Adipose-issue Tregs: Important Players In The Immunological Control Of Metabolis

Summary

Principal Investigator: Diane J Mathis
Abstract: DESCRIPTION (provided by applicant): Obesity - together with its co-morbidities insulin resistance, type-2 diabetes and cardiovascular disease - is one of America's major health challenges in the twenty-first century. One crucial link between obesity and downstream cardio-metabolic disorders is chronic low-grade inflammation of visceral adipose tissue, and ultimately systemically. Strikingly, macrophages can constitute as many as half of the cells residing in the visceral fat of obese humans and mouse models, and this cell-type is recognized to be one of the critical drivers of obesity-associated inflammation. It was recently reported that a substantial population of Foxp3? regulatory T cells (Tregs) resides in the visceral adipose tissue of lean, but not obese, mice (and humans). This population has a distinct gene-expression profile and T cell receptor (TCR) repertoire. Loss- and gain-of-function experiments established that Tregs are capable of regulating adipose-tissue inflammation and systemic metabolic indices, promoting insulin resistance, and thereby protecting from type-2 diabetes. The overall goal of this proposed project is to elucidate the generation, dynamics and function of visceral- fat Tregs. Specifically, we aim to: 1. Determine the origin of Tregs residing in visceral adipose tissue, utilizing a combination of approaches entailing cell transfers, imaging of cells photo-tagged in vivo, and construction and characterization of novel reporter and TCR-transgenic mouse lines. The role of candidate molecules in migration of visceral-fat Tregs will then be addressed. 2. Establish the role of PPARg in the emergence and function of fat-resident Tregs. The activities of this nuclear receptor super-family member -- highly and specifically induced in visceral-fat Tregs -- will be explored through functional experiments and gene-expression profiling on cells from mice lacking PPARg specifically in Tregs, mice with a greatly and specifically expanded visceral-fat Treg population, and ex vivo naive T cells retrovirally transduced with foxp3 pparg. 3. Define elements underlying the impressive reduction in Tregs in visceral adipose tissue of obese mice, addressing, in particular, whether their migration is blocked, whether their survival in the adipose tissue niche is compromised, and what pathways and molecules are implicated. Results from these studies should greatly enrich our understanding of how adipose tissue inflammation is regulated in the lean state and dysregulated with the onset of obesity, likely revealing novel therapeutic targets. Given increasing recognition of the unfortunate side-effects of the front-line diabetes-dampening thiazolidinedione (TZD) drugs, there is currently great interest in the discovery of new targets capable of protecting from or reducing insulin resistance and downstream cardio-metabolic diseases.
Funding Period: 2011-07-12 - 2015-05-31
more information: NIH RePORT

Top Publications

  1. pmc An N-terminal mutation of the Foxp3 transcription factor alleviates arthritis but exacerbates diabetes
    JAIME DARCE
    Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA
    Immunity 36:731-41. 2012
  2. pmc PPAR-γ is a major driver of the accumulation and phenotype of adipose tissue Treg cells
    Daniela Cipolletta
    Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA
    Nature 486:549-53. 2012
  3. pmc Treg cells, life history, and diversity
    Christophe Benoist
    Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA
    Cold Spring Harb Perspect Biol 4:a007021. 2012
  4. pmc The immune system's involvement in obesity-driven type 2 diabetes
    Chengyi Jenny Shu
    Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, United States
    Semin Immunol 24:436-42. 2012
  5. pmc Immunological goings-on in visceral adipose tissue
    Diane Mathis
    Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA
    Cell Metab 17:851-9. 2013
  6. ncbi Regulatory T cells in nonlymphoid tissues
    Dalia Burzyn
    Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA
    Nat Immunol 14:1007-13. 2013
  7. pmc A special population of regulatory T cells potentiates muscle repair
    Dalia Burzyn
    Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA
    Cell 155:1282-95. 2013
  8. pmc Ablation of PRDM16 and beige adipose causes metabolic dysfunction and a subcutaneous to visceral fat switch
    Paul Cohen
    Dana Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA Cardiovascular Division, Department of Medicine, Brigham and Women s Hospital, Boston, MA 02115, USA
    Cell 156:304-16. 2014

Research Grants

Detail Information

Publications8

  1. pmc An N-terminal mutation of the Foxp3 transcription factor alleviates arthritis but exacerbates diabetes
    JAIME DARCE
    Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA
    Immunity 36:731-41. 2012
    ..Thus, specific subfunctions of Treg cells and the immune diseases they regulate can be influenced by FoxP3's molecular interactions, which result in divergent immunoregulation...
  2. pmc PPAR-γ is a major driver of the accumulation and phenotype of adipose tissue Treg cells
    Daniela Cipolletta
    Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA
    Nature 486:549-53. 2012
    ....
  3. pmc Treg cells, life history, and diversity
    Christophe Benoist
    Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA
    Cold Spring Harb Perspect Biol 4:a007021. 2012
    ..We will review here the specification of this lineage, its population dynamics, and the diversity of subphenotypes that correlate with their diverse roles in controlling inflammation in a variety of settings...
  4. pmc The immune system's involvement in obesity-driven type 2 diabetes
    Chengyi Jenny Shu
    Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, United States
    Semin Immunol 24:436-42. 2012
    ..This review discusses the connection between inflammation in adipose tissue and systemic insulin resistance, focusing on the roles of innate and adaptive immune cell subsets in the pathogenesis of this metabolic disease...
  5. pmc Immunological goings-on in visceral adipose tissue
    Diane Mathis
    Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA
    Cell Metab 17:851-9. 2013
    ..This piece reviews the existing data on these new participants; discusses experimental uncertainties, inconsistencies, and complexities; and puts forward a minimalist synthetic scheme...
  6. ncbi Regulatory T cells in nonlymphoid tissues
    Dalia Burzyn
    Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA
    Nat Immunol 14:1007-13. 2013
    ..In this Review, we summarize recent findings in this new field, discussing knowns and unknowns about the origin, phenotype, function and memory of nonlymphoid tissue-resident Treg cells. ..
  7. pmc A special population of regulatory T cells potentiates muscle repair
    Dalia Burzyn
    Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA
    Cell 155:1282-95. 2013
    ..Thus, Treg cells and their products may provide new therapeutic opportunities for wound repair and muscular dystrophies...
  8. pmc Ablation of PRDM16 and beige adipose causes metabolic dysfunction and a subcutaneous to visceral fat switch
    Paul Cohen
    Dana Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA Cardiovascular Division, Department of Medicine, Brigham and Women s Hospital, Boston, MA 02115, USA
    Cell 156:304-16. 2014
    ..These findings indicate that PRDM16 and beige adipocytes are required for the "browning" of white fat and the healthful effects of subcutaneous adipose tissue. ..

Research Grants30

  1. 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. ..
  2. 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. ..
  3. 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. ..
  4. 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. ..
  5. 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. ..
  6. Hormonal Regulation of Fat Deposition
    Jonathan M Graff; Fiscal Year: 2013
    ....
  7. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  8. Zimmerman Program for the Molecular and Clinical Biology of VWD
    Robert R Montgomery; Fiscal Year: 2013
    ..Taken together this PPG will set the stage for the appropriate diagnosis and phenotypic understanding of VWD - both in the US and throughout the world. ..
  9. Developmental Genes and the Origin of Fat
    C Ronald Kahn; Fiscal Year: 2013
    ....
  10. Molecular and Cellular Basis for Digestive Diseases
    Richard M Peek; Fiscal Year: 2013
    ..The Administrative Core also contains Biostatistics and Enrichment Programs and oversees the financial management and operation of the VDDRC. ..
  11. Cardiac Fibrillation: Mechanisms and Therapy
    James N Weiss; Fiscal Year: 2013
    ..Together, these studies will provide critical groundwork necessary to develop and advance novel therapies for this major complication and cause of mortality from heart disease. ..
  12. Functional Consequences of Impaired Autophagy in Aging
    ANA M CUERVO; Fiscal Year: 2013
    ..Significance: These studies may ultimately lead to fundamental insights for understanding, treating or preventing the metabolic alterations and declined cognitive and immune function characteristic of elders. ..
  13. DEVELOPMENT OF NOVEL THERAPIES FOR NIDDM
    Christopher B Newgard; Fiscal Year: 2013
    ..abstract_text> ..
  14. Inflammation, Insulin Resistance, and Foxo factors
    Stephen M Hedrick; Fiscal Year: 2013
    ..These experiments will greatly enhance our knowledge of the interface between organismal metabolism and the immune system. ..
  15. Gene Networks controlling macrophage-adipocyte interactions in insulin
    Christopher K Glass; Fiscal Year: 2013
    ..abstract_text> ..