Xian-Man Zhang, PhD

BIOGRAPHY

Dr. Zhang has worked as a physical organic chemist/professor for near twenty years in various academia, industrial and national research laboratories. He has authored/co-authored over 70 scientific publications before joined Yale University in 2004. During the past decade, he mainly employed his broad chemistry knowledge and hands-on research experience to develop various practical analytical methods to characterize and quantitate any interesting metabolites in the related plasma/tissue biological samples using different analytical techniques. In the past few years, he and his analytical team has worked on many projects.

1. Can we develop well-tolerated therapeutic agents to reverse hypertriglyceridemia, insulin resistance, non-alcoholic steatohepatitis and non-alcoholic fatty liver disease?

A series of 2,4-dinitrophenol derivatives have been synthesized and characterized. Animal studies show that these novel chemicals are non-toxic and safe for in-vivo injections and are efficient mitochondrial protonophore to reverse diabetes and steatohepatitis in rats.

• Perry, R.J.; Kim, T.; Zhang, X.-M., Lee, H.-Y., Pesta, D., Popov, V.B., Zhang, D., Rahimi, Y., Jurczak, M.J., Cline, G.W., Spiegel, D.A., Shulman, G.I. Cell Metabolism, 2013, 18, 740-748.
• Perry, R.J., Zhang, D., Zhang, X.-M., Boyer, J.L., Shulman, G.I., Science, 2015, 347, 1253-1256.

2. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase.

Metformin is considered to be one of the most effective therapeutics for treating type 2 diabetes because it specifically reduces hepatic gluconeogenesis without increasing insulin secretion, inducing weight gain or posing a risk of hypoglycaemia.

• Madiraju, A.K., Erion, D.M., Rahimi, Y., Zhang, X.-M., Braddock, D.T., Albright, R.A., Prigaro, B.J., Wood, J.L., Bhanot, S., MacDonald, M.J., Jurczak, M.J., Camporez, J.-P., Lee, H.-Y., Cline, G.W., Samuel, V.T., Kibbey, R.G., Shulman, G.I. , Nature, 2014, 510, 542-546.

3. Leptin reverses diabetes by suppression of the hypothalamic-pituitary-adrenal axis.

The antidiabetic effect of leptin has been postulated to occur through suppression of glucagon production, suppression of glucagon responsiveness.

• Perry, R.J.; Zhang, X.-M., Zhang, D., Kumashiro, N., Camporez, J.-P.G., Cline, G.W., Rothman, D.L., Shulman, G.I, Nature Medicine, 2014, 20, 759-763.

4. How does inflammation contribute to insulin resistance and fasting hyperglycemia in diet-induced obesity in rodents and humans?

Using a novel in vivo metabolomics approach, we show that the major insulin suppresses HGP mechanism is through reductions in hepatic acetyl CoA by suppression of lipolysis.

• Perry, R.J., Camporez, J.-P.G., Kursawe, R., Titchenell, P.M., Zhang, D., Perry, C.J., Jurczak, M.J., Abudukadier, A., Han, M.S., Zhang, X.-M., Ruan, H.-B., Yang, X., Caprio, S., Kaech, S.M., Sul, H.S., Birnbaum, M.J., Davis, R.J., Cline, G.W., Petersen, K.F., Shulman, G.I. Cell, 2015, 160, 745-758.

Selected publications (from over 100 publications):

1. R. J. Perry, D. Zhang, X.-M. Zhang, J. L. Boyer, and G. I. Shulman, “Controlled-release mitochondrial protonophore reverses diabetes and protonophore reverses diabetes and steatohepatitis in rats”, Science, 2015, 347(6227), pp1253-1256.
2. Perry, R.J., Camporez, J.-P.G., Kursawe, R., Titchenell, P.M., Zhang, D., Perry, C.J., Jurczak, M.J., Abudukadier, A., Han, M.S., Zhang, X.-M., Ruan, H.-B., Yang, X., Caprio, S., Kaech, S.M., Sul, H.S., Birnbaum, M.J., Davis, R.J., Cline, G.W., Petersen, K.F., Shulman, G.I., “Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes”, Cell, 2015, 160(4), 745-758.
3. Perry RJ, Borders CB, Cline GW, Zhang XM, Alves TC, Petersen KF, Rothman DL, Kibbey RG, Shulman GI., “Propionate Increases Hepatic Pyruvate Cycling and Anaplerosis and Alters Mitochondrial Metabolism”, J Biol Chem. 2016, 291(23):12161-70.
4. A. Madiraju, D. M. Erion, Y. Rahimi, X.-M. Zhang, D. Braddock, R. A. Albright, B. J. Prigaro, J. L. Wood, S. Bhanot, G. W. Cline, V. T. Samuel, R. G. Kibbey, G. I. Shulman, “Metformin suppresses hepatic gluconeogenesis via inhibition of mitochondrial glycerophosphate dehydrogenase and modulation of the hepatocellular redox state”, Nature, 2014, 510(7506), pp542-546.
5. R. J. Perry, X. M. Zhang, D. Zhang, N. Kumashiro, J. P. Camporez, G. Cline, D. L. Rothman, G. I. Shulman, Mechanism for the anti-diabetic effect of leptin. Nature Medicine, 2014, 20, 759-763.
6. Mehra, V.C., Jackson, E., Zhang, X.M., Jiang, X.-C., Dobrucki, L.W., Yu, J., Bernatchez, P.,Sinusas, A.J., Shulman, G.I., Sessa, W.C., Yarovinsky, T.O., Bender, J.R. “Ceramide-activated phosphatase mediates fatty acid-induced endothelial VEGF resistance and impaired angiogenesis, American Journal of Pathology, 2014, 184, 1562-1576.
7. M. P. Gillum, D. Zhang, X.-M. Zhang,D. M. Erion,R. A. Jamison,C. Choi, J. Dong,M. Shanabrough,H. R. Duenas,D. W. Frederick,J. J. Hsiao, T. L. Horvath, C. M. Lo, P. Tso,G. W. Cline,and G. I. Shulman, Cell, 2008, 135, 813-824.
8. Zhang, X.-M.; Patel, A.B.; de Graaf, R.A.; Behar, K.L., Determination of liposomal encapsulation efficiency using proton NMR spectroscopy,. Chem. Phys. Lipid, 2004, 127, 113-120.
9. Zhang, X.-M. "Radical Substituent Effects of Fluorine and Trifluoromethyl Groups", J. Org. Chem. 1998, 63, 3590.
10. Zhang, X.-M.; Zhu, Q. “Olefinic Ozonation Electron Transfer Mechanisms”, J. Org. Chem. 1997, 62, 5934-5938.
11. X.-M. Zhang, F.G. Bordwell, "Bond Dissociation Energies of the Acidic H-A Bonds in HA+. Radical Cations and in HA-. Radical Anions in DMSO Solution", J. Am. Chem. Soc. 1994, 116(3), 904-908.
12. X.-M. Zhang, F.G. Bordwell,"Equilibrium Acidities and Homolytic Bond Dissociation Energies of the Acidic C-H Bonds in P-Substituted Triphenylphosphonium Cations", J. Am. Chem. Soc. 1994, 116(3), 968-972.
13. X.-M. Zhang, D.-L. Yang, Y.-C. Liu, " Effects of Electron Acceptors and Radical Scavengers on Non-chain Radical Nucleophilic Substitution Reactions", J. Org. Chem. 1993, 58, 224-227.
14. F.G. Bordwell, X.-M. Zhang," From Equilibrium Acidities to Radical Stabilization Energies", Acc. Chem. Res. 1993, 26(9), 510-517.