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.

Keywords:
Runx2, Insulin signaling, Adipocyte differentiation, Energy metabolism, Gene microarray
1.
Baumann, C., V. Ribon, M. Kanzaki, D. Thurmond, S. Mora, S. Shigematsu, P. Bickel, J. Pessin, A. Saltiel (2000) CAP defines a second signalling pathway required for insulin-stimulated glucose transport. Nature 407: 202–207.
2.
Cao, Z., R.M. Umek, S.L. McKnight (1991) Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells. Genes Dev 5: 1538–1552.
3.
Cheatham, B., C. Kahn (1995) Insulin action and the insulin signaling network. Endocr Rev 16: 117–142.
4.
Cong, L., H. Chen, Y. Li, L. Zhou, M. McGibbon, S. Taylor, M. Quon (1997) Physiological role of Akt in insulin-stimulated translocation of GLUT4 in transfected rat adipose cells. Mol Endocrinol 11: 1881–1890.
5.
Cusi, K., M. Katsumi, O. Abdullah, M. Pendergrass, M. Elizabeth, T. Pratipanawatr, R. DeFronzo, C. Kahn. L. Mandarino (2000) Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. J Clinical Invest 105: 311–320.
6.
Czech, M. (1977) Molecular basis of insulin action. Annu Rev Biochem 46: 359–384.
7.
de Paula, F., M. Horowitz, C. Rosen (2010) Novel insights into the relationship between diabetes and osteoporosis. Diabetes Metab Res Rev 26: 622–630.
8.
Duque, G. (2008) Bone and fat connection in aging bone. Curr Opin Rheumatol 20: 429–434.
9.
Isidro, M., B. Ruano (2010) Bone disease in diabetes. Curr Diabetes Rev 6: 144–155.
10.
Kahn, C., M. White (1988) The insulin receptor and the molecular mechanisms of insulin actions. J Clinical Invest 82: 1151–1156.
11.
Kim, S., J. Ha, S. Yun, E. Kim, S. Chung, K. Hong, C. Kim, S. Bae (2010) Transcriptional activation of peroxisome proliferator-activated receptor-gamma requires activation of both protein kinase A and Akt during adipocyte differentiation. Biochem Biophys Res Commun 399: 55–59.
12.
Komori, T., H. Yagi, S. Normura, et al. (1997) Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89: 755–764.
13.
Lian, J., A. Javed, S. Zaidi, C. Lengner, M. Montecino, A. van Mijnen, J. Stein, G. Stein (2004) Regulatory controls for osteoblast growth and differentiation: role of Runx/Cbfa/AML factors. Crit Rev Eurkaryot Gene Expr 14: 1–41.
14.
Moller, D., J. Flier (1991) Insulin resistance: mechanisms, syndromes, and implications. N Engl J Med 325: 938–948.
15.
Nakashima, K., X. Zhou, G. Kunkel, Z. Zhang, J.M. Deng, R.R. Behringer, B. de Crombrugghe (2002) The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 108: 17–29.
16.
Tadahiro, K., S. Kenta, S. Hara, M. Nakafukun, S. Okabayashi, T. Kadowaki, Y. Kaziron, M. Kasuga (1994) Signal transduction pathways from insulin receptors to Ras. J Biol Chem 269: 4634–4640.
17.
Walker, A., F. Yang, K. Jiang, et al. (2010) Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP. Genes Dev 24: 1403–1417.
18.
Yang, J., X. Zhang, W. Wang, J. Liu (2010) Insulin stimulates osteoblast proliferation and differentiation through ERK and PI3K in MG-63 cells. Cell Biochem Funct 28: 334–341.
19.
Yonezawa, K., A. Ando, Y. Kaburagi, R. Yamamoto-Honda, T. Kitamura, K. Hara, M. Nakafuku, Y. Okabayashi, T. Kadowaki, Y. Kaziro (1994) Signal transduction pathways from insulin receptors to Ras: analysis by mutant insulin receptors. J Biolo Chem 269: 4634–4640.
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2011
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