Regulation of energy and glucose balance through BDNF signaling in VMH astrocytes

项目摘要/摘要 能量和葡萄糖动态平衡是复杂的过程，部分由中枢神经回路控制。 在大脑内部，下丘脑接收和整合外周能量状态信号，并通过 改变摄食行为和能量消耗，以满足有机体的营养需求。大脑- 下丘脑腹内侧核(VMH)中的衍生神经营养因子(BDNF)信号转导通路对 调节食物摄入量、体重和葡萄糖平衡。BDNF在FED中的表达被强烈地诱导 BDNF激活其神经元受体酪氨酸受体激酶B(TrkB)驱动 厌食性VMH神经元减少食物摄入量和降低血糖水平。脑源性神经营养因子在两者中的突变 小鼠模型和人类模型都与严重肥胖和血糖控制受损有关。除了……之外 BDNF对神经元的可塑性有很强的作用，已被证明可以调节星形胶质细胞的形态和钙离子 通过激活TrkB剪接变异体TrkB.T1进行信号传递。众所周知，星形胶质细胞扮演着一种 积极作用，调节神经元的活动。他们与血液供应联系，并与 神经元，这使它们成为感知外周代谢信号的极好但尚未被研究的候选细胞 相应地，塑造适当的神经元和代谢反应。拟议中的工作将测试 假设VMH星形胶质细胞是能量和葡萄糖平衡的关键调节者，以及BDNF 这些细胞群中的信号对这些效应至关重要。在支持方面，初步数据表明，BDNF 能量状态动态调节VMH星形胶质细胞的功能和结构可塑性以调节能量 平衡控制。拟议的实验将使用先进的行为、分子和电生理学 确定VMH星形胶质细胞BDNF/TrkB.T1信号在能量和糖平衡中作用的技术， 并检测BDNF/TrkB.T1信号在VMH星形胶质细胞-神经元相互作用中的作用。 对控制能量和葡萄糖平衡的中央回路和细胞类型有更好的理解 是治疗我国肥胖症流行所必需的。这项拟议的研究将为新的分子 参与调节中央馈入回路的机制，并为识别提供了踏脚石 治疗肥胖症和代谢紊乱的潜在治疗靶点。重要的是，新的假设和 提出的多方面实验将为我作为一名发展中的 能量和葡萄糖平衡中央控制领域的科学家。 好了！

PROJECT SUMMARY/ ABSTRACT Energy and glucose homeostasis are complex processes controlled in part by central neural circuits. Within the brain, the hypothalamus receives and integrates peripheral energy status signals and responds by altering feeding behavior and energy expenditure to meet the nutritional demands of the organism. Brain- derived neurotrophic factor (BDNF) signaling in the ventromedial hypothalamus (VMH) is critical for the regulation of food intake, body weight and glucose balance. Expression of BDNF is robustly induced in the fed state, where BDNF activation of its neuronal receptor tyrosine receptor kinase B (TrkB) drives activity of anorexigenic VMH neurons to decrease food intake and lower blood glucose levels. BDNF mutations in both mouse models and in humans are associated with severe obesity and impaired glycemic control. In addition to its robust effects on neuronal plasticity, BDNF has been shown to regulate astrocyte morphology and calcium signaling through activation of a TrkB splice variant, TrkB.T1. It is well established that astrocytes play an active role regulating neuronal activity. They are in contact with the blood supply and communicate with neurons, which make them an excellent yet understudied candidate for sensing peripheral metabolic signals to accordingly shape the appropriate neuronal and metabolic responses. The proposed work will test the hypothesis that VMH astrocytes are key regulators of energy and glucose balance, and that BDNF signaling in this cell population is critical for these effects. In support, preliminary data suggest that BDNF and energy status dynamically regulate function and structural plasticity of VMH astrocytes to mediate energy balance control. Proposed experiments will use advanced behavioral, molecular and electrophysiological techniques to ascertain the role of VMH astrocyte BDNF/TrkB.T1 signaling on energy and glucose balance, and examine the effects of BDNF/TrkB.T1 signaling on VMH astrocyte-neuron interactions. A better understanding of the central circuitry and cell types controlling energy and glucose balance is required for treatment of our nations obesity epidemic. The proposed study will inform novel molecular mechanisms involved in the regulation of central feeding circuits and provide a stepping-stone for identification of potential therapeutic targets in treating obesity and metabolic disorder. Importantly, the novel hypothesis and multifaceted experiments proposed will provide an excellent training opportunity for me as a developing scientist in the field of central control of energy and glucose balance. !