肥胖与代谢综合征的节食/运动干预—肠道菌群与肝脏基因细胞学研究
文献类型：学位论文
| 作者 | 李守峰 |
| 学位类别 | 博士 |
| 答辩日期 | 2010-05 |
| 授予单位 | 中国科学院上海生命科学研究院营养科学研究所 |
| 授予地点 | 中国科学院上海生命科学研究院 |
| 导师 | 刘勇 |
| 关键词 | 衰老 寿命 肠道菌群 肝脏功能 肝脏基因组 |
| 学位专业 | 生物化学与分子生物学 |
| 中文摘要 | 肥胖症在发达国家和发展中国家已经发展成为威胁人类健康的主要疾病之一。肥胖症和一系列的健康问题相关，包括胰岛素抵抗、二型糖尿病、非酒精性脂肪肝、关节炎、神经退行性病变例如痴呆、呼吸道疾病以及一些癌症的发生。生活习惯的改变例如节食和运动，被认为是减轻肥胖症和代谢综合征的重要干预手段。在这项研究中，我们分别对高脂和低脂喂养的小鼠进行了节食/运动干预，比较了节食和运动对高脂诱导的肥胖症、代谢综合征以及健康损害、寿命缩短的影响。研究发现，节食比运动能够有效的防止高脂诱导的肥胖症和代谢功能的损害，更重要的是，高脂对照鼠寿命最短，节食在改善小鼠整体健康和延长寿命方面比运动有着更好的效果。其中，低脂节食小鼠的代谢指标、健康程度以及最终寿命都强于其它几组小鼠。我们分别在小鼠62、83、141周龄采集粪便样品分析了肠道菌群谱。用偏最小二乘回归法分析中年小鼠的肠道菌群与寿命正相关（R=0.54, P<0.01），并确定了53个phylotype 的肠道菌群与健康长寿最相关。低脂节食小鼠的肠道保护菌群例如乳酸菌和双歧杆菌的数目是所有组里最多的，而机会致病菌例如肠杆菌、TM7、链球菌数目是最少的。连接内毒素负荷和炎症的生物标志物——脂多糖结合蛋白，在低脂节食中最低而在高脂对照组中最高。节食有可能是通过调整肠道菌群减轻炎症反应来改善健康和延长寿命的。降低肠道菌群对宿主的致病负担有可能成为延缓衰老、延长寿命的新的营养干预手段。 我们对节食和运动干预了62周小鼠的肝脏分析发现，节食比运动更有效的防止高脂诱导的脂肪肝。节食和运动都可以改善高脂引起的肝脏功能损害、肝脏纤维化。节食还能增加高脂小鼠肝脏线粒体的数目，增大低脂和高脂小鼠肝脏线粒体的大小。我们通过基因芯片的方法分析了各种干预小鼠肝脏转录水平的变化。在基因表达的水平上，节食比运动更有效的逆转高脂引起的基因表达变化，有意思的是，低脂节食和高脂节食在基因表达水平上重叠的基因并不多，预示着在不同食物条件下，节食是通过不同的机制达到相似的生理功能的改变。高脂条件下节食和运动有很多重叠的信号通路逆转高脂引起的信号通路改变。节食和运动有可能是通过影响以上信号通路起到改善肝脏功能的效果。 |
| 索取号 | D2010-204 |
| 英文摘要 | Obesity has become a major health problem in developed countries and a growing one in developing countries. Lifestyle modifications such as calorie restriction (CR) and exercise are two interventional strategies known to effectively attenuate obesity and improve the metabolic syndromes. Here we compared the impact of caloric restriction (CR) and voluntary exercise (Ex) on promoting the overall health as well as longevity in a diet-induced obesity mouse model. Maximum lifespan in mice of the same gender and genetic background was expanded on both high-fat (HFD, 860 days) and low fat diet (LFD, 1033 days) with 30% CR (LFD,CR, 1291 days; HFD,CR, 1104 days), more than voluntary exercise (LFD,Ex, 1106 days; HFD,Ex, 964 days). Overweight and insulin resistance were with all groups except LFD,CR. Gut microbiota showed a significant reduction of the Phylum Firmicutes during aging. Partial Least Square regression between midlife gut microbiota and lifespan (R=0.54, P<0.01) identified 53 phylotypes most related with healthy longevity. Most notably, LFD,CR had the highest gut barrier protecting bacteria such as Lactobacilli and Bifidobacteria but drastically decreased opportunistic pathogens such as Enterobactereacae, TM7, Streptococcaceae etc. Lipopolysaccharide-binding protein (LBP), a biomarker linking endotoxin load and inflammation, was the lowest in LFD,CR, and highest in HFD group. CR may prolong healthy lifespan by rendering gut microbiota to be much less inflammation-provoking. Minimizing lifelong antigenic burden from gut microbiota to the host may become a highly effective target for anti-aging nutritional interventions. Both caloric restriction and exercise resulted in amelioration of HFD-incited liver dysfunction. High-throughput transcriptional analysis of the liver revealed a broad spectrum of diet-dependent alterations in the gene expression programs which accompanied the CR- or Ex-mediated alleviation of obesity-associated liver pathologies in parallel with amelioration of metabolic syndrome and extension of lifespan. In comparison with exercise, reduction in the high-fat diet intake markedly restored the expression of genes in a wide range of metabolic and stress pathways that were dysregulated in the obese state, whereas CR in the settings of low-fat diet intake elicited distinct patterns of metabolic pathway changes. Importantly, while CR prevented several gene expression patterns from shifting towards to those of aged livers, the most prominent common pathway elicited by CR regardless of diets was the gene expression program involved in peroxisome function. Together, these results demonstrate that CR incite distinct diet-dependent shift of genome-wide expression programs to rebalance metabolic homeostasis, exerting profound influences on health and longevity. |
| 语种 | 中文 |
| 公开日期 | 2015-12-24 |
| 源URL | [http://202.127.25.144/handle/331004/317]  |
| 专题 | 中国科学院上海生命科学研究院营养科学研究所_糖脂代谢与调控研究组 |
| 推荐引用方式 GB/T 7714 | 李守峰. 肥胖与代谢综合征的节食/运动干预—肠道菌群与肝脏基因细胞学研究[D]. 中国科学院上海生命科学研究院. 中国科学院上海生命科学研究院营养科学研究所. 2010. |
入库方式： OAI收割
来源：上海营养与健康研究所
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