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 the oligomerization state of adiponectin affects its signaling specificity and its ability to promote insulin action in different tissues.
2) 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.
Any link on the below references will take you off
of the BMCB site and to an abstract of that particular paper.
Tsao, T.S., E. Tomas, H.E. Murrey, C. Hug, D.H. Lee, N.B. Ruderman, J.E. Heuser, and H.F. Lodish. 2003. Role of disulfide bonds in Acrp30/Adiponectin structure and signaling specificity: Different oligomers activate different signal transduction pathways. Journal of Biological Chemistry 278: 50810-50817.
Tsao, T.S., C. Hug, and H.F. Lodish. 2003. 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.
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. 2002. Proceedings of the National Academy of Sciences U.S.A. 99: 16309-16313.
Tsao, T.S., H.E. Murrey, C. Hug, D.H. Lee, and H.F. Lodish. 2002. Oligomerization state-dependent activation of NF-kB signaling pathway by adipocyte complement-related protein of 30 kDa (Acrp30). Journal of Biological Chemistry 277: 29359-29362.
Tsao, T.S., H.F. Lodish, and J. Fruebis. 2002. ACRP30, a new hormone controlling fat and glucose metabolism. European Journal of Pharmacology 440: 213-221.
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. 2001. Metabolic adaptations in skeletal muscle overexpressing GLUT4: effects on muscle and physical activity. FASEB Journal 15: 958-969.
Fruebis, J., T.S. Tsao, S. Javorschi, D. Ebbets-Reed, M.R. Erickson, F.T. Yen, B.E. Bihain, and H.F. Lodish. 2001. Proteolytic cleavage product of 30-kDa adipocyte complement-related protein (Acrp30) increases fatty acid oxidation in muscle and causes weight loss in mice. Proceedings of the National Academy of Sciences U.S.A. 98: 2005-2010.
Tsao, T.S., E.B. Katz, D. Pommer, and M.J. Charron. 2000. Amelioration of insulin resistance but not hyperinsulinemia in obese mice overexpressing GLUT4 selectively in skeletal muscle. Metabolism 49: 340-346.
Tsao, T.S., A.E. Stenbit, S.M. Factor, W. Chen, L. Rossetti, and M.J. Charron. 1999. Prevention of insulin resistance and diabetes in mice heterozygous for GLUT4 ablation by transgenic complementation of GLUT4 in skeletal muscle. Diabetes 48:775-782.
