Hypothalamic NF-kB and astrocytic programs in obesity

摘要/摘要 在认识到促炎症的IKKβ/NF-κB通路在下丘脑机制中的作用后， 肥胖，这项研究的目的是研究下丘脑神经元和星形胶质细胞 以编程方式参与。通过最近的研究，包括在小鼠身上进行的初步实验 下丘脑星形胶质细胞IKKβ/NF-κB的激活或抑制，获得了支持证据提示 下丘脑内侧基底区星形胶质细胞通过IKKβ/NF-κB有多个程序 对新陈代谢失衡负责。因此，这一提议的假设是，持续激活 慢性高脂饮食致脑出血大鼠星形胶质细胞IKKβ/NF-κB表达改变 MBH中的关系，至少是由于星形胶质细胞依赖的GABA清除功能受损以及 增强星形细胞细胞因子的产生-利用GABA和细胞因子受体信号转导 影响负责神经元，导致多种形式的神经元代谢平衡失调 这是肥胖和糖尿病前期发展的基础。设计了三个目标来研究(1)星形细胞 IKKβ/NF-κB-将下丘脑神经元与代谢失调联系起来的自噬轴，(2)IKKβ/NF-κB- 依赖星形胶质细胞的GABA清除将前额叶神经元抑制与肥胖联系起来，以及(3)IKKβ/NF-κB- 驱动星形细胞细胞因子将其他反应灵敏的下丘脑神经元与疾病发展联系起来。一个 将使用细胞、分子、遗传、生理和药理学方法的组合来 分析星形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 肥胖症和糖尿病前期的作用。这个项目的成功完成将对理解 下丘脑是肥胖和糖尿病的基础，并为设计干预策略提供了新的范例。

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.