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

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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.