SCF/KIT信号通路在米色脂肪细胞产热中的作用机制研究

Beige adipocyte was recently identified in white adipose tissue for its ability of heat generation, which can further reduce body weight through the improvement of energy consumption. However, the regulation of the beige adipocyte’s function was remained unknown. We have previously demonstrated that mice with a loss-of-function mutation in Kit were cold intolerance. Moreover, our preliminary data indicated that the activity of SCF/Kit signaling pathway was significantly associated with the activation of beige adipocytes, but was negatively correlated with BMI in human subjects. Therefore, we hypothesize that SCF/KIT signal pathway is involved in regulating the function of beige adipocytes. To validate this, we will conduct a series of experiments at various levels in which the regulation and mechanisms between SCF/KIT signal pathway and beige adipocytes will be evidenced. More importantly, the effects from SCF/KIT signal pathway on obesity treatment will also be verified in our proposal. When the project is finished, we will delineate a novel function of SCF/Kit pathway as well as extend the understanding of the regulation of beige adipocytes. More importantly, we will also provide a possible new insight into the development of novel therapeutic strategies in obesity treatment.

米色脂肪细胞是白色脂肪组织中新发现的一类具有产热能力的细胞，因其能够消耗大量能量故具有治疗肥胖症的潜力，但是其调控机制还不清楚。我们曾发现kit缺失功能突变小鼠冷不耐受，而本课题的前期工作发现，SCF/KIT信号通路的活性与米色脂肪细胞的激活显著正相关，且与人类BMI值呈负相关。因此我们提出假设，SCF/KIT信号通路可以调控米色脂肪细胞的产热能力。为了证明这一假设，本课题将从整体动物水平、细胞水平和线粒体亚细胞水平设计实验，证明SCF/KIT信号通路在米色脂肪细胞产热过程中的重要作用，深入研究其调控机理，并验证其对肥胖症的治疗作用。本课题的完成，将验证SCF/KIT信号通路的新功能，拓展我们对米色脂肪细胞调控的认识，并为肥胖症的防治提供新的思路。

骨髓造血受到代谢稳态影响，在代谢压力下动态调节。然而造血系统如何感知代谢状态，进而调节造血的细胞和分子机制仍然不清楚。骨髓脂肪组织在各种代谢条件下重塑，最近的研究证明，在辐照后骨髓脂肪组织可以行使造血干细胞的干细胞巢的功能。在本研究中，我们使用Adipoq-Cre和Osx1-Cre分别在成熟脂肪细胞和骨髓基质细胞中选择性敲除Kitl基因，从而研究骨髓脂肪组织来源的干细胞因子（SCF）在正常生理情况下造血中的功能。我们发现Adipoq-Kitl敲除和Osx1-Kitl敲除小鼠骨髓中的造血干细胞、造血祖细胞以及髓系祖细胞都显著下降，在正常生理条件下即出现巨红细胞性贫血。当野生型小鼠受到高脂肪饮食，β3-肾上腺素能激活，热中性和衰老等代谢刺激时，骨髓中的造血祖细胞的组成以及随后的造血活动将随之变化。但是，在Adipoq-Kitl KO小鼠中，这种变化，尤其是在髓样区室内的变化，大大减少。我们的数据表明，骨髓脂肪组织提供SCF主要用于正常生理条件下和代谢应激时的造血。