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。
基本信息
- 批准号:10482414
- 负责人:
- 金额:$ 22.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AblationAffectAgeAmericanAnimal ModelAnimalsAnti-Inflammatory AgentsAntiinflammatory EffectAreaAttenuatedAutopsyBiochemicalBlood VesselsBody CompositionBody Weight decreasedBody mass indexBrainCardiovascular DiseasesCellsChronic DiseaseDataDevelopmentDietEatingEncephalitisEnergy MetabolismEpidemicEstradiolEstrogen AntagonistsEstrogen MetabolismEstrogen Receptor alphaEstrogen Receptor betaEstrogen Replacement TherapyEstrogen TherapyEstrogensFemaleFutureGeneticGliosisGonadal Steroid HormonesHealthHigh Fat DietHumanHyperphagiaHypertensionHypothalamic structureImmuneInfiltrationInflammationInflammatoryInflammatory ResponseKnockout MiceLinkMalignant NeoplasmsMediatingMediator of activation proteinMenopauseMetabolicMetabolic DiseasesMicrogliaModelingMusNeurogliaNeuronal InjuryNeuronsNon-Insulin-Dependent Diabetes MellitusNuclear ReceptorsObesityOvariectomyOverweightPharmacologyPredispositionPremenopausePrevalencePrimary PreventionPropertyPublic HealthRegulationResearchResistanceRiskRisk FactorsRodentRodent ModelRoleSelective Estrogen Receptor ModulatorsSignal TransductionTestingTherapeutic InterventionTherapeutic TrialsTissuesVisceralWeight GainWomanblood glucose regulationcancer riskcell typecellular targetingcomorbiditydeprivationdiet-induced obesitydietaryeffective therapyenergy balanceexcessive weight gainfeedingin vivomacrophagemalemenmetabolic ratemouse modelnovelpre-clinicalreduced food intakereproductiveresponsesexual dimorphismside effectstroke risktrendwestern diet
项目摘要
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
肥胖是一个严重的公共健康威胁,因为它极大地增加了高度病态慢性疾病的风险
疾病包括2型糖尿病、高血压、心血管疾病和许多癌症。目前,已结束
60%的美国人超重或肥胖,缺乏有效的肥胖治疗方法
减少肥胖使我们必须专注于解开肥胖及其相关机制的谜团
代谢紊乱。
这项提案关注的是性激素预防肥胖的大脑机制及其
相关的代谢性疾病。绝经前女性的代谢紊乱发生率低于男性。
同龄,但绝经后这一趋势逆转,体重增加,内脏蓄积
肥胖和相关合并症的增加。虽然雌激素替代疗法可以逆转许多
这些更年期的变化,癌症和中风风险的增加与这种疗法相关,排除了它
用于初级预防,创造了了解雌激素保护机制的需求
避免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、
反应性胶质细胞增多症,以局部小胶质细胞(脑的巨噬细胞)激活为特征。啮齿动物
研究表明,减少下丘脑炎症和小胶质细胞激活可以限制体重增加。
以及饮食引起的肥胖的代谢并发症。同样,雌激素会减少食物的摄入量,增加
能量消耗,并能有力地抑制脑部炎症。此外,雌性老鼠的抵抗力更强
与饮食相关的小胶质细胞激活和体重增加有关,提示雌激素和体重增加之间存在潜在联系
小胶质细胞信号。事实上,我们的初步观察表明,雌激素缺乏会增加体征
饮食引起的下丘脑炎症和胶质细胞增多症。这些发现支持在特定目标下提出的研究。
1使用消融小胶质细胞炎症的动物模型来确定下丘脑胶质细胞增生症是否
西式饮食和雌激素缺乏协同作用易患肥胖症
相关的代谢并发症。此外,我们还开发了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以防止饮食诱导的肥胖(目标2)。拟议的研究将会取得进展
我们对雌激素缺乏如何导致代谢风险的理解,并测试了一种新的雌激素模型-
通过在小胶质细胞中的作用介导代谢调节。更广泛地说,这项提议将提供新的中央
解释低雌激素水平女性更高代谢风险的机制,以及新的
小胶质细胞靶点用于临床前治疗试验,以降低这种风险。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
专利数量(0)
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Mauricio D Dorfman其他文献
Mauricio D Dorfman的其他文献
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{{ truncateString('Mauricio D Dorfman', 18)}}的其他基金
Central regulation of atherosclerosis by testosterone-deficiency
睾酮缺乏对动脉粥样硬化的中枢调节
- 批准号:
10482387 - 财政年份:2021
- 资助金额:
$ 22.06万 - 项目类别:
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 - 财政年份:2021
- 资助金额:
$ 22.06万 - 项目类别:
Central regulation of atherosclerosis by testosterone-deficiency
睾酮缺乏对动脉粥样硬化的中枢调节
- 批准号:
10281872 - 财政年份:2021
- 资助金额:
$ 22.06万 - 项目类别:
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:
10669772 - 财政年份:2021
- 资助金额:
$ 22.06万 - 项目类别:
Central regulation of atherosclerosis by testosterone-deficiency
睾酮缺乏对动脉粥样硬化的中枢调节
- 批准号:
10680457 - 财政年份:2021
- 资助金额:
$ 22.06万 - 项目类别:
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