Mitchell A. Lazar

About

Mitchell A. Lazar, MD, PhD, is the Willard and Rhoda Ware Professor in Diabetes and Metabolic Diseases at the Perelman School of Medicine at the University of Pennsylvania. He serves as the Director of the Penn Diabetes Research Center, Founding Director of the Institute for Diabetes, Obesity and Metabolism, and Director of the Cox Institute for Medical Research. His research focuses on the transcriptional regulation of metabolism, particularly the role played by nuclear receptors (NRs). Lazar's laboratory studies how nuclear receptors bind to DNA and function as transcriptional repressors in the absence of ligands, recruiting corepressor complexes that include histone deacetylase 3 (HDAC3). His work investigates the tissue-specific and physiological roles of these corepressor complexes using genomic, genetic, proteomic, bioinformatic, and metabolic phenotyping approaches. Lazar is especially interested in the circadian nuclear receptor Rev-erb alpha, which represses transcription to coordinate metabolism and biological rhythms, and PPAR gamma, a master regulator of adipocyte differentiation with potent antidiabetic activity. His research also explores resistin, a hormone linked to metabolism and inflammation in human metabolic diseases. Lazar's contributions include elucidating mechanisms underlying obesity-associated insulin resistance and diabetes, and understanding the epigenomic regulation of transcription and metabolism by nuclear receptors.

Research topics

• Biochemistry
• Cell biology
• Biology
• Endocrinology
• Chemistry

Selected publications

• The hepatocyte clock and feeding control chronophysiology of multiple liver cell types

  Science · 2020-07-30 · 175 citations

  articleOpen accessSenior authorCorresponding

  Most cells of the body contain molecular clocks, but the requirement of peripheral clocks for rhythmicity and their effects on physiology are not well understood. We show that deletion of core clock components REV-ERBα and REV-ERBβ in adult mouse hepatocytes disrupts diurnal rhythms of a subset of liver genes and alters the diurnal rhythm of de novo lipogenesis. Liver function is also influenced by nonhepatocytic cells, and the loss of hepatocyte REV-ERBs remodels the rhythmic transcriptomes and…

  PublisherOA PDFDOI

• Interconnections between circadian clocks and metabolism

  Journal of Clinical Investigation · 2021-08-01 · 157 citations

  reviewOpen accessSenior authorCorresponding

  Circadian rhythms evolved through adaptation to daily light/dark changes in the environment; they are believed to be regulated by the core circadian clock interlocking feedback loop. Recent studies indicate that each core component executes general and specific functions in metabolism. Here, we review the current understanding of the role of these core circadian clock genes in the regulation of metabolism using various genetically modified animal models. Additionally, emerging evidence shows tha…

  PublisherOA PDFDOI

• Dichotomous engagement of HDAC3 activity governs inflammatory responses

  Nature · 2020 · 147 citations

  Senior authorCorresponding
  PublisherOA PDFDOI

• Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy in male mice

  Nature Communications · 2023-08-25 · 75 citations

  articleOpen access

  Alzheimer's disease, the most common age-related neurodegenerative disease, is characterized by tau aggregation and associated with disrupted circadian rhythms and dampened clock gene expression. REV-ERBα is a core circadian clock protein which also serves as a nuclear receptor and transcriptional repressor involved in lipid metabolism and macrophage function. Global REV-ERBα deletion has been shown to promote microglial activation and mitigate amyloid plaque formation. However, the cell-autonom…

  PublisherOA PDFDOI

• Circadian REV-ERBs repress E4bp4 to activate NAMPT-dependent NAD+ biosynthesis and sustain cardiac function

  Nature Cardiovascular Research · 2021 · 66 citations

  Senior authorCorresponding
  PublisherOA PDFDOI

Recent grants

• University of Pennsylvania Diabetes Research Center

  NIH · $17.0M · 1997–2027

• Integrative Physiology of Thyroid Hormone Receptors and Nuclear Receptor Corepressors

  NIH · $6.6M · 1991–2029

• Nuclear Receptors in Metabolic Tissues

  NIH · $12.1M · 1995–2026

Frequent coauthors

• Ángel R. de Lera

  137 shared

• Pierre Chambon

  Institut de génétique et de biologie moléculaire et cellulaire

  132 shared

• Pierre Germain

  Courant Institute of Mathematical Sciences

  132 shared

• Hinrich Gronemeyer

  Centre National de la Recherche Scientifique

  129 shared

• David J. Mangelsdorf

  The University of Texas Southwestern Medical Center

  129 shared

• Ronald M. Evans

  Salk Institute for Biological Studies

  129 shared

• Reuben Lotan

  128 shared

• Gregor Eichele

  Max Planck Institute for Multidisciplinary Sciences

  128 shared

Labs

• Lazar LabPI

Education

• MA (Honorary)

  University of Pennsylvania

• MD

  Stanford University School of Medicine

  1982

• PhD (Neuroscience)

  Stanford University School of Medicine

  1981

• S.B. (Chemistry)

  Massachusetts Institute of Technology

  1976

Similar researchers at University of Pennsylvania

• John Q. Trojanowskih-296
• Craig B. Thompsonh-277
• Daniel J Raderh-236