OPN促前白色脂肪细胞向棕色脂肪细胞分化的CD44-PI3K-AKT-PPARγ依赖机制

Brown adipocytes (BA) play an important role in energy homeostasis maintenance and anti-obesity. However, it remains poorly understood concerning transcriptional regulation factors of BA-committed differentiation and underlying mechanisms.Osteopontin(OPN) is a secreted cytokine, which is involved in many pathophysiological processes. Our recent research demonstrated that OPN induced BA committed differentiation from white preadipocytes in a concnetration and time dependent manner. Nonetheless,there is no any report worldwide to date on OPN’s pro-differentiation of BA and its underlying mechanisms. As a result, this project will focus the cutting-edge on the transcriptional regulation of BA-committed differentiation, meet the urgent needs for prevention and treatment of obesity and its relate metabolic diseases, and surround the key scientific issue that OPN might play a pivotal role in BA-committed differentiation and its possible mechanism to be undertaken at the multilevels of animal model, tissues, cells and molecules. Moreover, this study will enrich and improve the regulational mechanisms of adipocyte-oriented differentiation, and offer a preventional/therapeutic strategy and potential targets for obesity and its relate metabolic diseases.

棕色脂肪细胞（BA）通过“燃烧”脂肪在维持机体能量内稳态和抗肥胖方面发挥重要作用。但有关BA定向分化的转录调控机制尚未完全阐明。Osteopontin(OPN)是一种参与了许多生理病理过程的细胞因子。我们近期的研究发现，OPN是能诱导BA定向分化的正性调控因子，但有关其参与BA定向分化的转录调控机制研究国内外尚未见报道。因此，本项目聚焦“脂肪细胞定向分化转录网络调控”研究领域国际前沿，结合我国肥胖及相关重大代谢性疾病防治的迫切需求，围绕“OPN促前白色脂肪细胞向棕色脂肪细胞分化的CD44-PI3K-AKT-PPARγ依赖机制”这一关键科学问题，拟从整体模型动物、组织、细胞和分子水平探讨OPN调控BA定向分化转录网络调控机制，为丰富和完善脂肪细胞定向分化转录调控机制，为肥胖及肥胖相关疾病的防治提供新的策略，也为以OPN为靶点的新药研发及临床上开展干细胞移植治疗和基因治疗奠定坚实的实验基础。

棕色脂肪细胞（BA）通过“燃烧”脂肪在维持机体能量内稳态和抗肥胖方面发挥重要作用。但有关BA定向分化的转录调控机制尚未完全阐明。Osteopontin(OPN)是一种参与了许多生理病理过程的细胞因子。我们研究发现，OPN是能诱导BA定向分化的正性调控因子，但有关其参与BA定向分化的转录调控机制研究国内外尚未见报道。因此，本项目聚焦“脂肪细胞定向分化转录网络调控”研究领域国际前沿，结合我国肥胖及相关重大代谢性疾病防治的迫切需求，围绕“OPN促前白色脂肪细胞向棕色脂肪细胞分化的CD44-PI3K-AKT-PPARγ依赖机制”这一关键科学问题，拟从整体模型动物、组织、细胞和分子水平研究OPN在BA定向分化中的作用并探讨其转录网络调控机制。在细胞模型和整体动物模型的结果表明， OPN在BA定向发育分化方面发挥了重要调控作用，它可促进前白色脂肪细胞向BA 分化；且在分子水平阐明了OPN转录调控BA定向分化机制是CD44-PI3K-AKT-PPARγ途径依赖的。该研究结果为丰富和完善脂肪细胞定向分化转录调控机制，为肥胖及肥胖相关疾病的防治提供新的分子靶点和治疗策略；此外，该研究首次构建的靶向OPN的脂肪特异性重组过表达和干扰腺病毒载体，将为临床上开展靶向OPN干细胞移植治疗和基因治疗提供有效工具。