脂联素介导脂肪组织与肠道之间相互对话调控胰岛素敏感性的作用及机理研究

Insulin resistance (IR), one of the most important characteristics in obesity, is attributed to multiple metabolic disorders including type 2 diabetes mellitus and metabolic syndrome. Apart from adipose tissue, more and more research discovered that bowel is also a key site for the development of insulin resistance. However, whether there exists cross-talk between adipose tissue and the intestine and how these two distant organs interact with each other still remain unknown. Adiponectin is a protective adipokine secreted from adipose tissue. Our previous studies demonstrated that insulin sensitivity was worsen in adiponectin knockout mice (ADN KO) fed on high fat diet (HFD) compared to their wild type littermates (WT) fed on HFD. Therefore, we propose that adiponectin may serve as an important player mediating the cross-talk between adipose tissue and the intestine. To test this hypothesis, we will adopt several unique approaches, including 16S metagenomics analysis of WT mice and ADN KO mice fed on normal chow diet (NCD) and HFD, isolation of immune cells in the intestinal lamina propria and fecal microbiota transplantation. The findings from this study will not only shed new light on the cross-talk between adipose tissue and intestine in regulating insulin sensitivity, but also providing evidence for correcting insulin resistance by targeting adipose tissue-adiponectin-intestine axis.

胰岛素抵抗(Insulin resistance)是贯穿肥胖相关的各种代谢性疾病的重要病理生理基础。肥胖时迅速增加的脂肪组织和肠道都是诱导及加重胰岛素抵抗发生发展的重要场所，但目前对这二者之间是否存在相互对话（cross-talk）以及介导二者之间相互对话的分子尚未阐明。脂联素(adiponectin)是一种由脂肪组织分泌的保护性脂肪因子。我们在前期研究中发现，与高脂喂养对照野生型小鼠相比，高脂喂养脂联素敲除小鼠的胰岛素抵抗明显加重。我们假设脂联素作为一个关键分子介导了脂肪组织与肠道的相互对话，共同调节机体胰岛素敏感性。为验证该研究假说，本课题将采用多种特异性的研究方案，包括宏基因组分析肠道微生物组成成分，肠道粘膜固有层免疫细胞分离检验，体外重组脂联素诱导免疫细胞分化以及肠道微生物移植等功能学实验，深入研究脂联素是否可以介导脂肪组织与肠道之间的对话调控胰岛素敏感性，并揭示其潜在的分子机制。

胰岛素抵抗是贯穿肥胖相关的各种代谢性疾病的重要病理生理基础。肥胖时迅速增加的脂肪组织和肠道都是诱导及加重胰岛素抵抗发生发展的重要场所，但是目前对于二者之间是否存在相互对话以及介导二者之间相互对话的分子机制尚未阐明。大量研究证明作为脂肪分泌因子之一的脂联素具有保护作用，可增加机体的胰岛素敏感性。我们发现脂联素发挥其保护性作用部分是由于其影响了肠道微生物的组成和功能来增加机体的胰岛素敏感性。通过肠道微生物移植实验，我们发现，来自于高脂饮食喂养的脂联素敲除小鼠的肠道微生物足以调控机体的胰岛素敏感性。进一步鸟枪测序分析结果显示脂联素的缺失改变了肠道微生物的组成成分，其中Lactobacillus reuteri, Alistipes unclassified and Anaerotruncus sp. G3含量明显降低。除此之外，脂联素的缺失还改变了其功能，降低了氨基酸合成通路的能力。由细菌代谢所产生的赖氨酸明显降低。而赖氨酸可以进入到血液循环中进而到达脂肪组织中，抑制巨噬细胞炎性因子的释放。因此，脂联素通过肠道微生物调控脂肪组织炎症是其发挥胰岛素增敏作用的部分机制。