Ph.D. University of Calcutta
Post-doc. University of Pittsburgh, Biochemisty & Molecular Biology
General field of research:
Affiliations other than medicine:
Evans Center for Interdisciplinary Biomedical Research
Department of Medicine, Section of Endocrinology
650 Albany Street, EBRC-827
Phone: (617)-638 7169
650 Albany Street, EBRC-820
Phone: (617)-638 7087
Fax: (617)-638 7094
Research group information
X. Xulia Xu (post-doc)
Ebony Lawson (graduate student)
Emma Stephens (graduate student)
Robert Petrocelli (undergraduate-student)
AMP-activated protein kinase; Acetyl CoA carboxylase; Protein synthesis; mTOR; p70S6 kinase
Summary of research interest:
AMP-activated protein kinase/malonyl CoA mechanism and its dysregulation in the pathogenesis of the metabolic syndrome.
The principal objective of our research is to determine the regulation of AMPK in mammalian tissues. We have established that exercise activates AMPK and enzymes of lipid metabolism in various tissues. Also, we have demonstrated that AMPK activity is diminished in numerous rodents with insulin resistance and that AMPK activation prevents insulin resistance in these and other rodents. Our studies showed that adiponectin, IL-6 and thiazolidinediones can activate AMPK in various settings. In the past, we have shown a novel inhibitor of acetyl CoA carboxylase, CP-640186, prevents insulin resistance caused by high glucose in incubated rat muscle.
Very recently we have demonstrated that incubation of skeletal muscle with a high concentration of glucose and branched chain amino acids (BCAA) decreases AMPK activity, increases mTOR/p70S6 kinase and causes insulin resistance in the apparent absence of a change in energy state (AMP/ATP ratio). Based on these studies we proposed that AMPK downregulation in this setting involves a decrease in the activity of SIRT1, an NAD+-dependent histone/protein deacetylase that has recently shown deacetylates and activates LKB1, the major AMPK-kinase in most tissues. Our overall objectives are to test this hypothesis and establish the mechanism by which an elevated glucose concentration downregulates SIRT1 and to determine whether suppression of SIRT1 and AMPK is responsible for the insulin resistance induced by hyperglycemia and BCAA. An understanding of the interaction of AMPK and SIRT1 could provide novel opportunities for both understanding the pathophysiology of diseases associated with insulin resistance and aging, and for developing new strategies for their therapy.
Park, H., Kaushik, V.K., Constant, S., Prentki, M., Przybytkowski, E., and Saha, A.K. 2002. 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: 32571-32577.
Tomas, E., Tsao, T.S., Saha, A.K., Murrey, H.E., Zhang, C.C., Itani, S.I., Lodish, H.F., and Ruderman, N.B. 2002. Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation. Proc. Natl Acad. Sci. (U S A) 99: 16309-16313.
Saha, A.K., Avilucea, P.R., Ye, J.M., Assifi, M.M., Kraegen, E.W., and Ruderman,
N.B. 2004. Pioglitazone treatment activates AMP-activated protein kinase in rat liver and adipose tissue in vivo. Biochem. Biophys. Res. Commun. 314: 580-585.
Kelly, M., Keller, C., Avilucea, P.R., Keller, P., Luo, Z., Xiang, X., Giralt, M.,
Hidalgo, J., Saha, A.K., Pedersen, B.K., and Ruderman, N.B. 2004. AMPK activity is depressed in tissues of the IL-6 knockout mice: the effect of exercise. Biochem. Biophys. Res. Commun. 320: 449-454.
LeBrasseur, N.K., Kelly, M., Tsao, T.S., Farmer, S.R., Saha, A.K., Ruderman, N.B., Tomas, E. 2006. Thiazolidinediones can rapidly activate AMP-activated protein kinase (AMPK) in mammalian tissues. Am. J. Physiol., 291:E175-E181.
López, M., Lage, R., Saha, A.K., Carling, D., Tschöp5, M., Diéguez1, C., Vidal-Puig, A. 2008. Hypothalamic fatty acid metabolism mediates the orexigenic action of ghrelin. Cell Metabolism 7: 389-399.
Gauthier MS, Miyoshi H, Souza SC, Cacicedo JM, Saha AK, Greenberg AS, Ruderman NB. 2008. AMP-activated protein kinase (AMPK) is activated as a consequence of lipolysis in the adipocyte: potential mechanism and physiological relevance. J Biol Chem. 283:16514-16524.
López, M., Saha, A.K., Diéguez1, C., Vidal-Puig, A. 2008. The AMPK-Malonyl CoA-CPT1 axis in the control of hypothalamic neuronal function. Cell Metabolism 7: 484-485.
Suchankova G, Nelson LE, Gerhart-Hines Z, Kelly M, Gauthier MS, Saha A.K., Ido Y, Puigserver P, Ruderman NB. 2009. Concurrent regulation of AMP-activated protein kinase and SIRT1 in mammalian cells. Biochem Biophys Res Commun. 378:836-841.
Lage, R, Saha, A.K., Vidal-Puig, A., López, M. 2009. Hypothalamic AMP-activated protein kinase: a master cellular sensor regulating feeding behavior. Obesity & Metabolism, 4:199-201.
Technologies available for sharing upon request:
Invitro muscle incubation; western-blot analysis; RT-PCR; Spectrophotometric and flurometric assay