Runx2 regulates the gene network associated with insulin signaling and energy homeostasis

Glucose intolerance seen in metabolic disorders, such as type II diabetes, is commonly associated with improper execution of the insulin signaling pathway, as well as an imbalance of bone and fat tissues, such that a gain in adipose tissue occurs at the expense of bone loss. Fat-producing adipocytes and bone-forming osteoblasts stem from a common mesenchymal progenitor cell. Runx2 positively regulates the commitment of the mesenchymal cell toward osteogenesis, but its effects on energy homeostasis and the insulin signaling pathway are unknown. To investigate the connection, focused microarray profiling of genes associated with the insulin signaling pathway was performed on calvarial cells from Runx2-null embryonic mice and 3T3-L1 preadipocytes treated with control and insulin-containing media. The microarray showed that addition of insulin resulted in a robust induction of genes (>95%) in 3T3-L1 cells. Surprisingly, Runx2-null cells cultured in control media were at an elevated state of energy metabolism and addition of insulin resulted in a marked suppression of genes required for insulin signaling. Clustering analysis revealed that the suppression occurred at all stages of the insulin pathway, from the receptors and transducers to nuclear effectors and target genes. Taken together, these results demonstrate that Runx2 is central for transduction and execution of the insulin regulatory signal. In conclusion, Runx2 actively regulates the gene network required for glucose metabolism and energy homeostasis in mesenchymal cells.