Description of Research Expertise

Research Interests
- Regulation of gene expression and metabolism by nuclear hormone receptors
- Mechanism of obesity-associated insulin resistance and diabetes

Key words: diabetes, endocrinology, adipocytes, gene regulation, nuclear receptors.

Description of Research
The Lazar laboratory is interested in mechanisms of signal transduction by nuclear receptors for small, lipophilic hormones such as thyroid hormone, which regulate gene expression related to cellular differentiation and metabolism.

Nuclear receptors are transcription factors. In the absence of hormone ligand, they bind to DNA and function as potent transcriptional repressors. Repression is mediated by corepressor proteins, which are scaffolds for large multiprotein chromatin modifying complexes that include histone deacetylases (HDACs). Ligand binding alters the conformation of the receptor, causing corepressor to dissociate, coactivator proteins to be recruited, and gene transcription to be turned on. We are studying all aspects of these interactions, with special interest in the corepressor complexes containing HDACs, and particular attention to the nuclear receptors for thyroid hormone and anti-diabetic drugs, as well as the orphan receptor Rev-erbα. Rev-erbα is a key repressive component of the circadian clock, and we have recently discovered a mechanism regulating Rev-erbα protein stability activity that governs the initiation and synchronization of circadian clocks. These findings are being translated into informative mouse gene knockin and knockout models.

We are also studying PPAR γ (peroxisome proliferator activated receptor), a nuclear receptor that is a master regulator of adipocyte (fat cell) differentiation. Ligands for PPAR γ have potent antidiabetic activity, and thus PPARγ represents a long sought after link between obesity and diabetes. We have been studying regulation of PPAR γ during adipocyte differentiation, as well regulation of its activity by ligands and by phosphorylation. We have discovered new PPARγ target genes that play critical roles in adipocyte lipid metabolism, and identified a novel pathway of corepressor control of these genes . We also have discovered resistin, which encodes a novel polypeptide hormone made and secreted by fat cells in rodents and by macrophages in humans. We have demonstrated that resistin regulates insulin responsiveness, and now studying the molecular physiology of resistin in both mouse and human models.

Rotation Projects for 2006-2007
There are numerous potential projects that I would be pleased to discuss in person.

Lab personnel:
Theresa Alenghat (DVM/PhD student)
Josh Curtin, Ph.D. (Post-doc)
Roy Kim, M.D. (Endocrine Fellow)
Martina Lefterova (M.D./Ph.D. student)
Shannon Mullican, Ph.D. (Post-doc)
Mo Qatanani, Ph.D. (Post-doc)
Caroline Phelan (Graduate Student)
Michael Schupp, Ph.D. (Post-doc)
David Steger, Ph.D. (Research Associate)
Takuya Tomaru, M.D. (Post-doc)
Jing Wang (M.D./Ph.D. student)
Lei Yin, PhD (Post-doc)