脂肪组织与肠道系统的“时空对话”调控糖代谢的作用与机制研究

White and brown adipose tissues (WAT and BAT) cooperatively maintain metabolic health via their differential ability on the regulation of energy balance, adipokine secretion and/or immunity. Too much (obesity) or too little or mislocation of fat (lipodystrophy), is causatively associated with type 2 diabetes (T2DM) and its complications such as cardiovascular diseases, the leading causes of morbidity and mortality in Hong Kong. In addition to adipose tissue dysfunction, intestinal dysbiosis, characterized by a shift in microbiota composition and defective gut barrier function, is also a major contributor of these chronic and incurable diseases. However, how the interplay between adipose tissues and intestinal system implicates in pathogenesis of T2DM is poorly understood...Here we identify that the adipose tissue-gut-microbiota axis is indispensable for glucose homeostasis, and its disruption causes T2DM. We employed a lipodystrophy mouse model in which adipocyte MDM2 is deleted and thus p53 is activated in this project, and showed that progressive loss of adipose tissues (due to adipocyte apoptosis and senescence) not only induces severe T2DM but also leads to gut microbiota dysbiosis, increased gut permeability and systemic endotoxemia. Treatment with antibiotics alleviates lipodystrophy-induced glucose intolerance and insulin resistance. Transplantation of fecal microbiota from the lipodystrophy mice to germ-free-like mice induces T2DM and intestinal dysbiosis, whereas transplantation of subcutaneous WAT reverses these lipodystrophy-associated disroders. Further analysis revealed that progressive loss of fat is accompanied with an aberrant production of antimicrobial peptides, IgA and pro-inflammatory cytokines in the intestines. These data suggest that adipose tissue is crucial for maintenance of intestinal microenvironment and immunity, and its dysregulation causes T2DM. ..In this project, we will further investigate the dynamic relationship between adipose tissues, intestinal system and metabolic health. We will validate whether and how disrupted gut-microbiota axis mediates lipodystrophy-induced T2DM. We will explore how subcutaneous WAT interacts with intestinal functions in the regulation of glucose metabolism by using fat transplantation approach. Furthermore, we will test whether modulation of intestinal microenvironment, in particular immunity and microbiota composition, is able to improve metabolic disorders. Apart from the well-established lipotoxicity theory, our result will provide additional mechanistic insight on how adipose tissue dysfunction leads to multiple metabolic diseases via the gut-microbiota axis. Our study will also indicate how metabolic tissues of host control the commensal microbiota composition, which in turn regulate our body homeostasis. Such information can also allow us to develop new therapeutic strategies for metabolic disease induced by adipose tissue dysfunction.

脂肪代谢异常和肠道生态失调均与2型糖尿病的发生发展直接相关，然而目前尚不清楚脂肪组织和肠道系统之间的相互作用是否参与糖尿病发病机制。 我们前期工作中建立了脂肪细胞选择性敲除MDM2 (KO)小鼠模型，由于脂肪细胞凋亡和衰老脂出现进行性肪组织萎缩，伴随血糖升高，合并肠道菌群失调，肠道通透性增加和全身内毒素血症。采用脂肪移植可以逆转KO小鼠的糖代谢异常及肠道功能异常。反之将KO小鼠的粪便移植到野生小鼠肠道中则引起糖尿病及肠道功能异常。 因此，我们推测脂肪组织对于维持肠道微环境和免疫功能至关重要，两者相互调控功能异常可能直接导致糖尿病发生。本研究拟进一步研究肠道－菌群轴介导脂肪萎缩KO小鼠糖代谢异常的作用；探讨脂肪组织如何与肠道相互作用调控机体糖代谢的机制；明确脂肪来源分泌因子影响肠道免疫功能的机制。我们的研究有望阐明宿主代谢组织如何控制共生的肠道菌群，进一步调节机体代谢稳态的“时空对话”机制。

白色脂肪组织(WAT)与肠道系统之间存在着相互作用，但其生理意义和调节机制尚不清楚。 为了研究脂肪减少对肠道功能的影响，我们设计了一种随着年龄的增长，脂肪逐步出现营养不良的小鼠模型，其本质是因为MDM2触发p53表达，从而诱导脂肪细胞凋亡和衰老(所谓的Adipo-MDM2-KO小鼠)。 我们在观察时发现，Adipo-MDM2-KO小鼠在无脂肪组织年龄时，肠道通透性和炎症增加，并伴随着全身性内毒素血症增加。 16S rRNA测序结果显示，与免疫球蛋白A (IgA) 相关的肠道微生物群在无脂肪Adipo-MDM2-KO小鼠中也发生了改变。 这些变化与小肠固有层中naïve B细胞到IgA+浆细胞的类转换缺陷有关，这导致Adipo-MDM2-KO小鼠中IgA+ B细胞和IgA生成显着减少。 值得注意的是，皮下WAT移植可缓解Adipo-MDM2-KO小鼠上述肠道缺陷。 而且我们在基因或手术介导性切除sWAT的小鼠模型中也观察到IgA+ B细胞分化和IgA产生的缺陷，且不依赖于肠道微生物群。在体外细胞实验中，我们发现用sWAT分泌的外泌小体培养naive B细胞，可成功诱导其分化和产生IgA。除此之外，在手术切除sWAT的小鼠中，口服维甲酸或注射含有维甲酸的外泌体亦可诱导B细胞的分化和产生IgA。 我们的研究结果表明， sWAT可能通过脂肪分泌因子作用于肠道B细胞的功能、诱导IgA的产生，从而维持肠道菌群稳态。

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