2型天然免疫调控褐色脂肪发育和功能的细胞与分子机制

Brown and beige fat can reestablish energy homeostasis through burning white fat, which makes them the most promising target tissues against obesity. However the cellular and molecular mechanisms controlling their development and function are largely unknown. Our and another laboratory’s previous work demonstrated for the first time that type 2 innate immune system including IL-33 cytokine and ILC2 cells plays an essential role in the recruitment and activation of beige fat. Whether this type 2 innate immune circuitry also plays a similar role in brown fat development and function is still an enigma. In the preliminary study, we found that IL-33 can regulate brown adipose tissue development and function. In this application, we hypothesize that type 2 innate immunity activates IL-33/ST2L module to mediate cell interaction between fibroblastic adipocyte progenitors and mature brown adipocytes and cell fate choice, which governs the development and function of brown fat. The knowledge generated through this project will further enhance our understanding of how immune system regulates fat metabolism. And the finding of novel cellular and molecular mechanisms will pave the way to target type 2 innate immunity as an obesity immunotherapy strategy.

褐色和米色脂肪可以通过燃烧白色脂肪来重建能量代谢平衡，这使它们成为当前最有前景的减肥靶标组织。然而对它们发育及功能调控的细胞分子机制并不清楚。我们和另外一个实验室的前期工作首次证明：以IL-33，ILC2细胞为代表的2型天然免疫系统对于米色脂肪的招募和激活发挥关键作用。但是这一2型天然免疫环路在褐色脂肪的发育和功能调控中的作用并不清楚。在初步实验中，我们发现IL-33以一种不依赖于ILC2细胞的方式调控褐色脂肪组织的发育和功能。在这份申请中，我们提出如下假说：2型天然免疫系统通过激活IL-33/ST2L来介导成纤维脂肪祖细胞和成熟褐色脂肪细胞间的交互作用及细胞命运决定，从而调控褐色脂肪组织的发育和功能。如果该假说得以证实，将进一步加深对脂代谢的免疫调控的了解。在临床转化上，将有望开发以2型天然免疫为靶点的肥胖免疫疗法。

褐色和米色脂肪可以通过燃烧白色脂肪来重建能量代谢平衡，这使它们成为当前最有前景的减肥靶标组织。然而对它们发育及功能调控的细胞分子机制并不清楚。我们和另外一个实验室的前期工作首次证明：以IL-33，ILC2细胞为代表的2型天然免疫系统对于米色脂肪的招募和激活发挥关键作用。但是这一2型天然免疫环路在褐色脂肪的发育和功能调控中的作用并不清楚。我们发现IL-33以一种不依赖于ILC2细胞的方式调控褐色脂肪组织的发育和功能。IL-33在成纤维祖细胞里调控了褐色脂肪细胞的命运决定，使它可以分化成褐色脂肪细胞。IL-33在褐色脂肪细胞里自主性地控制UCP1等产热相关基因的表达。另一方面，我们发现褐色脂肪组织里分泌IL-33的关键细胞群是成纤维脂肪祖细胞，IL-33可以通过自分泌及旁分泌的方式，结合褐色脂肪细胞上的受体ST2L，进而激活STAT3入核与PGC1形成转录调控复合物，从而控制产热基因的转录。IL-33的细胞自主调控及内分泌/旁分泌效应互相协同，增强了褐色脂肪细胞的产热功能。我们排除了STAT3通过与剪切体（splicesome）直接相互作用调控UCP1的可变剪切。该研究揭示了2型免疫通路在褐色脂肪发育和功能中的关键作用。IL-33有望成为治疗肥胖及其相关慢性代谢疾病的新靶标。