Mitchell A Lazar MD PhD

Dr. Mitchell Lazar is the Willard and Rhoda Ware Professor in Diabetes and Metabolic Diseases, the Chief of the Division of Endocrinology, Diabetes, and Metabolism, and the Director of the Institute for Diabetes, Obesity, and Metabolism at the University of Pennsylvania. He received his undergraduate degree in Chemistry from the Massachusetts Institute of Technology, then received a PhD in Neurosciences and an MD from Stanford University. He trained in Internal Medicine at Brigham and Women’s Hospital and in Endocrinology at the Massachusetts General Hospital before joining the University of Pennsylvania faculty in 1989.

Description of Research

The Lazar laboratory is studying the transcriptional regulation of metabolism. We are particularly focused on the role played by nuclear receptors (NRs). In the absence of ligand, NRs bind to DNA and function as potent transcriptional repressors by recruiting corepressor complexes that include the chromatin modulating enzyme histone deacetylase 3 (HDAC3). We are studying the tissue-specific and physiological roles of the corepressor complexes using by combining genomic, genetic, proteomic, bioinformatic, and metabolic phenotyping approaches. We are especially interested in the circadian NR Rev-erb alpha, which utilizes the corepressor complex to potently repress transcription. Rev-erb alpha is a key repressive component of the circadian clock that coordinates metabolism and biological rhythms. We are also studying PPAR gamma, a nuclear receptor that is a master regulator of adipocyte (fat cell) differentiation. Ligands for PPAR gamma have potent antidiabetic activity, and thus PPAR gamma represents a key transcriptional link between obesity and diabetes. The molecular, cellular, and integrative biology of these factors are being studied in mice and humans. We also have discovered resistin, a novel hormone and target of PPAR gamma that is made by fat cells in rodents and by macrophages in humans, and are testing the hypothesis that resistin links metabolism to inflammation in human metabolic diseases.