Estrogen Signaling in the Ventromedial Hypothalamus Modulates Adipose Tissue Metabolic Adaptation

虽然在脂肪组织对环境的新陈代谢适应中存在性别二态现象的报道 温度或营养挑战，调节脂肪组织反应的性别特异性机制是 没有完全理解。越来越多的证据表明，女性的性激素，雌激素，在 在脂肪组织代谢的性别二型性控制中起着至关重要的作用。我们和其他人一直在证明 雌激素受体α(ERα)介导的中枢雌激素信号增强交感神经活性，促进 棕色脂肪组织(BAT)产热和白色脂肪组织(WAT)褐变，并减少过度 肥胖症。ER-α在下丘脑腹内侧腹外侧区有丰富的表达。 性别-二态结构和大脑中唯一直接调节蝙蝠产热的ERα位点。尽管 大量证据支持ERαvlVMH在能量消耗和代谢功能中的作用，它仍然是 不清楚ERαvlVMH起源的网络是否对环境挑战做出反应，随后进行监管 脂肪组织代谢适应。在这里，我们的目的是测试雌激素启动的ERαvlVMH信号和 其下游回路参与脂肪组织代谢适应的性别二态调节。第一 目的是确定ERαv1 VMH性别二态是否调节BAT和WAT的代谢 温度或营养挑战。第二个目的是确定中缝背核(DRN)是否 内质网αvlVMH神经元向脂肪组织发出信号，调节代谢适应。这些研究的结果将 从总体上推进我们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ER-α起源的网络，这些网络对温度或营养挑战做出反应，并启动 随后脂肪组织代谢的变化。

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.