中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
调节胰岛素敏感性的新因子及其功能机制

文献类型:学位论文

作者于俊杰
学位类别博士
答辩日期2012-05-01
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
导师郭非凡
关键词胰岛素敏感性 催乳素受体 miR-130a 肝脏
其他题名Novel factors regulating insulin sensitivity
学位专业生物化学与分子生物学
中文摘要近年来,2型糖尿病的发病率逐年增加,严重影响人类健康。2型糖尿病发生的主要特征是出现胰岛素抵抗,所谓胰岛素抵抗是指胰岛素作用的靶器官对胰岛素的敏感性下降。影响胰岛素敏感性的因素有很多,但其具体的调节机制有待于进一步研究。 我们实验室之前研究发现,亮氨酸缺乏时,小鼠肝脏胰岛素敏感性增强,提示在这种情况下肝脏中表达发生改变的因子可能会影响胰岛素敏感性。所以本课题的目的就是通过对亮氨酸缺乏时肝脏基因表达芯片的筛选,寻找新的影响胰岛素敏感性的因子,并研究该因子作用的具体机制。 通过筛选,我们发现了两个很有意思的因子:催乳素受体(prolactin receptor, PRLR)和miR-130a。PRLR属于细胞因子受体家族,在泌乳、生长、增殖等很多过程中都起作用,但是对胰岛素敏感性的作用却没有文章报道过。miR-130a是一种脊椎动物特有的microRNA,在调节细胞周期和血管生成过程中起重要作用,但是在胰岛素敏感性方面的研究尚无文章报道。 对PRLR的研究发现:(1)在小鼠体内过表达PRLR可以提高胰岛素敏感性,而降低PRLR的表达会抑制胰岛素敏感性,在细胞水平也得到了一致的结果;(2)PRLR主要通过信号转导转录激活子(signal transducer and activator of transcription, STAT)5 来调节胰岛素敏感性;(3)在胰岛素抵抗小鼠模型(db/db小鼠)及胰岛素敏感性增加的模型(亮氨酸缺乏饮食喂养小鼠)中,PRLR表达会发生变化,在这两种条件下改变PRLR的表达会改变小鼠的胰岛素敏感性;(4)亮氨酸缺乏主要通过GCN2/mTOR/S6K1途径调节PRLR的表达。 对miR-130a的研究发现:(1)在细胞水平过表达miR-130a-3p可以提高胰岛素敏感性,而抑制miR-130a-3p会降低胰岛素敏感性;(2)在小鼠体内过表达miR-130a-3p可以提高小鼠的胰岛素敏感性;(3)miR-130a-3p主要通过作用于靶基因GRB10调节胰岛素敏感性;(4)在胰岛素抵抗小鼠模型db/db小鼠中,miR-130a-3p表达下降,过表达之后可以缓解db/db小鼠的胰岛素抵抗;(5)miR-130a-3p除了可以提高db/db小鼠胰岛素敏感性之外,也可以通过抑制脂肪酸合成酶(fatty acid synthase, FAS)缓解其脂肪肝。 总而言之,我们的研究发现了肝脏PRLR在胰岛素敏感性方面的新功能,为营养因素对PRLR表达的调节提供了新的研究思路,也发现了肝脏miR-130a-3p在调节胰岛素敏感性及脂肪肝方面的新功能,为代谢疾病提供潜在的治疗手段。
索取号D2014-135
英文摘要Insulin resistance is one of the major contributing factors in the development of metabolic diseases. The mechanisms responsible for insulin resistance, however, remain poorly understood. Our previous study found that leucine deprivation improves liver insulin sensitivity in mice, which indicate that leucine deprivation may be a good model for screening for novel factors regulating insulin sensitivity. So, the aim of our study is to find some novel factors that could regulate insulin sensitivity using liver microarray under leucine deprivation. Two interesting factors was found in our study: prolactin receptor and miR-130a. PRLR is classified as a cytokine type 1 receptor and plays an important role in milk production, growth and development. It is unknown, however, whether PRLR is involved in the regulation of insulin sensitivity. MiR-130a appears to be a vertebrate-specific miRNA, and exerts important functions on cell cycle, angiogenesis and so on. Whether miR-130a is involved in the regulation of insulin sensitivity or not, is still unknown. About PRLR, we found that insulin sensitivity is improved or impaired in mice injected with adenovirus that overexpress or knock down PRLR expression, respectively. Similar observations were obtained in in vitro studies. In addition, we discovered that the signal transducer and activator of transcription-5 pathway are required for regulating insulin sensitivity by PRLR. Moreover, we observed that PRLR expression is decreased or increased under insulin-resistant (db/db mice) or insulin-sensitive (leucine deprivation) conditions, respectively, and found that altering PRLR expression significantly reverses insulin sensitivity under both conditions. Finally, we found that PRLR expression levels are increased under leucine deprivation via a general control nonderepressible 2/mammalian target of rapamycin/ribosomal protein S6 kinase-1–dependent pathway. About miR-130a, we found that overexpression of miR-130a-3p increases insulin signaling in both HepG2 cells and primary mouse hepatocytes and silencing of miR-130a-3p has the opposite effects. However, miR-130a-5p has no effect in the regulation of insulin signaling. Consistently, whole body and hepatic insulin sensitivity is improved in mice injected with adenoviruses that over-express miR-130a-3p. Furthermore, we provided evidence showing that growth factor receptor-bound protein 10 is required for miR-130a-3p-regulated insulin sensitivity. On the other hand, we observed that expression of miR-130a-3p is decreased in the livers of db/db mice and that adenovirus-mediated overexpression of miR-130a-3p reverses insulin resistance and liver steatosis, the latter of which is achieved via suppressing fatty acid synthase expression in these mice. This study identifies a novel function for hepatic miR-130a-3p in the regulation of insulin sensitivity and liver steatosis. These results demonstrate a novel function for hepatic PRLR in the regulation of insulin sensitivity and provide important insights concerning the nutritional regulation of PRLR expression. This study also identifies a novel function for hepatic miR-130a-3p in the regulation of insulin sensitivity and liver steatosis.
语种中文
公开日期2016-02-26
源URL[http://202.127.25.144/handle/331004/395]  
专题中国科学院上海生命科学研究院营养科学研究所_代谢的遗传与营养调控研究组
推荐引用方式
GB/T 7714
于俊杰. 调节胰岛素敏感性的新因子及其功能机制[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. 2012.

入库方式: OAI收割

来源:上海营养与健康研究所

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