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 studying the transcriptional regulation of metabolism. We are particuarly interested in mechanisms by which nuclear receptors (NRs) regulate gene expression and metabolism. NRs are transcription factors that are activated by binding to small lipophilic ligands including hormones, vitamins, drugs, and metabolites. In the absence of ligand, NRs bind to DNA and function as potent transcriptional repressors. Repression is mediated by corepressor complexes that include chromatin modulating 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 corepressor complexes containing HDAC3, and with particular attention to the nuclear receptors for thyroid hormone as well as the orphan receptor Rev-erbα. Rev-erbα is a key repressive component of the circadian clock that senses heme levels to coordinate metabolism and biological rhythms. The molecular, cellular, and integrative biology of these factors are being studied in cell lines as well as mouse gene knockin and knockout models. We are also studying PPARγ (peroxisome proliferator activated receptor), a nuclear receptor that is a master regulator of adipocyte (fat cell) differentiation. Ligands for PPARγ have potent antidiabetic activity, and thus PPARγ represents a long sought after link between obesity and diabetes. We have discovered new PPARγ target genes, identified a novel pathway of corepressor control of these genes, and have recently used genome-wide methodology to identify the entire set of genes bound PPARγ in adipocytes. We are currently determining the role of PPARγ in epigenetic regulation of adipocyte function. We also have discovered resistin, a novel hormone made and secreted by fat cells in rodents and by macrophages in humans. We have demonstrated that resistin regulates insulin responsiveness, and are now studying the molecular physiology of resistin in mouse and human models.
Rotation Projects for 2009-2010
There are numerous potential projects that I would be pleased to discuss in person.
Lab personnel:
Martina Lefterova (M.D./Ph.D. student)
Shannon Mullican, 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)
Elyisha Hanniman, Ph.D. (Post-doc)
Nan Wu Chan (Graduate Student)
Seo-Hee You, Ph.D. (Post-doc)
Ana Cristancho (M.D./Ph.D. student)
Dan Feng (Graduate Student)
Fenfen Wang (Graduate Student)
Cheng Jia (Graduate Student)
Ray Soccio, M.D., Ph.D. (Post-doc)
Zheng Sun, Ph.D. (Post-doc)
Shree Joshi (Research Specialst)
Erika Briggs (Research Specialst)
Christine Gaddis (Research Specialst)
David Zhou (Research Specialst)
Joe Weaver, Lab Manager
Selected Publications
Wu N, Yin L, Hanniman EA, Joshi S, Lazar MA.: Negative feedback maintenance of heme homeostasis by its receptor, Rev-erb{alpha} Genes Dev. 23(18): 2201-9, Sept 2009.
Lefterova MI, Mullican SE, Tomaru T, Qatanani M, Schupp M, Lazar MA.: Endoplasmic Reticulum Stress Regulates Adipocyte Resistin Expression. Diabetes. 58(8): 1879-86, Aug 2009.
Seale P, Lazar MA.
: Brown Fat in Humans: Turning up the Heat on Obesity.
Diabetes 58(7): 1482-4, Jul 2009.
McKenna NJ, Cooney AJ, Demayo FJ, Downes M, Glass CK, Lanz RB, Lazar MA, Mangelsdorf DJ, Moore DD, Qin J, Steffen DL, Tsai MJ, Tsai SY, Yu R, Margolis RN, Evans RM, O'Malley BW.: Minireview: Evolution of NURSA, the Nuclear Receptor Signaling Atlas. Mol Endocrinol. 23(6): 740-6, Jun 2009.
Germain P, Gaudon C, Pogenberg V, Sanglier S, Van Dorsselaer A, Royer CA, Lazar MA, Bourguet W, Gronemeyer H.: Differential action on coregulator interaction defines inverse retinoid agonists and neutral antagonists. Chem Biol. 16(5): 479-89, May 2009.
Lefterova MI, Lazar MA.: New developments in adipogenesis. Trends Endocrinol Metab. 20(3): 107-14, April 2009.
Schupp M, Cristancho AG, Lefterova MI, Hanniman EA, Briggs ER, Steger DJ, Qatanani M, Curtin JC, Schug J, Ochsner SA, McKenna NJ, Lazar MA.: Re-expression of GATA2 cooperates With PPARgamma depletion to revert the adipocyte phenotype. J Biol Chem. 284(14): 9458-64, April 2009.
Tomaru T, Steger DJ, Lefterova MI, Schupp M, Lazar MA.: Adipocyte-specific expression of murine resistin is mediated by synergism between peroxisome proliferator-activated receptor gamma and CCAAT/enhancer binding proteins. J Biol Chem. 284(10): 6116-25, March 2009.
Qatanani M, Szwergold NR, Greaves DR, Ahima RS, Lazar MA: Macrophage-derived human resistin exacerbates adipose tissue inflammation and insulin resistance in mice. J Clin Invest in press, Feb 2009.
Schupp M, Lefterova MI, Janke J, Leitner K, Cristancho AG, Mullican SE, Qatanani M, Szwergold N, Steger DJ, Curtin JC, Kim RJ, Suh M, Albert MR, Engeli S, Gudas LJ, Lazar MA.: Retinol saturase promotes adipogenesis and is downregulated in obesity. Proc Natl Acad Sci 106(4): 1105-10, January 2009.
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Last updated: 09/28/2009
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