Bone formation is a highly energy-demanding process that can be impacted by metabolic disorders. Glucose has been considered the principal substrate for osteoblasts, although fatty acids are also important for osteoblast function. Here, we report that osteoblasts can derive energy from endogenous fatty acids stored in lipid droplets via lipolysis and that this process is critical for bone formation. As such, we demonstrate that osteoblasts accumulate lipid droplets that are highly dynamic and provide the molecular mechanism by which they serve as a fuel source for energy generation during osteoblast maturation. Inhibiting cytoplasmic lipolysis leads to both an increase in lipid droplet size in osteoblasts and an impairment in osteoblast function. The fatty acids released by lipolysis from these lipid droplets become critical for cellular energy production as cellular energetics shifts towards oxidative phosphorylation during nutrient-depleted conditions. In vivo, conditional deletion of the ATGL-encoding gene Pnpla2 in osteoblast progenitor cells reduces cortical and trabecular bone parameters and alters skeletal lipid metabolism. Collectively, our data demonstrate that osteoblasts store fatty acids in the form of lipid droplets, which are released via lipolysis to support cellular bioenergetic status when nutrients are limited. Perturbations in this process result in impairment of bone formation, specifically reducing ATP production and overall osteoblast function.

骨形成是一个高能量需求的过程，可能会受到代谢紊乱的影响。葡萄糖被认为是成骨细胞的主要底物，尽管脂肪酸对于成骨细胞功能也很重要。在这里，我们报告说，成骨细胞可以通过脂肪分解从储存在脂滴中的内源性脂肪酸中获取能量，并且这个过程对于骨形成至关重要。因此，我们证明成骨细胞积累高度动态的脂滴，并提供了在成骨细胞成熟过程中充当能量产生燃料来源的分子机制。抑制细胞质脂肪分解会导致成骨细胞中脂滴大小的增加和成骨细胞功能的损害。当细胞能量在营养耗尽的条件下转向氧化磷酸化时，这些脂滴通过脂肪分解释放的脂肪酸对于细胞能量产生至关重要。在体内，成骨祖细胞中ATGL 编码基因Pnpla2的条件性缺失会降低皮质骨和骨小梁参数，并改变骨骼脂质代谢。总的来说，我们的数据表明，成骨细胞以脂滴的形式储存脂肪酸，当营养有限时，脂滴通过脂肪分解释放，以支持细胞的生物能量状态。这一过程中的干扰会导致骨形成受损，特别是减少 ATP 生成和整体成骨细胞功能。