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.
Our Principal Investigator
Mitchell A. Lazar, M.D, Ph.D.
Willard and Rhoda Ware Professor in Diabetes and Metabolic Diseases
Director, Institute for Diabetes, Obesity, and Metabolism
Nicotinamide Riboside Improves Cardiac Function and Prolongs Survival After Disruption of the Cardiomyocyte Clock.
Dierickx P, Carpenter BJ, Celwyn I, Kelly DP, Baur JA, Lazar MA.
Front. Mol. Med. Epub 2022 May 09. PDF
Circadian REV-ERBs repress E4bp4 to activate NAMPT-dependent NAD+ biosynthesis and sustain cardiac function.
Dierickx P, Zhu K, Carpenter BJ, Jiang C, Vermunt MW, Xiao Y, Luongo TS, Yamamoto T, Martí-Pàmies I, Mia S, Latimer M, Diwan A, Zhao J, Hauck AK, Krusen B, Nguyen HCB, Blobel GA, Kelly DP, Pei L, Baur JA, Young ME, Lazar MA.
Nat Cardiovasc Res: 1-14. Epub 2021 Dec 23. PDF
REV-ERB nuclear receptors in the suprachiasmatic nucleus control circadian period and restrict diet-induced obesity.
Adlanmerini M, Krusen BM, Nguyen HCB, Teng CW, Woodie LN, Tackenberg MC, Geisler CE, Gaisinsky J, Peed LC, Carpenter BJ, Hayes MR, Lazar MA.
Sci Adv. 2021 Oct 29;7(44):eabh2007. doi: 10.1126/sciadv.abh2007. Epub 2021 Oct 27. PDF
Individual-specific functional epigenomics reveals genetic determinants of adverse metabolic effects of glucocorticoids.
Hu W, Jiang C, Kim M, Yang W, Zhu K, Guan D, Lv W, Xiao Y, Wilson JR, Rader DJ, Pui CH, Relling MV, Lazar MA.
Cell Metab. 2021 Aug 3;33(8):1592-1609.e7. doi: 10.1016/j.cmet.2021.06.004. Epub 2021 Jul 6. PDF
Dichotomous engagement of HDAC3 activity governs inflammatory responses.
Hoang C B Nguyen, Marine Adlanmerini, Amy K Hauck, Mitchell A Lazar.
Nature. 2020 Aug; 584(7820) : 286-290. doi: 10.1038/s41586-020-2576-2. Epub 2020 Aug 5. PDF
The hepatocyte clock and feeding control chronophysiology of multiple liver cell types.
Dongyin Guan, Ying Xiong, Trang Minh Trinh, Yang Xiao, Wenxiang Hu, Chunjie Jiang, Pieterjan Dierickx, Cholsoon Jang, Joshua D Rabinowitz, Mitchell A Lazar.
Science. 2020 Jul 30; eaba8984. doi: 10.1126/science.aba8984 PDF
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. PDF
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. PDF
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. PDF