The Role of PPAR Gamma in Fat-Resident Regulatory T Cells and Glucose Homeostasis


Principal Investigator: SAGAR PRADEEP BAPAT
Abstract: DESCRIPTION (provided by applicant): Insulin resistance and type-2 diabetes often accompany obesity and have been linked to obesity by the low- grade chronic inflammation of adipose tissue that occurs in the obese state. Recently, cells of the adaptive immune system have been shown to be involved in the regulation of adipose tissue inflammation. Specifically, regulatory T cells (Tregs), a subset of T lymphocytes with an immunosuppressive function, are enriched in adipose tissue of lean, but not obese, mice. These fat-resident Tregs (fTregs) may have a role in suppressing inflammation and preventing insulin resistance in the visceral fat. Their abundance in the visceral fat of mice inversely correlates with the level of inflammation in the visceral fat as well as insulin resistance. A recent study showed that fTregs have a different gene expression signature compared to Tregs isolated from the spleen or lymph nodes in mice. In particular, one of the genes specifically upregulated in fTregs is peroxisome proliferator-activated receptor gamma (PPAR!), a key regulator of adipogenesis and organismal metabolism. In addition, preliminary studies have shown that when PPAR! is specifically deleted in Tregs in mice, Tregs are no longer enriched in the visceral fat. It is thus hypothesized that th fat-specific adaptation of fTregs is dependent upon the expression and transcriptional activity of PPAR! in these cells. This proposal seeks to characterize the key molecular mechanisms involved in the upstream induction of PPAR!"and its downstream transcriptional targets in fTregs. Furthermore, the necessity of PPAR!"in fTregs for the therapeutic mechanism of action of thiazolidinediones (TZDs), an important anti-diabetic class of drugs that are PPAR!"agonists, will be investigated using a mouse model generated in our lab. First, it is hypothesized that the unique expression of PPAR! in fTregs is due to a distinct adipokine/cytokine milieu within visceral adipose tissue. The upstream signaling pathways involved in PPAR! induction in fTregs will be dissected using in vitro loss-of-function experiments. Second, it is hypothesized that, once expressed, PPAR! acts in a unique way to reshape the transcriptional signature of fTregs and to enable fTreg-specific function, including maintenance of Treg enrichment in visceral fat and potentially protection against insulin resistance. Thus, ChIP-Seq and microarray expression technologies will be used to map the PPAR! cistrome in fTregs and identify key PPAR! downstream targets that could potentially mediate fTreg function. Third, it is hypothesized that expression of PPAR! in fTregs is critical for TZDs to exert their full therapeutic, insulin-sensitizing potential in mice under metabolic stress. Mice with a Treg-specific PPAR! deletion will be generated and fed high fat diet with or without TZD. The ability of TZDs to protect against progression of insulin resistance and metabolic syndrome in these mice will be compared to their wild-type counterparts. Taken together, these studies will systematically characterize the role of PPAR! in fTregs and illuminate the role of fTregs in the pathogenesis of obesity-related type-2 diabetes.
Funding Period: 2012-09-30 - 2015-09-29
more information: NIH RePORT

Detail Information

Research Grants31

  1. 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. ..
  2. Novel Methods to Assess the Effects of Chemicals on Child Development
    Susan L Schantz; Fiscal Year: 2013
    ..This Center's research will fill an important gap in our knowledge by investigating the effects of these chemicals, both alone and combination with a high fat diet on reproductive and neural development. ..
  3. Program Project: Growth, Differentiation and Disease of Urothelium
    Tung Tien Sun; Fiscal Year: 2013
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  4. Role of Eicosanoids in Renal Function
    NANCY JOAN BROWN; Fiscal Year: 2013
    ..These are needed for the development of meaningful approaches for: a) the unequivocal definition of human pathophysiological significance, and b) future pharmacological targeting, and clinical diagnosis and intervention. ..
  5. Function and specificity of thiazolinedione induced eRNAs
    Jill M Marinis; Fiscal Year: 2013
    ..Identification of novel adipocyte specific factors and understanding their mechanism of action has the potential of tailoring therapeutics for cell specific actions to minimize adverse side-effects of TZDs. ..
  6. Notch and Regulators of Notch Signaling Impact Both Glucose and Lipid Metabolism
    UTPAL BHAGIRATH PAJVANI; Fiscal Year: 2013
    ..Pajvani will need in order to become an independent translational medical researcher and a productive member of the academic medical community. ..
  7. Development of iPS Cells for Treatment of Hemoglobinopathies
    Yuet Wai Kan; Fiscal Year: 2013
    ..The science in the Projects will be augmented by an administrative (Core A) and 2 scientific Cores: Core B: Cell and Molecular Biology, and Core C: Cell Transplantation and Analysis. ..
  8. Modulation of PPAR-gamma phosphorylation at S273 regulates insulin sensitivity
    ALEXANDER BANKS; Fiscal Year: 2013
  9. Genomic Analysis of the genotype-phenotype map
    Simon Tavare; Fiscal Year: 2013
    ..The goal of this project is to increase our understanding of the general principles that underlie the genotype-phenotype map by studying model organisms. ..
  10. Genetic and Metabolic Fingerprints of Coativators "Program Project"
    BERT W O'MALLEY; Fiscal Year: 2013
    ..When complete, this PPG will afford a much greater understanding of NR and coregulator biology and will help define novel therapeutic leverage points for intervention of diseases associated with MS. ..
  11. Metabolic syndrome and hippocampal Ca2+ dysregulation in aging memory decline
    Olivier Thibault; Fiscal Year: 2013
    ..Therefore, even if the central hypothesis is rejected, the studies proposed will provide more definitive evidence for the impact o metabolic syndrome, as well as the actions of TZDs, on the brain. ..
  12. A novel axis regulates adipocyte plasticity
    Sean Hartig; Fiscal Year: 2013
    ..I anticipate that my studies will provide new clues into the complex regulatory networks controlling energy balance in fat cells. If my hypothesis is true, the Ubc9/miR-30a axis might be exploited in novel therapies to manage T2DM. ..
  13. Pathobiology of the Enteric System
    Joseph H Szurszewski; Fiscal Year: 2013
    ..This highly-integrated Program will make significant progress toward understanding the pathobiology of the enteric system in gastric emptying disorders and translate this knowledge into new diagnostic tools and therapy. ..
  14. 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. ..
  15. 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. ..
  16. Therapeutic Opportunities of Targeting Tissue Factor Signaling in Obesity
    Fahumiya Samad; Fiscal Year: 2013
    ..These studies will provide fundamental insights into the role of TF signaling in obesity, and test an innovative therapeutic approach in these pathways to improve metabolic complications of obesity. ..
    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. ..
  18. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
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  19. 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. ..
  20. 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 ..
    Mitchell A Lazar; Fiscal Year: 2013
    ..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. ..
  22. Role of Eosinophils in Airway Inflammation and Remodeling
    Nizar N Jarjour; Fiscal Year: 2013
    ..Given the prominence of eosinophilic inflammation in a significant proportion of severe asthma patients, these advances will have direct implications for the patients most affected by this very common illness. ..
  23. Adipose-issue Tregs: Important Players In The Immunological Control Of Metabolis
    Diane J Mathis; Fiscal Year: 2013