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.

项目四总结