BADERC Welcome

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 fifteen years has been on their regulation by AMPK and, more recently, by the sirtuins, a group of NAD-dependent histone/protein deacetylases that have many of the same biological actions as AMPK. His group has proposed that dysregulation of the AMPK fuel-sensing mechanism is both a pathogenetic factor for many metabolic syndrome-associated disorders and a target for their therapy. Ongoing studies from his laboratory have tested this theory in skeletal muscle, liver, and adipose tissue using cultured cells, incubated tissues and intact animals—and occasionally humans—as models. In addition, his group is examining whether a similar dysregulation of AMPK underlies the endothelial cell dysfunction that leads to accelerated atherosclerosis and impaired angiogenesis in the setting of the metabolic syndrome. Most recently, it has been testing the existence of a SIRT1/AMPK cycle that regulates multiple cellular functions (e.g., growth, inflammation, aging) and whether such a cycle links cellular redox and energy state.

The techniques employed by the Ruderman laboratory include reporter gene assays, adenoviral, lentiviral, and retroviral gene transfer (cultured vascular and other 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 (including transgenic mice) and, in some collaborative efforts, humans. Many Boston University faculty are co-investigators in this work including Drs. Kenneth Walsh and Richard Cohen (vascular cell studies). Collaborators from other institutions include Drs. Marc Prentki, University of Montreal (malonyl CoA and AMPK regulation); E.W. Kraegen, Garvan Institute, Australia (insulin resistance in rodents in vivo); David Sinclair, Harvard (the sirtuins); and David Carling, Hammersmith Hospital, U.K. (molecular biological approaches to study AMPK action in vascular cells).

References:

Ruderman, N.B., Prentki, M. AMP Kinase and Malonyl-CoA: Targets for Therapy of the Metabolic Syndrome. Nature: Drug Discovery, 3(4): 340-51, 2004.
Kelly, M., Keller, C., Avilucea, P.R., Keller, P., Luo, Z., Xiang, X., Giralt, M., Hidalgo, J., Saha, A.K., Pedersen, B.K., Ruderman, N.B. AMPK activity is diminished in tissues of IL-6 knockout mice: the effect of exercise. BBRC, 320: 449-454, 2004.
Kraegan, E., Saha, A., Preston, E., Wilks, D., Hoy, A., Cooney, G., Ruderman N.B. Increased malonyl CoA and diacylglycerol content and reduced AMPK activity accompany insulin resistance induced by glucose infusion in muscle and liver of rats. Am J Physiol Endocrinol Metab, 290: E471-479, 2006.
Ruderman, N.B., Keller, C., Richard, A., Saha, A.K., Luo, Z., Xiang, X., Giralt, M., Ritov, V.B., Menshikova, E.V., Kelley, D.E., Hidalgo, J., Pedersen, B.K., Kelly, M. Interleukin-6 Regulation of AMPK-activated Protein Kinase: Potential Role in the Systemic Response to Exercise and Prevention of the Metabolic Syndrome. Diabetes, 55 (Suppl 2): S48-S54, 2006.
Saha, A.K., Persons, K., Safer, J.D., Luo, Z., Holick, M.F., Ruderman, N.B. AMPK regulation of the growth of cultured human keratinocytes. BBRC, 349: 519-524, 2006.
Hamburg, N.M., McMackin, C.J., Huang, A.L., Shenouda, S.M., Widlansky, M.E., Shulz, E., Gokce, N., Ruderman, N.B., Keaney, J.F., Vita, J.A. Physical inactivity rapidly induces insulin resistance and microvascular dysfunction in healthy volunteers. Arterioscl Thromb Vasc Biol, 27(12): 2650-6, 2007.
Lan, F., Cacicedo, J.M., Ruderman, N., Ido, Y. SIRT1 modulation of the acetylation status, cytosolic localization and activity of LKB1; possible role in AMP-activated protein kinase activation. J Biol Chem, 283(41): 27628-35, 2008.
Gauthier, M-S., Miyoshi, H., Souza, S.C., Cacicedo, J.M., Saha, A.K., Greenberg, A.S., Ruderman, N.B. AMP-activated protein kinase (AMPK) is activated as a consequence of lipolysis in the adipocyte: Potential mechanism and physiological relevance. J Biol Chem, 283(24): 16514-24, 2008.
Richter, E., Ruderman, N.B. AMPK and the biochemistry of exercise: Implications for human health and disease. The Biochemical Journal, 418(2): 261-75, 2009.
Suchankova, G., Nelson, L., Gerhart-Hines, Z., Kelly, M., Gauthier, M-S., Saha, A.K., Ido, Y., Puigserver, P., Ruderman, N.B. Concurrent regulation of AMP-activated protein kinase and SIRT1 in mammalian cells. Biochem Biophys Res Commun, 378: 836-841, 2009.
Ruderman, N.B., Shulman, G.I. “The metabolic syndrome.” In Endocrinology, 6th Ed., DeGroot L.J., Jameson, J.L., Eds., Philadelphia, Elsevier/Saunders, in press.






			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 fifteen years has been on their regulation by AMPK and, more recently, by the sirtuins, a group of NAD-dependent histone/protein deacetylases that have many of the same biological actions as AMPK. His group has proposed that dysregulation of the AMPK fuel-sensing mechanism is both a pathogenetic factor for many metabolic syndrome-associated disorders and a target for their therapy. Ongoing studies from his laboratory have tested this theory in skeletal muscle, liver, and adipose tissue using cultured cells, incubated tissues and intact animals—and occasionally humans—as models. In addition, his group is examining whether a similar dysregulation of AMPK underlies the endothelial cell dysfunction that leads to accelerated atherosclerosis and impaired angiogenesis in the setting of the metabolic syndrome. Most recently, it has been testing the existence of a SIRT1/AMPK cycle that regulates multiple cellular functions (e.g., growth, inflammation, aging) and whether such a cycle links cellular redox and energy state. The techniques employed by the Ruderman laboratory include reporter gene assays, adenoviral, lentiviral, and retroviral gene transfer (cultured vascular and other 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 (including transgenic mice) and, in some collaborative efforts, humans. Many Boston University faculty are co-investigators in this work including Drs. Kenneth Walsh and Richard Cohen (vascular cell studies). Collaborators from other institutions include Drs. Marc Prentki, University of Montreal (malonyl CoA and AMPK regulation); E.W. Kraegen, Garvan Institute, Australia (insulin resistance in rodents in vivo); David Sinclair, Harvard (the sirtuins); and David Carling, Hammersmith Hospital, U.K. (molecular biological approaches to study AMPK action in vascular cells). References: Ruderman, N.B., Prentki, M. AMP Kinase and Malonyl-CoA: Targets for Therapy of the Metabolic Syndrome. Nature: Drug Discovery, 3(4): 340-51, 2004. Kelly, M., Keller, C., Avilucea, P.R., Keller, P., Luo, Z., Xiang, X., Giralt, M., Hidalgo, J., Saha, A.K., Pedersen, B.K., Ruderman, N.B. AMPK activity is diminished in tissues of IL-6 knockout mice: the effect of exercise. BBRC, 320: 449-454, 2004. Kraegan, E., Saha, A., Preston, E., Wilks, D., Hoy, A., Cooney, G., Ruderman N.B. Increased malonyl CoA and diacylglycerol content and reduced AMPK activity accompany insulin resistance induced by glucose infusion in muscle and liver of rats. Am J Physiol Endocrinol Metab, 290: E471-479, 2006. Ruderman, N.B., Keller, C., Richard, A., Saha, A.K., Luo, Z., Xiang, X., Giralt, M., Ritov, V.B., Menshikova, E.V., Kelley, D.E., Hidalgo, J., Pedersen, B.K., Kelly, M. Interleukin-6 Regulation of AMPK-activated Protein Kinase: Potential Role in the Systemic Response to Exercise and Prevention of the Metabolic Syndrome. Diabetes, 55 (Suppl 2): S48-S54, 2006. Saha, A.K., Persons, K., Safer, J.D., Luo, Z., Holick, M.F., Ruderman, N.B. AMPK regulation of the growth of cultured human keratinocytes. BBRC, 349: 519-524, 2006. Hamburg, N.M., McMackin, C.J., Huang, A.L., Shenouda, S.M., Widlansky, M.E., Shulz, E., Gokce, N., Ruderman, N.B., Keaney, J.F., Vita, J.A. Physical inactivity rapidly induces insulin resistance and microvascular dysfunction in healthy volunteers. Arterioscl Thromb Vasc Biol, 27(12): 2650-6, 2007. Lan, F., Cacicedo, J.M., Ruderman, N., Ido, Y. SIRT1 modulation of the acetylation status, cytosolic localization and activity of LKB1; possible role in AMP-activated protein kinase activation. J Biol Chem, 283(41): 27628-35, 2008. Gauthier, M-S., Miyoshi, H., Souza, S.C., Cacicedo, J.M., Saha, A.K., Greenberg, A.S., Ruderman, N.B. AMP-activated protein kinase (AMPK) is activated as a consequence of lipolysis in the adipocyte: Potential mechanism and physiological relevance. J Biol Chem, 283(24): 16514-24, 2008. Richter, E., Ruderman, N.B. AMPK and the biochemistry of exercise: Implications for human health and disease. The Biochemical Journal, 418(2): 261-75, 2009. Suchankova, G., Nelson, L., Gerhart-Hines, Z., Kelly, M., Gauthier, M-S., Saha, A.K., Ido, Y., Puigserver, P., Ruderman, N.B. Concurrent regulation of AMP-activated protein kinase and SIRT1 in mammalian cells. Biochem Biophys Res Commun, 378: 836-841, 2009. Ruderman, N.B., Shulman, G.I. “The metabolic syndrome.” In Endocrinology, 6th Ed., DeGroot L.J., Jameson, J.L., Eds., Philadelphia, Elsevier/Saunders, in press.