Neil Ruderman, M.D., D.Phil.

Fuel Sensing and Signaling

Dr. Ruderman’s research deals with the effects of insulin, exercise and fuels on cellular metabolism, signal transduction and, most recently, gene expression. Its focus in the past ten years has been on malonyl CoA fuel sensing and signaling mechanism described by his laboratory and its regulation by AMPK. His group has proposed that dysregulation of this mechanism, leading to increases in fatty acid esterification and/or the generation of reactive O₂ species, plays a causal role in the pathogenesis of many forms of insulin resistance in skeletal muscle and the early endothelial cell damage that antedates atherosclerosis in diabetes. Their research also examines the notion that activation of AMPK prevents this dysregulation and, perhaps independently, later events that it causes (e.g. NF-kB-mediated gene expression). Some of the investigators in his unit and their fellows work primarily with skeletal muscle (Asish Saha), some with cultured vascular cells (Yasuo Ido), and still others with adipocytes and cancer cells (Zhijun Luo). Thus, from a conceptual perspective, mechanisms worked out in one system are often tested in others.

The techniques employed by the Ruderman Laboratory include reporter gene assays, adenoviral gene transfer (cultured vascular cells), immunoflouresence microscopy, protein separation, enzyme analysis, gradient PCR and real time PCR and metabolite determination by spectrophotometric and chromatographic methods. The models used include incubated tissues, cultured cells, intact rodents and, in some collaborative efforts, humans. Many Boston University faculty are co-investigators in this work including Drs. John Keaney and Richard Cohen (vascular cell studies) and Paul Pilch (regulation of glucose transport and uncoupling proteins by AMPK). Collaborators from other institutions include Drs. Marc Prentki, University of Montreal (malonyl CoA regulation); E.W. Kragen, Garvan Institute, Australia (insulin resistance in rodents in vivo); Guenther Boden, Temple University (insulin resistance in humans); and David Carling, Hammersmith Hospital, U.K. (molecular biological approaches to study AMPK action in vascular cells).

 

References:

1.     Ruderman, N.B., Chisholm, D., Pi-Sunyer, X., Schneider, S.: The metabolically-obese, normal-weight individual: Revisited. Diabetes 47: 699-713, 1998.

2.     Ruderman, N.B., Saha, A.K., Vavvas, D., Witters, L.A.: Malonyl CoA, fuel sensing and insulin resistance. AJP, 276: E1-E18, 1999.

3.     Dagher, Z., Ruderman, N.B., Tornheim, K., Ido, Y.: Fatty acid oxidation, glucose metabolism and ATP generation in human umbilical vein endothelial cells (HUVEC): Effects of AICAR. Circ. Res., 88: 1276-1282, 2001.

4.     Ido, Y., Carling, D., Ruderman, N.B.: Hyperglycemia-induced apoptosis in human umbilical vein endothelial cells: inhibition by the AMP-activated protein kinase activation. Diabetes, 51(1): 159-67, 2002.

5.     Xiang, X-Q, Yuan, M.S., Ruderman, N., Luo, Z.J.: 14-3-3 facilitates insulin-stimulated intracellular trafficking of IRS-1. Mol. End. 16(3): 552-62, 2002.

6.     Ruderman, N.B., Flier, J.S.: Chewing the fat—ACC and energy balance. Science, 291: 2558-2559, 2001.

7.     Tomas, E., Zorzano, A., Ruderman, N.B.: Exercise effects on muscle insulin signaling and action. Exercise and insulin signaling: A historical perspective. J. Appl. Physiol., 93: 765-72, 2002.

8.     Itani, S.I., Ruderman, N.B., Schmeider, F., Boden, G.: Lipid induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and Ikβ-α. Diabetes, 51: 2005-2011, 2002.

9.     Park, H., Kaushik, V., Constant, S., Prentki, M., Przybytkowski, E., Ruderman, N.B., Saha, A.K.: Coordinate regulation of malonyl-CoA decarboxylase, sn-glycerol-3-phosphate acyltransferase and acetyl-CoA carboxylase by AMP-activated protein kinase in rat tissues in response to exercise. J. Biol. Chem., 277(36): 32571-32577, 2002.

10. Ruderman, N.B., Cacicedo, J., Itani, S., Yagihashi, N., Saha, A.K., Ye, J., Chen, K., Zou, M., Carling, D., Cohen, R.A., Keaney, J.F., Jr., Kraegen, E.W., Ido, Y.: Malonyl-CoA and AMP-activated protein kinase (AMPK): possible links between insulin resistance in muscle and early endothelial cell damage in diabetes. Biochem. Soc. Trans. 31(Pt 1): 202-6, 2003.

11.  Iglesias, M.A., Ye, J., Frangioudakis, G., Saha, A.K., Tomas, E., Ruderman, N.B., Cooney, G.J., Kraegen, E.W.: AICAR administration causes an apparent enhancement of muscle and liver insulin action in insulin resistant high-fat-fed rats. Diabetes, 51: 2886-94, 2002.

12.  Tomas, E., Tsao, T.-S., Saha, A.K., Murrey, H.E., Zhang, C.C., Itani, S.I., Lodish, H.F., Ruderman, N.B.: Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: acetyl CoA carboxylase inhibition and AMP-activated protein kinase activation. PNAS, 99(25): 16309-13, 2002.

13. Itani SI, Saha AK, Kurowski TG, Coffin HR, Tornheim K, Ruderman NB. Glucose autoregulates its uptake in skeletal muscle: involvement of AMP-activated protein kinase. Diabetes. 2003;52:1635-40.

14. Saha AK, Ruderman NB. Malonyl-CoA and AMP-activated protein kinase: an expanding partnership. Mol Cell Biochem. 2003;253:65-70.