The liver plays a central role in the maintenance of normal blood glucose levels (euglycemia), which is essential for good health. Dysregulation of blood glucose levels leads either to hypoglycemia or diabetes. In that regard, we study the small molecule, fructose-2,6-bisphosphate, which is a key regulator of liver metabolism with respect to maintaining euglycemia. By engineering the bifunctional enzyme, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, which both synthesizes and degrades fructose-2,6-bisphosphate, and expressing it in an adenovirus vector, we are able to manipulate the concentration of fructose-2,6-bisphosphate, in vivo, in mice. We study how the changes in level of this biofactor alter metabolism of the liver. We have recently demonstrated that fructose-2,6-bisphosphate is involved in signaling pathways that control the gene expression of hepatic metabolic genes and are currently mapping out these pathways. We also have evidence that the liver communicates with other tissues as a result of changes in fructose-2,6-bisphosphate levels, either by hepatokine secretion or through the neural circuits, and thereby can regulate metabolism in extra-hepatic tissues, such as adipose and muscle. We are currently persevering to unravel these novel roles for fructose-2,6-bisphosphate.

Peer Reviewed

Wu, C., Okar, D.A., Newgard, C. B., and Lange, A. J. (2001). Overexpression of 6-Phosphofructo-2, 6-bisphosphatase in Mouse Liver lowers Blood Glucose by Suppression of Hepatic Glucose Production. . J. Clin. Invest. 107: 1-8.

Wu, C., Okar, D.A., Newgard, C.B., and Lange, A.J. (2002). Increasing Fructose-2,6-bisphosphate Overcomes Hepatic Insulin Resistance of Type 2 Diabetes, Am. J. Physiol Endocrinol Metab, 282: E38-E45.

Choi, I-Y., Wu, C., Okar, D.A., Lange, A.J., and Gruetter, R. (2002). Elucidation of the Role of Fructose-2,6-bisphosphate in the Regulation of Glucose Fluxes in Mice using In Vivo 13C-NMR Measurements of Hepatic Carbohydrate Metabolism. Eur. J. Biochem., 269: 4418-4426.

Wu, C., Okar, D.A., Stoeckman, A.K., Peng, L-J., Herrera, A.H., Herrera, J.E., and Lange, A.J. (2004). Fructose-2, 6-bisphosphate Regulates Hepatic Gene Expression of Glucokinase and Glucose-6-phosphatase in the Absence of Insulin. Endocrinology 145(2):650?658.

Wu, C., Kang, J.E., Peng, L.-J., Li, H., Khan, S.A., Hillard, C.J., Okar, D.A., and Lange, A.J. (2005) Enhancing Hepatic Glycolysis Reduces Obesity: Differential Effects on Lipogenesis Depend on Site of Glycolytic Modulation. Cell Metabolism, 2: 131-140.

Wu, C., Khan, S., Peng, L.J., Li, H., Carmella, S.S., and Lange, A.J. (2006) Perturbation of Glucose Flux in the Liver by Decreasing Fructose-2,6-bisphosphate Levels Causes Hepatic Insulin Resistance and Hyperglycemia. Am J Physiol Endocrinol Metab, Apr 2006; doi:10.1152/ajpendo.00126.2006

Invited Reviews

Okar, D.A., Manzano, A., Navarro-Sabate, A. Riera, L., Bartrons, R., and Lange, A. J. (2001). PFK-2/FBPase-2: Maker and Breaker of the Essential Biofactor Fructose-2,6-Bisphosphate. Trends in Biological Sciences, 26:30-35.

Okar, D. A., Wu, C., Lange, A. J. (2004) Regulation of the Regulatory Enzyme, 6-Phosphofructo-2-kinase/Fructose-2,6-bisphosphatase. Advances in Enzyme Regulation, (G. Weber, Ed.) 44: 123-154.

Wu, C., Khan, S., and Lange, A.J. (2005) Regulation of Glycolysis ? Role of Insulin. Experimental Gerontology, 40: 894-899.

Wu, C. Khan, S. Peng, L.-J., and Lange, A.J. (2006) Roles For Fructose-2,6-Bisphosphate In The Control Of Fuel Metabolism: Beyond Its Allosteric Effects On Glycolytic And Gluconeogenic Enzymes. Advances in Enzyme Regulation 46, (G. Weber and L. Cocco, eds.) In press.