Modulation of PPAR-gamma phosphorylation at S273 regulates insulin sensitivity

Summary

Principal Investigator: ALEXANDER BANKS
Abstract: DESCRIPTION (provided by applicant): PPAR-gamma is the target of highly effective but controversial diabetes medications, the thiazolidinediones. We recently demonstrated that these drugs reverse insulin resistance through a previously unappreciated mechanism-reversing an inhibitory PPAR-gamma-phosphorylation event. Phosphorylation of PPAR-gamma at serine 273 occurs shortly after the onset of high fat diet feeding and increases with progressive obesity. This phosphorylation correlates with dysregulation of PPAR-gamma target genes, such as adiponectin. Treatment of patients or mice with thiazolidinediones reverses phosphorylation as it improves insulin sensitivity. Utilizing a new mouse model we will investigate whether preventing this obesity-mediated PPAR-gamma S273 phosphorylation will alter adipose tissue morphology, gene expression and systemic insulin-sensitivity in vivo. To do this, we have generated mice with an adipose-specific knock-out of the relevant PPAR-gamma kinase, Cdk5. We predict that these mice will be a model of healthy obesity due to insulin-sensitive adipose tissue. Following the induction of diet-induced obesity in these mice, we will examine body composition, glucose homeostasis and PPAR-gamma target gene expression in adipose tissue from obese mice. We will compare the metabolic and transcriptional consequences of treating wild type Cdk5 KO mice treated with full agonists such as rosiglitazone against non-agonists such as SR1664. Furthermore, we will examine whether a diabetes susceptibility gene, Cdkal1, regulates PPAR-gamma S273 phosphorylation and adipocyte gene expression in mouse and human cells. This proposal defines a new mechanism whereby selectively targeting PPAR-gamma S273 phosphorylation may allow for specifically promoting the beneficial effects of PPAR-gamma activation without the adverse effects. The candidate, Dr. Alexander Banks, has a strong track record of innovative research with a focus on generating and characterizing genetically modified mouse models of human metabolic disease. He has performed postdoctoral training at Columbia and Harvard Universities and has experience in the study of mammalian physiologic response to aging, obesity, and diabetes. The candidate's career goal is to become an independent academic investigator and faculty mentor with a research laboratory contributing towards understanding and reversing metabolic diseases. This research will be conducted in the laboratory of Bruce Spiegelman, PhD at Harvard Medical School, who is a leader in field of molecular diabetes research. Co-mentorship will be contributed by David Altshuler, MD, PhD also of Harvard Medical School. Career development activities to augment the training experience include instruction using cutting-edge methods, attending scientific meetings, and the support of a scientific advisory committee with broad expertise in relevant subjects.
Funding Period: 2012-09-01 - 2015-06-30
more information: NIH RePORT

Research Grants

Detail Information

Research Grants31

  1. 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. ..
  2. DF/HCC Kidney Cancer SPORE
    David McDermott; Fiscal Year: 2013
    ..The overall goal of the DF/HCC Kidney Cancer SPORE is the translation of biological and technological advances into clinically meaningful advances for patients with kidney cancer. ..
  3. Program Project: Growth, Differentiation and Disease of Urothelium
    Tung Tien Sun; Fiscal Year: 2013
    ..abstract_text> ..
  4. 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. ..
  5. 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. ..
  6. 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. ..
  7. Penn TREC Survivor Center
    Kathryn H Schmitz; Fiscal Year: 2013
    ..abstract_text> ..
  8. Hopkins Center for Health Disparities Solutions
    THOMAS ALEXIS LAVEIST; Fiscal Year: 2013
    ..abstract_text> ..
  9. High-Content Screening for Peroxisome Biogenesis for Type-II Diabetes.
    JONATHAN ZACHARY SEXTON; Fiscal Year: 2013
    ..We have validated a known therapeutic compound in mice as a potent activator in our assay to use for compound screening and secondary/orthogonal assay development. ..
  10. Mechanisms of Health Effects of Exercise in Children
    Dan M Cooper; Fiscal Year: 2013
    ..Collectively, the PPG will promote novel preventive and adjunctive exercise therapies in children with chronic inflammation- therapies grounded in a firm understanding of biological mechanisms. ..
  11. 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. ..
  12. 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. ..
  13. DIABETES AND ENDOCRINOLOGY RESEARCH CENTER
    Domenico Accili; Fiscal Year: 2013
    ....
  14. 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. ..
  15. NEW MODALITIES FOR TREATMENT OF PAIN AND DRUG ABUSE
    Victor J Hruby; Fiscal Year: 2013
    ....
  16. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  17. 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. ..
  18. 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 ..
  19. Gene Networks controlling macrophage-adipocyte interactions in insulin
    Christopher K Glass; Fiscal Year: 2013
    ..abstract_text> ..
  20. Basic and Clinical Studies of Cystic Fibrosis
    Raymond A Frizzell; Fiscal Year: 2013
    ..The Core Center will operate a Pilot and Feasibility Program to bring new investigators into CF research. This Center emphasizes the translation of basic knowledge into applied therapeutics. ..
  21. 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. ..