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

Inoue SI, Emmett MJ, Lim HW, Midha M, Richter HJ, Celwyn IJ, Mehmood R, Chondronikola M, Klein S, Hauck AK, Lazar MA.: Short-term cold exposure induces persistent epigenomic memory in brown fat. Cell Metab. 36 (8): 1764-1778,2024.

Paneru BD, Chini J, McCright SJ, DeMarco N, Miller J, Joannas LD, Henao-Mejia J, Titchenell PM, Merrick DM, Lim HW, Lazar MA, Hill DA.: Myeloid-derived miR-6236 potentiates adipocyte insulin signaling and prevents hyperglycemia during obesity. Nat Commun. 15 (1): 5394,2024.

Hauck AK, Mehmood R, Carpenter BJ, Frankfurter MT, Tackenberg MC, Inoue SI, Krieg MK, Cassim Bawa FN, Midha MK, Zundell DM, Batmanov K, Lazar MA.: Nuclear receptor corepressors non-canonically drive glucocorticoid receptor-dependent activation of hepatic gluconeogenesis. Nat Metab. 6 (5): 825-836,2024.

Woodie LN, Melink LC, Alberto AJ, Burrows M, Fortin SM, Chan CC, Hayes MR, Lazar MA.: Hindbrain REV-ERB nuclear receptors regulate sensitivity to diet- induced obesity and brown adipose tissue pathophysiology. Mol Metab. 79 : Article 101861,2024.

Woodie LN, Melink LC, Midha M, de Araújo AM, Geisler CE, Alberto AJ, Krusen, BM, Zundell DM, de Lartigue G, Hayes MR, Lazar MA.: Hepatic Vagal Afferents Convey Clock-Dependent Signals to Regulate Circadian Food Intake. bioRxiv[Preprint] : 2023.

Latimer MN, Williams LJ, Shanmugan G, Carpenter BJ, Lazar MA, Dierickx P, Young ME.: Cardiomyocyte-specific disruption of the circadian BMAL1-REV-ERBα/β regulatory network impacts distinct miRNA species in the murine heart. Commun Biol 6 (1): 1149,2023.

Zhu K, Celwyn IJ, Guan D, Xiao Y, Wang X, Hu W, Jiang C, Cheng L, Casellas R, Lazar MA.: An intrinsically disordered region controlling condensation of a circadian clock component and rhythmic transcription in the liver. Mol Cell. 83 (19): 3457-3469.e7,2023.

Lee J, Dimitry JM, Song JH, Son M, Sheehan PW, King MW, Travis Tabor G, Goo, YA, Lazar MA, Petrucelli L, Musiek ES.: Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy in male mice. Nat Commun 14 (1): 5197,2023.

Mia S, Sonkar R, Williams L, Latimer MN, Rawnsley DR, Rana S, He J, Dierickx, P, Kim T, Xie M, Habegger KM, Kubo M, Zhou L, Thomsen MB, Prabhu SD, Frank SJ, Brookes PS, Lazar MA, Diwan A, Young ME.: Novel Roles for the Transcriptional Repressor E4BP4 in Both Cardiac Physiology and Pathophysiology. JACC Basic Transl Sci. 8 (9): 1141-1156,2023.

Yamamoto T, Maurya SK, Pruzinsky E, Batmanov K, Xiao Y, Sulon SM, Sakamoto T, Wang Y, Lai L, McDaid KS, Shewale SV, Leone TC, Koves TR, Muoio DM, Dierickx P, Lazar MA, Lewandowski ED, Kelly DP.: RIP140 deficiency enhances cardiac fuel metabolism and protects mice from heart failure. J Clin Invest 133 (9): e162309,2023.

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Academic Contact Information

12-102 Smilow Center for Translational Research
3400 Civic Center Boulevard / 5160
Philadelphia, PA 19104-5160
Phone: 215-898-0198