能的变化。我们的初步观察显示雌二醇 治疗改善了卵巢切除（OVX）动物的葡萄糖水平。此外，肝脏相关的神经元在 高脂饮食（HFD）处理小鼠的室旁核（PVN）更活跃，HFD干扰胰岛素- 依赖性抑制交感神经前PVN神经元的兴奋性神经传递。此外，雌二醇 增强中年OVX动物海马神经元的长时程增强（LTP）。基于这些发现得出 中心假设，中年雌二醇治疗OVX小鼠提供了有益的影响， 维持脑-肝通路、海马LTP（一种与学习相关的细胞）的正常功能， 记忆，以及依赖于大脑的认知功能，但这些有益的作用在小鼠中减弱， 胰岛素抵抗引起的HFD。拟议的研究将确定中年雌二醇治疗对1） PVN前自主神经元的细胞特性，2）突触可塑性和细胞特性， 海马，和3）对照和HFD小鼠中的葡萄糖稳态和认知。这些研究可能会导致 改善认知障碍期间葡萄糖稳态的新策略以及更好地理解 中年雌二醇治疗对下丘脑和海马功能的影响。