Research

The Lazar lab studies the transcriptional regulation of metabolism. Metabolic diseases, including diabetes and obesity, have a strong genetic basis, yet their increasing prevalence has been fueled by an environmental replete with fattening diets, insufficient physical activity, and exposure to light around the clock. The goal of the Lazar lab is to understand the homeostatic mechanisms that control physiological metabolism and how these are overcome by harmful environmental factors. The focus is on nuclear receptors and HDAC3-containing corepressor complexes, whose functions are interrogated using a combination of genomic, proteomic, bioinformatic, and metabolic phenotyping methods. Of particular interest is the circadian nuclear receptor Rev-erbα, a key repressive component of the circadian clock that coordinates biological rhythms of metabolism in liver, adipose, and other tissues. Another focus is on nuclear receptor PPARγ, the master regulator of adipocyte differentiation. Ligands for PPARγ have potent antidiabetic activity, and thus PPARγ represents a key transcriptional link between obesity and diabetes. HDAC3 is also of great interest as an integrator of the activities of nuclear receptors and other transcription factors, with tissue-specific functions that protect from challenges to the circadian, nutritional, and thermal environment.

Recent Publications

An HDAC3-PROX1 corepressor module acts on HNF4α to control hepatic triglycerides.

Armour SM, Remsberg JR, Damle M, Sidoli S, Ho WY, Li Z, Garcia BA, Lazar MA.

Nat Commun. 2017 Sep 15;8(1):549. doi: 10.1038/s41467-017-00772-5. PMID: 28916805

The hepatic circadian clock fine-tunes the lipogenic response to feeding through RORα/γ.

Zhang Y, Papazyan R, Damle M, Fang B, Jager J, Feng D, Peed LC, Guan D, Sun Z, Lazar MA.

Genes Dev. 2017 Jul 26. doi: 10.1101/gad.302323.117. [Epub ahead of print] PMID: 28747429

Histone deacetylase 3 prepares brown adipose tissue for acute thermogenic challenge.

Emmett MJ, Lim HW, Jager J, Richter HJ, Adlanmerini M, Peed LC, Briggs ER, Steger DJ, Ma T, Sims CA, Baur JA, Pei L, Won KJ, Seale P, Gerhart-Hines Z, Lazar MA.

Nature. 2017 Jun 22;546(7659):544-548. doi: 10.1038/nature22819. Epub 2017 Jun 14. PMID: 28614293

Targeting PPARγ in the epigenome rescues genetic metabolic defects in mice.

Soccio RE, Li Z, Chen ER, Foong YH, Benson KK, Dispirito JR, Mullican SE, Emmett MJ, Briggs ER, Peed LC, Dzeng RK, Medina CJ, Jolivert JF, Kissig M, Rajapurkar SR, Damle M, Lim HW, Won KJ, Seale P, Steger DJ, Lazar MA.

J Clin Invest. 2017 Apr 3;127(4):1451-1462. doi: 10.1172/JCI91211. Epub 2017 Feb 27. PMID: 28240605

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