LCN2通过肠-骨-脑轴调控下丘脑神经元参与胃袖状切除术改善血糖代谢的机制研究

Sleeve gastrectomy (SG) is effective in reducing weight and improving blood sugar, and it has become the main surgical methods of metabolic surgery. Our previous studies have found that SG can improve blood glucose through intestinal hormones. Besides, SG can affect the function of hypothalamic neurons, however, the specific mechanism is not clear. Recent studies have found that, as a new energy metabolism control factor, LCN2 protein secreted by osteoblasts can regulates appetite by acting on hypothalamic neurons through blood brain barrier. Based on the above results, we hypothesized that SG can play a central regulatory role through gut-bone-brain axis; SG can affect the secretion of intestinal hormones which is closely related to bone metabolism and osteoblast activity. Increased activity of osteoblasts can enhance the expression of LCN2; which can act on the MC4R receptor; through circulatory system. As a result,appetiteis inhibited with weight loss and improved blood sugar. In this study we intend to operate SG diabetic mice to explore the role of gut-bone-brain axis in the regulation of central neurons, aiming to provide a new theoretical basis and therapeutic target for SG to prevent and treat diabetes.

胃袖状切除术（SG）在减轻体重、改善血糖方面效果显著，已成为目前代谢手术的主流术式。我们前期研究发现，SG手术可通过影响肠道激素的分泌改善血糖，还可影响下丘脑神经元功能，但具体机制不明确。最新研究发现，LCN2蛋白是一种全新的能量代谢调控因子，由成骨细胞分泌，可通过血脑屏障作用于下丘脑神经元调控食欲。本课题假设，SG手术可通过肠-骨-脑轴发挥中枢调节作用：SG手术影响肠道激素分泌，肠道激素与骨代谢、成骨细胞活性密切相关，成骨细胞活性增强可增加LCN2的表达，LCN2通过血脑屏障作用于下丘脑MC4R受体，进而抑制食欲，减轻体重并改善血糖水平。本课题组拟以糖尿病小鼠为动物模型，建立SG手术模型，探讨肠-骨-脑轴对下丘脑神经元的调控作用，以期为SG手术预防及治疗糖尿病提供新的理论依据及治疗靶点。

胃袖状切除术（SG）在减轻体重、改善血糖方面效果显著，已成为目前代谢手术的主流术式。我们前期研究发现，SG手术可通过影响肠道激素的分泌改善血糖，还可影响下丘脑神经元功能，但具体机制不明确。最新研究发现，LCN2蛋白是一种全新的能量代谢调控因子，由成骨细胞分泌，可通过血脑屏障作用于下丘脑神经元调控食欲。本课题假设，SG手术可通过肠-骨-脑轴发挥中枢调节作用：SG手术影响肠道激素分泌，肠道激素与骨代谢、成骨细胞活性密切相关，成骨细胞活性增强可增加LCN2的表达，LCN2通过血脑屏障作用于下丘脑MC4R受体，进而抑制食欲，减轻体重并改善血糖水平。本课题组拟以糖尿病小鼠为动物模型，建立SG手术模型，探讨肠-骨-脑轴对下丘脑神经元的调控作用。围绕以上研究方向，本课题完成以下研究内容：评估SG手术对骨代谢的变化影响和5-羟色胺（5-HT）参与SG手术对骨代谢影响，以及FOXO1/LCN2信号通路参与SG手术改善血糖的可能作用机制。研究结果证实SG手术对骨代谢有不良影响，SG手术后骨密度降低，骨代谢呈骨破坏趋势，SG手术会影响血清或骨组织中5-HT水平及5-HT参与了SG影响骨代谢的这一过程。但SG手术有助于明显改善糖代谢。SG手术后骨组织中LCN2的表达升高，FOXO1的表达降低；SG手术后下丘脑LCN2和MC4R结合率也明显升高；成骨细胞中FOXO1表达的下调伴随着LCN2表达的上调。上述研究结果，一方面有助于临床全面监测接受代谢减重手术的患者，防止术后的骨丢失和发生骨折的可能性；同时扩展了骨质疏松症新的发病机制，探索5-HT及其相关系统的作用机制，提高代谢减重手术所致骨质疏松症的防治水平；另一方面为代谢减重手术的作用机制提供了新的见解和治疗靶点。