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

项目总结/摘要 能量和葡萄糖稳态是部分由中枢神经回路控制的复杂过程。 在大脑内，下丘脑接收并整合外周能量状态信号，并通过以下方式作出反应： 改变摄食行为和能量消耗以满足生物体的营养需求。大脑- 下丘脑腹内侧（VMH）中的衍生神经营养因子（BDNF）信号传导对于 调节食物摄入、体重和葡萄糖平衡。BDNF的表达在进食的小鼠中被强烈诱导， 状态，其中BDNF激活其神经元受体酪氨酸受体激酶B（Trk B）驱动 VMH神经元减少食物摄入和降低血糖水平。BDNF基因突变 在小鼠模型和人类中与严重肥胖和血糖控制受损有关。除了 由于其对神经元可塑性的强大作用，BDNF已被证明可以调节星形胶质细胞的形态和钙离子浓度。 通过激活TrkB剪接变体TrkB.T1进行信号传导。已经确定星形胶质细胞在神经细胞中发挥重要作用。 调节神经元活动的积极作用。它们与血液供应接触， 神经元，这使它们成为感知外周代谢信号的优秀但未充分研究的候选者， 相应地形成适当的神经元和代谢反应。拟议的工作将测试 假设VMH星形胶质细胞是能量和葡萄糖平衡的关键调节器，而BDNF 该细胞群中的信号传导对于这些效应至关重要。作为支持，初步数据表明BDNF 和能量状态动态调节VMH星形胶质细胞的功能和结构可塑性， 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信号传导对能量和葡萄糖平衡的作用的技术， 并检测BDNF/TrkB.T1信号对VMH星形胶质细胞-神经元相互作用的影响。 更好地了解控制能量和葡萄糖平衡的中央电路和细胞类型， 治疗我国肥胖症流行所需的药物。这项研究将为新的分子生物学提供信息。 参与中枢进食回路调节的机制，并为识别 肥胖和代谢紊乱的潜在治疗靶点。重要的是，新的假设和 多方面的实验建议将提供一个很好的培训机会，我作为一个发展中国家 能量和葡萄糖平衡中央控制领域的科学家。 !

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. !