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

• 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
• 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

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.

虽然在脂肪组织的代谢适应环境中已经报道了性二态性 温度或营养挑战，调节脂肪组织反应的性别特异性机制是 不完全理解。越来越多的证据表明女性性激素，雌激素，发挥作用 在脂肪组织代谢的性二态控制中至关重要的作用。我们和其他人一直表明 由雌激素受体α（ERα）介导的中枢雌激素信号传导增加了交感性活性，促进 棕色脂肪组织（BAT）生热和白色脂肪组织（WAT）褐变，并减少过量 肥胖。 ERα在腹侧下丘脑（VLVMH）的腹外侧区域明显表达 性二态结构和大脑中唯一直接调节蝙蝠热发生的ERα位点。尽管 支持ERαVLVMH在能量消耗和代谢功能中的作用的大量证据仍然是 尚不清楚ERαVLVMH原始网络是否应对环境挑战，随后调节 脂肪组织代谢适应。在这里，我们旨在测试雌激素引起的ERαVLVMH信号传导和 它的下游回路有助于脂肪组织代谢适应的性二态调节。第一个 目的是确定ERαVLVMH性别是否对响应于BAT和WAT代谢进行调节 温度或营养挑战。第二个目的是确定背侧raphe核（DRN）继电器是否 ERαVLVMH神经元对脂肪组织的信号调节代谢适应。这些研究的结果将 一般而言，我们当前对脂肪组织可塑性和适应性的理解。此外，我们的研究 将揭示大脑ERα原始网络应对温度或营养挑战的反应并启动 随后的脂肪组织代谢变化。