A novel axis regulates adipocyte plasticity

Summary

Principal Investigator: Sean Hartig
Abstract: DESCRIPTION (provided by applicant): Obesity, insulin resistance, and type 2 diabetes mellitus (T2DM) affects one in 10 U.S. adults with direct annual medical costs near $120 billion. It is clear chronic alterations in energy storage and utilization, as in obesity, causes lipid deposition in non-adipose tissues, which is tightly associated with insulin resistance and T2DM. Thus, the ability of adipocytes to store energy as lipids is a crucial component of T2DM, and their production of key metabolic adipokines to regulate systemic insulin sensitivity, strongly reinforces their importance. Characteristics of adipocyte function, including fat metabolism and adipokine expression, are tightly regulated by peroxisome proliferator activated receptor gamma (PPAR?). Therapeutic PPAR? activation by thiazolidinediones increases insulin sensitivity and fat storage efficiency in T2DM with serious, negative side effects including edema, bone loss, bladder cancer, and heart failure. These findings highlight the inadequacy of current T2DM drugs and the need for innovative treatments to promote the beneficial effects of PPAR?, while minimizing undesirable effects. I discovered the small ubiquitin-related modifier (SUMO) E2-conjugation enzyme Ubc9 and its cognate microRNA (miR-30a) as a novel signaling loop which regulates PPAR? transactivation and energy balance genes in adipocytes. My findings suggest the Ubc9/miR-30a axis is regulated by PPAR? and promotes a gene expression profile which reflects beige adipocytes. Therefore, I hypothesize miR-30a down-regulates Ubc9 to promote insulin sensitivity and energy expenditure in adipose tissue. The following specific aims will use modern biochemical approaches and in vivo experiments to identify how the Ubc9/miR-30a axis regulates energy balance in adipocytes. Aim 1 will define the role of the Ubc9/miR-30a axis in promoting a metabolic profile associated with increased energy expenditure. Aim 2 will define the molecular mechanism of miR-30a regulation by anti-diabetic PPAR? ligands. Aim 3 will use mouse models of T2DM to define the impact of exogenous miR-30a expression in adipocytes on insulin sensitivity. 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.
Funding Period: 2013-04-01 - 2016-01-31
more information: NIH RePORT

Top Publications

  1. pmc Androgen receptor agonism promotes an osteogenic gene program in preadipocytes
    Sean M Hartig
    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
    Biochem Biophys Res Commun 434:357-62. 2013
  2. pmc Identification of a pan-cancer oncogenic microRNA superfamily anchored by a central core seed motif
    Mark P Hamilton
    Department of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza Houston M822, Houston, Texas 77030, USA
    Nat Commun 4:2730. 2013
  3. pmc Protein kinase C inhibitors sensitize GNAQ mutant uveal melanoma cells to ionizing radiation
    Jasmina Ziva Cerne
    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States
    Invest Ophthalmol Vis Sci 55:2130-9. 2014

Research Grants

  1. Metabolic regulation of adipocyte-macrophage crosstalk in obesity
    Chaodong Wu; Fiscal Year: 2013
  2. Pathobiology of the Enteric System
    Joseph H Szurszewski; Fiscal Year: 2013
  3. Penn TREC Survivor Center
    Kathryn H Schmitz; Fiscal Year: 2013
  4. Functional Consequences of Impaired Autophagy in Aging
    ANA M CUERVO; Fiscal Year: 2013
  5. Transcriptional role of TLE3 in brown adipose tissue development and metabolism
    Claudio J Villanueva; Fiscal Year: 2013
  6. DIABETES AND ENDOCRINOLOGY RESEARCH CENTER
    Domenico Accili; Fiscal Year: 2013
  7. Alterations in Adipocyte Lipid Metabolism by Trans-10, Cis-12 CLA Supplementation
    LAURA JANE DEN HARTIGH; Fiscal Year: 2013
  8. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
  9. NEW MODALITIES FOR TREATMENT OF PAIN AND DRUG ABUSE
    Victor J Hruby; Fiscal Year: 2013
  10. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013

Detail Information

Publications3

  1. pmc Androgen receptor agonism promotes an osteogenic gene program in preadipocytes
    Sean M Hartig
    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
    Biochem Biophys Res Commun 434:357-62. 2013
    ..Collectively, our results suggest androgens promote an osteogenic gene program at the expense of adipocyte differentiation...
  2. pmc Identification of a pan-cancer oncogenic microRNA superfamily anchored by a central core seed motif
    Mark P Hamilton
    Department of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza Houston M822, Houston, Texas 77030, USA
    Nat Commun 4:2730. 2013
    ..These combined analyses identify pan-cancer oncogenic cotargeting of the phosphoinositide 3-kinase, TGFβ and p53 pathways by the miR-17-19-130 superfamily members. ..
  3. pmc Protein kinase C inhibitors sensitize GNAQ mutant uveal melanoma cells to ionizing radiation
    Jasmina Ziva Cerne
    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States
    Invest Ophthalmol Vis Sci 55:2130-9. 2014
    ..In this study, we investigated the impact of small-molecule PKC inhibitors bisindolylmaleimide I (BIM) and sotrastaurin (AEB071), combined with ionizing radiation (IR), on survival in melanoma cell lines...

Research Grants30

  1. Metabolic regulation of adipocyte-macrophage crosstalk in obesity
    Chaodong Wu; Fiscal Year: 2013
    ..Together, the proposed research will illustrate a new paradigm on metabolic regulation of adipocyte-macrophage crosstalk, and provide the experimental basis for insulin sensitization by means of selective PFKFB3 activation. ..
  2. 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. ..
  3. Penn TREC Survivor Center
    Kathryn H Schmitz; Fiscal Year: 2013
    ..abstract_text> ..
  4. 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. ..
  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. DIABETES AND ENDOCRINOLOGY RESEARCH CENTER
    Domenico Accili; Fiscal Year: 2013
    ....
  7. Alterations in Adipocyte Lipid Metabolism by Trans-10, Cis-12 CLA Supplementation
    LAURA JANE DEN HARTIGH; Fiscal Year: 2013
    ....
  8. 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. ..
  9. NEW MODALITIES FOR TREATMENT OF PAIN AND DRUG ABUSE
    Victor J Hruby; Fiscal Year: 2013
    ....
  10. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  11. 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. ..
  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. The Role of Substrate Metabolism and Macrophage Activation in Obesity
    Amy Johnson; Fiscal Year: 2013
    ....
  14. Regulation of Bile Acid Synthesis by Nuclear Receptors
    John Y L Chiang; Fiscal Year: 2013
    ..The long-term objectives of this research are to elucidate the molecular mechanism of regulation of CYP7A1 and bile acid metabolism, and pathogenesis and treatment of metabolic diseases such as fatty liver disease, diabetes and obesity. ..
  15. Function of the Myo-adipo Axis in Human Obesity and Type 2 Diabetes
    ROBERT ROY HENRY; Fiscal Year: 2013
    ..Results from this project will provide molecular mechanisms for metabolic dysfunction seen in vivo in obesity and T2D and identify possible targets for therapeutic interventions. ..
  16. Translational Research in Cystic Fibrosis
    Mitchell L Drumm; Fiscal Year: 2013
    ..This goal is also a function of the Biomedical Research Cores. ..
  17. 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. ..