Mitchell A. Lazar, MD, PhD

faculty photo
Willard and Rhoda Ware Professor in Diabetes and Metabolic Diseases
Medical Staff, Hospital of the University of Pennsylvania
Director, Penn Diabetes Research Center
Founding Director, Institute for Diabetes, Obesity and Metabolism
Director, Cox Institute for Medical Research
Chair, Center and Institute Directors Forum, Perelman School of Medicine
Department: Medicine

Contact information
12-102 Smilow Center for Translational Research
3400 Civic Center Boulevard / 5160
Philadelphia, PA 19104-5160
Office: (215) 898-0198
Fax: (215) 898-5408
Education:
S.B. (Chemistry)
Massachusetts Institute of Technology, 1976.
Ph.D. (Neuroscience)
Stanford Univerity, 1981.
M.D.
Stanford Univerity, 1982.
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Description of Research Expertise

Research Interests
Epigenomic regulation of transcription and metabolism by nuclear receptors; mechanism of obesity-associated insulin resistance and diabetes; circadian regulation of metabolism

Key words: diabetes, endocrinology, epigenomics, nuclear receptors, circadian rhythms

Description of Research
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.


Rotation Projects for 2021-2022
There are numerous potential projects that I would be pleased to discuss in person.

Lab personnel:
Amy Hauck, Ph.D., (Post-doc)
Yang Xiao, Ph.D., (Post-doc)
Kun Zhu, Ph.D., (Post-doc)
Lauren Woodie, Ph.D., (Post-doc)
Michael Tackenberg, Ph.D., (Post-doc)
Shin-Ichi Inoue, Ph.D., (Post-doc)
Tiffany Fleet, M.D., Ph.D., (Post-doc)
Yoon Jeong Park, Ph.D., (Post-doc)
Rashid Mehmood, Ph.D., (Post-doc)
Mohit Midha, Ph.D., (Post-doc)
Delaine Zayas-Bazan Burgos (Graduate Student)
Isaac Celwyn (Research Specialist)
Maria Krieg (Research Specialist)
Lily Melink (Research Specialist)
Yifan Liu (Research Specialist)
Michelle Burrows (Lab Manager)

Selected Publications

Richter HJ, Hauck AK, Batmanov K, Inoue SI, So BN, Kim M, Emmett MJ, Cohen RN, Lazar MA.: Balanced control of thermogenesis by nuclear receptor corepressors in brown adipose tissue. Proc Natl Acad Sci U S A 119(33): e2205276119, Aug 2022 Notes: doi: 10.1073/pnas.2205276119.

Chen Z, Ye Z, Soccio RE, Nakadai T, Hankey W, Zhao Y, Huang F, Yuan F, Wang H, Cui Z, Sunkel B, Wu D, Dzeng RK, Thomas-Ahner JM, Huang THM, Clinton SK, Huang J, Lazar MA, Jin VX, Roeder RG, Wang Q.: Phosphorylated MED1 links transcription recycling and cancer growth. Nucleic Acids Res 50(8): 4450-4463, May 2022 Notes: doi: 10.1093/nar/gkac246.

Santoleri D, Lim HW, Emmett MJ, Stoute J, Gavin MJ, Sostre-Colón J, Uehara K, Welles JE, Liu KF, Lazar MA, Titchenell PM.: Global-run on sequencing identifies Gm11967 as an Akt-dependent long noncoding RNA involved in insulin sensitivity. iScience 25(6): 104410, May 2022.

Guan D, Lazar MA.: Circadian Regulation of Gene Expression and Metabolism in the Liver. Semin Liver Dis. 42(2): 113-121, Mar 2022 Notes: doi: 10.1055/a-1792-4240.

Hu W, Jiang C, Kim M, Xiao Y, Richter HJ, Guan D, Zhu K, Krusen BM, Roberts AN, Miller J, Steger DJ, Lazar MA.: Isoform-specific functions of PPARγ in gene regulation and metabolism. Genes Dev. 36(5-6): 300-312, Mar 2022 Notes: doi: 10.1101/gad.349232.121.

Dierickx P, Zhu K, Carpenter BJ, Jiang C, Vermunt MW, Xiao Y, Luongo TS, Yamamoto T, Martí-Pàmies Í, 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.: Circadian REV-ERBs repress E4bp4 to activate NAMPT-dependent NAD+ biosynthesis and sustain cardiac function. Nat Cardiovasc Res. 1(1): 45-58, Jan 2022 Notes: doi: 10.1038/s44161-021-00001-9.

Dierickx P, Zhu K, Carpenter BJ, Jiang C, Vermunt MW, Xiao Y, Luongo TS, Yamamoto T, Martí-Pàmies Í, Mia S, Latimer M, Diwan A, Nguyen HC, Blober GA, Kelly DP, Pei L, Baur JA, Young ME, Lazar MA. : Circadian REV-ERBs repress E4bp4 to activate NAMPT-dependent NAD+ biosynthesis and sustain cardiac function. Nature Cardiovascular Research 1(1): 45–58, Dec 2021 Notes: doi: https://doi.org/10.1038/s44161-021-00001-9.

Adlanmerini M, Krusen BM, Nguyen HCB, Teng CW, Woodie LN, Tackenberg MC, Geisler CE, Gaisinsky J, Peed LC, Carpenter BJ, Hayes MR, Lazar MA.: REV-ERB nuclear receptors in the suprachiasmatic nucleus control circadian period and restrict diet-induced obesity. Sci Adv. 7(44): eabh200, Oct 2021 Notes: doi: 10.1126/sciadv.abh2007. Epub 2021 Oct 27.

Mitchell A Lazar: Novel biomedical research must not be a work of fiction. J Clin Invest 131(18): e150827, Sep 2021.

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.: Individual-specific functional epigenomics reveals genetic determinants of adverse metabolic effects of glucocorticoids. Cell Metab. 33(8): 1592-1609, Aug 2021.

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Last updated: 08/29/2022
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