Role of estrogens in hypothalamic inflammation and metabolic regulation.

雌激素在下丘脑炎症和代谢调节中的作用。

• 批准号: 10300979
• 负责人: Mauricio D Dorfman
• 金额: $ 22.06万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-06 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10300979
• 关键词: Ablation; Affect; Age; American; Animal Model; Animals; Anti-Inflammatory Agents; Antiinflammatory Effect; Area; Attenuated; Autopsy; Biochemical; Blood Vessels; Body Composition; Body Weight decreased; Body mass index; Brain; Cardiovascular Diseases; Cells; Chronic Disease; Data; Development; Diet; Eating; Encephalitis; Energy Metabolism; Epidemic; Estradiol; Estrogen Antagonists; Estrogen Metabolism; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Replacement Therapy; Estrogen Therapy; Estrogens; Female; Future; Genetic; Gliosis; Gonadal Steroid Hormones; Health; High Fat Diet; Human; Hyperphagia; Hypertension; Hypothalamic structure; Immune; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Knockout Mice; Link; Malignant Neoplasms; Mediating; Mediator of activation protein; Menopause; Metabolic; Metabolic Diseases; Microglia; Modeling; Mus; Neuroglia; Neuronal Injury; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Obesity; Ovariectomy; Overweight; Pharmacology; Predisposition; Premenopause; Prevalence; Primary Prevention; Property; Public Health; Regulation; Research; Resistance; Risk; Risk Factors; Rodent; Rodent Model; Role; Selective Estrogen Receptor Modulators; Signal Transduction; Testing; Therapeutic Intervention; Therapeutic Trials; Tissues; Visceral; Weight Gain; Woman; blood glucose regulation; cancer risk; cell type; cellular targeting; comorbidity; deprivation; diet-induced obesity; dietary; effective therapy; energy balance; excessive weight gain; feeding; in vivo; macrophage; male; men; metabolic rate; mouse model; novel; pre-clinical; reduced food intake; reproductive; response; sexual dimorphism; side effect; stroke risk; trend; western diet

Project Summary Obesity is a grave public health threat since it greatly increases the risk of highly morbid chronic diseases including type 2 diabetes, hypertension, cardiovascular disease, and many cancers. Currently, over 60 percent of Americans are overweight or obese, and the lack of effective therapies available for weight reduction make it imperative to focus on unraveling the mechanisms underlying obesity and its associated metabolic disorders. This proposal focuses on brain mechanisms by which sex steroids protect from obesity and its associated metabolic diseases. Premenopausal women have a lower rate of metabolic disorders than men of the same age, but this trend reverses after menopause with increase of weight gain, accumulation of visceral adiposity and increase in associated comorbidities. While estrogen replacement therapy can reverse many of these menopausal changes, the increased cancer and stroke risks associated with this therapy preclude its use for primary prevention, creating a demand for understanding the mechanisms by which estrogen protects from obesity and its associated metabolic risks. Growing evidence suggests that obesity is associated with hypothalamic neuronal injury, inflammation, and reactive gliosis, characterized by activation of local microglia (the macrophage of the brain). Rodent studies have demonstrated that reducing hypothalamic inflammation and microglial activation limits weight gain and the metabolic complications of diet-induced obesity. Similarly, estrogen reduces food intake, increases energy expenditure, and can potently suppress brain inflammation. In addition, female mice are more resistant to diet-associated microglial activation and weight gain, suggesting a potential link between estrogen and microglial signaling. Indeed, our preliminary observations demonstrate that estrogen deficiency increases signs of diet-induced hypothalamic inflammation and gliosis. These findings support studies proposed in Specific Aim 1 to use animal models with ablation of microglial inflammation to determine whether hypothalamic gliosis is required for Western-type diet and estrogen deficiency to synergistically predispose to obesity and its associated metabolic complications. Additionally, we have developed mouse models with microglia-specific deletion of either estrogen receptor alpha (ERα) or estrogen receptor beta (ERβ) to determine the requirement of microglial estrogen signaling to protect from diet-induced obesity (Aim 2). The proposed studies will advance our understanding of how estrogen deficiency confers metabolic risk and test a novel model of estrogen- mediated metabolic regulation through action in microglia. More broadly, this proposal will provide new central mechanisms to explain the higher metabolic risk observed in women with low estrogen levels, and new microglial targets for preclinical therapeutic trials to reduce this risk.

项目摘要 肥胖是严重的公共卫生威胁 包括2型糖尿病，高血压，心血管疾病和许多癌症在内的疾病。目前，结束 60％的美国人超重或肥胖，缺乏可用于体重的有效疗法 减少必须专注于揭开肥胖及其相关机制的机制 代谢障碍。 该提案重点是性类固醇免受肥胖及其的脑机制 相关的代谢疾病。绝经前妇女的代谢疾病发生率低于 同一年龄，但是这种趋势在更年期后随体重增加，内脏积累而逆转 肥胖和相关合并症的增加。雌激素替代疗法可以扭转许多 这些更年期的变化，与这种疗法相关的癌症和中风风险的增加排除了 用于一级预防，提出了理解雌激素保护的机制的需求 肥胖及其相关的代谢风险。 越来越多的证据表明肥胖与下丘脑神经元损伤，炎症， 和反应性神经病，其特征是激活局部小胶质细胞（大脑的巨噬细胞）。啮齿动物 研究表明，减少下丘脑感染和小胶质激活限制了体重增加 以及饮食引起的肥胖症的代谢并发症。同样，雌激素减少食物摄入量，增加 能量消耗，并可能抑制大脑感染。此外，雌性小鼠更具耐药性 与饮食相关的小胶质细胞激活和体重增加，表明雌激素与 小胶质信号传导。实际上，我们的初步观察表明雌激素缺乏增加了体征 饮食诱导的下丘脑感染和神经胶质病。这些发现支持在特定目标中提出的研究 1使用烧蚀小胶质注射的动物模型来确定下丘脑神经胶质病是否是 西方型饮食和雌激素缺乏对肥胖及其协同性易感性所必需的 相关的代谢并发症。此外，我们开发了具有小胶质细胞特异性的小鼠模型 删除雌激素受体α（ERα）或雌激素受体β（ERβ）以确定需求 小胶质细胞雌激素信号传导以防止饮食诱导的肥胖症（AIM 2）。拟议的研究将进步 我们对雌激素缺乏症如何承认代谢风险的理解并测试一种新型雌激素模型 通过小胶质细胞的作用进行介导的代谢调节。更广泛地，该提议将提供新的中央 解释雌激素水平低的女性观察到的较高代谢风险的机制，新的 临床前治疗试验的小胶质靶标，以降低这种风险。