Welcome to the Lazar Lab
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.
Understanding the molecular mechanisms underlying circadian and metabolic physiology, and how these contribute to homeostasis yet may be overcome by harmful environmental factors, leading to metabolic diseases.
- Nuclear receptor REV-ERBα, a key repressive component of the circadian clock that coordinates biological rhythms of metabolism in liver, adipose, and other tissues.
- Nuclear receptor PPARγ, the master regulator of adipocyte biology, whose ligands have potent antidiabetic activity, a key transcriptional link between obesity and diabetes.
- Thyroid hormone receptors, mediating the powerful metabolic effects of thyroid hormones, controlling energy metabolism
- Nuclear receptor corepressors and histone deacetylase 3 (HDAC3), functioning as a multiprotein integrator of the function of nuclear receptors and other transcription factors, with tissue-specific functions that protect from challenges to the circadian, nutritional, and thermal environment.
- Transcriptional regulation of circadian rhythms and metabolism, focused on the specific factors above as well as unbiased discovery of critical additional factors and pathways.
The Lazar lab has pioneered a systems approach to physiology that combines state-of-the-art in vivo "omics" with genetic and environmental manipulations and detailed metabolic phenotyping. This approach has had a major impact on our current understanding of the pathophysiology of obesity and diabetes, leading to new concepts linking the epigenome to metabolism and stimulating novel translational approaches for the treatment and prevention of metabolic diseases.
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Circadian lipid synthesis in brown fat maintains murine body temperature during chronic cold.
Adlanmerini M, Carpenter BJ, Remsberg JR, Aubert Y, Peed LC, Richter HJ, Lazar MA.
Proc Natl Acad Sci U S A. 2019 Aug 26. pii: 201909883. doi: 10.1073/pnas.1909883116.
SR9009 has REV-ERB-independent effects on cell proliferation and metabolism.
Dierickx P, Emmett MJ, Jiang C, Uehara K, Liu M, Adlanmerini M, Lazar MA.
Proc Natl Acad Sci U S A. 2019 Jun 18;116(25):12147-12152. doi: 10.1073/pnas.1904226116. Epub 2019 May 24.
Patient Adipose Stem Cell-Derived Adipocytes Reveal Genetic Variation that Predicts Antidiabetic Drug Response.
Hu W, Jiang C, Guan D, Dierickx P, Zhang R, Moscati A, Nadkarni GN, Steger DJ, Loos RJF, Hu C, Jia W, Soccio RE, Lazar MA.
Cell Stem Cell. 2019 Feb 7;24(2):299-308.e6. doi: 10.1016/j.stem.2018.11.018. Epub 2019 Jan 10.
Work featured on CellPress cover, click here to see the cover.
Diet-Induced Circadian Enhancer Remodeling Synchronizes Opposing Hepatic Lipid Metabolic Processes
Guan D, Xiong Y, Borck PC, Jang C, Doulias PT, Papazyan R, Fang B, Jiang C, Zhang Y, Briggs ER, Hu W, Steger D, Ischiropoulos H, Rabinowitz JD, Lazar MA.
Cell. 2018 Aug 9;174(4):831-842.e12. doi: 10.1016/j.cell.2018.06.031. Epub 2018 Jul 26.
PPARγ is a nexus controlling alternative activation of macrophages via glutamine metabolism.
Nelson VL, Nguyen HCB, Garcìa-Cañaveras JC, Briggs ER, Ho WY, DiSpirito JR, Marinis JM, Hill DA, Lazar MA.
Genes Dev. 2018 Jul 13. doi: 10.1101/gad.312355.118. [Epub ahead of print] PMID:30006480
Distinct macrophage populations direct inflammatory versus physiological changes in adipose tissue.
Hill DA, Lim HW, Kim YH, Ho WY, Foong YH, Nelson VL, Nguyen HCB, Chegireddy K, Kim J, Habertheuer A, Vallabhajosyula P, Kambayashi T, Won KJ, Lazar MA.
Proc Natl Acad Sci U S A. 2018 May 29;115(22):E5096-E5105. doi: 10.1073/pnas.1802611115. Epub 2018 May 14. PMID: 29760084
Rev-erbα dynamically modulates chromatin looping to control circadian gene transcription.
Kim YH, Marhon SA, Zhang Y, Steger DJ, Won KJ, Lazar MA.
Science. 2018 Feb 8. pii: eaao6891. doi: 10.1126/science.aao6891. [Epub ahead of print]. PMID: 29439026