NUCLEAR HORMONE RECEPTORS IN ADIPOCYTE DIFFERENTIATION

Summary

Principal Investigator: Mitchell A Lazar
Abstract: DESCRIPTION (provided by applicant): A major goal of this laboratory is to understand the molecular mechanisms by which the nuclear hormone receptor peroxisome proliferator-activated receptor ? (PPAR?) controls adipogenesis and mediates antidiabetic effects of thiazolidinedione (TZD) drugs that improve insulin sensitivity but cause unwanted side effects. We hypothesize that target gene- and tissue- selective modulation of gene expression by PPAR? are dictated by different modes of PPAR? binding and synergy between PPAR? and cooperating transcription factors. Specific Aim 1 is to determine the direct transcriptional effect of TZDs in adipocytes and their relation to PPAR? binding on a genome-wide scale. We hypothesize that the direct effects of TZDs on transcription cannot be predicted from transcriptomic analysis. Preliminary Global Run-On sequencing (GRO-seq) results demonstrate the feasibility of measuring nascent transcripts in adipocytes on a genome-wide scale. Specific Aim 2 is to delineate the adipocyte epigenome and corepressor cistromes, and their relation to PPAR? binding and the effects of TZD treatment on a genome-wide scale. We hypothesize that TZD treatment of adipocytes alters coregulator recruitment to PPAR? at a subset of target genes, leading to epigenomic changes that alter gene transcription. This will be tested by ChIP-seq for coregulators and epigenomic marks in adipocytes treated with TZDs and non-TZD ligands with potentially fewer side effects. Specific Aim 3 is to understand the mechanisms of cell-type specific genomic binding and regulation by PPAR?. We hypothesize that PPAR? functions as a pioneer factor on some binding sites, particularly in adipocytes, whereas macrophage binding sites are more influenced by cell- specific transcription factors and epigenomic marks. This will be tested using cistromic approaches, and the ability of PPAR? and cell type-specific factors such as PU.1 to shape each other's genomic binding, as well as the adipocyte and macrophage epigenomes, will be explored using gain and loss of function studies. Our innovative approach will elucidate mechanisms underlying target gene- and tissue-specificity of PPAR?, which can be translated to the design of more selective insulin sensitizers to combat the epidemic of metabolic disorders.
Funding Period: 1995-07-01 - 2017-05-31
more information: NIH RePORT

Top Publications

  1. ncbi CXCL16 is a marker of inflammation, atherosclerosis, and acute coronary syndromes in humans
    Michael Lehrke
    Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
    J Am Coll Cardiol 49:442-9. 2007
  2. pmc Species-specific strategies underlying conserved functions of metabolic transcription factors
    Raymond E Soccio
    Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6149, USA
    Mol Endocrinol 25:694-706. 2011
  3. pmc Repressor transcription factor 7-like 1 promotes adipogenic competency in precursor cells
    Ana G Cristancho
    Division of Endocrinology, Department of Medicine and Genetics and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
    Proc Natl Acad Sci U S A 108:16271-6. 2011
  4. ncbi Forming functional fat: a growing understanding of adipocyte differentiation
    Ana G Cristancho
    Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, The Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine at University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Nat Rev Mol Cell Biol 12:722-34. 2011
  5. pmc Cell-specific integration of nuclear receptor function at the genome
    Logan J Everett
    Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Institute of Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
    Wiley Interdiscip Rev Syst Biol Med 5:615-29. 2013
  6. pmc Pruning of the adipocyte peroxisome proliferator-activated receptor γ cistrome by hematopoietic master regulator PU.1
    Joanna R DiSpirito
    Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Department of Genetics, and The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
    Mol Cell Biol 33:3354-64. 2013
  7. pmc The orphan nuclear receptors at their 25-year reunion
    Shannon E Mullican
    Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Mol Endocrinol 51:T115-40. 2013
  8. pmc Lipoatrophy and severe metabolic disturbance in mice with fat-specific deletion of PPARγ
    Fenfen Wang
    Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Department of Genetics, and The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104
    Proc Natl Acad Sci U S A 110:18656-61. 2013
  9. pmc Metabolite and transcriptome analysis during fasting suggest a role for the p53-Ddit4 axis in major metabolic tissues
    Michael Schupp
    Institute for Genomics and Bioinformatics, Graz University of Technology, Petersgasse 14, Graz 8010, Austria
    BMC Genomics 14:758. 2013
  10. pmc Anti-diabetic rosiglitazone remodels the adipocyte transcriptome by redistributing transcription to PPARγ-driven enhancers
    Sonia E Step
    Division of Endocrinology, Diabetes, and Metabolism
    Genes Dev 28:1018-28. 2014

Detail Information

Publications22

  1. ncbi CXCL16 is a marker of inflammation, atherosclerosis, and acute coronary syndromes in humans
    Michael Lehrke
    Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
    J Am Coll Cardiol 49:442-9. 2007
    ..This study was designed to determine the association of CXCL16 with inflammation, atherosclerosis, and acute coronary syndromes...
  2. pmc Species-specific strategies underlying conserved functions of metabolic transcription factors
    Raymond E Soccio
    Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6149, USA
    Mol Endocrinol 25:694-706. 2011
    ..Analysis of factor binding in multiple species may be necessary to distinguish apparent species-unique noise and reveal functionally relevant information...
  3. pmc Repressor transcription factor 7-like 1 promotes adipogenic competency in precursor cells
    Ana G Cristancho
    Division of Endocrinology, Department of Medicine and Genetics and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
    Proc Natl Acad Sci U S A 108:16271-6. 2011
    ..These results establish TCF7L1 as a transcriptional hub coordinating cell-cell contact with the transcriptional repression required for adipogenic competency...
  4. ncbi Forming functional fat: a growing understanding of adipocyte differentiation
    Ana G Cristancho
    Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, The Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine at University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Nat Rev Mol Cell Biol 12:722-34. 2011
    ..Improving our understanding of these mechanisms may allow us to identify therapeutic targets against metabolic diseases that are rapidly becoming epidemic globally...
  5. pmc Cell-specific integration of nuclear receptor function at the genome
    Logan J Everett
    Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Institute of Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
    Wiley Interdiscip Rev Syst Biol Med 5:615-29. 2013
    ..Emerging genomic technologies such as ChIP-seq and GRO-seq provide insights on a larger scale leading to deeper understanding of the complexities of transcriptional regulation by NRs...
  6. pmc Pruning of the adipocyte peroxisome proliferator-activated receptor γ cistrome by hematopoietic master regulator PU.1
    Joanna R DiSpirito
    Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Department of Genetics, and The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
    Mol Cell Biol 33:3354-64. 2013
    ..Together, these data reveal unexpected lability within the adipocyte PPARγ cistrome and show that, even in terminally differentiated cells, PU.1 can remodel the cistrome of another master regulator. ..
  7. pmc The orphan nuclear receptors at their 25-year reunion
    Shannon E Mullican
    Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Mol Endocrinol 51:T115-40. 2013
    ..Here we provide a compendium of these so-called orphan receptors and focus on what has been learned about their modes of action, physiological functions, and therapeutic promise. ..
  8. pmc Lipoatrophy and severe metabolic disturbance in mice with fat-specific deletion of PPARγ
    Fenfen Wang
    Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Department of Genetics, and The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104
    Proc Natl Acad Sci U S A 110:18656-61. 2013
    ..Together, our data reveal the necessity of fat PPARγ in adipose formation, whole-body metabolic homeostasis, and normal development of fat-containing tissues. ..
  9. pmc Metabolite and transcriptome analysis during fasting suggest a role for the p53-Ddit4 axis in major metabolic tissues
    Michael Schupp
    Institute for Genomics and Bioinformatics, Graz University of Technology, Petersgasse 14, Graz 8010, Austria
    BMC Genomics 14:758. 2013
    ..Because there is a lack of standardization for this procedure, we need a deeper understanding of the dynamics and the molecular mechanisms in fasting...
  10. pmc Anti-diabetic rosiglitazone remodels the adipocyte transcriptome by redistributing transcription to PPARγ-driven enhancers
    Sonia E Step
    Division of Endocrinology, Diabetes, and Metabolism
    Genes Dev 28:1018-28. 2014
    ..Thus, rosi activates and represses transcription by fundamentally different mechanisms that could inform the future development of anti-diabetic drugs. ..
  11. pmc Autoimmune kidney disease and impaired engulfment of apoptotic cells in mice with macrophage peroxisome proliferator-activated receptor gamma or retinoid X receptor alpha deficiency
    Tamas Roszer
    Departamento de Cardiología Regenerativa, Centro Nacional de Investigaciones Cardiovasculares, 28029 Madrid, Spain
    J Immunol 186:621-31. 2011
    ..These results demonstrate that stimulation of PPARγ and RXRα in macrophages facilitates apoptotic cell engulfment, and they provide a potential strategy to avoid autoimmunity against dying cells and to attenuate SLE...
  12. pmc Endogenous ligands for nuclear receptors: digging deeper
    Michael Schupp
    Department of Endocrinology, Diabetes, and Nutrition and Center for Cardiovascular Research, Institute of Pharmacology, Charite University Medicine Berlin, 10115 Berlin, Germany
    J Biol Chem 285:40409-15. 2010
    ..This knowledge about the nature and physiology of these ligands may create new opportunities for therapeutic drug development...
  13. pmc PPARgamma regulates adipose triglyceride lipase in adipocytes in vitro and in vivo
    Erin E Kershaw
    Div of Endocrinology and Metabolism, Dept of Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215, USA
    Am J Physiol Endocrinol Metab 293:E1736-45. 2007
    ..Thus, PPARgamma positively regulates ATGL mRNA and protein expression in mature adipocytes in vitro and in adipose tissue in vivo, suggesting a role for ATGL in mediating PPARgamma's effects on lipid metabolism...
  14. ncbi Resistin- and Obesity-associated metabolic diseases
    M A Lazar
    Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and The Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 6149, USA
    Horm Metab Res 39:710-6. 2007
    ..Given the emerging interrelationship between inflammation and metabolic disease, hyperresistinemia may be a biomarker, and/or a mediator, of metabolic and inflammatory diseases in humans as well as in rodents...
  15. pmc Stereospecificity of retinol saturase: absolute configuration, synthesis, and biological evaluation of dihydroretinoids
    Alexander R Moise
    Department of Pharmacology, Case School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106 4965, USA
    J Am Chem Soc 130:1154-5. 2008
  16. pmc DOT1L/KMT4 recruitment and H3K79 methylation are ubiquitously coupled with gene transcription in mammalian cells
    David J Steger
    Division of Hematology, Abramson Research Center 315A, The Children s Hospital of Philadelphia, 3400 Civic Center Blvd, Philadelphia, PA 19104, USA
    Mol Cell Biol 28:2825-39. 2008
    ....
  17. pmc Re-expression of GATA2 cooperates with peroxisome proliferator-activated receptor-gamma depletion to revert the adipocyte phenotype
    Michael Schupp
    Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Univ of Pennsylvania School of Medicine, 700 CRB, 415 Curie Blvd, Philadelphia, PA 19104 6149, USA
    J Biol Chem 284:9458-64. 2009
    ..These results suggest that PPARgamma-independent down-regulation of GATA2 prevents reversion of mature adipocytes after PPARgamma depletion...
  18. pmc Retinol saturase promotes adipogenesis and is downregulated in obesity
    Michael Schupp
    Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
    Proc Natl Acad Sci U S A 106:1105-10. 2009
    ..Thus, RetSat plays an important role in the biology of adipocytes, where it favors normal differentiation, yet is reduced in the obese state. RetSat is thus a novel target for therapeutic intervention in metabolic disease...
  19. pmc Cell-specific determinants of peroxisome proliferator-activated receptor gamma function in adipocytes and macrophages
    Martina I Lefterova
    University of Pennsylvania School of Medicine, 700 CRB, 415 Curie Blvd, Philadelphia, PA 19104 6149, USA
    Mol Cell Biol 30:2078-89. 2010
    ..Our data support the existence of an epigenomic hierarchy in which PPARgamma binding to cell-specific sites not marked by repressive marks opens chromatin and leads to local activation marks, including histone acetylation...
  20. pmc Propagation of adipogenic signals through an epigenomic transition state
    David J Steger
    Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Genes Dev 24:1035-44. 2010
    ..Thus, the conversion of preadipocyte to adipocyte involves the formation of an epigenomic transition state that is not observed in cells at the beginning or end of the differentiation process...
  21. pmc PPARγ and the global map of adipogenesis and beyond
    Martina I Lefterova
    Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
    Trends Endocrinol Metab 25:293-302. 2014
    ..These emerging considerations inform our understanding of PPARγ function as well as of adipocyte development and physiology. ..

Research Grants30

  1. An integrative approach to construct a regulatory network effected by TDZs
    Kyoung Jae Won; Fiscal Year: 2013
    ....
  2. Transcriptional and epigenomic control of adipose tissue development and function
    David J Steger; Fiscal Year: 2013
    ....
  3. Role of NCoR in Adipose Tissue
    Maryam Ahmadian; Fiscal Year: 2013
    ..abstract_text> ..
  4. Circadian Repressors Cry1 and Cry2 Modulate Nuclear Hormone Receptor Function
    Katja A Lamia; Fiscal Year: 2013
    ..This project involves the study of a novel regulator for nuclear hormone receptor function and will contribute to the knowledge base needed for the development of therapeutic strategies to treat metabolic disease. ..
  5. Transcriptional role of TLE3 in brown adipose tissue development and metabolism
    Claudio J Villanueva; Fiscal Year: 2013
    ..The proposed studies are a logical transition from my postdoctoral studies in adipogenesis to the burgeoning field of brown adipocyte biology. ..
  6. Epigenetics of Obesity and Insulin Resistance
    Jane Kim; Fiscal Year: 2013
    ..Jerrold Olefsky. This approach is designed to draw on my strengths as a bench scientist and pediatric endocrinologist, providing an independent focus of research and platform for future R01 funding. ..
  7. DIABETES AND ENDOCRINOLOGY RESEARCH CENTER
    Domenico Accili; Fiscal Year: 2013
    ....
  8. OBESITY, ADIPOGENESIS, AND LIPID LIGANDS
    Clay F Semenkovich; Fiscal Year: 2013
    ..Identifying novel pathways for altering the function of fat cells has the potential to improve the metabolic milieu of obesity and treat obesity-associated diseases. ..
  9. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  10. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  11. HORMONAL REGULATION OF MAMMALIAN GENE EXPRESSION
    Ronald M Evans; Fiscal Year: 2013
    ....
  12. Connection of Mineral and Energy Metabolism by the Nuclear Receptor PPAR-gamma
    Yihong Wan; Fiscal Year: 2013
    ..Therefore, this investigation will significantly impact the broader scientific, clinical, and patient community. ..
  13. Translating human PPARy binding regions to gene regulation and metabolic disease
    RAYMOND EDWARD SOCCIO; Fiscal Year: 2013
    ..Soccio from the mentored to the independent phase of this 5 year career development award. These studies of the human PPAR cistrome have potentially great translational relevance to the epidemics of diabetes and obesity. . ..
  14. Regulatory Mechanisms In Intestinal Motility
    Kenton M Sanders; Fiscal Year: 2013
    ..The investigative team is highly synergistic and collaborative, and the PPG has a long track-record of productivity and novel discovery ..
  15. Gene Networks controlling macrophage-adipocyte interactions in insulin
    Christopher K Glass; Fiscal Year: 2013
    ..abstract_text> ..
  16. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
    ..5) To prepare and empower our diverse Native and Pacific People communities to take ownership of their own health and wellness. ..