Dr. Leff’s research interest is the regulation of gene expression by metabolic and nutritional signals. The laboratory of Dr. Leff is focused on understanding the molecular mechanism that underlie the metabolic diseases of diabetes and obesity, and in deciphering the role that gene expression plays in both the etiology and treatment of these diseases. Specific areas of focus are the molecular biology of two transcription factors whose activity is specifically regulated by metabolic and nutritional signals - the nuclear receptors PPARγ and HNF4α. The work on PPARγ seeks to identify the mechanism by which it regulates insulin sensitivity and glucose homoeostasis. HNF4α regulates many genes of metabolic significance and this work is directed toward understanding how its activity is regulated by upstream kinases, especially AMP-activated protein kinase. Additional areas of interest are the suppression of diabetic cardiomyopathy by the hormone adiponectin and the effect of environmental toxicants on the expression of metabolic genes.
Gene transcription, nuclear receptors, metabolic regulation, insulin resistance, and diabetes
Ph.D. (1982): Indiana University, Bloomington, IN, USA
1982-1985: Université Louis Pasteur, Strasbourg, France
1. Hong YH, Varanasi US, Yang W and Leff T, 2003, AMP-activated protein kinase regulates HNF4Î± transcriptional activity by inhibiting dimmer formation and decreasing protein stability, J Biol Chem, 278: 27495-501.
2. Hegele RA and Leff T, 2004, Unbuckling lipodystrophy from insulin resistance and hypertension, J Clin Invest, 114: 163-5.
3. Li G & Leff T, 200, Altered promoter recycling rates contribute to dominant/negative activity of human PPAR Î³ mutations associated with diabetes,Â Mol Endocrinol, 21:Â 857-64.
4. Monajemi H, Zhang L, Li G, Cao H, Maas M, Brouwer CB, Kalkhoven E, Stroes E, Hegele RA, and Leff T, 2007, Familial partial lipodystrophy phenotype resulting from a single-base mutation in DNA binding domain of peroxisome proliferator-activated receptor gamma,Â J Clin Endocrinol Metab, 92: 1606-12.