下丘脑TfR1介导的铁代谢在肥胖进展中的作用和机制研究

肥胖的患病率正以惊人的速度增长，严重影响人类的生活质量和威胁人类的健康。下丘脑在肥胖发生发展中占有重要的作用，是食物摄入、能量平衡与体重稳态调控的中枢。转铁蛋白受体(TfR1)介导的铁代谢与糖脂代谢关系密切。但下丘脑TfR1介导铁代谢是否在肥胖发生发展中发挥作用仍未知。我们发现，高脂诱导的肥胖小鼠(DIO)下丘脑铁含量与TfR1表达均增多。通过建立中枢铁超载和铁清除模型发现，下丘脑铁代谢可以直接影响肥胖的进展，且下丘脑TfR1过表达后促进肥胖。进一步研究证实中枢铁增多后可以引起线粒体氧化应激，NF-κB激活以及AGRP表达。因此我们提出下丘脑TfR1介导铁代谢通过线粒体氧化应激影响NF-κB调控AGRP转录，从而在肥胖进展中产生作用。本项目将在现有研究基础上，通过各种模型小鼠结合体外实验，重点阐述下丘脑TfR1介导的铁代谢在肥胖的进展作用以及相关的机制，这将为肥胖的治疗提供新的思路。

The prevalence of obesity is increasing at an alarming rate, seriously affecting the quality of human life and threatening human health. Hypothalamus, the center of food intake, energy balance and weight homeostasis, plays an important role in the development of obesity. The iron metabolism mediated by transferrin receptor (TfR1) is closely related to glucose and lipid metabolism. However, whether hypothalamic TfR1 mediates iron metabolism plays a role in the development of obesity remains unknown. We found that iron content and TfR1 expression in hypothalamus of obese mice (DIO) were increased. Through establishment of central iron overload and iron clearance models, we found that hypothalamic iron metabolism can directly affect the progress of obesity. In accordance with this, hypothalamic TfR1 overexpression can promote obesity. Further studies have confirmed that increased central iron can cause increased mitochondrial oxidative stress, activation of NF-κB and changes in AGRP neuron. Hence, we propose that hypothalamic TfR1 mediates iron metabolism through mitochondrial oxidative stress to influence NF-κB to regulate AGRP transcription. Based on existing research, this project will focus on the role of hypothalamic TfR1 mediated iron metabolism in the progress of obesity and related mechanisms through various model mice and in vitro experiments, which will provide new ideas for the treatment of obesity.