Estrogen Signaling in the Ventromedial Hypothalamus Modulates Adipose Tissue Metabolic Adaptation

下丘脑腹内侧区的雌激素信号调节脂肪组织代谢适应

基本信息

批准号：
10604611
负责人：
Valeria Cecilia Torres Irizarry
金额：
$ 4.77万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-16 至 2025-06-15
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10604611
关键词：
Adipocytes Adipose tissue Brain Brown Fat Chronic Clinical Comprehension Data Electrophysiology (science)Energy Metabolism Estradiol Estrogen Receptor alpha Estrogens Fasting Fatty acid glycerol esters Female Fiber Functional disorder Hypothalamic structure Impairment Mediating Metabolic Metabolic syndrome Metabolism Modeling Monitor Mus Neurons Nutrient Nutritional Obesity Output Ovarian hormone Pathologic Photometry Physiologic Thermoregulation Physiological Play Property Regulation Reporting Research Proposals Role Signal Transduction Site Structure Supplementation Synapses Temperature Testing Thermogenesis Tracer Woman Work brain tissue combat dorsal raphe nucleus energy balance female sex hormone improved in vivo insight male men neural neural circuit neural network neurotransmission optogenetics response sex sexual dimorphism subcutaneous

项目摘要

While sexual dimorphisms have been reported in the adipose tissue’s metabolic adaptation to environmental temperature or nutritional challenges, the sex-specific mechanisms regulating adipose tissue’s responses are not fully understood. There is increasing evidence demonstrating that the female sex hormone, estrogen, plays a vital role in sex dimorphic control of adipose tissue metabolism. We and others have consistently shown that central estrogen signaling mediated by estrogen receptor α (ERα) increases sympathetic activity, promotes brown adipose tissue (BAT) thermogenesis and white adipose tissue (WAT) browning, and diminishes excessive adiposity. ERα is abundantly expressed in the ventrolateral region of the ventromedial hypothalamus (vlVMH), a sex-dimorphic structure and the only ERα site in the brain that directly modulates BAT thermogenesis. Despite the abundant evidence supporting the role of ERαvlVMH in energy expenditure and metabolic function, it is still unclear whether ERαvlVMH-originated networks respond to environmental challenges, subsequently regulating adipose tissue metabolic adaptations. Here, we aim to test whether estrogen-initiated ERαvlVMH signaling and its downstream circuit contribute to sex dimorphic regulation of adipose tissue metabolic adaptation. The first aim is to determine if ERαvlVMH sex-dimorphically modulates BAT and WAT metabolism in response to temperature or nutritional challenge. The second aim is to determine if the dorsal raphe nucleus (DRN) relays ERαvlVMH neuron signals to adipose tissue to modulate metabolic adaptation. Results from these studies will advance our current understanding of adipose tissue plasticity and adaptation in general. Further, our studies will reveal the brain ERα-originated networks that respond to temperature or nutritional challenges and initiate subsequent changes in adipose tissue metabolism.

虽然脂肪组织对环境的代谢适应存在性别二态性温度或营养挑战，调节脂肪组织反应的性别特异性机制是尚未完全了解。越来越多的证据表明，雌性激素发挥着作用。我们和其他人一致证明，在脂肪组织代谢的性别二态性控制中起着至关重要的作用。由雌激素受体α（ERα）介导的中枢雌激素信号传导增加交感神经活性，促进棕色脂肪组织 (BAT) 生热作用和白色脂肪组织 (WAT) 褐变，并减少过度 ERα 在下丘脑腹内侧区 (vlVMH) 大量表达。性别二态性结构，并且是大脑中唯一直接调节 BAT 生热作用的 ERα 位点。大量证据支持 ERαvlVMH 在能量消耗和代谢功能中的作用，但仍尚不清楚 ERαvlVMH 起源的网络是否对环境挑战做出反应，随后进行调节在这里，我们的目的是测试雌激素是否启动 ERαvlVMH 信号传导和其下游回路有助于脂肪组织代谢适应的性别二态性调节。目的是确定 ERαvlVMH 是否响应性别二态性调节 BAT 和 WAT 代谢第二个目标是确定中缝背核（DRN）是否传递。 ERαvlVMH 神经元向脂肪组织发出信号以调节代谢适应。进一步推进我们目前对脂肪组织可塑性和适应性的理解。将揭示大脑 ERα 起源的网络，该网络对温度或营养挑战做出反应并启动随后脂肪组织代谢发生变化。