白色脂肪组织过度积累营养物质会造成肥胖，这不仅诱发糖尿病和高血脂等代谢性疾病，还损伤骨骼重塑，导致骨质疏松。常见的噻唑类药物在治疗糖尿病的同时也可能恶化病人的骨质疏松进程。相反，白色脂肪组织棕色化形成的米色脂肪组织通过产热方式消耗营养物质，平衡人体代谢稳态，对抗肥胖发生。在本项目的前期研究中，申请人在小鼠体内发现关键成骨转录因子RUNX2能够促进白色脂肪细胞棕色化和产热基因的表达，并初步鉴定出这种促进作用受到单泛素化修饰的调控。申请人据此提出RUNX2活性受抑制可能是代谢失调与骨质疏松这两类疾病共有的一种发病机理。因此，阐明RUNX2在米色脂肪组织转分化中信号调控模式，揭示调控脂肪组织棕色化和骨质合成代谢的共同机体信号分子，将有助于代谢综合症和骨质疏松的临床联合诊疗策略的制定与新型药物的开发。申请人拟以分子细胞学和动物模型等手段深入研究RUNX2在维持生物体代谢稳态中的功能和信号调控机理。

Excessive accumulation of nutrients in white adipose tissues (WAT) develops obesity, which not only causes type 2 diabetes and hyperlipidemia, but also damages bone remodeling, leading to osteoporosis. Unfortunately, thiazolidinediones may also worsen the osteoporosis process of patients when they are used to treat type 2 diabetes. Instead, beige adipose tissues derived from WAT browning can consume excessive nutrients as a form of heat to balance metabolic homeostasis and counteract obesity. In the present studies, the applicant explored that bone lineage-specific transcription factor RUNX2 can promote the “browning” of and thermogenesis of WAT in mice, and preliminarily proved that this role of RUNX2 is regulated by mono-ubiquitination. Based on these findings, the applicant proposed that the inhibition of RUNX2 activity may act as a common pathogenesis in the development of both metabolic disorders and osteoporosis. There will be contributed to the development of combination of clinical treatment strategies and new drugs for metabolic syndrome and osteoporosis, if the common signal transducers and the signaling mechanisms employed by RUNX2 are fully elucidated in the “browning” of WAT and bone anabolism. Hence, the applicant plans to investigate the regulatory function and signaling mechanism of RUNX2 in metabolic homeostasis of whole body by molecular and cell biological technologies and animal models.