Exploring the molecular mechanisms underlying defective primary cilia in obese-derived mesenchymal stem cells and its significance in obesity

食物摄取和能量消耗的不平衡是全球主要的健康问题之一，导致肥胖，导致各种健康后果，包括增加患2型糖尿病、心血管疾病和癌症的风险。肥胖会扰乱下丘脑和胰腺、肝脏和脂肪组织等外围器官的功能。脂肪来源的间充质干细胞(ASCs)是监测脂肪组织动态平衡的基础细胞，在肥胖时受损。这种改变背后的机制还没有被很好地理解。初级纤毛存在于几乎所有脊椎动物的细胞中，感受和传递大量的信号。它在调节ASCs分化等多种功能中起着至关重要的作用。我们最近发现，在肥胖的ASCs中，初级纤毛变短，非动态，不能传递不同的信号。我们的工作表明，肥胖相关因素包括白细胞介素6、肿瘤坏死因子α和低氧损害了初级纤毛，使ASCs功能障碍，助长了炎症，加重了肥胖症的代谢功能障碍。这一有趣的观察引发了一些重要的问题。根据这一建议，基于对人/鼠原代ASCs和脂肪组织进行的体内和体外研究，使用转录图谱分析、敲除/敲除基因操作、电子显微镜断层扫描、特定小分子抑制物、活细胞成像以及其他分子/生化方法，我们希望解决以下问题：1.肥胖症ASCs纤毛缩短的分子机制是什么？2.ASCs纤毛缩短是如何导致ASCs功能障碍的？3.ASC纤毛缺陷在肥胖症的发生发展中的意义是什么？4.初级纤毛缩短是肥胖症纤毛细胞的普遍现象吗？我们开始认识到初级纤毛在健康、衰老和肥胖等疾病中的重要作用。纤毛缺陷可能是肥胖发病机制中的一个关键事件。这项研究可能会提供一种替代的合理策略，通过恢复纤毛细胞等纤毛细胞的功能来对抗肥胖。

An imbalance of food uptake and energy consumption is one of the predominant health problems worldwide, resulting in obesity with various health consequences including increased risk for type 2 diabetes, cardiovascular diseases and cancer. Obesity perturbs the function of the hypothalamus and peripheral organs like the pancreas, the liver and adipose tissue. Adipose-derived mesenchymal stem/stromal cells (ASCs) are fundamental in the surveillance of adipose tissue homeostasis and become impaired in obesity. The mechanisms underlying this alteration are not well understood. The primary cilium, presented on almost all vertebrate cells, senses and transduces numerous signals. It is crucial in the regulation of ASCs in their various functions such as differentiation. We have recently shown that primary cilia are shortened, non-dynamic and incapable of mediating diverse signals in obese ASCs. Our work suggests a phenomenon whereby obesity related factors including IL6, TNFα and hypoxia impair primary cilia, which render ASCs dysfunctional, fostering inflammation and worsening metabolic dysfunction in obesity. This interesting observation evokes important questions. With this proposal, based on in vivo and in vitro studies using transcriptomic profile analysis, knock-down/knockout gene manipulation, electron microscopy tomography, specific small molecule inhibitors, living cell imaging, as well as other molecular/biochemical methodology with human/mouse primary ASCs and adipose tissues, we would like to address following issues:1. What are the molecular mechanisms responsible for shortening cilia of ASCs in obesity?2. How do shortened cilia lead to dysfunction of ASCs?3. What is the significance of defective ASC cilia in the development of obesity?4. Are shortened primary cilia a general phenomenon for ciliated cells in obesity?We are beginning to appreciate the cardinal importance of primary cilia in health, aging and in diseases like obesity. Defective cilia could be a key event in the pathogenesis of obesity. This study may deliver an alternative and rational strategy to combat obesity by restoring functional cilia in ciliated cells like ASCs.