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.
项目总结
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)
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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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