• Faculty Directory

Tsu-Shuen Tsao

Education and Appointments

• Ph.D. 1997, Albert Einstein College of Medicine
  

Research Interests

• Biochemistry
  
• "Metabolism, Signaling, and Regulation"
  
• Protein and Membrane Biochemistry
  

Research Summary

Obesity and type 2 diabetes mellitus;
Hormonal regulation of energy homeostasis;
Adipose tissue biology;
Signal transduction pathways involved in cellular and whole body energetics;
Redox-based assembly of protein complexes;
Metabolic disturbances associated with aging

Energy expenditure is, in part, determined by the metabolic efficiency with which an organism converts energy into work. Evolution favors high metabolic efficiency which results in lower energy expenditure and helps organisms survive starvation. However, with the ready availability of high calorie food, high metabolic efficiency also predisposes organisms to obesity. Obesity has reached epidemic proportions globally, particularly in the US where it afflicts one third of the adult population. Studies have shown that obesity is tightly linked to insulin resistance and dyslipidemia and often leads to type II diabetes mellitus and coronary artery disease. The prevalence of these conditions suggests that coronary artery disease and type II diabetes are intrinsic responses to excess fat both in circulation and in metabolically important tissues such as muscle and adipocytes. The focus of my group is to understand the molecular, cellular, as well as the whole body physiological basis of obesity and the metabolic adaptation that develops in response to this condition.

Students and postdoctoral fellows will have the opportunity to use state of the art genomic and proteomic tools to identify novel secreted factors and components of signal transduction pathways. They will employ modern as well as classic molecular biology, cell biology, and biochemistry techniques to study protein function and structure. They will also be expected to learn the methodology used to study cellular and whole body metabolism.

Areas of research include:

1) Hormonal regulation of obesity and diabetes by adipokine adiponectin (also known as Acrp30). Adiponectin is an adipocyte-secreted hormone whose expression and serum concentration are decreased in obese or diabetic humans and animals. For example, recent studies have show that in Arizona's Pima tribe, occurrence of diabetes later in life is accompanied by decreased adiponectin levels before onset of diabetes. Adiponectin exerts multiple metabolic actions at a number of tissue sites to enhance insulin sensitivity. Remarkably, adiponectin exists in a number of distinct forms, each of which activates different signal transduction pathways. We are currently investigating the molecular mechanisms by which adiponectin oligomers are assembled and how the assembly process is disrupted in people with metabolic syndrome.

2) Adipose tissue dysfunction is one of several deleterious outcomes of aging in mammals. As adipose tissue is essential for many critical physiological processes, including regulation of energy homeostasis and substrate mobilization and utilization, appetite control, and support of both native and adaptive immunity, its functional impairment likely has serious consequences. Aging is associated with a dramatic change in body composition, with many older adults experiencing a decrease in total muscle or fat-free mass and a concomitant increase in total fat mass. The increase in total fat mass during aging is mostly restricted to the visceral adipose tissue depot. Expansion of visceral adipose tissue is associated with the development of a constellation of diseases that disproportionately affect the elderly, including cancer, hypertension, stroke, coronary artery disease, obstructive sleep apnea syndrome, osteoarthritis, and type 2 diabetes mellitus. We are currently investigating the molecular and physiological mechanisms by which visceral adipose tissue expansion increases the risks for such wide range of diseases.

3) Regulation of AMP-activated protein kinase (AMPK) and cellular energetics by adipokines/cytokines. AMPK is a serine/threonine protein kinase that integrates cellular energetics with metabolic pathways and cell growth or proliferation. Under conditions of cellular energy deficit, manifested in low ATP/AMP ratio, AMPK becomes activated to shut off biosynthetic pathways and turn on catabolic pathways. It is the target through which two different adipokines, leptin and adiponectin, increase fatty acid oxidation. Currently we are examining the signaling mechanisms used by leptin and adiponectin to modulate AMPK activity.

Selected Publications

Briggs DB, RM Giron, DD Sarkar, PR Malinowski, M Nuñez, and T.S. Tsao. Role of Redox Environment on the Oligomerization of Higher Molecular Weight Adiponectin. BMC Biochem 12:24 (2011). PMCID: PMC3117782

Briggs DB, CM Jones, EH Mashalidis, M Nuñez, AC Hausrath, VH Wysocki, and T.S. Tsao. Disulfide-dependent self-assembly of adiponectin octadecamers from trimers and presence of stable octadecameric adiponectin lacking disulfide bonds in vitro. Biochemistry 48:12345-12357 (2009). PMCID: PMC2807922

Yeh, T.Y., K.K. Beiswenger, P. Li, K.E. Bolin, R.M. Lee, T.S. Tsao, A.N. Murphy, A.L. Hevener, and N.W. Chi. Hypermetabolism, hyperphagia, and reduced adiposity in tankyrase-deficient mice. Diabetes 58:2476-2485 (2009). PMCID: PMC2768175

Ranalletta M, X. Du, Y. Seki, A.S. Glenn, M. Kruse, A. Fiallo, I. Estrada, T.S. Tsao, A.E. Stenbit, E.B. Katz, and M.J. Charron. Hepatic response to restoration of GLUT4 in skeletal muscle of GLUT4 Null mice. Am J Physiol Endocrinol Metab 293:E1178-1187 (2007).

Suzuki S, E.M. Wilson-Kubalek, D. Wert, T.S. Tsao, and D.H. Lee. The oligomeric structure of high molecular weight adiponectin. FEBS Lett 581:809-814 (2007).

LeBrasseur N.K., M. Kelly, T.S. Tsao, S.R. Farmer, A.K. Saha, N.B. Ruderman, E. Tomas. Thiazolidinediones can rapidly activate AMP-activated protein kinase in mammalian tissues. Am J Physiol Endocrinol Metab 291:E175-E181 (2006).

Ranalletta M, H. Jiang, J. Li, T.S. Tsao, A.E. Stenbit, M. Yokoyama, E.B. Katz, and M.J. Charron. Altered hepatic and muscle substrate utilization provoked by GLUT4 ablation. Diabetes 54:935-943 (2005).

Wong G.W., J. Wang, C. Hug, T.S. Tsao, and H.F. Lodish. A family of Acrp30/adiponectin structural and functional paralogs. Proc Natl Acad Sci U S A 101:10302-10307 (2004).

Hug C., J. Wang, N.S. Ahmad, J.S. Bogan, T.S. Tsao, and H.F. Lodish. T-cadherin is a receptor for hexameric and high-molecular-weight forms of Acrp30/adiponectin. Proc Natl Acad Sci U S A 101:10308-10313 (2004).

Tsao T.S., E. Tomas, H.E. Murrey, C. Hug, D.H. Lee, N.B. Ruderman, J.E. Heuser, and H.F. Lodish. Role of disulfide bonds in Acrp30/Adiponectin structure and signaling specificity: Different oligomers activate different signal transduction pathways. J Biol Chem 278:50810-50817 (2003).

Bogan J.S., N. Hendon, A.E. McKee, T.S. Tsao, and H.F. Lodish. Functional cloning of TUG as a regulator of GLUT4 glucose transporter trafficking. Nature 425:727-733 (2003).

Tsao, T.S., C. Hug, and H.F. Lodish. Adipokines: Regulators of Metabolic Integration and Energy Metabolism. Chapter 65 of Diabetes Mellitus: A Fundamental and Clinical Text, 3rd Edition. D. LeRoith, S.I. Taylor, and J.M. Olefsky, editors. Lippincott Williams & Wilkins, publisher (2003)

Tomas E., T.S. Tsao, A.K. Saha, H.E. Murrey, C. Zhang Cc, S.I. Itani, H.F. Lodish, and N.B. Ruderman. 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 (2002).

Tsao T.S., H.E. Murrey, C. Hug, D.H. Lee, and H.F. Lodish. Oligomerization state-dependent activation of NF-kB signaling pathway by adipocyte complement-related protein of 30 kDa (Acrp30). J Biol Chem 277:29359-29362 (2002).

Tsao T.S., H.F. Lodish, and J. Fruebis. ACRP30, a new hormone controlling fat and glucose metabolism. Eur J Pharmacol 440:213-221 (2002).

Fruebis J., T.S. Tsao, S. Javorschi, D. Ebbets-Reed, M.R. Erickson, F.T. Yen, B.E. Bihain, and H.F. Lodish. Proteolytic cleavage product of 30-kDa adipocyte complement-related protein (Acrp30) increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci U S A 98:2005-2010 (2001).

Tsao T.S., J. Li, K.S. Chang, A.E. Stenbit, D. Galuska, J.E. Anderson, J.R. Zierath, R.J. McCarter, and M.J. Charron. Metabolic adaptations in skeletal muscle overexpressing GLUT4: effects on muscle and physical activity. Faseb J 15:958-969 (2001).

Stenbit A.E., E.B. Katz, J.C. Chatham, D.L. Geenen, S.M. Factor, R.G. Weiss, T.S. Tsao, A. Malhotra, V.P. Chacko, C. Ocampo, L.A. Jelicks, and M.J. Charron. Preservation of glucose metabolism in hypertrophic GLUT4-null hearts. Am J Physiol Heart Circ Physiol 279:H313-318 (2000).

Tsao T.S., E.B. Katz, D. Pommer, and M.J. Charron. Amelioration of insulin resistance but not hyperinsulinemia in obese mice overexpressing GLUT4 selectively in skeletal muscle. Metabolism 49:340-346 (2000).

Ryder J.W., Y. Kawano, A.V. Chibalin, J. Rincon, T.S. Tsao, A.E. Stenbit, T. Combatsiaris, J. Yang, G.D. Holman, M.J. Charron, and J.R. Zierath. In vitro analysis of the glucose-transport system in GLUT4-null skeletal muscle. Biochem J 342:321-328 (1999).

Tsao T.S., A.E. Stenbit, S.M. Factor, W. Chen, L. Rossetti, and M.J. Charron. Prevention of insulin resistance and diabetes in mice heterozygous for GLUT4 ablation by transgenic complementation of GLUT4 in skeletal muscle. Diabetes 48:775-782 (1999).

Zierath J.R., T.S. Tsao, A.E. Stenbit, J.W. Ryder, D. Galuska, and M.J. Charron. Restoration of hypoxia-stimulated glucose uptake in GLUT4-deficient muscles by muscle-specific GLUT4 transgenic complementation. J Biol Chem 273:20910-20915 (1998).

Stenbit A.E., T.S. Tsao, J. Li, R. Burcelin, D.L. Geenen, S.M. Factor, K. Houseknecht, E.B. Katz, and M.J. Charron. GLUT4 heterozygous knockout mice develop muscle insulin resistance and diabetes. Nat Med 3:1096-1101 (1997).

Tsao T.S., A.E. Stenbit, J. Li, K.L. Houseknecht, J.R. Zierath, E.B. Katz, and M.J. Charron. Muscle-specific transgenic complementation of GLUT4-deficient mice: Effects on glucose but not lipid metabolism. J Clin Invest 100:671-677 (1997).

Stenbit A.E., R. Burcelin, E.B. Katz, T.S. Tsao, N. Gautier, M.J. Charron, and Y. Le Marchand-Brustel. Diverse effects of Glut 4 ablation on glucose uptake and glycogen synthesis in red and white skeletal muscle. J Clin Invest 98:629-634 (1996).

Tsao T.S., R. Burcelin, and M.J. Charron. Regulation of hexokinase II gene expression by glucose flux in skeletal muscle. J Biol Chem 271:14959-14963 (1996).

Tsao T.S., R. Burcelin, E.B. Katz, L. Huang, and M.J. Charron. Enhanced insulin action due to targeted GLUT4 overexpression exclusively in muscle. Diabetes 45:28-36 (1996).