EDUCATION:

University of Iowa, Iowa City, B.A., 1977, Zoology

Indiana University, Bloomington, Ph.D., 1982, Biology

PROFESSIONAL AND FACULTY APPOINTMENTS:
1985-1991 Assistant Professor, Biochemical Genetics and Metabolism, Rockefeller University, New York, NY

1991-1994 Senior Research Associate, Department of Biotechnology, Parke-Davis Pharmaceutical Research, Ann Arbor, MI

1994-1997 Associate Research Fellow, Department of Cell Biology, Parke-Davis Pharmaceutical Research, Ann Arbor, MI

1999-2001 Research Fellow, Department of Cell Biology, Parke-Davis Pharmaceutical Research (now Pfizer), Ann Arbor, MI

2002 Associate Professor of Pathology, Center for Integrative Metabolic and Endocrine Research, WSU

POSTDOCTORAL TRAINING
Laboratoire de Génétique Moléculaire des Eukaryotes du CNRS, University of Louis Pasteur, Strasbourg France, 1982-1985

RESEARCH INTEREST
My area of interest is the regulation of gene expression in metabolic diseases such as obesity and type-2 diabetes. In particular we are interested in the general question of how the cell communicates information about metabolic status to the molecular machinery that regulates gene expression. We study several specific gene regulatory systems that are known to play key roles in metabolic homeostasis in liver, adipose, and pancreatic islets.
Much of the work in the lab is concerned with the ligand-activated transcription factor PPAR-gamma. This member of the nuclear receptor superfamily plays a key role in formation of adipose tissue and in regulating the expression of genes that control whole-body metabolic homeostasis. Mutations that reduce the activity of PPAR-gamma cause diabetes, while drugs that activate its activity correct metabolic defects in patients with type-2 diabetes. We are examining the molecular, cellular and physiological effects of human mutations in PPAR-gamma as well as the effects of activating ligands in both in vitro and in vivo models of diabetes. Our goal is to develop a clearer understanding of the mechanism by which this key transcription factor has such a profound effect on metabolism.
A second major gene regulatory system that we study is centered around the transcription factor HNF4-alpha. HNF4-alpha regulates key glucose metabolism genes in both the liver and the endocrine pancreas, and mutations in the HNF4 gene have been shown to cause diabetes. We have recently shown that the transcriptional activity of HNF4 is regulated by the metabolic signaling enzyme AMP-activated protein kinase. We believe that this newly identified AMP-kinase/HNF4 signaling pathway may be an important component of the system that regulates glucose metabolism in several organs and tissues and that it may also play a key role in the development and treatment of diabetes. The goal of our research in this area is to characterize the biochemical details of the AMP-kinase mediated phosphorylation of HNF4, and the role that this signaling pathway has in regulating metabolism in animal models of diabetes.
Other areas of research in the lab are the regulation of gene expression by insulin and the effect of abnormal intracellular lipid accumulation on gene expression and on the development of metabolic disorders associated with diabetes. Our overall plan for all projects is to use a combination of in vitro, cell culture and animal model systems to develop an understanding of how specific transcriptional events affect metabolic balance and physiology in cells and animals, and how defects in transcriptional regulation contribute to the development of diabetes. In addition, we would like to use knowledge gained from these studies to identify novel therapeutic approaches for the treatment of type II diabetes and related disorders.

IN THE NEWS
Link to WSU Scribe article

SELECTED PUBLICATIONS
1. Leff, T., Elkaim, R., Goding, C., Jalinot, P., Sassone-Corsi, P., Perricaudet, M., Kedinger, C., and Chambon, P. (1984) The individual products of the adenovirus 12S and 13S EIA mRNAs stimulate viral EIIa and EIII expression at the transcriptional level. Proc. Natl. Acad. Sci. USA 81:4381-4385. [Medline]

2. Leff, T., and Chambon, P. (1986) Sequence-specific activation of transcription by adenovirus EIA products is observed in Hela cells but not in 293 cells. Mol. Cell. Biol. 6:201-208 [Medline]

3. Leff, T., Reue, K., Melian, A., Culver, H., and Breslow, J.L. (1989) A regulatory element in the apo CIII promoter that directs hepatic specific transcription binds to proteins in expressing and non-expressing cell types. J. Biol. Chem. 264:16132-16137. [Medline]

4. Chen M., Breslow, J.L., Li, W.W., and Leff, T. (1994) Transcriptional regulation of the apo CIII gene by insulin in diabetic mice: correlation with changes in plasma triglyceride levels. J. Lipid Res. 35:1918-1924. [Medline]

5. Gruber, P.J., Torres-Rosado, A., Wolak, M.L., and Leff, T. (1994) Apo CIII gene transcription is regulated by a cytokine inducible NF-kB element. Nucl. Acids Res. 22:2417-2422 [Medline]

6. Li, W.W., Dammerman, M.M., Smith, J.D., Metzger, S., Breslow, J.L., and Leff, T. (1995) Common genetic variation in the promoter of the human apo CIII gene abolishes regulation by insulin and may contribute to hypertriglyceridemia. J. Clin. Invest. 96:2601-2605. [Medline]

7. Taylor, D.G., Haubenwallner, S. and Leff, T. (1996) Characterization of a dominant-negative mutant form of the HNF-4 orphan receptor. Nucleic Acids Res. 24:2930-2935. [Medline]

8. Leff, T., and Gruber, P.J. (1996) Cardiovascular Diseases. In: The Encyclopedia of Molecular Biology and Molecular Medicine. Ed. Meyers R.A., VCH Publishers, New York. pp 283-292.

9. Camp, H. S., Tafuri, S.R., and Leff, T. (1999) C-Jun N-terminal kinase phosphorylates peroxisome proliferator-activated receptor-g1 and negatively regulates its transcriptional activity. Endocrinology 140:392-397 [Medline]

10. Reddy, S., Yang, W., Taylor, D.G., Shen, X., Oxender, D., Kust, G., and Leff, T. (1999) Mitogen-activated protein kinase regulates transcription of the Apo CIII gene: Involvement of the orphan nuclear receptor HNF4. J. Biol. Chem. 274:33050-33056 [Medline]

11. Camp, S.H., Li, O., Wise, S.C., Hong, H., Frankowski, C., Shen, X., Vanbogelen, R. and Leff, T. (2000) Differential activation of PPARg by troglitazone and rosiglitazone. Diabetes 49:539-547[Medline]

12. Camp HS, Chaudhry A, and Leff T. (2001) A novel potent antagonist of PPARg blocks adipocyte differentiation but does not revert the phenotype of terminally differentiated adipocytes. Endocrinology 142:3207-13 [Medline]

13. Yang, W., Hong, H., Shen, X-Q, Frankowski, C., Camp, H., and Leff, T. (2001) AMP Activated Protein Kinase Regulates Nuclear Receptor Activity by Phosphorylation of P300 J. Biol. Chem. 276:38341-4 [Medline]

14. Johnson, J., Saltiel, A.R., and Leff, T. (2002) Pharmacological approaches to insulin resistance in the Zucker Diabetic Fatty rat. In: Frontiers in Animal Diabetes Research. Vol. 3, Eds. Grunberger, G., and Zick Y., Harwood Academic Press, New York, pp 331-343.

15. Leff, T., and Reed, J., (2002) The Antidiabetic PPARg Ligands: An Update on Compounds in Development. Current Medicinal Chemistry: Immunlogy, Endocrine and Metabolic Agents, (in the press)

16. Hegele, R. A., Cao, H., Frankowski, C., Mathews, S.T., and Leff, T. (2002) PPARG F388L, a loss-of-function mutation, in familial partial lipodystrophy Diabetes 51:3586-90

17. Hong, Y.H., Varanasi, U. S., Yang W. and Leff, T. (2003) AMP-Activated Protein Kinase Regulates HNF4 Transcriptional Activity by Inhibiting Dimer Formation and Decreasing Protein Stability J. Biol. Chem. In Press.