Recent studies have established that the skeleton functions as an endocrine organ affecting metabolism through the osteoblast-derived hormone osteocalcin (Ocn). However, it is not fully understood how many transcription factors expressed in osteoblasts regulate the endocrine function. Here, we show that mice with osteoblast-specific deletion of Fra-2 (Fosl2) have low bone mass but increased body weight. In contrast, transgenic expression of Fra-2 in osteoblasts leads to increased bone mass and decreased body weight accompanied by reduced serum glucose and insulin levels, improved glucose tolerance and insulin sensitivity. In addition, mice lacking Fra-2 have reduced levels of circulating Ocn, but high adiponectin (Adipoq), whereas Fra-2 transgenic mice exhibit high Ocn and low Adipoq levels. Moreover, we found that Adipoq was expressed in osteoblasts and that this expression was transcriptionally repressed by Fra-2. These results demonstrate that Fra-2 expression in osteoblasts represents a novel paradigm for a transcription factor controlling the endocrine function of the skeleton.
