Hypothalamic NF-kB and astrocytic programs in obesity

肥胖症中的下丘脑 NF-kB 和星形细胞程序

• 批准号: 9758638
• 负责人: Dongsheng Cai
• 金额: $ 52.34万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9758638
• 关键词: Acute; Address; Affect; Antidiabetic Drugs; Astrocytes; Autophagocytosis; Biology; Brain; Cells; Cellular Metabolic Process; Chronic; Cytokine Receptors; Data; Development; Diabetes Mellitus; Diet; Disease; Equilibrium; FRAP1 gene; GABA Receptor; GABA transporter; Gene Expression; Genetic; High Fat Diet; Hypothalamic structure; Impairment; In Vitro; Inflammatory; Insulin; Interleukin-9; Intervention; Lead; Leptin; Link; Metabolic; Metabolic Diseases; Modeling; Molecular; Molecular Genetics; Mus; NF-kappa B; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Pharmacology; Phosphotransferases; Physiological; Prediabetes syndrome; Process; Production; Publishing; Receptor Signaling; Regulation; Research; Resistance; Role; STAT3 gene; Series; Signal Transduction; Structure of nucleus infundibularis hypothalami; Therapeutic Effect; Tyrosine 3-Monooxygenase; cytokine; design; dopaminergic neuron; energy balance; experimental study; extracellular; feeding; gamma-Aminobutyric Acid; in vivo; inhibitor/antagonist; insulin signaling; knock-down; metabolic abnormality assessment; novel; obesogenic; programs; response; success; therapy design; uptake

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.

摘要/摘要 欣赏促炎的IKKβ/NF-κB途径在下丘脑机制中的作用 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如何 以编程方式参与。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激活或抑制作用，获得了支持的证据表明 中质下丘脑（MBH）中的星形胶质细胞具有多个通过IKKβ/NF-κB的程序 负责代谢失衡。因此，该提议的假设是持续激活的 在慢性高脂饮食下，MBH中的星形胶质细胞IKKβ/NF-κB导致星形胶质细胞神经元改变 MBH的关系，至少是由于星形胶质细胞依赖性GABA清除率的损害以及 星形细胞细胞因子产生的增强 - 员工GABA和细胞因子接收器信号传导 影响负责任的神经元，导致多种形式的神经元失调对代谢平衡 这是肥胖和糖尿病前发育的基础。三个目标旨在研究（1）星形细胞 IKKβ/NF-κB-自助轴轴将下丘脑神经元与代谢失调联系起来，（2）IKKβ/NF-κB- GABA在将POMC神经元抑制与肥胖相关的依赖性星形细胞清除率和（3） 驱动的星形细胞细胞因子将其他反应性下丘脑神经元与疾病发育联系起来。一个 细胞，分子，遗传，物理和药物方法的结合将用于 分析星形细胞生物学和功能，对神经元的整体和局部影响及其机械的影响 肥胖和糖尿病前的角色。成功完成该项目对于理解 肥胖和糖尿病的下丘脑基础，并在设计介入策略方面提供了新的范式。