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.

Recent Publications

Genetic Variation Determines PPAR gamma Function and Anti-diabetic Drug Response In Vivo.

Soccio RE, Chen ER, Rajapurkar SR, Safabakhsh P, Marinis JM, Dispirito JR, Emmett MJ, Briggs ER, Fang B, Everett LJ, Lim HW, Won KJ, Steger DJ, Wu Y, Civelek M, Voight BF, Lazar MA.

Cell. 2015 Jul 2;162(1):33-44. doi: 10.1016/j.cell.2015.06.025.PMID: 26140591

Discrete functions of nuclear receptor Rev-erb alpha couple metabolism to the clock.

Zhang Y, Fang B, Emmett MJ, Damle M, Sun Z, Feng D, Armour SM, Remsberg JR, Jager J, Soccio RE, Steger DJ, Lazar MA..

Science. 2015 Jun 26;348(6242):1488-92. doi: 10.1126/science.aab3021. Epub 2015 Jun 4.PMID: 26044300

Circadian enhancers coordinate multiple phases of rhythmic gene transcription in vivo.

Fang B, Everett LJ, Jager J, Briggs E, Armour SM, Feng D, Roy A, Gerhart-Hines Z, Sun Z, Lazar MA.

Cell. 2014 Nov 20;159(5):1140-52. doi: 10.1016/j.cell.2014.10.022. PMID: 25416951

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