肥胖反弹起因于免疫系统介导的肥胖记忆

发布时间：2018-02-28 01:54

本文关键词： 肥胖肥胖记忆体重反弹免疫系统 CD4+T淋巴细胞骨髓移植　出处：《南京大学》2017年博士论文　论文类型：学位论文

【摘要】：肥胖是体内脂肪过度积累的一种疾病,它会导致其他许多严重的病症,例如心血管疾病,二型糖尿病和多种不同类型的癌症。目前治疗肥胖有多种方法,包括生活方式干预,控制能量摄入,增加运动量,各种减肥药物的使用以及肥胖外科手术。但不幸的是,这些治疗方法往往效果不好,原因是治疗结束后甚至治疗过程中病人就会出现体重反弹。体重反弹似乎难以避免,部分病人的体重甚至比治疗前更重,这使得体重反弹成为肥胖治疗中亟待解决的难题。本课题中,我们在小鼠模型中发现肥胖状态会被身体记住,并且这种记忆会促使身体重新回到肥胖状态。通过在C57BL/6J小鼠品系中建立增重-减肥-再增重的模型我们发现,经历过肥胖和减肥的小鼠相比从未经历肥胖的小鼠而言,无论给予高脂饲料或者普通饲料,体重增加的速率都更快。不仅如此,肥胖记忆不是短期存在的,在小鼠中高脂诱导肥胖所产生的肥胖记忆能够维持至少2个月的时间。这些现象说明肥胖会被身体长期记忆并导致机体即使瘦下来也会更快回到肥胖状态。前人研究中提出过多种关于体重反弹的机制的假说,包括食欲增加,产热下降和代谢水平降低。但我们发现这些猜测在肥胖记忆形成过程中并不成立。事实上,我们发现肥胖记忆形成时免疫系统被显著激活,并且在免疫缺陷的Rag1敲除小鼠和免疫抑制剂处理的C57BL/6J小鼠中,肥胖记忆的现象消失了。有趣的是,通过把来自有肥胖记忆的小鼠的脾细胞注射入Rag1敲除小鼠体内,能够重新建立肥胖记忆。这提示我们免疫系统的功能对于建立肥胖记忆是不可或缺的。不仅如此,通过移植有肥胖记忆小鼠的骨髓细胞可以向正常小鼠体内引入对肥胖的记忆。反之,用正常小鼠的骨髓细胞在肥胖记忆小鼠中重建免疫系统也能够消除已有的记忆。进一步研究发现,在肥胖记忆产生过程中,白色脂肪组织中CD4+T淋巴细胞数量显著上升,尤其是促进炎症发生的辅助T细胞Th1和Th17。在正常的C57BL/6J小鼠中剔除CD4+T淋巴细胞后则肥胖记忆被抑制。更惊人的是,单独移植骨髓来源的CD4+ T淋巴细胞就足以向正常小鼠中引入肥胖记忆。这些结果说明CD4+T细胞在肥胖记忆的产生过程中起到至关重要的作用。总而言之,我们的研究结果揭示了肥胖可以被机体记忆这一新的理论,为反复出现并且无法避免的减肥后体重反弹现象提供了新的解释。更重要的是,我们发现免疫系统,特别是CD4+T淋巴细胞是产生和承载肥胖记忆的关键,为肥胖相关的研究以及关于肥胖和相关疾病的治疗提供了新的见解。
[Abstract]:Obesity is a disease that accumulates too much fat in the body. It can lead to many other serious diseases, such as cardiovascular disease, type 2 diabetes, and many different types of cancer. There are many ways to treat obesity, including lifestyle interventions. Control of energy intake, increased exercise, use of various weight loss drugs, and obesity surgery. Unfortunately, these treatments tend to be ineffective. The reason is that at the end of the treatment and even during the course of treatment, the patient has a weight rebound. It seems inevitable that some patients' weight is even heavier than before the treatment. This makes weight rebound an urgent problem for obesity treatment. In this study, we found that obesity is remembered by the body in mouse models. And this memory can push the body back to obesity. By creating a weight-weight, weight-weight-reweight-gain model in the C57BL / 6J strain, we found that mice that had experienced obesity and lost weight were less likely to have experienced obesity than those who had never experienced obesity. Weight gain is faster whether given high-fat or regular diet. Not only that, obesity memory does not exist in the short term. Obese memory produced by hyperlipidemia in mice can last for at least two months. These phenomena suggest that obesity can be remembered by the body for a long time and lead to a faster return to obesity even if the body loses weight. Many hypotheses have been put forward about the mechanism of weight rebound. These include increased appetite, decreased heat production, and reduced metabolic levels. But we found that these assumptions don't hold true in obese memory formation. In fact, we found that the immune system was significantly activated during obese memory formation. And in the immunodeficient Rag1 knockout mice and the C57BL / 6J mice treated with immunosuppressants, the obese memory disappeared. Interestingly, by injecting spleen cells from the obese memory mice into the Rag1 knockout mice, The ability to recreate the memory of obesity suggests that the function of our immune system is essential for building memory of obesity. Not only that, By transplanting bone marrow cells from mice with obese memories, you can introduce the memory of obesity into normal mice. Using bone marrow cells of normal mice to reconstruct the immune system in obese memory mice could also eliminate the existing memory. Further studies showed that the number of CD4 T lymphocytes in white adipose tissue increased significantly during obese memory production. In particular, helper T cells Th1 and Th17. in normal C57BL / 6J mice, obese memory is suppressed after CD4 T lymphocytes are removed. Transplantation of CD4 T lymphocytes from bone marrow alone is sufficient to introduce obese memory into normal mice. These results suggest that CD4 T cells play a crucial role in the production of obese memory. Our findings reveal a new theory that obesity can be remembered by the body, providing a new explanation for repeated and unavoidable weight rebounding after weight loss. More importantly, we found the immune system. In particular, CD4 T lymphocytes are the key to the generation and carrying of obese memory, which provides new insights for the study of obesity and the treatment of obesity and related diseases.
【学位授予单位】：南京大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R589.2

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