β-葡聚糖抑制NF-κB信号通路在调节肥胖小鼠中枢瘦素敏感性中的作用

The prevalence of obesity-associated life-threating diseases such as type 2 diabetes, liver steatosis, hypertension and atherosclerosis is increasing rapidly. The key to obesity and its associated complications is in studying the mechanism of body energy balance regulation. Importantly, obesity is associated with hypothalamic inflammation and injury in rodents and humans. Mice and rats fed a high-fat diet prior and after obesity show increased inflammatory signalling molecules, IKK/NFκB, and TNFα, in the hypothalamus. Obese humans (as assessed by MRI) show increased gliosis in the mediobasal hypothalamus. Leptin, an adipocyte-derived hormone, reduces food intake and increases energy expenditure primarily through its action in the hypothalamus. Obese individuals have a high plasma leptin level and a dysfunctional leptin signalling system, and hence display leptin resistance. .SOCS3 and PTP1B are negative regulators of this hypothalamic leptin signalling pathway and, when their levels are elevated, can cause central leptin resistance. Blocking or downregulating these two negative regulatory pathways may significantly improve central leptin signalling and may in turn reverse obesity. While SOCS3 and PTP1B is increased by proinflammatory signalling molecules NFκB. Therefore, inhibition of the hypothalamic NFκB signaling pathway plays a significant role in altering body energy balance regulation and peripheral metabolism. Determining a treatment strategy to reverse the hypothalamic inflammation of obesity has become extremely important and timely..β-glucan is a complex homopolymer of glucose found in the cell walls of yeast, fungi, and cereal plants. Several recent studies have shown that β-glucan has anti-inflammatory effects. We will investigate the effect of β-glucan on the inhibition of NFκB signaling pathway. We will test the effects of the β-glucan to inhibit the NFκB signaling pathway and improve central leptin sensitivity in obese mice.

肥胖已经成为威胁人类健康的重大问题。已知肥胖与下丘脑炎症具有密切关系，高脂饮食可以诱导啮齿类下丘脑中促炎信号通路NF-κB的活化；此外，肥胖发生时，下丘脑瘦素信号通路的负调节因子SOCS3 与 PTP1B表达水平升高，抑制下丘脑瘦素信号通路的调节作用，促进肥胖的发生。而下丘脑中活化的NF-κB信号通路有利于SOCS3与PTP1B的表达，从而促进瘦素抵抗的发生。因此，抑制NF-κB信号通路可以减缓或阻止饮食诱导的肥胖。.我们以日常食物为切入口，寻找可以抑制NF-κB信号通路的天然食物成分。已知β-葡聚糖广泛存在于多种食物中，且能够下调炎症因子的表达。那么β-葡聚糖是否能通过抑制NF-κB信号通路间接调控瘦素信号通路的表达呢？本研究欲证明β-葡聚糖通过抑制NF-κB信号通路，下调负调节因子SOCS3与PTP1B的表达，改变瘦素抵抗现象，从而达到治疗肥胖的目的。

膳食纤维包括β-葡聚糖，在维持人类健康过程中发挥着重要的生理功能，是人体必不可少的营养物质。膳食纤维经肠道菌群发酵产生的代谢产物如乙酸、丙酸和丁酸等短链脂肪酸（short chain fatty acid，SCFA），通过血液循环穿过血脑屏障进入中枢神经系统从而影响脑功能。肠道微生物和其代谢产物可通过此应答系统调节神经系统功能，即"菌群-肠-脑轴"。本研究以"菌群-肠-脑轴"为切入点，研究3种不同的β-葡聚糖饮食对小鼠肠道菌群、代谢产物SCFAs、肠道通透性和炎症状态、海马组织炎症因子的表达水平、突触生长和认知功能的影响，探讨不同结构的β-葡聚糖对于小鼠肠道炎症和认知功能的干预作用和机制。.本研究通过营养-肠道微生物-肠脑轴对机体的调控作用，为饮食与健康的关系提供新的思路。