高压氧通过Nesfatin-1促进“中枢-脂肪”对话改善胰岛素抵抗的机制研究

肥胖相关胰岛素抵抗为糖尿病等代谢性疾病提供了重要的发病基础。新发现高压氧（HBO）干预可改善肥胖及糖尿病患者胰岛素抵抗，但机制尚不明确。既往机制研究侧重于HBO对骨骼肌氧化能力的调节，本项目前期研究发现HBO增加肥胖小鼠循环中脂肪因子Nesfatin-1的水平，促进棕色脂肪（BAT）脂代谢。因此推测：Nesfatin-1通过调节“中枢-BAT”对话，促进脂代谢并降低炎症状态，从而介导HBO改善肥胖小鼠胰岛素抵抗的作用。本项目拟应用高脂饮食诱导肥胖小鼠和基因敲除小鼠模型，采用在体电生理、中枢核团置管及微量注射等技术，探究HBO是否通过Nesfatin-1调节BAT脂代谢和炎症状态；探讨HBO是否通过Nesfatin-1信号增加支配BAT的交感神经活性；揭示HBO通过Nesfatin-1信号激活“交感神经-BAT”的中枢靶核团和作用机制。将为HBO治疗胰岛素抵抗的合理化临床应用提供理论基础。

Obesity-associated insulin resistance is an important etiological factor for metabolic diseases such as diabetes. It has been discovered that hyperbaric oxygen (HBO) intervention could improve insulin sensitivity in obese and diabetic patients, but the mechanism is yet to be elucidated. Previous mechanistic investigations on HBO intervention focused on its regulatory effects on skeletal muscle’s oxidative capacity. In contrast, our preliminary work revealed that HBO intervention increased circulatory Nesfatin-1 levels and enhanced brown adipose tissue (BAT) lipolysis. Based on this fact, we propose a hypothesis that Nesfatin-1 could improve fatty acid metabolism and decrease inflammation via regulation of “Central-BAT” crosstalking, thus mediate the improvement of insulin sensitivity in obese mice following HBO intervention. In the current project, high fat diet (HFD) induced obese mouse and gene knock out mouse models will be established, in which the roles of Nesfatin-1 in HBO treatment-induced BAT metabolism/inflammation improvement will be investigated with in vivo electrophysiological techniques, central nucleus catherization and microinjection. Furthermore, the roles of Nesfatin-1 in HBO treatment-induced sympathetic activation as well as the central target nucleus of HBO treatment will also be elucidated. This project will provide theoretical basis and evidence for the clinical application of HBO in obesity-related metabolic diseases.