内脏脂肪堆积是骨质疏松症的高危因素，其机制不明。我们前期研究发现：肥胖成年人内脏脂肪巨噬细胞（ATMs）外泌体调节骨髓间充质干细胞（BMSCs）成骨与成脂命运，并筛选出外泌体中关键因子：miR-1945。本课题拟从此着手，提出“肥胖ATMs外泌体-miRNA-1945通过影响BMSCs成骨与成脂命运调节骨代谢”的假说。为了验证此假说，我们首先在细胞及体内水平示踪ATMs外泌体-miR-1945转移至BMSCs中，并检测其调控BMSCs成骨与成脂命运的作用；其次构建巨噬细胞特异性miR-1945基因敲除小鼠，观察其在高脂饮食诱导骨丢失模型中BMSCs分化命运及骨量的变化；最后预测并验证miR-1945下游靶基因，构建ATMs外泌体-miR-1945调控BMSCs成骨与成脂命运的通路网络。本课题的顺利开展将为肥胖调节骨质疏松的作用及机制提供新理论。

Visceral fat accumulation is a high risk factor of osteoporosis, but the mechanism is unclear. We found that obese adult visceral adipose tissue macrophages (ATMs) derived exosomes regulate the lineage fate of bone marrow mesenchymal stem cells (BMSCs) between osteoblasts and adipocytes. We identified a key factor in ATMs exosomes: miR-1945. Therefore, we hypothesize that “obese ATMs derived-exosomal miRNA-1945 regulates bone metabolism through affecting osteogenic and adipogenic lineage fate of BMSCs”. To test this hypothesis, first, we will determine whether the ATMs-derived exosomal-miR-1945 can be transported into BMSCs and regulate the osteogenic and adipogenic fate of BMSCs in vivo and in vitro; second, the macrophage-specific miR-1945 knockout mice will be constructed to test the role of miR-1945 on the lineage fate of BMSCs in the bone loss mouse model induced by high-fat diet; at last, we will predict and validate the target genes of miR-1945 to construct downstream network of ATMs-derived exosomal-miR-1945 regulating the osteogenic and adipogenic fate of BMSCs. Completion of this project will provide new theories for the molecular mechanisms of obesity-induced osteoporosis.