Hypothalamic NF-kB and astrocytic programs in obesity

摘要/总结 在了解了促炎性IKKβ/NF-κB通路在下丘脑炎症机制中的作用后， 肥胖症，这项研究的目的是研究下丘脑神经元和星形胶质细胞是如何 参与编程。通过最近的研究，包括对小鼠的初步实验， 下丘脑星形胶质细胞IKKβ/NF-κB激活或抑制，获得的支持性证据表明， 下丘脑内侧基底核（MBH）中的星形胶质细胞通过IKKβ/NF-κB有多个程序， 导致代谢失衡因此，该建议的假设是，持续激活 慢性高脂饮食喂养下MBH中星形胶质细胞IKKβ/NF-κB导致星形胶质细胞-神经元改变 在MBH的关系，至少由于星形胶质细胞依赖的GABA清除障碍，也是一个 星形胶质细胞细胞因子产生的增强-其利用GABA和细胞因子受体信号传导， 影响负责的神经元，导致多种形式的神经元代谢平衡失调 导致肥胖和糖尿病前期的发展。本研究的目的有三：（1）星形胶质细胞 IKKβ/NF-κ B-自噬轴与下丘脑神经元代谢紊乱的关系;（2）IKKβ/NF-κ B-自噬轴与下丘脑神经元代谢紊乱的关系; GABA依赖性星形胶质细胞清除将POMC神经元抑制与肥胖联系起来，以及（3）IKKβ/NF-κB- 驱动的星形胶质细胞细胞因子将其他反应性下丘脑神经元与疾病发展联系起来。一 将使用细胞、分子、遗传、生理和药理学方法的组合， 分析星形胶质细胞的生物学和功能，对神经元的整体和局部影响，及其机制 肥胖和糖尿病前期的作用。这个项目的成功完成将是重要的了解 肥胖和糖尿病下丘脑基础，并为设计干预策略提供新的范例。

ABSTRACT/SUMMARY Having appreciated the role of pro-inflammatory IKKβ/NF-κB pathway in the hypothalamic mechanism of obesity, the objective of this research is to study how hypothalamic neurons and astrocytes are programmatically involved. Through recent studies including preliminary experiments on mice with hypothalamic astrocytic IKKβ/NF-κB activation or inhibition, supportive evidence was obtained to suggest that astrocytes in the mediobasal hypothalamus (MBH) have multiple programs through IKKβ/NF-κB for being responsible for metabolic imbalance. Hence, the hypothesis of this proposal is, sustained activation of astrocytic IKKβ/NF-κB in the MBH under chronic high-fat diet feeding leads to altered astrocyte-neuron relationships in the MBH, at least due to an impairment in astrocyte-dependent GABA clearance and also an enhancement in astrocytic cytokine production – which employ GABA and cytokine receptor signaling to influence the responsible neurons, resulting in multiple forms of neuronal dysregulation on metabolic balance which underlie obesity and pre-diabetic development. Three Aims are designed to study (1) astrocytic IKKβ/NF-κB–autophagy axis in linking hypothalamic neurons to metabolic dysregulation, (2) IKKβ/NF-κB- dependent astrocytic clearance of GABA in linking POMC neuronal inhibition to obesity, and (3) IKKβ/NF-κB- driven astrocytic cytokines in linking other responsive hypothalamic neurons to disease development. A combination of cellular, molecular, genetic, physiological and pharmacological approaches will be used to analyze astrocytic biology and functions, the overall and local influences on neurons, and their mechanistic roles for obesity and pre-diabetes. Successful completion of this project will be important for understanding the hypothalamic basis of obesity and diabetes and provide new paradigms in designing interventional strategies.